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Patient Management Algorithms AGING FIG. 11-16 Algorithm depicting assessment and management of delirium in hospitalized older patients. . . . . . . . 79 FIG. 11-17 Algorithm depicting assessment and management of falls in older patients. . . . . . . . . . . . . . . . . . . . . 80
ALLERGY, IMMUNOLOGY, RHEUMATOLOGY FIG. 376-4 The diagnosis and management of rhinitis. . . FIG. 378-2 The diagnosis and initial therapy of systemic lupus erythematosus. . . . . . . . . . . . . . . . . . . FIG. 383-1 Treatment for Sjögren’s syndrome. . . . . . . . . FIG. 385-1 Approach to the patient with a suspected diagnosis of vasculitis. . . . . . . . . . . . . . . . . . FIG. 390-8 Patient management for sarcoidosis. . . . . . . . FIG. 390-9 Management of acute sarcoidosis. . . . . . . . . . FIG. 390-10 Management of chronic sarcoidosis. . . . . . . . FIG. 393-1 The diagnosis of musculoskeletal complaints. . FIG. 393-2 The consideration of the most common musculoskeletal conditions. . . . . . . . . . . . . . FIG. 393-6 Approach to synovial fluid aspiration and analysis. . . . . . . . . . . . . . . . . . . . . . . . .
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2123
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2128 2168
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2181 2210 2211 2211 2217
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2224
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FIG. 293-2 Evaluation of the patient with known or suspected ischemic heart disease. . . . . . . . . FIG. 293-3 Management of the patient with ischemic heart disease. . . . . . . . . . . . . . . . . . . . . . . FIG. 294-3 Algorithm for evaluation and management of patients with suspected acute coronary syndrome. . . . . . . . . . . . . . . . . . . . . . . . . FIG. 295-5 The assessment of need for implantation of a cardioverter-defibrillator.. . . . . . . . . . . . .
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1609
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448
CLINICAL GENETICS FIG. 84-2 Approach to genetic testing. . . . . . . . . . . FIG. 85e-6 Clinical and laboratory investigation of a suspected mitochondrial DNA (mtDNA) disorder.. . . . . . . . . . . . . . . . . . . . . . . . FIG. 101e-6 Genetic testing in a family with cancer predisposition. . . . . . . . . . . . . . . . . . . .
85e-7
. . . . .
101e-8
. . . .
CLINICAL NUTRITION FIG. 98e-1 Decision-making for the implementation of specialized nutritional support (SNS). .
98e-2
. . . . .
ALTERATIONS IN CIRCULATORY AND RESPIRATORY FUNCTIONS
CORONARY AND PERIPHERAL VASCULAR DISEASE
FIG. 50-1
Clinical conditions in which a decrease in cardiac output and a systemic vascular resistance cause arterial underfilling.. . . . . . . . . . . . . . . . . . . . . . 251 FIG. 51e-5 Differential diagnosis of a holosystolic murmur. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51e-5
FIG. 295-4 Reperfusion therapy for patients with T-segment elevation myocardial infarction (STEMI). . . . . . . 1604 FIG. 296e-4 Algorithm for patients requiring revascularization: factors to consider when choosing between bare metal stents, drug-eluting stent, or CABG. . . . . 296e-3
CARDIOLOGY
DISORDERS OF THE URINARY TRACT
FIG. 9-1 FIG. 51e-9 FIG. 264-1 FIG. 276-9
FIG. 283-2 FIG. 283-6 FIG. 284-1 FIG. 284-4 FIG. 285-1 FIG. 287-18
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Cardiac risk assessment and stratification in patients undergoing noncardiac surgery. . . Strategy for evaluating heart murmurs. . . . . . Approach to the evaluation of a heart murmur. . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment algorithm for patients presenting with hemodynamically stable paroxysmal supraventricular tachycardia. . . . . . . . . . . . . Management strategy for patients with aortic stenosis. . . . . . . . . . . . . . . . . . . . . . . Management of patients with aortic regurgitation. . . . . . . . . . . . . . . . . . . . . . . . Management of rheumatic mitral stenosis. . . . Management of mitral regurgitation. . . . . . . . Management of tricuspid regurgitation. . . . . . Treatment algorithm for hypertrophic cardiomyopathy. . . . . . . . . . . . . . . . . . . . . .
52 51e-8
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1441
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1483
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1533
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1537 1541 1545 1549
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FIG. 337-2 Typical algorithm for early posttransplant care of a kidney recipient. . . . . . . . . . . . . . . . . . . .
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1830
EMERGENCY AND CRITICAL CARE FIG. 263e-1 General guidelines for treatment of radiation casualties. . . . . . . . . . . . . . . . . . . FIG. 263e-2 Evacuation in a multicasualties radiologic event. . . . . . . . . . . . . . . . . . . . . FIG. 321-2 Approach to the patient in shock. . . . . . . . . FIG. 322-5 Algorithm for the initial management of acute respiratory distress syndrome. . . . . . . FIG. 326-2 Emergency management of patients with cardiogenic shock, acute pulmonary edema, or both. . . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 327-3A Cardiac arrest management: ventricular fibrillation. . . . . . . . . . . . . . . . . . . . . . . . .
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263e-4
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263e-5 1731
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1739
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1761
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Management of recurrent variceal hemorrhage Treatment of refractory ascites . . . . . . . . . . . . A stepwise diagnostic approach to the patient with suspected chronic pancreatitis . . . . . . . .
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FIG. 365-3 FIG. 365-5 FIG. 370-1
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1769
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FIG. 327-3B Cardiac arrest management: bradyarrhythmia/ asystole . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2413 2416 2425
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257 267 271 273
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279 281 1924
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1994
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1996 2054
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2327 2367 2367 2395
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2320
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2432 2479
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FIG. 424-6 FIG. 428-3
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FIG. 418-3 FIG. 419-4 FIG. 420-2
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FIG. 411-5 FIG. 411-6 FIG. 416-1 FIG. 418-2
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FIG. 406-16
2274
The physiologic classification of anemia . . . . . . . 398 An approach to diagnosing patients with polycythemia . . . . . . . . . . . . . . . . . . . . . . . . . . 400 FIG. 104-2 Diagnosis and treatment of fever and neutropenia . . . . . . . . . . . . . . . . . . . . . . . . 490 FIG. 106-1 Evaluation of a patient with cervical adenopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 503 FIG. 107-3 Algorithm for management of non-small-cell lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 FIG. 107-5 Algorithm for management of small-cell lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 FIG. 107-6 Approach to a solitary pulmonary nodule . . . . . . 517 FIG. 107-7 Management of recurrent small-cell lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522 FIG. 107-8 Approach to first-line therapy in a patient with stage IV non-small-cell lung cancer . . . . . . 523 FIG. 108-1 Approach to a palpable breast mass . . . . . . . . . . 525 FIG. 108-2 The “triple diagnosis” technique in suspected breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 525 FIG. 108-3 Management of a breast cyst . . . . . . . . . . . . . . . 525 FIG. 108-4 Approaches to abnormalities detected by mammogram . . . . . . . . . . . . . . . . . . . . . . . . . . 526 FIG. 111-2 Treatment approach to patients with hepatocellular carcinoma. . . . . . . . . . . . . . . . . . 548 FIG. 120e-2 Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma of unknown primary. . . . . . . . . . . . . . . . . . . . . 120e-3 FIG. 120e-3 Treatment algorithm for squamous cell carcinoma of unknown primary . . . . . . . . . . 120e-4 FIG. 127-3 Pathophysiology of sickle cell crisis. . . . . . . . . . . 634 FIG. 132-2 The therapy of newly diagnosed acute myeloid leukemia . . . . . . . . . . . . . . . . . . . . . . . 684 FIG. 137-1 Algorithm for the diagnosis of amyloidosis and determination of type . . . . . . . . . . . . . . . . . 720 FIG. 140-2 Evaluating the thrombocytopenic patient . . . . . . 726 FIG. 143-1 Classification of antithrombotic drugs . . . . . . . . 745 FIG. 331-2 Management of cancer patients with back pain . . . 1791 FIG. 331-4 Management of patients at high risk for the tumor lysis syndrome . . . . . . . . . . . . . . . . . . . . 1796
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FIG. 406-13
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FIG. 77-17 FIG. 77-18
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FIG. 406-12
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2260 2268 2270 2273
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FIG. 406-10
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HEMATOLOGY AND ONCOLOGY
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FIG. 405-13
334
2088
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FIG. 403-3 FIG. 403-5 FIG. 403-6 FIG. 403-7
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FIG. 402-1
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The evaluation and differential diagnosis of hirsutism . . . . . . . . . . . . . . . . . . . . . . . . . . Management of adult growth hormone (GH) deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of prolactinoma . . . . . . . . . . . . . Management of acromegaly . . . . . . . . . . . . . . . Management of Cushing’s syndrome . . . . . . . . Management of a nonfunctioning pituitary mass . . . . . . . . . . . . . . . . . . . . . . . . Approach to the patient with a thyroid nodule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of the patient with suspected Cushing’s syndrome . . . . . . . . . . . . . . . . . . . . Diagnostic flowchart for evaluating patients with possible mineralocorticoid excess . . . . . . . Management of the patient with an incidentally discovered adrenal mass . . . . . . . . . . . . . . . . . Diagnostic flowchart for evaluating patients with suspected adrenal insufficiency . . . . . . . . . Evaluation of gynecomastia . . . . . . . . . . . . . . . Evaluation of hypogonadism . . . . . . . . . . . . . . Algorithm for the treatment of obesity . . . . . . . Essential elements in comprehensive care of type 2 diabetes . . . . . . . . . . . . . . . . . . . Glycemic management of type 2 diabetes . . . . . Screening for microalbuminuria. . . . . . . . . . . . Hypoglycemia-associated autonomic failure in insulin-deficient diabetes . . . . . . . . . . . . . . . The evaluation of patients with hypercalcemia . . Algorithm for screening for HFE-associated hemochromatosis . . . . . . . . . . . . . . . . . . . . . . .
FIG. 68-2
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ENDOCRINOLOGY AND METABOLISM
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FIG. 44-2 Diagnosis and treatment of acute pharyngitis . . . 232 FIG. 152e-1 Syndromic approach to differential diagnosis of suspected infection in a veteran who has returned from a foreign war. . . . . . . . . . . . . . 152e-7 FIG. 155-4 Diagnostic use of transesophageal and transtracheal echocardiography in infective endocarditis . . . . . 821
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INFECTIOUS DISEASES
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Approach to the patient with dysphagia . . . Management of acute diarrhea . . . . . . . . . . Management of chronic diarrhea . . . . . . . . Management of constipation . . . . . . . . . . . Management of acute upper gastrointestinal bleeding . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 57-2 Algorithm for patients with acute lower gastrointestinal bleeding . . . . . . . . . . . . . . FIG. 58-1 Evaluation of the patient with jaundice . . . . FIG. 348-12 Overview of new-onset dyspepsia . . . . . . . . FIG. 357-1 Algorithm for evaluation of abnormal liver tests . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 358-1 Algorithm for the evaluation of chronically abnormal liver tests . . . . . . . . . . . . . . . . . FIG. 363-2 Treatment algorithm for alcoholic hepatitis .
FIG. 53-2 FIG. 55-2 FIG. 55-3 FIG. 55-4 FIG. 57-1
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GASTROENTEROLOGY AND HEPATOLOGY
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The pathophysiology of the neurologic complications of bacterial meningitis . . . . . . FIG. 445-2 Evaluation of the adult patient with a seizure. . . . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 445-3 Pharmacologic treatment of generalized tonic-clonic status epilepticus in adults . . . . . FIG. 446-1 Medical management of stroke and transient ischemic attack . . . . . . . . . . . . . . . . . . . . . . FIG. 449-7 Treatment algorithm for the management of Parkinson’s disease . . . . . . . . . . . . . . . . . FIG. 458-4 Therapeutic decision-making for multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 459-1 Approach to the evaluation of peripheral neuropathies . . . . . . . . . . . . . . . . . . . . . . . FIG. 461-2 The management of myasthenia gravis . . . . . FIG. 462e-1 Diagnostic evaluation of intermittent weakness . . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 462e-2 Diagnostic evaluation of persistent weakness . . . . . . . . . . . . . . . . . . . . . . . . . . FIG. 466-1 Medical management of major depressive disorder . . . . . . . . . . . . . . . . . . .
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FIG. 164-2
Management of patients with intraabdominal abscesses using percutaneous drainage . . . . . . . . 850 FIG. 160-1 Approach to patients with communityacquired infectious diarrhea or bacterial food poisoning . . . . . . . . . . . . . . . . . . . . . . . . . 854 FIG. 162-4 Diagnostic approach to urinary tract infection . . . 865 FIG. 177-1 Clinical and pathologic progression of tetanus . . . 985 FIG. 188-1 Schematic of the relationships between colonization with Helicobacter pylori and diseases of the upper gastrointestinal tract among persons in developed countries . . . . . . . . 1039 FIG. 188-2 Management of Helicobacter pylori infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041 FIG. 206-4 Interpretation of results from syphilis enzyme immunoassays used for screening . . . . . . . . . . . . 1137 FIG. 209-3 Treatment of relapsing fever . . . . . . . . . . . . . . . 1148 FIG. 210-2 Treatment of the various early or late manifestations of Lyme borreliosis . . . . . . . . . . . 1153 FIG. 226-32 Acute HIV infection . . . . . . . . . . . . . . . . . . . . . 1249 FIG. 226-36 Evaluation of diarrhea in patients with HIV infection. . . . . . . . . . . . . . . . . . . . . . . . . . 1257 FIG. 232-5 Rabies postexposure prophylaxis . . . . . . . . . . . . 1303
FIG. 159-3
PULMONOLOGY
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FIG. 26-1
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The management of patients with suspected central nervous system infection . . . . . . . . .
FIG. 164-1
FIG. 69-2 FIG. 75-1 . . . .
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Algorithm for evaluation of amenorrhea . An algorithm for the diagnosis of a patient with photosensitivity. . . . . . . . . . . . . . . . .
FIG. 30-3 FIG. 43-2
NEUROLOGY AND PSYCHIATRY
Common and uncommon clinical courses in the last days of terminally ill patients . . . . . Structured approach to patients with fever of unknown origin . . . . . . . . . . . . . . . . . . . . The initial workup of a patient with weakness . An algorithm for the approach to hearing loss . .
FIG. 10-2
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SYSTEMIC CONDITIONS
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FIG. 316-1
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FIG. 300-7
327
The evaluation of the patient with dyspnea . . . Algorithm for the evaluation of hemoptysis . . . How to decide whether diagnostic imaging is needed in suspected pulmonary thromboembolism and deep venous thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . Imaging tests to diagnose deep venous thrombosis and pulmonary embolism . . . . . . . Acute management of pulmonary thromboembolism . . . . . . . . . . . . . . . . . . . . Approach to the diagnosis of pleural effusions . .
FIG. 300-6
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FIG. 343-1
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FIG. 340-1
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FIG. 337-2
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Approach to the patient with azotemia . . . . . . . . Approach to the patient with hematuria . . . . . . . Approach to the patient with proteinuria . . . . . . Approach to the patient with polyuria . . . . . . . . The diagnostic approach to hyponatremia . . . . . . The diagnostic approach to hypernatremia . . . . . The diagnostic approach to hypokalemia . . . . . . The diagnostic approach to hyperkalemia . . . . . . The evaluation and management of patients with erectile dysfunction . . . . . . . . . . . . . . . . . . A typical algorithm for early posttransplant care of the kidney recipient . . . . . . . . . . . . . . . . Algorithm for the treatment of allergic and other immune-mediated acute interstitial nephritis. . . . Diagnostic approach for urinary tract obstruction in unexplained renal failure . . . . . . . . . . . . . . . . .
FIG. 61-1 FIG. 61-2 FIG. 61-3 FIG. 61-4 FIG. 63-5 FIG. 63-6 FIG. 63-7 FIG. 63-8 FIG. 67-3
FIG. 47e-2 FIG. 48-2 FIG. 300-3
NEPHROLOGY
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. L. Hauser
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. L. Longo
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Joseph Loscalzo, M , Ph
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J. Larry Jameson, M , Ph
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Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine, and Physician-in-Chief, Brigham and Women’s Hospital Boston, Massachusetts
Mexico City
Chicago San Francisco Athens London Madrid Milan New Delhi Singapore Sydney Toronto
Robert G. Dunlop Professor of Medicine; Dean, Perelman School of Medicine at the University of Pennsylvania; Executive Vice President, University of Pennsylvania for the Health System Philadelphia, Pennsylvania
New York
D
Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts D
Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco San Francisco, California
an L. Longo, M
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Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, Maryland
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tephen L. Hauser, M
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Anthony . auci, M
William Ellery Channing Professor of Medicine, Professor of Microbiology and Immunobiology, Department of Microbiology and Immunobiology, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital Boston, Massachusetts
ennis L. Kasper, M
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Contents CONTRIBUTORS. . PREFACE. . . . . . .
xix xxxvii
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1
24 Fever and Rash. .
7
1 The Practice of Medicine..
2 Global Issues in Medicine. .
3 Decision-Making in Clinical Medicine. .
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18
4 Screening and Prevention of Disease. .
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26
5 Principles of Clinical Pharmacology.
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31
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Daniel B. Mark, John B. Wong
Katrina Armstrong, Gary J. Martin Dan M. Roden
6e Women’s Health. Andrea Dunaif
7e Men’s Health. .
Robert L. Barbieri, John T. Repke Wei C. Lau, Kim A. Eagle
10 Palliative and End-of-Life Care. . Ezekiel J. Emanuel
11 Clinical Problems of Aging. .
Luigi Ferrucci, Stephanie Studenski
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12e The Safety and Quality of Health Care. David W. Bates
13e Primary Care in Low- and Middle-Income Countries. . . . .
14e Complementary, Alternative, and Integrative Health Practices. . . . . . . . . .
15e The Economics of Medical Care. . Joseph P. Newhouse
16e Racial and Ethnic Disparities in Health Care.. . . . . . . . . . . . . . . . . . . . Joseph R. Betancourt, Alexander R. Green
51 55 70
85
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86 86
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17e Ethical Issues in Clinical Medicine. . Bernard Lo, Christine Grady
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85
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Josephine P. Briggs
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Tim Evans, Kumanan Rasanathan
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9 Medical Evaluation of the Surgical Patient. .
45
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Shalender Bhasin, Shehzad Basaria
8 Medical Disorders During Pregnancy. .
45
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Presentation of Diseases
Section 1 Pain
18 Pain: Pathophysiology and Management. . James P. Rathmell, Howard L. Fields
19 Chest Discomfort. David A. Morrow
20 Abdominal Pain.
21 Headache. .
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103
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107
Danny O. Jacobs, William Silen
Peter J. Goadsby, Neil H. Raskin
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Elaine T. Kaye, Kenneth M. Kaye
25e Atlas of Rashes Associated with Fever.
127
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135
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135
Kenneth M. Kaye, Elaine T. Kaye
26 Fever of Unknown Origin. .
123
Chantal P. Bleeker-Rovers, Jos W. M. van der Meer
Section 3 Nervous System Dysfunction
27 Syncope.
28 Dizziness and Vertigo. .
29 Fatigue. .
30 Neurologic Causes of Weakness and Paralysis.
31 Numbness, Tingling, and Sensory Loss. .
32 Gait and Balance Disorders..
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Roy Freeman
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148
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151
Mark F. Walker, Robert B. Daroff
Jeffrey M. Gelfand, Vanja C. Douglas
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154
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158
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162
Michael J. Aminoff Michael J. Aminoff Lewis Sudarsky
33e Video Library of Gait Disorders. .
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165
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166
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170
Gail Kang, Nicholas B. Galifianakis, Michael D. Geschwind
34 Confusion and Delirium.
35 Dementia.
36 Aphasia, Memory Loss, and Other Focal Cerebral Disorders. . . . . . . . . . . . . . . . . .
S. Andrew Josephson, Bruce L. Miller William W. Seeley, Bruce L. Miller
M.-Marsel Mesulam
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37e Primary Progressive Aphasia, Memory Loss, and Other Focal Cerebral Disorders. . . . . . . . . . . .
38 Sleep Disorders.
176
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184
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184
Maria Luisa Gorno-Tempini, Jennifer Ogar, Joel Kramer, Bruce L. Miller, Gil Rabinovici, Maria Carmela Tartaglia
142
Charles A. Czeisler, Thomas E. Scammell, Clifford B. Saper
Section 4 Disorders of Eyes, Ears, Nose, and Throat
Part 2 Cardinal Manifestations and
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Charles A. Dinarello, Reuven Porat
86
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111
Contents
23 Fever.
Paul Farmer, Joseph Rhatigan
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John W. Engstrom, Richard A. Deyo
Clinical Medicine
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22 Back and Neck Pain.
Section 2 Alterations in Body Temperature
Part 1 General Considerations in The Editors
vii
39 Disorders of the Eye. . Jonathan C. Horton
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195
40e Use of the Hand-Held Ophthalmoscope.
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211
41e Video Library of Neuro-Ophthalmology.
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211
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211
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217
Homayoun Tabandeh, Morton F. Goldberg Shirley H. Wray
42 Disorders of Smell and Taste.
43 Disorders of Hearing.
44 Sore Throat, Earache, and Upper Respiratory Symptoms. . . . . . . . .
Richard L. Doty, Steven M. Bromley Anil K. Lalwani
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Michael A. Rubin, Larry C. Ford, Ralph Gonzales
225
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45 Oral Manifestations of Disease. . Samuel C. Durso
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46e Atlas of Oral Manifestations of Disease. . Samuel C. Durso, Janet A. Yellowitz
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235
68 Hirsutism.
242
69 Menstrual Disorders and Pelvic Pain.
Section 5 Alterations in Circulatory and Respiratory Functions
47e Dyspnea.
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Richard M. Schwartzstein
Contents
48 Cough and Hemoptysis.
49 Hypoxia and Cyanosis.
50 Edema.
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247
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250
Eugene Braunwald, Joseph Loscalzo
51e Approach to the Patient with a Heart Murmur. . . . . . . . . . . . . . . . . . . . . . . . . . .
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253
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254
Patrick T. O’Gara, Joseph Loscalzo
243 243
Joseph Loscalzo
52 Palpitations.
Joseph Loscalzo
Section 6 Alterations in Gastrointestinal Function
53 Dysphagia.
54 Nausea, Vomiting, and Indigestion..
55 Diarrhea and Constipation. .
56 Involuntary Weight Loss..
57 Gastrointestinal Bleeding. .
58 Jaundice. .
59 Abdominal Swelling and Ascites..
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Ikuo Hirano, Peter J. Kahrilas
254
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258
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264
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274
William L. Hasler
Michael Camilleri, Joseph A. Murray
Russell G. Robertson, J. Larry Jameson
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276
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279
Loren Laine
Savio John, Daniel S. Pratt
Kathleen E. Corey, Lawrence S. Friedman
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Janet E. Hall
285
70 Approach to the Patient with a Skin Disorder..
71 Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders. . . . . . . . . .
Thomas J. Lawley, Kim B. Yancey
60e Dysuria, Bladder Pain, and the Interstitial Cystitis/Bladder Pain Syndrome. . . . . . . . . . . . .
288
61 Azotemia and Urinary Abnormalities. .
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289
Julie Lin, Bradley M. Denker
62e Atlas of Urinary Sediments and Renal Biopsies. . . . . . . . . . . . . . . . . . Agnes B. Fogo, Eric G. Neilson
63 Fluid and Electrolyte Disturbances. . David B. Mount
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64e Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples. . . .
74 Cutaneous Drug Reactions. .
75 Photosensitivity and Other Reactions to Light. .
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313
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315
65 Hypercalcemia and Hypocalcemia.
66 Acidosis and Alkalosis.
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370
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377
Kim B. Yancey, Thomas J. Lawley
Kanade Shinkai, Robert S. Stern, Bruce U. Wintroub
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385
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391
Alexander G. Marneros, David R. Bickers
76e Atlas of Skin Manifestations of Internal Disease. . . . . . . . . . . . . . . . .
Thomas J. Lawley, Calvin O. McCall, Robert A. Swerlick
Section 10 Hematologic Alterations
77 Anemia and Polycythemia.
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392
78 Bleeding and Thrombosis. .
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400
79 Enlargement of Lymph Nodes and Spleen.
80 Disorders of Granulocytes and Monocytes. .
John W. Adamson, Dan L. Longo Barbara A. Konkle
Patrick H. Henry, Dan L. Longo
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413
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424
Steven M. Holland, John I. Gallin
81e Atlas of Hematology and Analysis of Peripheral Blood Smears. . . . . . . . . . . . . .
407
Part 3 Genes, the Environment, and Disease
312
Thomas D. DuBose, Jr.
295
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David B. Mount, Thomas D. DuBose, Jr. Sundeep Khosla
295
353
73 Immunologically Mediated Skin Diseases..
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Jean L. Bolognia, Irwin M. Braverman
339
344
72 Skin Manifestations of Internal Disease.
Dan L. Longo
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John W. Warren
335
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Leslie P. Lawley, Calvin O. McCall, Thomas J. Lawley
Section 7 Alterations in Renal and Urinary Tract Function
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331
Section 9 Alterations in the Skin
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Patricia A. Kritek, Christopher H. Fanta
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David A. Ehrmann
82 Principles of Human Genetics. . J. Larry Jameson, Peter Kopp
83e Chromosome Disorders. Nancy B. Spinner, Laura K. Conlin
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425
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445
84 The Practice of Genetics in Clinical Medicine. Susan M. Domchek, J. Larry Jameson, Susan Miesfeldt
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85e Mitochondrial DNA and Heritable Traits and Diseases.. . . . . . . . . . . . . . . . . . . . . . . . . .
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451
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451
Karl Skorecki, Doron Behar
86e The Human Microbiome.
87e Network Medicine: Systems Biology in Health and Disease. . . . . . . . . . . . . . . . . . . . .
Jeffrey I. Gordon, Rob Knight
Joseph Loscalzo
446
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451
Section 8 Alterations in Sexual Function and Reproduction
67 Sexual Dysfunction..
HPIM19_VOlI_FM.indd 8
Kevin T. McVary
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Part 4 Regenerative Medicine
88 Stem Cell Biology. . Minoru S. H. Ko
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89e Hematopoietic Stem Cells. . David T. Scadden, Dan L. Longo
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90e Applications of Stem Cell Biology in Clinical Medicine. . . . . . . . . . . . . . . . . . . .
455
91e Gene Therapy in Clinical Medicine. Katherine A. High
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456
92e Tissue Engineering. Anthony Atala
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456
Part 5 Aging
93e World Demography of Aging. Richard M. Suzman, John G. Haaga
94e The Biology of Aging..
Breast Cancer. .
109
Upper Gastrointestinal Tract Cancers. .
110
Lower Gastrointestinal Cancers.
111
Tumors of the Liver and Biliary Tree. .
112
Pancreatic Cancer. .
113
Endocrine Tumors of the Gastrointestinal Tract and Pancreas. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Marc E. Lippman
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Rafael de Cabo, David G. Le Couteur
457 457
Part 6 Nutrition and Weight Loss
532
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537
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544
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554
Brian I. Carr
Elizabeth Smyth, David Cunningham
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557
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575
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579
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588
Robert T. Jensen 114
Bladder and Renal Cell Carcinomas.
115
Benign and Malignant Diseases of the Prostate. . . . . . . . . . . . . .
Howard I. Scher, Jonathan E. Rosenberg, Robert J. Motzer
Howard I. Scher, James A. Eastham . . . . . . . . . . . . . . .
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Robert J. Mayer Robert J. Mayer
116
Testicular Cancer.
117
Gynecologic Malignancies.
118
Primary and Metastatic Tumors of the Nervous System. . . . . . . . . . . . . . . . . .
Robert J. Motzer, Darren R. Feldman, George J. Bosl Michael V. Seiden
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Lisa M. DeAngelis, Patrick Y. Wen
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119e Soft Tissue and Bone Sarcomas and Bone Metastases.. . . . . . . . . . . . . . . . . . . .
95e Nutrient Requirements and Dietary Assessment. . . . . . . . . . . . . . . . . . . . . . . Johanna Dwyer
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96e Vitamin and Trace Mineral Deficiency and Excess. . . . . . . . . . . . . . . . . . . . . . . . . . Robert M. Russell, Paolo M. Suter
97 Malnutrition and Nutritional Assessment. . Douglas C. Heimburger
459
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459
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459
98e Enteral and Parenteral Nutrition Therapy. . Bruce R. Bistrian, L. John Hoffer, David F. Driscoll
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465
Part 7 Oncology and Hematology Section 1 Neoplastic Disorders
Dan L. Longo
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100
Prevention and Early Detection of Cancer.
101e Cancer Genetics.
102e Cancer Cell Biology. .
103e Principles of Cancer Treatment. .
104
475
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483
Jennifer M. Croswell, Otis W. Brawley, Barnett S. Kramer
Pat J. Morin, Jeffrey M. Trent, Francis S. Collins, Bert Vogelstein
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Edward A. Sausville, Dan L. Longo
Infections in Patients with Cancer.
105
Cancer of the Skin..
106
Head and Neck Cancer.
107
Neoplasms of the Lung. .
483
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484
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Leora Horn, Christine M. Lovly, David H. Johnson
HPIM19_VOlI_FM.indd 9
483
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Walter J. Urba, Brendan D. Curti Everett E. Vokes
467
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Robert W. Finberg
121
608
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608
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608
120e Carcinoma of Unknown Primary. . Gauri R. Varadhachary, James L. Abbruzzese
Paraneoplastic Syndromes: Endocrinologic/Hematologic. J. Larry Jameson, Dan L. Longo
122
Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis. . . . . . . . . . . . . .
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614
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619
Josep Dalmau, Myrna R. Rosenfeld
123e Thymoma.
124e Neoplasia During Pregnancy..
125
Dan L. Longo
598
Michael F. Greene, Dan L. Longo
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Late Consequences of Cancer and Its Treatment.
620
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620
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625
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631
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640
Carl E. Freter, Dan L. Longo
Section 2 Hematopoietic Disorders
99 Approach to the Patient with Cancer.
Jeffrey W. Clark, Dan L. Longo
ix
592
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Shreyaskumar R. Patel, Robert S. Benjamin
523
Contents
455
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John A. Kessler
453
108
493 502 506
126
Iron Deficiency and Other Hypoproliferative Anemias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . John W. Adamson
127
Disorders of Hemoglobin. .
128
Megaloblastic Anemias..
129
Hemolytic Anemias and Anemia Due to Acute Blood Loss. . . . . . . . . . . . . . . . . .
Edward J. Benz, Jr.
A. Victor Hoffbrand
Lucio Luzzatto 130
. . . . . . . . . . .
Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia. . . . . . . . . . . . . . . . . . . .
.
662
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672
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678
Neal S. Young 131
Polycythemia Vera and Other Myeloproliferative Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jerry L. Spivak
132 Acute Myeloid Leukemia.
649
Guido Marcucci, Clara D. Bloomfield
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133 134
136 137
Chronic Myeloid Leukemia. . Hagop Kantarjian, Jorge Cortes
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Malignancies of Lymphoid Cells. . Dan L. Longo
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135e Less Common Hematologic Malignancies. . Ayalew Tefferi, Dan L. Longo
Plasma Cell Disorders. .
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Nikhil C. Munshi, Dan L. Longo, Kenneth C. Anderson
Amyloidosis.
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David C. Seldin, John L. Berk
Contents
138e Transfusion Biology and Therapy. .
139e Hematopoietic Cell Transplantation. .
Jeffery S. Dzieczkowski, Kenneth C. Anderson
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Frederick R. Appelbaum
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687 695 710 710 719 724 725
140
Disorders of Platelets and Vessel Wall.
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725
141
Coagulation Disorders.
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732
142
Arterial and Venous Thrombosis.
143
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs. . . . . . . . . . . . .
Barbara A. Konkle
Valder R. Arruda, Katherine A. High
Jeffrey I. Weitz
Infective Endocarditis. .
156
Infections of the Skin, Muscles, and Soft Tissues.
157
Infectious Arthritis. .
158
Osteomyelitis. .
159
Intraabdominal Infections and Abscesses..
160
Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning. . . . . . . . . . . . .
Adolf W. Karchmer
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827
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833
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838
Lawrence C. Madoff Werner Zimmerli
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740 745
Part 8 Infectious Diseases
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846
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852
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857
Miriam Baron Barshak, Dennis L. Kasper
Regina C. LaRocque, Edward T. Ryan, Stephen B. Calderwood 161
162
Clostridium difficile Infection, Including Pseudomembranous Colitis. . . . . . . . . .
Urinary Tract Infections, Pyelonephritis, and Prostatitis. . . . . . . . . . . . . . . . . . . . . Kalpana Gupta, Barbara W. Trautner
163
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Sexually Transmitted Infections: Overview and Clinical Approach.. . . . . . . . . . . . . . . . .
869
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883
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906
Meningitis, Encephalitis, Brain Abscess, and Empyema.. . . . . . . . . . . . . . . . . . . . . Karen L. Roos, Kenneth L. Tyler
165
Chronic and Recurrent Meningitis.
166e Infectious Complications of Burns..
167e Infectious Complications of Bites.
Walter J. Koroshetz, Avindra Nath
861
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Jeanne M. Marrazzo, King K. Holmes 164
816
. . . .
Dennis L. Stevens
Dale N. Gerding, Stuart Johnson
Section 3 Disorders of Hemostasis
Jane E. Freedman, Joseph Loscalzo
155
Lawrence C. Madoff, Florencia Pereyra Lawrence C. Madoff, Florencia Pereyra
. . . . . . . . . .
911
. . . . . . . . . . .
911
Section 1 Basic Considerations in Infectious Diseases 144
Approach to the Patient with an Infectious Disease.. . . . . . . . . . . . Neeraj K. Surana, Dennis L. Kasper
145e Molecular Mechanisms of Microbial Pathogenesis. . . . . . . . Gerald B. Pier
Section 3 Clinical Syndromes: Health Care–Associated Infections . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . .
146
Genomics and Infectious Disease. .
147
Approach to the Acutely Ill Infected Febrile Patient. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
Roby P. Bhattacharyya, Yonatan H. Grad, Deborah T. Hung
Tamar F. Barlam, Dennis L. Kasper
. . . . . . . . . . . . .
148
Immunization Principles and Vaccine Use.
149
Health Recommendations for International Travel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anne Schuchat, Lisa A. Jackson
. . . . . . . . .
Jay S. Keystone, Phyllis E. Kozarsky
150e Laboratory Diagnosis of Infectious Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander J. McAdam, Andrew B. Onderdonk
. . . . . . .
. . . . . . . . .
151e Climate Change and Infectious Disease.. Aaron S. Bernstein
152e Infections in Veterans Returning from Foreign Wars. . . . . . . . . . . . . . . . . . . . . . . . . Andrew W. Artenstein
. . . . . .
. . . . . . .
761 768 768 779 785 793 802 803 803
Section 2 Clinical Syndromes: Community-Acquired Infections 153
Pneumonia. .
154
Lung Abscess.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lionel A. Mandell, Richard G. Wunderink
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Rebecca M. Baron, Miriam Baron Barshak
HPIM19_VOlI_FM.indd 10
803 813
168
Infections Acquired in Health Care Facilities..
. . . . . . .
911
169
Infections in Transplant Recipients..
. . . . . . . . . . . . . .
919
Robert A. Weinstein
Robert W. Finberg, Joyce Fingeroth
Section 4 Approach to Therapy for Bacterial Diseases 170
Treatment and Prophylaxis of Bacterial Infections. .
. .
930
. . . . . . . . . . . . . . . . . . . . . .
946
David C. Hooper, Erica S. Shenoy, Christy A. Varughese
Section 5 Diseases Caused by Gram-Positive Bacteria 171 Pneumococcal Infections.
David Goldblatt, Katherine L. O’Brien
172
Staphylococcal Infections. .
. . . . . . . . . . . . . . . . . . . . .
954
173
Streptococcal Infections. .
. . . . . . . . . . . . . . . . . . . . . .
963
174
Enterococcal Infections..
. . . . . . . . . . . . . . . . . . . . . . .
971
175
Diphtheria and Other Corynebacterial Infections. .
176
Listeria monocytogenes Infections.
177
Tetanus.
178
Botulism. .
179
Gas Gangrene and Other Clostridial Infections. .
Franklin D. Lowy
Michael R. Wessels
Cesar A. Arias, Barbara E. Murray
. . .
977
. . . . . . . . . . . . . . .
982
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
984
William R. Bishai, John R. Murphy
Elizabeth L. Hohmann, Daniel A. Portnoy C. Louise Thwaites, Lam Minh Yen
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Susan Maslanka, Agam K. Rao
Amy E. Bryant, Dennis L. Stevens
. . . . .
987 990
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Section 6 Diseases Caused by Gram-Negative Bacteria 180
Meningococcal Infections. .
181
Gonococcal Infections.
182
Haemophilus and Moraxella Infections. .
183e Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria. . . . . . .
Andrew J. Pollard
Sanjay Ram, Peter A. Rice
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . .
Timothy F. Murphy
. . . . . . . . . .
186
Diseases Caused by G ram-Negative Enteric Bacilli. . . . . . . . . . . . . . . . . .
Victor L. Yu, M. Luisa Pedro-Botet, Yusen E. Lin
207e Endemic Treponematoses. .
1010
208
Leptospirosis.
209
Relapsing Fever.
210
Lyme Borreliosis. .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1140
Rudy A. Hartskeerl, Jiři F. P. Wagenaar Alan G. Barbour Allen C. Steere
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1025
211 Rickettsial Diseases.
. . . . . . . . . . . . . . . . . . . . .
1036
212 Infections Due to Mycoplasmas.
1038
213 Chlamydial Infections. .
188
Helicobacter pylori Infections.
189
Infections Due to Pseudomonas Species and Related Organisms. . . . . . . . . . . . . .
David L. Paterson, Anton Y. Peleg
John C. Atherton, Martin J. Blaser
. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . .
David H. Walker, J. Stephen Dumler, Thomas Marrie
. . . . . . . . . . . . . . . . . . . . . . .
1165
Charlotte A. Gaydos, Thomas C. Quinn
1049
214e Medical Virology. .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1055
215e Antiviral Chemotherapy, Excluding Antiretroviral Drugs. . . . . . . . . . . . . . . . . .
191
Shigellosis.
192
Infections Due to Campylobacter and Related Organisms. . . . . . . . . . . . . . . .
David A. Pegues, Samuel I. Miller
Philippe J. Sansonetti, Jean Bergounioux
Cholera and Other Vibrioses..
1058
. . . . . . . . . . . . . . . . . .
1061
Matthew K. Waldor, Edward T. Ryan
194e Brucellosis..
. . . . . . . . . . . . . . . . . . . . . . . . . . .
Nicholas J. Beeching, Michael J. Corbel
195
Tularemia. .
196
Plague and Other Yersinia Infections.
197
Bartonella Infections, Including Cat-Scratch Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Richard F. Jacobs, Gordon E. Schutze Michael B. Prentice
. . . . . . . . . . . .
Nigel O’Farrell
1066 1066 1070
. . . . . .
1078
. . . . . . . . . . . . . . . . . . . . . . . . .
1083
Michael Giladi, Moshe Ephros
198e Donovanosis. .
Section 11 Viral Diseases: General Considerations Fred Wang, Elliott Kieff
. . . . . . . . . . . . . . . . . . . . . .
1174
216 Herpes Simplex Virus Infections. .
. . . . . . . . . . . . . . .
1175
217 Varicella-Zoster Virus Infections. .
. . . . . . . . . . . . . . .
1183
Section 12 Infections Due to DNA Viruses Lawrence Corey
Richard J. Whitley
218 Epstein-Barr Virus Infections, Including Infectious Mononucleosis. . . . . . . . . . . . . Jeffrey I. Cohen
. . . . . . . . .
219 Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8. . . . . . . . . . . . . . . . . . . . . . Camille Nelson Kotton, Martin S. Hirsch
. . . . . . .
220e Molluscum Contagiosum, Monkeypox, and Other Poxvirus Infections. . . . . . . . . . . . .
199
Nocardiosis..
200
Actinomycosis and Whipple’s Disease.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gregory A. Filice
Thomas A. Russo
. . . . . . . . . . .
201 Infections Due to Mixed Anaerobic Organisms. . Ronit Cohen-Poradosu, Dennis L. Kasper
. . . .
1084
. . . . . . . . . . . . . . . . . . . . . . . .
1195
1094
Section 8 Mycobacterial Diseases 202
Tuberculosis. .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1102
203
Leprosy..
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1122
204
Nontuberculous Mycobacterial Infections.
205e Antimycobacterial Agents..
Mario C. Raviglione Robert H. Gelber
. . . . . . . .
1128
. . . . . . . . . . . . . . .
1132
Steven M. Holland
Max R. O’Donnell, Divya Reddy, Jussi J. Saukkonen
Parvovirus Infections.
222
Human Papillomavirus Infections..
1088
1190 1194
221
Kevin E. Brown
1186
. . . . .
Fred Wang
Section 7 Miscellaneous Bacterial Infections
1174
. . . . . . . .
Lindsey R. Baden, Raphael Dolin . . . . . . . . . . .
Martin J. Blaser
1154 1163
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Salmonellosis. .
1149
. . . . . . . . . . . . . . . .
R. Doug Hardy
1042
190
1146
Section 10 D iseases Caused by Rickettsiae, Mycoplasmas, and Chlamydiae
. . . . . . . . .
Reuben Ramphal
HPIM19_VOlI_FM.indd 11
1140
. . . . . . . . . . . . .
Acinetobacter Infections. .
1132
. . . . . . . . . . . . . . .
Sheila A. Lukehart
1021
187
. . . . . . . .
Karina A. Top, Scott A. Halperin
Thomas A. Russo, James R. Johnson
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sheila A. Lukehart
Contents
Pertussis and Other Bordetella Infections. .
1003
1014
185
Syphilis..
. . . . . . . . . . . . . . . . . . . . . . . .
Legionella Infections..
206
1014
Tamar F. Barlam, Dennis L. Kasper
193
995
. . . .
184
xi
Section 9 Spirochetal Diseases
Aaron C. Ermel, Darron R. Brown
. . . . . . . . . . . . . .
1197
Section 13 Infections Due to DNA and RNA Respiratory Viruses 223
Common Viral Respiratory Infections. .
. . . . . . . . . . .
1202
224
Influenza.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1209
Raphael Dolin
Yehuda Z. Cohen, Raphael Dolin
Section 14 I nfections Due to Human Immunodeficiency Virus and Other Human Retroviruses
225e The Human Retroviruses. . Dan L. Longo, Anthony S. Fauci
. . . . . . . . . . . . . . . .
1215
1/30/15 2:34 PM
xii
226
Human Immunodeficiency Virus Disease: AIDS and Related Disorders. . . . . . . . . . . . . . . . . . . . Anthony S. Fauci, H. Clifford Lane
. . . .
1215
249 Babesiosis..
Section 15 Infections Due to RNA Viruses Viral Gastroenteritis. .
228
Enterovirus, Parechovirus, and Reovirus Infections. . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . .
Umesh D. Parashar, Roger I. Glass
1289
. . . . . . . . . . . . . . . . . . . . . . . . . .
1295
Jeffrey I. Cohen
Contents
230e Rubella (German Measles)..
Kaitlin Rainwater-Lovett, William J. Moss Laura A. Zimmerman, Susan E. Reef
231e Mumps.
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Steven A. Rubin, Kathryn M. Carbone
232
Rabies and Other Rhabdovirus Infections..
233
Arthropod-Borne and Rodent-Borne Virus Infections.. . . . . . . . . . . . . . . . .
Alan C. Jackson
Jens H. Kuhn, Clarence J. Peters 234
1285
. . . . . . . . .
Measles (Rubeola).
. . . . . . . .
1299
. . . . . . . . . . . .
Jens H. Kuhn
. . . . . . . . .
253 Toxoplasma Infections. Kami Kim, Lloyd H. Kasper
Peter F. Weller
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1342
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
244 Pneumocystis Infections. Henry Masur, Alison Morris
1409
. . . . . . . .
1410
. . . . . . . . . . . . . . . .
1413
. . . . . . . . . . . . . . . . .
1417
Peter F. Weller
Thomas B. Nutman, Peter F. Weller
1345 1350
. . . . . . . . . .
1353
. . . . . . . . . . . . . . . . . . . . . .
1358
245e Laboratory Diagnosis of Parasitic Infections. . . . . . . . . . . . . . . . . . . . . . . . . Sharon L. Reed, Charles E. Davis Thomas A. Moore
. . . .
1362 1363
1363
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1368
Nicholas J. White, Joel G. Breman
1430
Part 9 Terrorism and Clinical Medicine
261e Microbial Bioterrorism.
. . . . . . . . . . . . . . . . . .
1437
262e Chemical Terrorism. .
. . . . . . . . . . . . . . . . . . . .
1437
263e Radiation Terrorism.
. . . . . . . . . . . . . . . . . . . .
1437
H. Clifford Lane, Anthony S. Fauci
Charles G. Hurst, Jonathan Newmark, James A. Romano, Jr. Christine E. Hill-Kayser, Eli Glatstein, Zelig A. Tochner
Part 10 Disorders of the
Cardiovascular System
264 Approach to the Patient with Possible Cardiovascular Disease.. . . . . . . . . . . . Joseph Loscalzo
. . . . . . . .
Rosa M. Andrade, Sharon L. Reed
. . . . . . . . . . . . . . . . . . . . . . . . . .
A. Clinton White, Jr., Peter F. Weller
. . . . . . . . . . .
265e Basic Biology of the Cardiovascular System. . . . . . . . . . . . . . . . . . . . . . . . . . . . Joseph Loscalzo, Peter Libby, Jonathan A. Epstein
Section 18 Protozoal Infections 247 Amebiasis and Infection with Free-Living Amebas. . . . . . . . . . . . . . . . . . . . . . . . . . .
1423
Section 1 Introduction to Cardiovascular Disorders
. . . . . . . . .
246e Agents Used to Treat Parasitic Infections.
. .
Charles H. King, Adel A. F. Mahmoud
Section 17 P rotozoal and Helminthic Infections: General Considerations
HPIM19_VOlI_FM.indd 12
. . . . . .
Peter F. Weller
256 Trichinellosis and Other Tissue Nematode Infections. . . . . . . . . . . . . . . . . . . . . . . . . .
1337 1339
Carol A. Kauffman
248 Malaria. .
255e Introduction to Helminthic Infections. .
260 Cestode Infections.
243 Superficial Mycoses and Less Common Systemic Mycoses. . . . . . . . . . . . . . . . . .
1334
. . . . . . . . . . . . . . . . . . . . . . . . .
1405
Section 19 Helminthic Infections
259 Schistosomiasis and Other Trematode Infections. .
Brad Spellberg, Ashraf S. Ibrahim
. . . . . . . . . . . . .
1332
David W. Denning
1398
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
John E. Edwards, Jr.
. . . . . . . . . . . . . . . . . . . . . . .
254 Protozoal Intestinal Infections and Trichomoniasis. . . . . . . . . . . . . . . . .
1304
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
242 Mucormycosis..
1394
258 Filarial and Related Infections.
Donna C. Sullivan, Rathel L. Nolan, III
241 Aspergillosis. .
. . . . .
Louis V. Kirchhoff, Anis Rassi Jr.
1329
237 Coccidioidomycosis.
240 Candidiasis. .
1387
. . . .
Chadi A. Hage, L. Joseph Wheat
Arturo Casadevall
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Peter F. Weller, Thomas B. Nutman
John E. Edwards, Jr.
239 Cryptococcosis. .
1387
252 Chagas Disease and African Trypanosomiasis.
1299
1323
1384
. . . . . . .
257 Intestinal Nematode Infections.
235 Diagnosis and Treatment of Fungal Infections. .
238 Blastomycosis..
Shyam Sundar
1299
Section 16 Fungal Infections
Neil M. Ampel
251 Leishmaniasis. .
Ebolavirus and Marburgvirus Infections. .
236 Histoplasmosis. .
250e Atlas of Blood Smears of Malaria and Babesiosis.. . . . . . . . . . . . . . . . . . . . . . . . . . Nicholas J. White, Joel G. Breman
227
229
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Edouard G. Vannier, Peter J. Krause
. . . . . . . .
266e Epidemiology of Cardiovascular Disease. Thomas A. Gaziano, J. Michael Gaziano
1439 1441
. . . .
1442
. . . . . .
1442
Section 2 Diagnosis of Cardiovascular Disorders 267 Physical Examination of the Cardiovascular System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patrick T. O’Gara, Joseph Loscalzo
1/30/15 2:34 PM
268 Electrocardiography. . Ary L. Goldberger
. . . . . . . . . . . . . . . . . . . . . . . .
269e Atlas of Electrocardiography..
270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ary L. Goldberger
. . . . . . . . . . . . .
271e Atlas of Noninvasive Imaging. .
1459
293 Ischemic Heart Disease. .
. . . . .
1459
. . . . . . . . . . . .
1460
Marcelo F. Di Carli, Raymond Y. Kwong, Scott D. Solomon
Marcelo F. Di Carli, Raymond Y. Kwong, Scott D. Solomon
Jane A. Leopold, David P. Faxon
David D. Spragg, Gordon F. Tomaselli
. . . . . . . . . . .
David D. Spragg, Gordon F. Tomaselli
275 The Bradyarrhythmias: Disorders of the Atrioventricular Node.. . . . . . . . . . . . . . .
1466
295 ST-Segment Elevation Myocardial Infarction. Elliott M. Antman, Joseph Loscalzo
. . . . . . . . .
1466
. . . . . . . . . . . .
1476
. . . . . . . . . . . . . . . . . . . . .
1489
David D. Spragg, Gordon F. Tomaselli
Gregory F. Michaud, William G. Stevenson Roy M. John, William G. Stevenson
278e Atlas of Cardiac Arrhythmias. Ary L. Goldberger
. . . . . . . . . . . . .
1500
. . . .
1500
. . . . . . . . . . . . . . . . . . .
1507
Douglas L. Mann, Murali Chakinala
281 Cardiac Transplantation and Prolonged Assisted Circulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sharon A. Hunt, Hari R. Mallidi
282 Congenital Heart Disease in the Adult. Jamil A. Aboulhosn, John S. Child
283 Aortic Valve Disease.
. .
. . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . .
Patrick T. O’Gara, Joseph Loscalzo
284 Mitral Valve Disease. .
. . . . . . . . . . . . . . . . . . . . . . . .
Patrick T. O’Gara, Joseph Loscalzo
285 Tricuspid and Pulmonic Valve Disease. Patrick T. O’Gara, Joseph Loscalzo
. . . . . . . . . . .
286 Multiple and Mixed Valvular Heart Disease.
1528 1539 1547
. . . . . . . . . . . . . .
1553
. . . . . . . . . . . . . . . . . . . . . . . . .
1571
Neal K. Lakdawala, Lynne Warner Stevenson, Joseph Loscalzo
1519
1550
Patrick T. O’Gara, Joseph Loscalzo
Eugene Braunwald
1516
. . . . . . .
287 Cardiomyopathy and Myocarditis. 288 Pericardial Disease. .
289e Tumors and Trauma of the Heart. Eric H. Awtry, Wilson S. Colucci
. . . . . . . . . .
290e Cardiac Manifestations of Systemic Disease. Eric H. Awtry, Wilson S. Colucci
. .
1577 1577
Section 5 Coronary and Peripheral Vascular Disease
1599 1611
. . . .
1611
. . . . . . . . . . . . . . . .
1611
. . . . . . . . . . . . . . . . . . . . . . .
1627
297e Atlas of Percutaneous Revascularization.
Jane A. Leopold, Deepak L. Bhatt, David P. Faxon
299 Renovascular Disease. .
300 Deep Venous Thrombosis and Pulmonary Thromboembolism. . . . . . . . . . . . . . . . . . .
. . . . . . . .
1631
301 Diseases of the Aorta.
. . . . . . . . . . . . . . . . . . . . . . . .
1637
Mark A. Creager, Joseph Loscalzo
302 Arterial Diseases of the Extremities. Mark A. Creager, Joseph Loscalzo
. . . . . . . . . . . . .
303 Chronic Venous Disease and Lymphedema . . 304 Pulmonary Hypertension.
1643
. . . . . .
1650
. . . . . . . . . . . . . . . . . . . . .
1655
Mark A. Creager, Joseph Loscalzo
Aaron B. Waxman, Joseph Loscalzo
xiii
Part 11 Disorders of the
279 Heart Failure: Pathophysiology and Diagnosis. . Mandeep R. Mehra
. . . . . .
. . .
Theodore A. Kotchen
Section 4 Disorders of the Heart
280 Heart Failure: Management.
1593
David P. Faxon, Deepak L. Bhatt
Samuel Z. Goldhaber
1470
.
296e Percutaneous Coronary Interventions and Other Interventional Procedures. . . . . . . . . . . . .
Stephen C. Textor
. . . . . . . . .
276 Supraventricular Tachyarrhythmias. .
1578
298 Hypertensive Vascular Disease. .
274 The Bradyarrhythmias: Disorders of the Sinoatrial Node.. . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . .
Christopher P. Cannon, Eugene Braunwald
273e Principles of Electrophysiology. .
277 Ventricular Arrhythmias. .
1578
294 Non-ST-Segment Elevation Acute Coronary Syndrome (Non-ST-Segment Elevation Myocardial Infarction and Unstable Angina).. . . . . . . . . . . . . . .
1460
Section 3 Disorders of Rhythm
. . . . . . . . . . . . . . . . .
Peter Libby
Elliott M. Antman, Joseph Loscalzo
. . . . . . . . .
Contents
272 Diagnostic Cardiac Catheterization and Coronary Angiography. . . . . . . . . . . . . . .
292e Atlas of Atherosclerosis.
1450
291e The Pathogenesis, Prevention, and Treatment of Atherosclerosis.. . . . . . . . . . . . . . . . . . . . . . . . . . . 1578
Respiratory System
Section 1 Diagnosis of Respiratory Disorders 305 Approach to the Patient with Disease of the Respiratory System.. . . . . . . . . . . . . . . . . . . .
. . . . . .
1661
306e Disturbances of Respiratory Function. .
. . . . . .
1663
Patricia A. Kritek, Augustine M. K. Choi
Edward T. Naureckas, Julian Solway
307 Diagnostic Procedures in Respiratory Disease.
. . . . .
1663
. . . . . . . . . . . . . . . . . .
1669
Anne L. Fuhlbrigge, Augustine M. K. Choi
308e Atlas of Chest Imaging. Patricia A. Kritek, John J. Reilly, Jr.
Section 2 Diseases of the Respiratory System 309 Asthma. .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Peter J. Barnes
310 Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia. . . . . . . . . . . . . . .
1669
. . . . .
1681
. . . . . . . . . .
1687
312 Bronchiectasis.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1694
313 Cystic Fibrosis..
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1697
Praveen Akuthota, Michael E. Wechsler
311 Occupational and Environmental Lung Disease. . . . . . . . . . . . . . . . . . . . . . . . . . John R. Balmes, Frank E. Speizer
Rebecca M. Baron, Miriam Baron Barshak Eric J. Sorscher
314 Chronic Obstructive Pulmonary Disease..
. . . . . . . . .
John J. Reilly, Jr., Edwin K. Silverman, Steven D. Shapiro
1700
Peter Libby
HPIM19_VOlI_FM.indd 13
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xiv
. . . . . . . . . . . . . . . . . . . .
1708
335 Chronic Kidney Disease.
. . . . . . . . . . . . . . . . . . . . . .
1716
336 Dialysis in the Treatment of Renal Failure.
1719
337 Transplantation in the Treatment of Renal Failure. . . . . . . . . . . . . . . . . . .
315 Interstitial Lung Diseases. . Talmadge E. King, Jr.
316 Disorders of the Pleura. . Richard W. Light
317 Disorders of the Mediastinum. Richard W. Light
318 Disorders of Ventilation. .
. . . . . . . . . . . . . . . . .
Contents
1822
. . . . . . . . . . . .
1825
. . . . . . . . . . . . . . . . . . . . . . . .
1831
Jamil Azzi, Edgar L. Milford, Mohamed H. Sayegh, Anil Chandraker
1720
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1723
338 Glomerular Diseases..
1727
339 Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development.
Andrew Wellman, Susan Redline
320e Lung Transplantation. . Elbert P. Trulock
. . . . . . . . . . . . . . . . . .
Julia B. Lewis, Eric G. Neilson
. . . .
1850
. . . . . . . .
1856
. . . . . . . . . . . . . . . . .
1863
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
1866
Jing Zhou, Martin R. Pollak
340 Tubulointerstitial Diseases of the Kidney. .
Part 12 Critical Care Medicine
Laurence H. Beck, David J. Salant
341 Vascular Injury to the Kidney. . Nelson Leung, Stephen C. Textor
342 Nephrolithiasis. .
Section 1 Respiratory Critical Care 321 Approach to the Patient with Critical Illness. . John P. Kress, Jesse B. Hall
322 Acute Respiratory Distress Syndrome.. Bartolome R. Celli
1729
. . . . . . . . . . .
1736
. . . . . . . . . . . . . . .
1740
Bruce D. Levy, Augustine M. K. Choi
323 Mechanical Ventilatory Support. .
. . . . . .
Gary C. Curhan
343 Urinary Tract Obstruction. . Julian L. Seifter
Ronald V. Maier
325 Severe Sepsis and Septic Shock. Robert S. Munford
. . . . . . . . . . . . . . . .
1751
344 Approach to the Patient with Gastrointestinal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1759
345 Gastrointestinal Endoscopy.
Judith S. Hochman, David H. Ingbar
327 Cardiovascular Collapse, Cardiac Arrest, and Sudden Cardiac Death. . . . . . . . . . . . . . . . . . . Robert J. Myerburg, Agustin Castellanos
1764
329e Examination of the Comatose Patient. . S. Andrew Josephson
. . . . . .
. . . . . . . . . . . . . . . . . . . . . .
Rasim Gucalp, Janice P. Dutcher
334 Acute Kidney Injury.
HPIM19_VOlI_FM.indd 14
. . . . . . . . . . . . . . . . . . .
1900
. . . . . . .
1911
Henry J. Binder
. . . . . . . . . . . . . . . . . . . . .
1932
350e The Schilling Test. Henry J. Binder
. . . . . . . . . . . . . . . . . . . . . .
1946
351 Inflammatory Bowel Disease.
1787
. . . . . . . . . . . . . . . . . .
1947
. . . . . . . . . . . . . . . . . . . .
1965
Sonia Friedman, Richard S. Blumberg
352 Irritable Bowel Syndrome. . Chung Owyang
353 Diverticular Disease and Common Anorectal Disorders. . . . . . . . . . . .
. . . . . . . . . . . . . .
1971
354 Mesenteric Vascular Insufficiency..
. . . . . . . . . . . . . .
1978
. . . . . . . . . . . . . . . . . .
1981
Rizwan Ahmed, Susan L. Gearhart
. . . . . . . . . . .
355 Acute Intestinal Obstruction.. Danny O. Jacobs
356 Acute Appendicitis and Peritonitis. . Danny O. Jacobs
1799
. . . . . . . .
1799
. . . . . . . . . . . . . . . . . . . . . . . . .
1799
Sushrut S. Waikar, Joseph V. Bonventre
1900
Rizwan Ahmed, Mahmoud Malas
333e Adaptation of the Kidney to Injury. . Joseph V. Bonventre
347 Diseases of the Esophagus. .
and Urinary Tract
. .
Louis Michel Wong Kee Song, Mark Topazian
1777
Part 13 Disorders of the Kidney Alfred L. George, Jr., Eric G. Neilson
346e Video Atlas of Gastrointestinal Endoscopy. .
349 Disorders of Absorption. .
Section 4 Oncologic Emergencies
332e Cellular and Molecular Biology of the Kidney. . . . . . . . . . . . . . . . . . . .
1771
J. Claude Hemphill, III, Wade S. Smith, Daryl R. Gress
1880
John Del Valle
330 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy, and Subarachnoid Hemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1777
. . . . . . . . . . . . . . . . . . .
348 Peptic Ulcer Disease and Related Disorders.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
331 Oncologic Emergencies.
1875
Louis Michel Wong Kee Song, Mark Topazian
Peter J. Kahrilas, Ikuo Hirano
Allan H. Ropper
. . . .
William L. Hasler, Chung Owyang
. . . . .
Section 3 Neurologic Critical Care
Section 1 Disorders of the Alimentary Tract
1744
. . . . . . .
1871
Gastrointestinal System
. . . . . . . . . . . .
326 Cardiogenic Shock and Pulmonary Edema. .
328 Coma.
. . . . . . . . . . . . . . . . . . . .
Part 14 Disorders of the
Section 2 SHOCK AND CARDIAC ARREST 324 Approach to the Patient with Shock. .
1811
. . . . . . . .
Kathleen D. Liu, Glenn M. Chertow
. . . . . . . . . . . . . . . . . . . . .
John F. McConville, Babak Mokhlesi, Julian Solway
319 Sleep Apnea. .
. . . . . . . . . . . . . . . . . . . . . .
Joanne M. Bargman, Karl Skorecki
. . . . . . . . . . . . .
1985
Section 2 Liver and Biliary Tract Disease 357 Approach to the Patient with Liver Disease. Marc G. Ghany, Jay H. Hoofnagle
358 Evaluation of Liver Function. . Daniel S. Pratt
. . . . . . .
1989
. . . . . . . . . . . . . . . . . .
1995
1/30/15 2:34 PM
359 The Hyperbilirubinemias.
. . . . . . . . . . . . . . . . . . . . .
1999
381 Acute Rheumatic Fever..
. . . . . . . . . . . . . . . . . . . . . . . .
2004
382 Systemic Sclerosis (Scleroderma) and Related Disorders. . . . . . . . . . . . . . . . .
Allan W. Wolkoff
360 Acute Viral Hepatitis.. Jules L. Dienstag
361 Toxic and Drug-Induced Hepatitis.
. . . . . . . . . . . . . .
2023
. . . . . . . . . . . . . . . . . . . . . . . . . . .
2031
William M. Lee, Jules L. Dienstag
362 Chronic Hepatitis. Jules L. Dienstag
363 Alcoholic Liver Disease. .
. . . . . . . . . . . . . . . . . . . . . .
Mark E. Mailliard, Michael F. Sorrell
. . . . . . . . . . .
2054
. . . . . . . . . . . . . . . .
2058
. . . . . . . . . . . . . . . . . .
2067
Manal F. Abdelmalek, Anna Mae Diehl
365 Cirrhosis and Its Complications. Bruce R. Bacon
366e Atlas of Liver Biopsies. .
367e Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver. . . . . . . . . . . .
Jules L. Dienstag, Atul K. Bhan
383 Sjögren’s Syndrome. .
2154
. . . . . . . . . . . . . . . . . . . . . . . .
2166
Haralampos M. Moutsopoulos, Athanasios G. Tzioufas
384 The Spondyloarthritides.. Joel D. Taurog, John D. Carter
. . . . . . . . . . . . . . . . . . . . .
385 The Vasculitis Syndromes. .
. . . . . . . . . . . . . . . . . . . .
Carol A. Langford, Anthony S. Fauci
386e Atlas of the Vasculitic Syndromes. .
. . . . . . . . . . . . . . . . . . . . . . . . .
2194
2067
388 Polymyositis, Dermatomyositis, and Inclusion Body Myositis. . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . .
2067
389 Relapsing Polychondritis.
2075
390 Sarcoidosis. .
Raymond T. Chung, Jules L. Dienstag
369 Diseases of the Gallbladder and Bile Ducts. . Norton J. Greenberger, Gustav Paumgartner
. . . . . . .
2194
. . . . . . . . . . . . . . . . . . . . .
2202
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2205
Carol A. Langford
370 Approach to the Patient with Pancreatic Disease. .
. .
2086
. . . . . . . . . . . . . . . .
2090
Darwin L. Conwell, Norton J. Greenberger, Peter A. Banks
371 Acute and Chronic Pancreatitis..
. . . .
Marinos C. Dalakas
Robert P. Baughman, Elyse E. Lower
Section 3 Disorders of the Pancreas
Darwin L. Conwell, Peter A. Banks, Norton J. Greenberger
2179 2193
Haralampos M. Moutsopoulos
391e IgG4-Related Disease. John H. Stone
. . . . . . . . . . . . . . . . . . .
392 Familial Mediterranean Fever and Other Hereditary Autoinflammatory Diseases. . Daniel L. Kastner
. . . . . . . . .
xv
2169
. . . . . . . . .
Carol A. Langford, Anthony S. Fauci
387 Behçet’s Syndrome. .
2149
. . . . . . . . . . .
John Varga
. . . . . . . .
Bruce R. Bacon
368 Liver Transplantation. .
. . . . . . . . . . . . . . . . . . . . . .
Contents
364 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis. . . . . . . .
2052
Jonathan R. Carapetis
2212
2212
Section 3 Disorders of the Joints and Adjacent Tissues
Part 15 Immune-Mediated,
Inflammatory, and Rheumatologic Disorders
393 Approach to Articular and Musculoskeletal Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Osteoarthritis. . David T. Felson
Section 1 The Immune System in Health and Disease
372e Introduction to the Immune System. .
373e The Major Histocompatibility Complex. .
Barton F. Haynes, Kelly A. Soderberg, Anthony S. Fauci
Alain Fischer
2103
. . . . .
2103
. . . . . . . . . . .
2103
Gerald T. Nepom
374 Primary Immune Deficiency Diseases. .
. . . . . . .
375e Primary Immunodeficiencies Associated with (or Secondary to) Other Diseases. . . . . . . . .
376 Allergies, Anaphylaxis, and Systemic Mastocytosis.. . . . . . . . . . . . . . . . . . . . Joshua A. Boyce, K. Frank Austen
. . . .
2113
. . . . . . . . . . . . .
2233
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2238
H. Ralph Schumacher, Lan X. Chen
396 Fibromyalgia.
Leslie J. Crofford
397 Arthritis Associated with Systemic Disease, and Other Arthritides. . . . . . . . . . . . . . . . . . 398 Periarticular Disorders of the Extremities. . Carol A. Langford
. . . . . . . . . . .
. . . . . . . . . . . . . . . .
2124
. . . . . . . . . . . . . . . . . .
2134
. . . . . . . . . . . . . . . . . . . . . . . .
2136
Bevra Hannahs Hahn
379 Antiphospholipid Syndrome.
Haralampos M. Moutsopoulos, Panayiotis G. Vlachoyiannopoulos Ankoor Shah, E. William St. Clair
2240
. . . . . . . .
2247
2113 2124
378 Systemic Lupus Erythematosus.
. . . . . . .
Part 16 Endocrinology and . . .
Betty Diamond, Peter E. Lipsky
HPIM19_VOlI_FM.indd 15
2226
Metabolism
377e Autoimmunity and Autoimmune Diseases.
380 Rheumatoid Arthritis.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
395 Gout and Other Crystal-Associated Arthropathies. . . . . . . . . . . . . . . . . .
Section 2 Disorders of Immune-Mediated Injury
2216
Carol A. Langford, Brian F. Mandell
Alain Fischer
. . . . . . .
John J. Cush
Section 1 Endocrinology 399 Approach to the Patient with Endocrine Disorders. . . . . . . . . . . . . . . . . . . . . . . . . J. Larry Jameson
. . . . . . . . .
2251
400e Mechanisms of Hormone Action. .
. . . . . . . . . .
2255
401e Anterior Pituitary: Physiology of Pituitary Hormones. . . . . . . . . . . . . . . .
. . . . . . . . . .
2255
J. Larry Jameson
Shlomo Melmed, J. Larry Jameson
1/30/15 2:35 PM
xvi
402 Hypopituitarism. .
2255
425 Osteoporosis.
. . . . . . . . . . . .
2261
. . . . . . . . . . . . .
2274
. . . . . . . . . . . . . . . .
2283
Section 5 Disorders of Intermediary Metabolism
2309
427 Heritable Disorders of Connective Tissue. .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
Shlomo Melmed, J. Larry Jameson
403 Anterior Pituitary Tumor Syndromes. Shlomo Melmed, J. Larry Jameson
404 Disorders of the Neurohypophysis. . Gary L. Robertson
405 Disorders of the Thyroid Gland..
J. Larry Jameson, Susan J. Mandel, Anthony P. Weetman
406 Disorders of the Adrenal Cortex. . Wiebke Arlt
Contents
407 Pheochromocytoma. . Hartmut P. H. Neumann
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . .
408 Multiple Endocrine Neoplasia.. Rajesh V. Thakker
. . . . . . . . . . . . . . . . .
409 Autoimmune Polyendocrine Syndromes. Peter A. Gottlieb
. . . . . . . . .
2329 2335 2344
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Robert Lindsay, Felicia Cosman
426e Paget’s Disease and Other Dysplasias of Bone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . .
2504
. . . . . . . .
2504
. . . . . . . . . . . . . . . . . . . . . . . . . .
2514
. . . . . . . . . . . . . . . . . . . . . . . . . . .
2519
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
2521
Murray J. Favus, Tamara J. Vokes
Darwin J. Prockop, John F. Bateman
428 Hemochromatosis. Lawrie W. Powell
429 Wilson’s Disease. . George J. Brewer
430 The Porphyrias. .
Robert J. Desnick, Manisha Balwani
Section 2 Reproductive Endocrinology 410 Disorders of Sex Development. . John C. Achermann, J. Larry Jameson
. . . . . . . . . . . . . . . .
411 Disorders of the Testes and Male Reproductive System. . . . . . . . . . Shalender Bhasin, J. Larry Jameson
. . . . . . . . . . . . . . .
412 Disorders of the Female Reproductive System. . Janet E. Hall
413 Menopause and Postmenopausal Hormone Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Janet E. Hall
2349
415e Biology of Obesity..
. . . . . . . . . . . . . . . . . .
2387
. . . . . . . . . . . . . . . . . . . . .
Jeffrey S. Flier, Eleftheria Maratos-Flier Robert F. Kushner
. . . . . . . . .
417 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology. . . . . . . . . . . . . . . . . . . Alvin C. Powers
. . . . . .
418 Diabetes Mellitus: Management and Therapies.
433e Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . .
Robert J. Hopkin, Gregory A. Grabowski
. . . . . .
2534
434e Inherited Disorders of Amino Acid Metabolism in Adults. . . . . . . . . . . . . . . . Nicola Longo
. . . . . . . . .
2534
435e Inherited Defects of Membrane Transport.
436e Atlas of Clinical Manifestations of Metabolic Diseases. . . . . . . . . . . . . . . . . .
2392
J. Larry Jameson
2392
. . .
2534
. . . . . . . . .
2534
Nicola Longo
Part 17 Neurologic Disorders
2399
Section 1 Diagnosis of Neurologic Disorders
. . . . . . . . . . . . . .
2422
438e The Neurologic Screening Exam.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2430
439e Video Atlas of the Detailed Neurologic Examination. . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . .
2540
. . . . .
2540
. . . . . . . . . . . . . . . . . .
2541
Alvin C. Powers
. . . .
Philip E. Cryer, Stephen N. Davis
421 Disorders of Lipoprotein Metabolism. . Daniel J. Rader, Helen H. Hobbs
422 The Metabolic Syndrome.
. . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
2435 2449
423 Bone and Mineral Metabolism in Health and Disease. . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
F. Richard Bringhurst, Marie B. Demay, Stephen M. Krane, Henry M. Kronenberg
424 Disorders of the Parathyroid Gland and Calcium Homeostasis. . . . . . . . . . . . . . . . John T. Potts, Jr., Harald Jüppner
. . . . . . . . .
. .
2535
. . . . . . . . . . .
2540
Daniel H. Lowenstein, Joseph B. Martin, Stephen L. Hauser Daniel H. Lowenstein
Martin A. Samuels
440e Neuroimaging in Neurologic Disorders. .
441e Atlas of Neuroimaging.
442e Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG. . . . . . . 2541
443e Technique of Lumbar Puncture. .
. . . . . . . . . . .
2541
444e Biology of Neurologic Diseases. .
. . . . . . . . . . .
2541
Section 4 Disorders of Bone and Mineral Metabolism
William P. Dillon
Andre D. Furtado, William P. Dillon
Michael J. Aminoff
2454
2466
Elizabeth Robbins, Stephen L. Hauser
Stephen L. Hauser, Stanley B. Prusiner, M. Flint Beal
Section 2 Diseases of the Central Nervous System 445 Seizures and Epilepsy. . Daniel H. Lowenstein
HPIM19_VOlI_FM.indd 16
2533
432e Lysosomal Storage Diseases. .
437 Approach to the Patient with Neurologic Disease.
419 Diabetes Mellitus: Complications. .
Robert H. Eckel
. . . . . . . . . . . . .
2407
Alvin C. Powers
420 Hypoglycemia.
2533
Priya S. Kishnani, Yuan-Tsong Chen
2381
416 Evaluation and Management of Obesity..
. . . . . . . .
2375
Section 3 Obesity, Diabetes Mellitus, and Metabolic Syndrome
431e Disorders of Purine and Pyrimidine Metabolism. . . . . . . . . . . . . . . . . . . . . . . . Christopher M. Burns, Robert L. Wortmann
2357
. . . . . .
JoAnn E. Manson, Shari S. Bassuk
414 Infertility and Contraception.
. . . .
2488
. . . . . . . . . . . . . . . . . . . . . . .
2542
1/30/15 2:35 PM
446 Cerebrovascular Diseases. .
. . . . . . . . . . . . . . . . . . . .
Wade S. Smith, S. Claiborne Johnston, J. Claude Hemphill, III
447 Migraine and Other Primary Headache Disorders..
. .
2586
. . . . . . .
2598
Peter J. Goadsby, Neil H. Raskin
448 Alzheimer’s Disease and Other Dementias. . William W. Seeley, Bruce L. Miller
. . . . . . .
2609
. . . . . . . . . . . . . . . . . . . . . . . . . . .
2626
C. Warren Olanow, Anthony H.V. Schapira, Jose A. Obeso
451e Classification of the Spinocerebellar Ataxias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roger N. Rosenberg
452 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. . . . . . . . . . . . . . .
453e Prion Diseases..
. . . . .
2637
. . . . . . . . . .
2645
. . . . . . . . . . . . . . . . . . .
2650
457e Concussion and Other Traumatic Brain Injuries. . . . . . . . . . . . . . . . . . . . . Allan H. Ropper
. . . . . . . . . .
458 Multiple Sclerosis and Other Demyelinating Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stephen L. Hauser, Douglas S. Goodin
. . . . . .
2660 2661
Section 3 Nerve and Muscle Disorders 459 Peripheral Neuropathy. .
. . . . . . . . . . . . . . . . . . . . . .
Anthony A. Amato, Richard J. Barohn
460 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies. . . . Stephen L. Hauser, Anthony A. Amato
. . . . . . . . . . . .
Daniel B. Drachman, Anthony A. Amato
. . . . . . . .
. . . . . . . . . .
463e Special Issues in Inpatient Neurologic Consultation. . . . . . . . . . . . . . . . . . . . . . . . . . S. Andrew Josephson, Martin A. Samuels
2674
472e Heavy Metal Poisoning. .
473e Poisoning and Drug Overdose.
Gijs Bleijenberg, Jos W. M. van der Meer
. . . . . .
. . . . . . . . . . . . . . .
465e Biology of Psychiatric Disorders. Victor I. Reus
Marc A. Schuckit
476e Altitude Illness.
477e Hyperbaric and Diving Medicine. .
478e Hypothermia and Frostbite..
479e Heat-Related Illnesses. .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
2708
HPIM19_VOlI_FM.indd 17
. . . . . . . . . . . . . . . .
2723 2728
2733 2744
2753
. . . . . . . . . . . . . .
2753
. . . . . . . . . . . . . . . . . .
2753
Daniel F. Danzl Daniel F. Danzl
480e The Clinical Laboratory in Modern Health Care.. . . . . . . . . . . . . . . . . . . . . . . Anthony A. Killeen
. . . .
2754
. . . . . . . . .
2770
481e Clinical Procedure Tutorial: Central Venous Catheter Placement. . . . . . . . . . . .
. . . . . . . .
Maria A. Yialamas, William E. Corcoran, Gyorgy Frendl, Kurt Fink
482e Clinical Procedure Tutorial: Thoracentesis.. .
483e Clinical Procedure Tutorial: Abdominal Paracentesis. . . . . . . . . . . . . . . . . . . . . . . . . . .
2770
. . . . .
2770
484e Clinical Procedure Tutorial: Endotracheal Intubation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . .
485e Clinical Procedures Tutorial: Percutaneous Arterial Blood Gas Sampling.. . . . . . . . . . . . . . . . . Christian D. Becker Medical Editors: Sean Sadikot, Jeremy Matloff
486e Clinical Procedures Tutorial: Lumbar Puncture.. . . . . . . . . . . . . . . . . . . . . . . . . . . Beth Rapaport, Stephen Krieger, Corey McGraw Medical Editors: Sean Sadikot, Jeremy Matloff
Index. .
2770
. .
Charles A. Morris, Andrea S. Wolf
Charles A. Morris, Emily Page Nelson
2753
. . . . . . . . . .
Michael H. Bennett, Simon J. Mitchell
Alexander Kratz, Michael A. Pesce, Robert C. Basner, Andrew J. Einstein
. . . . . . . . . . . . . . . . . . . . . .
Thomas R. Kosten, Colin N. Haile
. . . . . . . . . . . . . . . . . . . . . . . .
Buddha Basnyat, Geoffrey Tabin
APPENDIX: Laboratory Values of Clinical Importance.
2707
2707
. .
2733
Environmental Exposures
2707
2708
468e Opioid-Related Disorders.
. . . . . .
2733
Part 19 Disorders Associated with
2701
. . . . . . . . . . .
467 Alcohol and Alcoholism.
. . . . . . . . . . . .
Richard J. Pollack, Scott A. Norton
Section 5 PSYCHIATRIC AND ADDICTION DISORDERS Robert O. Messing, Eric J. Nestler
Mark B. Mycyk
Maria A. Yialamas, Anna E. Rutherford, Lindsay King
464e Chronic Fatigue Syndrome.
466 Mental Disorders.
. . . . . . . . . . . . . . . . .
Charles Lei, Natalie J. Badowski, Paul S. Auerbach, Robert L. Norris
Howard Hu
xvii
2732
and Envenomation
2694
Section 4 Chronic Fatigue Syndrome
. . . . . . . . . . . . .
Part 18 Poisoning, Drug Overdose,
462e Muscular Dystrophies and Other Muscle Diseases. . . . . . . . . . . . . . . . . . . Anthony A. Amato, Robert H. Brown, Jr.
471e Neuropsychiatric Illnesses in War Veterans. . . . . . . . . . . . . . . . . . Charles W. Hoge
461 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction.. . . . . . . . . . .
475 Ectoparasite Infestations and Arthropod Injuries. .
Stephen L. Hauser, Allan H. Ropper
2729
474 Disorders Caused by Venomous Snakebites and Marine Animal Exposures. . . . . . . . . . . .
456 Diseases of the Spinal Cord.
David M. Burns
2637
M. Flint Beal, Stephen L. Hauser
. . . . . . . . . . . . . . . . . . . . . . . . . .
Nancy K. Mello, Jack H. Mendelson
470 Nicotine Addiction.
. . . . . . . . . . . . . . . . . . . . . . . .
Stanley B. Prusiner, Bruce L. Miller
455 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders. . . . . . . .
2729
Phillip A. Low, John W. Engstrom
. . . . . . . . . . . .
2631
454 Disorders of the Autonomic Nervous System. .
2631
469e Cocaine and Other Commonly Abused Drugs. . . . . . . . . . . . . . . . . . .
. . . . . . . .
Robert H. Brown, Jr.
. . . . . . .
Contents
Roger N. Rosenberg
449 Parkinson’s Disease and Other Movement Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 450 Ataxic Disorders. .
2559
2770
. .
2770
. . . . . . .
2770
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Contributors James L. Abbruzzese, MD
Valder R. Arruda, MD, PhD
Manal F. Abdelmalek, MD, MPH
Andrew W. Artenstein, MD
Chief, Division of Medical Oncology, Department of Medicine; Associate Director, Clinical Research, Duke Cancer Institute, Durham, North Carolina [120e]
Jamil Aboulhosn, MD
Assistant Professor of Medicine; Director Ahmanson/UCLA Adult Congenital Heart Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California [282]
John C. Achermann, MD, PhD, MB
Wellcome Trust Senior Research Fellow in Clinical Science, University College London; Professor of Paediatric Endocrinology, UCL Institute of Child Health, University College London, London, United Kingdom [410]
John W. Adamson, MD
Associate Professor, Division of Hematology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [141] Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Adjunct Professor of Medicine and Health Services, Policy and Practice, Alpert Medical School, Brown University, Providence, Rhode Island; Chair, Department of Medicine, Baystate Health, Springfield, Massachusetts [152e]
Anthony Atala, MD
Professor and Director, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina [92e]
John C. Atherton, MD, FRCP
Professor of Gastroenterology and Dean of the School of Medicine, University of Nottingham, Nottingham, United Kingdom [188]
Clinical Professor, Division of Hematology/Oncology, Department of Medicine, University of California at San Diego, San Diego, California [77, 126]
Paul S. Auerbach, MD, MS, FACEP, FAWM
Rizwan Ahmed, MD
K. Frank Austen, MD
General Surgery Resident, Department of General Surgery, Johns Hopkins Hospital, Baltimore, Maryland [353, 354]
Praveen Akuthota, MD
Assistant Professor of Medicine, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, Massachusetts [310]
Anthony A. Amato, MD
Redich Family Professor of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California [474] AstraZeneca Professor of Respiratory and Inflammatory Diseases, Director, Inflammation and Allergic Diseases Research Section, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [376]
Eric H. Awtry, MD
Cardiology Division, Boston Medical Center, Boston, Massachusetts [289e, 290e]
Professor of Neurology, Harvard Medical School; Vice-Chairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [459-462e]
Jamil Azzi, MD
Michael J. Aminoff, MD, DSc, FRCP
Bruce R. Bacon, MD
Professor of Neurology, School of Medicine, University of California, San Francisco, San Francisco, California [30, 31, 442e]
Neil M. Ampel, MD
Professor of Medicine, University of Arizona; Staff Physician, Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona [237]
Kenneth C. Anderson, MD
Kraft Family Professor of Medicine, Harvard Medical School; Chief, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts [136, 138e]
Rosa M. Andrade, MD
Department of Medicine, Division of Infectious Diseases, University of California, San Diego, San Diego, California [247]
Elliott M. Antman, MD
Professor of Medicine, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital; Associate Dean for Clinical/Translational Research, Harvard Medical School, Boston, Massachusetts [293, 295]
Frederick R. Appelbaum, MD
Director, Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington [139e]
Cesar A. Arias, MD, PhD, MSc
Associate Professor of Medicine, Microbiology and Molecular Genetics; Director, Laboratory for Antimicrobial Research, University of Texas Medical School at Houston, Houston, Texas; Director, Molecular Genetics and Antimicrobial Unit; Co-Director, International Center for Microbial Genomics, Universidad, El Bosque, Bogota, Colombia [174]
Wiebke Arlt, MD, DSc, FRCP, FMedSci
Instructor in Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts [337] James F. King, MD Endowed Chair in Gastroenterology; Professor of Internal Medicine, Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri [365, 367e]
Lindsey R. Baden, MD
Associate Professor of Medicine, Harvard Medical School; Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts [215e]
Natalie J. Badowski, MD
Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California [474]
John R. Balmes, MD
Professor of Medicine, University of California, San Francisco; Professor, School of Public Health, University of California, Berkeley; Chief, Division of Occupational and Environmental Medicine, San Francisco General Hospital, San Francisco, California [311]
Manisha Balwani, MD, MS
Assistant Professor, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York [430]
Peter A. Banks, MD
Professor of Medicine, Harvard Medical School; Senior Physician, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts [370, 371]
Robert L. Barbieri, MD
Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School; Chair, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts [8]
Professor of Medicine, Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham; Consultant Endocrinologist, University Hospital Birmingham, Birmingham, United Kingdom [406]
Alan G. Barbour, MD
Katrina Armstrong, MD, MS
Professor of Medicine, University of Toronto; Staff Nephrologist, University Health Network, Toronto, Canada [335]
Jackson Professor of Clinical Medicine, Physician in Chief, Massachusetts General Hospital, Boston Massachusetts [4]
HPIM19_VOlI_FM.indd 19
Contributors
Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina [364]
xix
Professor of Medicine and Microbiology and Molecular Genetics, University of California Irvine, Irvine, California [209]
Joanne M. Bargman, MD, FRCPC
1/30/15 2:35 PM
xx
Tamar F. Barlam, MD, MSc
Associate Professor of Medicine, Infectious Disease Section, Boston University School of Medicine, Boston, Massachusetts [147, 183e]
Peter J. Barnes, DM, DSc, FMedSci, FRS
Head of Respiratory Medicine, Imperial College, London, United Kingdom [309]
Richard J. Barohn, MD
Chairman, Department of Neurology; Gertrude and Dewey Ziegler Professor of Neurology, University of Kansas Medical Center, Kansas City, Kansas [459]
Contributors
Rebecca M. Baron, MD
Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston, Massachusetts [154, 312]
Miriam Baron Barshak, MD
Assistant Professor, Harvard Medical School; Associate Physician, Massachusetts General Hospital, Boston, Massachusetts [154, 159, 312]
Shehzad Basaria, MD
Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Boston, Massachusetts [7e]
Robert C. Basner, MD
Professor of Clinical Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York [Appendix]
Buddha Basnyat, MD, MSc, FACP, FRCP (Edinburgh)
Director, Oxford University Clinical Research Unit, Patan Academy of Health Sciences; Medical Director, Nepal International Clinic, Kathmandu, Nepal [476e]
Shari S. Bassuk, ScD
Epidemiologist, Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [413]
John F. Bateman, PhD
Director, Cell Biology, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia; Murdoch Children’s Research Institute, Parkville, Victoria, Australia [427]
David W. Bates, MD, MSc
Professor of Medicine, Harvard Medical School; Chief, General Internal Medicine and Primary Care Division, Brigham and Women’s Hospital; Medical Director, Clinical and Quality Analysis, Partners HealthCare System, Inc., Boston, Massachusetts [12e]
Robert P. Baughman, MD
Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio [390]
M. Flint Beal, MD
University Professor of Neurology and Neuroscience; Neurologist, New York Presbyterian Hospital; Weill Cornell Medical College, New York, New York [444e, 455]
Laurence H. Beck, MD, PhD
Assistant Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts [340]
Christian D. Becker, MD, PhD, FCCP
Assistant Professor, Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai New York, New York [485e]
Nicholas J. Beeching, MA, BM BCh, FRCP, FRACP, FFTM RCPS(Glasg), DCH, DTM&H
Senior Lecturer (Clinical) in Infectious Diseases, Liverpool School of Tropical Medicine; Clinical Director, Tropical and Infectious Disease Unit, Royal Liverpool University Hospital; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool; Honorary Consultant, Public Health England and Honorary Civilian Consultant in Infectious Diseases, Army Medical Directorate, United Kingdom [194e]
Doron Behar, MD, PhD
Institute of Genetics, Rambam Health Care Campus, Haifa, Israel [85e]
Robert S. Benjamin, MD
Michael H. Bennett, MD, MBBS, MM (Clin Epi)
Conjoint Associate Professor in Anesthesia and Hyperbaric Medicine; Faculty of Medicine, University of New South Wales; Academic Head of Department, Wales Anaesthesia, Prince of Wales Hospital, Sydney, Australia [477e]
Edward J. Benz, Jr., MD
Richard and Susan Smith Professor of Medicine; Professor of Genetics, Harvard Medical School; President and CEO, Dana-Farber Cancer Institute; Director and Principal Investigator, Dana-Farber/Harvard Cancer Center; Boston, Massachusetts [127]
Jean Bergounioux, MD, PhD, PhC
Pediatric Intensive Care Unit, Hôpital Raymond-Poincaré, Université de Versailles-Saint Quentin, Garches, France [191]
John L. Berk, MD
Associate Professor of Medicine, Boston University School of Medicine; Clinical Director, Amyloidosis Center, Boston Medical Center, Boston, Massachusetts [137]
Aaron S. Bernstein, MD, MPH
Instructor, Harvard Medical School; Associate Director, Center for Health and the Global Environment, Harvard School of Public Health; Pediatric Hospitalist, Boston Children’s Hospital, Boston, Massachusetts [151e]
Joseph R. Betancourt, MD, MPH
Associate Professor of Medicine, Harvard Medical School; Director, The Disparities Solutions Center, Massachusetts General Hospital, Boston, Massachusetts [16e]
Atul K. Bhan, MD, MBBS
Professor of Pathology, Harvard Medical School, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts [366e]
Shalender Bhasin, MBBS
Professor of Medicine, Harvard Medical School; Director, Research Program in Men’s Health: Aging and Metabolism; Director, Boston Claude D. Pepper Older Americans Independence Center; Site Director, Harvard Catalyst Clinical Research Center at BWH, Brigham and Women’s Hospital, Boston, Massachusetts [7e, 411]
Deepak L. Bhatt, MD, MPH
Professor of Medicine, Harvard Medical School; Chief of Cardiology, VA Boston Healthcare System; Senior Physician, Brigham and Women’s Hospital; Senior Investigator, TIMI Study Group, Boston, Massachusetts [296e, 297e]
Roby P. Bhattacharyya, MD, PhD
Instructor in Medicine, Harvard Medical School; Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts [146]
David R. Bickers, MD
Carl Truman Nelson Professor and Chair, Department of Dermatology, Columbia University Medical Center, New York, New York [75]
Henry J. Binder, MD
Professor Emeritus of Medicine, Senior Research Scientist, Yale University, New Haven, Connecticut [349, 350e]
William R. Bishai, MD, PhD
Professor and Co-Director, Center for Tuberculosis Research, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland [175]
Bruce R. Bistrian, MD, PhD, MPH
Professor of Medicine, Harvard Medical School; Chief, Clinical Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts [98e]
Martin J. Blaser, MD
Muriel and George Singer Professor of Medicine; Professor of Microbiology; Director, Human Microbiome Program, New York University Langone Medical Center, New York, New York [188, 192]
Chantal P. Bleeker-Rovers, MD, PhD
Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands [26]
Gijs Bleijenberg, PhD
Professor Emeritus, Expert Centre for Chronic Fatigue, Radboud University Medical Centre, Nijmegen, The Netherlands [464e]
P. H. and Faye E. Robinson Distinguished Professor of Medicine, Department of Sarcoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [119e]
HPIM19_VOlI_FM.indd 20
1/30/15 2:35 PM
Clara D. Bloomfield, MD
Distinguished University Professor; William G. Pace, III Professor of Cancer Research; Cancer Scholar and Senior Advisor, The Ohio State University Comprehensive Cancer Center; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio [132]
Richard S. Blumberg, MD
Christopher M. Burns, MD
Associate Professor, Department of Medicine, Section of Rheumatology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire [431e]
David M. Burns, MD
Chief, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts [351]
Professor Emeritus, Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, San Diego, California [470]
Jean L. Bolognia, MD
Stephen B. Calderwood, MD
Joseph V. Bonventre, MD, PhD
Samuel A. Levine Professor of Medicine, Harvard Medical School; Chief, Renal Division; Chief, Division of Biomedical Engineering, Brigham and Women’s Hospital, Boston, Massachusetts [333e, 334]
George J. Bosl, MD
Professor of Medicine, Weill Cornell Medical College; Chair, Department of Medicine; Patrick M. Byrne Chair in Clinical Oncology, Memorial SloanKettering Cancer Center, New York, New York [116]
Joshua A. Boyce, MD
Morton N. Swartz, MD Academy Professor of Medicine (Microbiology and Immunobiology), Harvard Medical School; Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [160]
Michael Camilleri, MD
Atherton and Winifred W. Bean Professor; Professor of Medicine, Pharmacology, and Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota [55]
Christopher P. Cannon, MD
Professor of Medicine, Harvard Medical School; Senior Physician, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts [294]
Professor of Medicine and Pediatrics; Albert L. Sheffer Professor of Medicine, Harvard Medical School; Director, Inflammation and Allergic Disease Research Section, Brigham and Women’s Hospital, Boston, Massachusetts [376]
Jonathan R. Carapetis, MBBS, PhD, FRACP, FAFPHM
Eugene Braunwald, MD, MA (Hon), ScD (Hon), FRCP
Deputy Scientific Director, Division of Intramural Research, National Institute of Dental and Craniofacial Research, Bethesda, Maryland [231e]
Distinguished Hersey Professor of Medicine, Harvard Medical School; Founding Chairman, TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts [50, 288, 294]
Irwin M. Braverman, MD
Professor Emeritus; Senior Research Scientist, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut [72]
Otis W. Brawley, MD, FACP
Professor of Hematology, Medical Oncology, Medicine and Epidemiology, Emory University; Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia [100]
Joel G. Breman, MD, DTPH
Senior Scientific Advisor, Fogarty International Center, National Institutes of Health, Bethesda, Maryland [248, 250e]
George J. Brewer, MD
Morton S. and Henrietta K. Sellner Emeritus, Professor of Human Genetics, Emeritus Professor of Internal Medicine, University of Michigan Medical School; Senior Vice President for Research and Development, Adeona Pharmaceuticals, Inc., Ann Arbor, Michigan [429]
Josephine P. Briggs, MD
Director, National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH), Bethesda, Maryland [14e]
F. Richard Bringhurst, MD
Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [423]
Steven M. Bromley, MD
Director, Outpatient Services, Virtua Neuroscience, Voorhees, New Jersey; Director, Bromley Neurology, PC, Audubon, New Jersey [42]
Darron R. Brown, MD
Professor of Medicine, Microbiology and Immunology, Division of Infectious Diseases, Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana [222]
Kevin E. Brown, MD, MRCp, FRCPath
Virus Reference Department, Public Health England, London, United Kingdom [221]
Robert H. Brown, Jr., MD, PhD
Chairman, Department of Neurology, University of Massachusetts Medical School, Worchester, Massachusetts [452, 462e]
Amy E. Bryant, PhD
Affiliate Assistant Professor, University of Washington School of Medicine, Seattle, Washington; Research Scientist, Veterans Affairs Medical Center, Boise, Idaho [179]
HPIM19_VOlI_FM.indd 21
Contributors
Professor, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut [72]
xxi
Director, Telethon Kids Institute, The University of Western Australia, Crawley, Western Australia [381]
Kathryn M. Carbone, MD
Brian I. Carr, MD, PhD, FRCP
IRCCS de Bellis National Center for GI Diseases, Castellana Grotte, BA, Italy [111]
John D. Carter, MD
Professor of Medicine, Division of Rheumatology; Director, University of South Florida Morsani College of Medicine, Tampa, Florida [384]
Arturo Casadevall, MD, PhD
Chair, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York [239]
Agustin Castellanos, MD, FACC, FAHA
Professor of Medicine; Director, Clinical Electrophysiology, University of Miami Miller School of Medicine, Cardiovascular Division, Miami, Florida [327]
Bartolome R. Celli, MD
Professor of Medicine, Harvard Medical School; Staff Physician, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [323]
Murali Chakinala, MD
Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri [279]
Anil Chandraker, MBChB, FRCP
Associate Professor of Medicine, Harvard Medical School; Medical Director of Kidney and Pancreas Transplantation; Interim Director, Schuster Family Transplantation Research Center, Brigham and Women’s Hospital, Boston, Massachusetts [337]
Lan X. Chen, MD, PhD
Penn Presbyterian Medical Center, Philadelphia, Pennsylvania [395]
Yuan-Tsong Chen, MD, PhD
Duke University Medical Center, Division of Medical Genetics, Department of Pediatrics, Durham, North Carolina [433e]
Glenn M. Chertow, MD, MPH
Norman S. Coplon/Satellite Healthcare Professor of Medicine; Chief, Division of Nephrology, Stanford University School of Medicine, Palo Alto, California [336]
John S. Child, MD, FACC, FAHA, FASE
Streisand Professor of Medicine and Cardiology; Director, Ahmanson-UCLA Adult Congenital Heart Disease Center; Director, UCLA Adult Noninvasive Cardiodiagnostics Laboratory Ronald Reagan-UCLA Medical Center, Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California [282]
1/30/15 2:35 PM
xxii
Augustine M. K. Choi, MD
Jennifer M. Croswell, MD, MPH
Raymond T. Chung, MD
Philip E. Cryer, MD
Chairman, Department of Medicine, Weill Cornell Medical College, Physicianin-Chief, New York-Presbyterian Hospital-Weill Cornell Medical Center, New York, New York [305, 307, 322] Associate Professor of Medicine, Harvard Medical School; Director of Hepatology and Liver Center; Vice Chief, Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts [368]
Jeffrey W. Clark, MD
Contributors
Associate Professor of Medicine, Harvard Medical School; Medical Director, Clinical Trials Core, Dana-Farber Harvard Cancer Center; Massachusetts General Hospital, Boston, Massachusetts [102e]
Jeffrey I. Cohen, MD
Chief, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [218, 228]
Yehuda Z. Cohen, MD
Clinical Fellow, Department of Medicine, Division of Infectious Diseases and Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, Massachusetts [224]
Ronit Cohen-Poradosu, MD
Senior Physician, Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel [201]
Francis S. Collins, MD, PhD
Director, National Institutes of Health, Bethesda, Maryland [101e]
Wilson S. Colucci, MD, FAHA, FACC
Medical Officer, Center for Oncology Prevention Trials Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland [100] Professor of Medicine Emeritus, Washington University in St. Louis; Physician, Barnes-Jewish Hospital, St. Louis, Missouri [420]
David Cunningham, MD, MB, ChB, FRCP
Professor, Head of Gastrointestinal/Lymphoma Unit; Director of Clinical Research, Royal Marsden NHS Trust, London, United Kingdom [112]
Gary C. Curhan, MD
Professor of Medicine, Harvard Medical School, Professor of Epidemiology, Harvard School of Public Health, Channing Division of Network Medicine/ Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts [342]
Brendan D. Curti, MD
Director, Biotherapy Program, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, Oregon [105]
John J. Cush, MD
Professor of Medicine and Rheumatology, Baylor University Medical Center; Director of Clinical Rheumatology, Baylor Research Institute, Dallas, Texas [393]
Charles A. Czeisler, MD, PhD
Frank Baldino, Jr., PhD Professor of Sleep Medicine, Professor of Medicine and Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [38]
Thomas J. Ryan Professor of Medicine, Boston University School of Medicine; Chief of Cardiovascular Medicine, Boston Medical Center, Boston, Massachusetts [289e, 290e]
Marinos C. Dalakas, MD
Laura K. Conlin, PhD
Josep Dalmau, MD, PhD
Darwin L. Conwell, MD, MS
Daniel F. Danzl, MD
Scientific Director, CytoGenomics Lab, The Children’s Hospital of Philadelphia, Assistant Professor of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [83e] Professor of Medicine, The Ohio State University College of Medicine; Director, Division of Gastroenterology, Hepatology and Nutrition; The Ohio State University Wexner Medical Center, Columbus, Ohio [370, 371]
Michael J. Corbel, PhD, DSc, FRCPath
Professor of Neurology, University of Athens Medical School, Athens, Greece; Thomas Jefferson University, Philadelphia, Pennsylvania [388] ICREA Professor, Institut d’Investigació Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Adjunct Professor, University of Pennsylvania, Philadelphia, Pennsylvania [122] University of Louisville, Department of Emergency Medicine, Louisville, Kentucky [478e, 479e]
Robert B. Daroff, MD
Retired (previously Head, Division of Bacteriology, National Institute for Biological Standards and Control, Hertfordshire, United Kingdom) [194e]
Professor and Chair Emeritus, Department of Neurology, Case Western Reserve University School of Medicine; University Hospitals–Case Medical Center, Cleveland, Ohio [28]
William E. Corcoran, V, MD
Charles E. Davis, MD
Kathleen E. Corey, MD, MPH
Stephen N. Davis, MBBS, FRCP
Staff Anesthesiologist, Allcare Clinical Associates; Medical Director of Analgesia and Sedation, Mission Health; Patient Safety Officer, Mission Health, Asheville, North Carolina [481e] Clinical and Research Fellow, Harvard Medical School; Fellow, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts [59]
Lawrence Corey, MD
Professor, Medicine and Laboratory Medicine, University of Washington; President Emeritus, Fred Hutchinson Cancer Research Center; Member, Vaccine and Infectious Disease Division; Principal Investigator, HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, Washington [216]
Jorge Cortes, MD
D. B. Lane Cancer Research Distinguished Professor for Leukemia Research; Deputy Chairman; Section Chief of AML and CML, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [133]
Felicia Cosman, MD
Professor of Medicine, Columbia University College of Physicians and Surgeons, New York, New York [425]
Mark A. Creager, MD
Professor of Medicine, Harvard Medical School; Simon C. Fireman Scholar in Cardiovascular Medicine; Director, Vascular Center, Brigham and Women’s Hospital, Boston, Massachusetts [301-303]
Leslie J. Crofford, MD
Professor, Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee; Chief, Division of Rheumatology, University of Kentucky, Lexington, Kentucky [396]
HPIM19_VOlI_FM.indd 22
Professor of Pathology and Medicine, Emeritus, University of California, San Diego School of Medicine; Director Emeritus, Microbiology, University of California, San Diego Medical Center, San Diego, California [245e] Theodore E. Woodward Professor and Chairman of the Department of Medicine, University of Maryland School of Medicine; Physician-in-Chief, University of Maryland Medical Center, Baltimore, Maryland [420]
Rafael de Cabo, PhD
Senior Investigator, Experimental Gerontology Section, TGB, National Institute on Aging, National Institutes of Health, Baltimore, Maryland [94e]
Lisa M. DeAngelis, MD
Professor of Neurology, Weill Cornell Medical College; Chair, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York [118]
John Del Valle, MD
Professor and Senior Associate Chair of Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan [348]
Marie B. Demay, MD
Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [423]
Bradley M. Denker, MD
Associate Professor of Medicine, Harvard Medical School; Renal Division, Beth Israel Deaconess Medical Center; Chief of Nephrology and Associate Chief of Medical Specialties, Harvard Vanguard Medical Associates, Boston, Massachusetts [61]
1/30/15 2:35 PM
David W. Denning, MBBS, FRCP, FRCPath, FMedSci
Andrea Dunaif, MD
Robert J. Desnick, MD, PhD
Samuel C. Durso, MD, MBA
Richard A. Deyo, MD, MPH
Janice P. Dutcher, MD
Professor of Medicine and Medical Mycology; Director, National Aspergillosis Centre, The University of Manchester and Wythenshawe Hospital, Manchester, United Kingdom [241] Dean for Genetics and Genomics, Professor and Chairman Emeritus, Department of Human Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York [430]
Betty Diamond, MD
The Feinstein Institute for Medical Research, North Shore LIJ Health System; Center for Autoimmunity and Musculoskeletal Diseases, Manhasset, New York [377e]
Marcelo F. Di Carli, MD
Professor, Department of Radiology, Harvard Medical School; Chief, Division of Nuclear Medicine and Molecular Imaging; Executive Director, Noninvasive Cardiovascular Imaging Program, Brigham and Women’s Hospital, Boston, Massachusetts [270e, 271e]
Anna Mae Diehl, MD
Florence McAlister Professor of Medicine; Chief, Division of Gastroenterology, Duke University, Durham, North Carolina [364]
Jules L. Dienstag, MD
Carl W. Walter Professor of Medicine and Dean for Medical Education, Harvard Medical School; Physician, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts [360-362, 366e, 368]
Mason F. Lord Professor of Medicine; Director, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland [45, 46e] Associate Director, Cancer Research Foundation of New York, Chappaqua, New York; Former Professor, New York Medical College, Valhalla, New York [331]
Johanna Dwyer, DSc, RD
Jean Mayer USDA Human Nutrition Research Center on Aging; Professor, Tufts Medical Center and Director, Frances Stern Nutrition Center, Tufts Medical Center, Boston, Massachusetts [95e]
Jeffrey S. Dzieczkowski, MD
Physician, St. Alphonsus Regional Medical Center; Medical Director, Coagulation Clinic, Saint Alphonsus Medical Group, International Medicine and Travel Medicine, Boise, Idaho [138e]
Kim A. Eagle, MD
Albion Walter Hewlett Professor of Internal Medicine; Chief of Clinical Cardiology; Director, Frankel Cardiovascular Center, University of Michigan Health System, Ann Arbor, Michigan [9]
James A. Eastham, MD
Chief, Urology Service, Florence and Theodore Baumritter/Enid Ancell Chair of Urologic Oncology, Department of Surgery, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, New York [115]
Robert H. Eckel, MD
Professor and Executive Vice-Chair; Chief, Section of Neuroradiology, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California [440e, 441e]
Professor of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Cardiology; Professor of Physiology and Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis, University of Colorado School of Medicine, Anschutz Medical Campus, Director Lipid Clinic, University of Colorado Hospital, Aurora, Colorado [422]
Charles A. Dinarello, MD
John E. Edwards, Jr., MD
William P. Dillon, MD
Professor of Medicine and Immunology, University of Colorado Denver, Aurora, Colorado; Professor of Experimental Medicine, Radboud University Medical Center, Nijmegen, The Netherlands [23]
Raphael Dolin, MD
Maxwell Finland Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Beth Israel Deaconess Medical Center; Brigham and Women’s Hospital, Boston, Massachusetts [215e, 223, 224]
Susan M. Domchek, MD
Basser Professor of Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania [84]
Richard L. Doty, PhD, MA
Director, Smell and Taste Center; Professor, Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [42]
Vanja C. Douglas, MD
Assistant Professor of Clinical Neurology and Sara and Evan Williams Foundation Endowed Neurohospitalist Chair, University of California, San Francisco, San Francisco, California [29]
Daniel B. Drachman, MD
Professor of Neurology and Neuroscience, W. W. Smith Charitable Trust Professor of Neuroimmunology, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland [461]
David F. Driscoll, PhD
Associate Professor of Medicine, University of Massachusetts Medical School, Worchester, Massachusetts [98e]
Thomas D. DuBose, Jr., MD, MACP
Emeritus Professor of Internal Medicine and Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina [64e, 66]
J. Stephen Dumler, MD
Professor, Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland [211]
HPIM19_VOlI_FM.indd 23
xxiii
Contributors
Kaiser Permanente Professor of Evidence-Based Family Medicine, Department of Family Medicine, Department of Medicine, Department of Public Health and Preventive Medicine, Oregon Institute of Occupational Health Sciences; Oregon Health and Science University; Clinical Investigator, Kaiser Permanente Center for Health Research, Portland, Oregon [22]
Charles F. Kettering Professor of Endocrinology and Metabolism and ViceChair for Research, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [6e]
Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California; Chief, Division of Infectious Diseases, Harbor/UCLA Medical Center, Torrance, California [235, 240]
David A. Ehrmann, MD
Professor, Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago Pritzker School of Medicine, Chicago, Illinois [68]
Andrew J. Einstein, MD, PhD
Victoria and Esther Aboodi Assistant Professor of Medicine; Director, Cardiac CT Research; Co-Director, Cardiac CT and MRI, Department of Medicine, Cardiology Division, Department of Radiology, Columbia University College of Physicians and Surgeons, New York-Presbyterian Hospital, New York, New York [Appendix]
Ezekiel J. Emanuel, MD, PhD
Chair, Department of Medical Ethics and Health Policy, Levy University Professor, Perelman School of Medicine and Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania [10]
John W. Engstrom, MD
Betty Anker Fife Distinguished Professor and Vice-Chairman; Neurology Residency Program Director, University of California, San Francisco, San Francisco, California [22, 454]
Moshe Ephros, MD
Clinical Associate Professor, Faculty of Medicine, Technion-Israel Institute of Technology; Pediatric Infectious Disease Unit, Carmel Medical Center; Haifa, Israel [197]
Jonathan A. Epstein, MD
William Wikoff Smith Professor; Chair, Department of Cell and Developmental Biology; Scientific Director, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [265e]
1/30/15 2:35 PM
im Evans, M , Ph
oy reeman, M
D
Professor of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [142]
F
Assistant Professor; Director of Surgical Critical Care Research Center, Department of Anesthesiology, Perioperative Critical Care and Pain Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [481e]
D
D
F
Paul armer, M , Ph
D
F
D
F
Professor of Medicine, Harvard Medical School; Pulmonary and Critical Care Division, Brigham and Women’s Hospital; Director, Partners Asthma Center, Boston, Massachusetts [48]
D
Gyorgy rendl, M , Ph , CCM
D
Christopher H. anta, M
D
Senior Director, Health, Nutrition and Population, The World Bank Group, Washington, DC [13e]
Professor of Neurology, Harvard Medical School; Director, Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Boston, Massachusetts [27]
T
F
D
D
D
F
S
D
D
icholas B. Galifianakis, M , MPH
Assistant Clinical Professor, Surgical Movement Disorders Center, Department of Neurology, University of California, San Francisco, San Francisco, California [33e] D
Director, Clinical Center, National Institutes of Health, Bethesda, Maryland [80] D
Charlotte A. Gaydos, rPh
Professor of Medicine, Johns Hopkins University, Division of Infectious Diseases, Baltimore, Maryland [213]
Professor of Medicine, Medical School, and Adjunct Professor of Epidemiology and Community Health, School of Public Health, University of Minnesota; Chief, Infectious Disease Section, Veterans Affairs Healthcare System, Minneapolis, Minnesota [199]
Professor of Medicine, Harvard Medical School; Chief, Division of Aging, Brigham and Women’s Hospital; Director, Massachusetts Veterans Epidemiology Center, Boston VA Healthcare System, Boston, Massachusetts [266e]
F
Agnes B. ogo, M
D
Larry C. ord, M
D
John L. Shapiro Professor of Pathology; Professor of Medicine and Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee [62e] Clinical Infectious Diseases, Intermountain Healthcare, Provo, Utah [44]
S
D
Jeffrey M. Gelfand, M , MA
S
Caroline Shields Walker Professor of Medicine and Dean, Harvard Medical School, Boston, Massachusetts [415e]
obert H. Gelber, M
Clinical Professor of Medicine and Dermatology, University of California, San Francisco, San Francisco, California [203] D
F
Jeffrey . lier, M
D
Director of INSERM U768; Director of Imagine Institute; Professor of Immunology and Pediatric Hematology; Université Paris Descartes, Paris, France [374, 375e]
usan L. Gearhart, M
Associate Professor, Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland [353] R
D
D
Alain ischer, M , Ph
D
S
Palo Alto Medical Foundation, Palo Alto, California [481e]
D
D
Professor of Medicine and MAPS, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, Massachusetts [169]
homas A. Gaziano, M , M c
Assistant Professor of Medicine, Harvard Medical School; Assistant Professor, Health Policy and Management, Center for Health Decision Sciences, Harvard School of Public Health; Faculty Co-Leader, Chronic and Cardiovascular Diseases Working Group, Harvard Institute for Global Health, Harvard University; Associate Physician in Cardiovascular Medicine, Department of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [266e]
Assistant Professor of Clinical Neurology, Department of Neurology, University of California, San Francisco, San Francisco, California [29]
Alfred L. George, Jr., M
D
F
Joyce ingeroth, M
D
Chair, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [104, 169]
T
D
F
obert W. inberg, M
J. Michael Gaziano, M , MPH D
F
Gregory A. ilice, M
John . Gallin, M
D
Professor, Department of Neurology, University of California, San Francisco, San Francisco, California [18]
F
F
D
Assistant Professor, Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania [441e]
D
D
F
Howard L. ields, M , Ph
Kurt ink, M
Andre . urtado, M
I
Scientific Director, National Institute of Aging, National Institutes of Health, Baltimore, Maryland [11]
S
D
F
Assistant Professor of Medicine, Harvard Medical School, Pulmonary and Critical Care Division; Brigham and Women’s Hospital, Boston, Massachusetts [307]
D
D
F
Luigi errucci, M , Ph
F
F
S
D
F
T
avid . elson, M , MPH
Professor of Medicine and Epidemiology; Chair, Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts [394]
F
Anne L. uhlbrigge, M , M
N
Associate Professor in Medicine, Weill Cornell Medical Center; Assistant Attending, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York [116]
HPIM19_VOlI_FM.indd 24
onia riedman, M
Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts [351]
D
F
arren . eldman, M R
D
Vice Chair of Medicine for Strategic Planning, Department of Medicine, Brigham and Women’s Hospital; Senior Lecturer, Harvard Medical School, Boston, Massachusetts [272, 296e, 297]
D
Professor of Medicine, Harvard Medical School; Professor of Medicine, Tufts University School of Medicine; Assistant Chief of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Anton R. Fried, MD Chair, Department of Medicine, Newton-Wellesley Hospital, Newton, Massachusetts [59]
D
avid P. axon, M F
D
Professor of Medicine, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, Director Bone Program, University of Chicago Pritzker School of Medicine, Chicago, Illinois [426e]
R
Professor of Medicine; Director, Division of Hematology and Oncology; Associate Director, Cancer Center, Saint Louis University, St. Louis, Missouri [125]
S
F
D
Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [1, 225e, 226, 261e, 372e, 385, 386e]
Murray J. avus, M
D
Lawrence . riedman, M
F
Anthony . auci, M
D
Carl E. reter, M , Ph , ACP
F
Kolokotrones University Professor, Harvard University; Chair, Department of Global Health and Social Medicine, Harvard Medical School; Chief, Division of Global Health Equity, Brigham and Women’s Hospital; Co-Founder, Partners In Health, Boston, Massachusetts [2] S
Contri utors b
D
F
Jane E. reedman, M
R
Assistant Research Professor; Assistant Professor of Clinical Medicine, Department of Internal Medicine, Division of Infectious Disease, Indiana University School of Medicine, Indianapolis, Indiana [222]
F
Aaron C. Ermel, M
D
xxiv
Magerstadt Professor and Chair, Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [332e]
1/30/15 2:35 PM
D
Yonatan H. Grad, M , Ph D
Assistant Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Associate Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts [146]
D
D
I
OS
F
S
D
S
D
Professor of Medicine, University of California, San Francisco, San Francisco, California [44]
D
I
Jeffrey . Gordon, M
S
FN
F
N
F
D
R
D
D
Bevra Hannahs Hahn, M
D
Colin . Haile, M , Ph
D
Professor Emerita Division of Rheumatology, University of California, Los Angeles, Los Angeles, California [378] Assistant Professor, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Michael E. DeBakey VA Medical Center, Houston, Texas [468e]
Janet E. Hall, M , M c
Professor of Medicine, Harvard Medical School and Associate Chief, Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts [69, 412, 414]
Jesse B. Hall, M , CCP
Professor of Medicine, Anesthesia and Critical Care; Chief, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois [321] S
Dr. Robert J. Glaser Distinguished University Professor and Director, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri [86e]
D
Assistant Professor of Medicine, Thoracic Transplant Program, Indiana University Health, Indianapolis, Indiana [236]
D
Professor, Department of Neurology, School of Medicine, University of California, San Francisco, San Francisco, California [458]
Chadi A. Hage, M
S
S
alph Gonzales, M , M PH D
R
Professor of Medicine, Harvard Medical School; Director, Thrombosis Research Group, Brigham and Women’s Hospital, Boston, Massachusetts [300]
ouglas . Goodin, M
Deputy Associate Director, Behavioral and Social Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland [93e]
cott A. Halperin, M
D
D
S
Professor of Vaccinology and Immunology; Consultant in Paediatric Immunology; Director of Clinical Research and Development; Director, NIHR Biomedical Research Centre, Institute of Child Health; University College London; Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom [171]
amuel Z. Goldhaber, M
John G. Haaga, Ph
D
avid Goldblatt, MB, ChB, Ph
Associate Professor, Department of Medicine, Boston University School of Medicine; Chief, Section of Infectious Diseases, VA Boston Healthcare System, Boston, Massachusetts [162]
D
D
Professor of Medicine, Harvard Medical School; Wyss Institute for Biologically Inspired Engineering, Harvard University; Beth Israel Deaconess Medical Center, Boston, Massachusetts [268, 269e, 278e]
Kalpana Gupta, M , MPH
F
Ary L. Goldberger, M
D
Director Emeritus and Joseph Green Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, Maryland [40e]
asim Gucalp, M
Professor of Clinical Medicine, Albert Einstein College of Medicine; Associate Chairman for Educational Programs, Department of Oncology; Director, Hematology/Oncology Fellowship, Montefiore Medical Center, Bronx, New York [331]
N
F
D
F
Morton . Goldberg, M , AC , A
C
D
CP
Professor, NIHR-Wellcome Trust Clinical Research Facility, King’s College, London, United Kingdom; Professor, Department of Neurology, University of California, San Francisco, San Francisco, California [21, 447]
aryl . Gress, M , AA , CCM,
Associate Professor of Neurology, University of Virginia, Charlottesville, Virginia [330]
D
ACp,
FR
c,
DS
D
D
Peter J. Goadsby, M , Ph ,
FR
Professor and Vice Chairman, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania [263e]
D
Eli Glatstein, M
Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School; Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, Massachusetts [124e]
D
Director, Fogarty International Center, Bethesda, Maryland [227]
D
Michael . Greene, M
R
R
oger . Glass, M , Ph
D
D
orton J. Greenberger, M
Clinical Professor of Medicine, Harvard Medical School; Senior Physician, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts [369-371] F
Associate Professor of Medicine, Sackler Faculty of Medicine, Tel Aviv University; The Infectious Disease Unit and the Bernard Pridan Laboratory for Molecular Biology of Infectious Diseases, Tel Aviv Medical Center, Tel Aviv, Israel [197]
D
N
S
Michael Giladi, M , M c
Assistant Professor of Medicine, Harvard Medical School; Associate Director, The Disparities Solutions Center, Massachusetts General Hospital, Boston, Massachusetts [16e]
Adjunct Professor of Pediatrics and Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine; Division of Human Genetics Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Chief Scientific Officer, Synageva BioPharma Corp., Lexington, Massachusetts [432e]
udy A. Hartskeerl, Ph
D
D
. oug Hardy, M
Director WHO/FAO/OIE and National Leptospirosis Reference Centre, KIT Biomedical Research, KIT (Royal Tropical Institute), Amsterdam, The Netherlands [208]
William L. Hasler, M
D
Gregory A. Grabowski, M
D
Professor of Pediatrics and Medicine, Barbara Davis Center, University of Colorado School of Medicine, Aurora, Colorado [409]
R
D
R
Professor, Department of Neurology; Language Neurobiology Lab, Memory and Aging Center; Dyslexia Center, University of California, San Francisco, San Francisco, California [37e]
D
Infectious Diseases Specialists, PA; Medical City Dallas Hospital and Medical City Children’s Hospital, Dallas; Baylor Regional Medical Center, Plano, Texas [212]
D
Peter A. Gottlieb, M
D
Professor of Pediatrics and Microbiology and Immunology Head, Pediatric Infectious Diseases, Director, Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada [185]
T
Maria Luisa Gorno- empini, M , Ph
HPIM19_VOlI_FM.indd 25
Contri utors
Staff Physician, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [357] D
, Ph
Chief, Department of Bioethics, National Institutes of Health Clinical Center, Bethesda, Maryland [17e] R
S
D
Associate Professor of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [33e]
RN
Alexander . Green, M , MPH
D
Marc G. Ghany, M , MH c
D
Christine Grady,
D
Michael . Geschwind, M , Ph
xxv
b
D
N
D
ale . Gerding, M
Professor of Medicine, Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Research Physician, Edward Hines Jr. Veterans Affairs Hospital, Hines, Illinois [161]
Professor, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan [54, 344]
1/30/15 2:35 PM
avid C. Hooper, M
D
D
Director, Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [357] D
S
ouglas C. Heimburger, M , M D
D
Frederic M. Hanes Professor of Medicine and Immunology, Departments of Medicine and Immunology; Director, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina [372e]
Professor, Harvard Medical School; Chief, Infection Control Unit; Associate Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [170]
obert J. Hopkin, M
Professor of Medicine, Associate Director for Education and Training, Vanderbilt Institute for Global Health, Vanderbilt University School of Medicine, Nashville, Tennessee [97]
Associate Professor, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio [432e]
J. Claude Hemphill,
Assistant Professor, Division of Hematology and Medical Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee [107]
Dean; Professor of Environmental Health, Epidemiology and Global Health, Dalla Lana School of Public Health; Professor of Medicine, University of Toronto, Toronto, Ontario, Canada [472e] D
D
F
D
I
S
D FR
CPC
Professor of Medicine (Neurology) and of Medical Microbiology, University of Manitoba; Section Head of Neurology, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada [232]
D
D
S
F
D
Executive Vice President, Provost, and Dean of the School of Medicine; Thomas N. and Gleaves T. James Distinguished Chair, The University of Texas Medical Branch at Galveston, Galveston, Texas [20, 355, 356]
D
Chair, Global Health; Professor of Medicine and Global Health; Adjunct Professor, Epidemiology; Director, Center for AIDS and STD; University of Washington School of Medicine; Head, Infectious Diseases Section, Harborview Medical Center, Seattle, Washington [163]
D
F
D
J. Larry Jameson, M , Ph D
Chief, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [80, 204]
ichard . Jacobs, M
Robert H. Fiser, Jr., MD Endowed Chair in Pediatrics; Professor and Chairman, Department of Pediatrics, University of Arkansas for Medical Sciences; President, Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas [195] Robert G. Dunlop Professor of Medicine; Dean, Perelman School of Medicine at the University of Pennsylvania; Executive Vice President, University of Pennsylvania for the Health System, Philadelphia, Pennsylvania [1, 56, 82, 84, 121, 399-403, 405, 410, 411, 436e]
obert . Jensen, M
D
D
Associate Professor of Medicine and Infectious Diseases, Harvard Medical School; Massachusetts General Hospital, Boston, Massachusetts [176]
King K. Holmes, M , Ph
anny . Jacobs, M , MPH, AC O
D
Elizabeth L. Hohmann, M
D
Senior Investigator, Group Health Research Institute, Seattle, Washington [148]
D
Senior Scientist, Center for Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland [471e]
teven M. Holland, M
Lisa A. Jackson, M , MPH
R
Charles W. Hoge, M
D
Professor, Faculty of Medicine, McGill University; Senior Physician, Divisions of Internal Medicine and Endocrinology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada [98e]
T
D
L. John Hoffer, M , Ph
Alan C. Jackson, M , D
Emeritus Professor of Haematology, University College, London; Honorary Consultant Haematologist, Royal Free Hospital, London, United Kingdom [128]
S
avid H. ngbar, M
Professor of Medicine, Pediatrics, and Physiology; Director, Pulmonary Allergy, Critical Care and Sleep Division, University of Minnesota School of Medicine, Minneapolis, Minnesota [326]
D
V
A. ictor Hoffbrand, M
Professor, Department of Medicine, Geffen School of Medicine, University of California, Los Angeles (UCLA); Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California [242] D
Harold Snyder Family Professor of Cardiology, Clinical Chief, Leon Charney Division of Cardiology, Co-Director, NYU-HHC Clinical and Translational Science Institute; Director, Cardiovascular Clinical Research Center, New York University School of Medicine, New York, New York [326]
Ashraf . brahim, Ph
I
S
Judith . Hochman, M
D
Professor, Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center; Investigator, Howard Hughes Medical Institute, Dallas, Texas [421]
HPIM19_VOlI_FM.indd 26
Chief, Chemical Casualty Care Division, United States Medical Research Institute of Chemical Defense, APG-Edgewood Area, Maryland [262e]
D
Helen H. Hobbs, M
Charles G. Hurst, M
D
Professor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Physician, Massachusetts General Hospital, Boston, Massachusetts [219]
haron A. Hunt, M , ACC
Professor of Medicine, Cardiovascular Medicine, Stanford University, Palo Alto, California [281] D
S
Martin . Hirsch, M
D
Professor of Medicine, Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois [53, 347]
R
kuo Hirano, M
D
I
Assistant Professor of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [263e]
eborah . Hung, M , Ph
Associate Professor of Microbiology and Molecular Genetics, Assistant Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital; Massachusetts General Hospital, Boston, Massachusetts; Co-director, Infectious Disease Initiative, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts [146] S
Christine E. Hill-Kayser, M
D
D
William H. Bennett Professor of Pediatrics, Perelman School of Medicine, University of Pennsylvania; Investigator, Howard Hughes Medical Institute, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania [91e, 141]
T
D
Katherine A. High, M
D
D
Howard Hu, M , MPH, c D
Clinical Adjunct Professor of Medicine, University of Iowa, Iowa City, Iowa [79]
William F. Hoyt Professor of Neuro-ophthalmology, Professor of Ophthalmology, Neurology and Physiology, University of California, San Francisco School of Medicine, San Francisco, California [39] D
Patrick H. Henry, M
Jonathan C. Horton, M , Ph
S
Professor of Neurology and Neurological Surgery, University of California, San Francisco; Chief of Neurology, San Francisco General Hospital, San Francisco, California [330, 446]
S
Leora Horn, M , M c D
S
D
III
, M , MA
D
Contri utors b
Jay H. Hoofnagle, M
R
F
Barton . Haynes, M
D
Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California [1, 437, 443e, 444e, 455, 456, 458, 460]
D
tephen L. Hauser, M
D
S
xxvi
Chief, Cell Biology Section, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [113]
1/30/15 2:35 PM
Elliott Kieff, M , Ph
Anthony A. Killeen, M , Ph
D
S
tuart Johnson, M
Charles H. King, M , M
Professor, Center for Global Health and Diseases, School of Medicine, Case Western Reserve University, Cleveland, Ohio [259]
Lindsay King, M , MPH
Advanced Transplant/Hepatology Fellow, Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts [483e]
. Andrew Josephson, M
D
S
Professor and Chair, Department of Medicine, University of California, San Francisco, San Francisco, California [315]
Louis . Kirchhoff, M , MPH V
Associate Professor; Vice Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California [34, 329e, 463e]
almadge E. King, Jr., M
D
T
Dean, Dell Medical School; Frank Denius Distinguished Dean’s Chair in Medical Leadership; Vice President for Medical Affairs, University of Texas, Austin, Austin, Texas [446]
Harald Jüppner, M
D
D
. Clairborne Johnston, M , Ph D
S
D
Associate Professor of Medicine, Loyola University Chicago Stritch School of Medicine; Staff Physician, Edward Hines Jr. VA Hospital, Hines, Illinois [161]
Peter J. Kahrilas, M
Priya . Kishnani, M S
Carol A. Kauffman, M
D
Scientific Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland [392]
D
D
S
D
D
Peter Kopp, M
Walter J. Koroshetz, M
D
Associate Professor, Division of Endocrinology, Metabolism and Molecular Science and Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [82] National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland [165]
homas . Kosten, M
J. H. Waggoner Professor of Psychiatry, Pharmacology, Immunology, Neuroscience, Baylor College of Medicine, Houston, Texas [468e]
heodore A. Kotchen, M
Professor Emeritus, Department of Medicine; Associate Dean for Clinical Research, Medical College of Wisconsin, Milwaukee, Wisconsin [298] FIDS
D
N
Professor of Medicine and Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia [149] F
Barnett . Kramer, M , MPH, ACP
Director, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland [100]
T
CPC, M c(C M) S
D
Jay . Keystone, M ,
FR
Davee Professor of Stem Cell Biology, Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [90e]
D
John A. Kessler, M
Phyllis E. Kozarsky, M
D
Associate Professor of Medicine, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts [24, 25e]
A
Clinical Director, Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital; Harvard Medical School, Boston, Massachusetts [219] D
D
Kenneth M. Kaye, M
Camille elson Kotton, M ,
S
T
Assistant Clinical Professor of Dermatology, Harvard Medical School; Boston Children’s Hospital, Boston, Massachusetts [24, 25e]
S
Professor of Medicine, Hematology, University of Washington; Director, Translational Research, Puget Sound Blood Center, Seattle, Washington [78, 140]
D
Professor of Internal Medicine, University of Michigan Medical School; Chief, Infectious Diseases Section, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan [243]
Barbara A. Konkle, M
D
D
aniel L. Kastner, M , Ph D
D
Professor of Microbiology/Immunology and Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire [253]
Mitsunada Sakaguchi Professor and Chair, Department of Systems Medicine, Keio University School of Medicine, Tokyo, Japan [88]
D
Lloyd H. Kasper, M
D
William Ellery Channing Professor of Medicine, Professor of Microbiology and Immunobiology, Department of Microbiology and Immunobiology, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts [1, 144, 147, 159, 183e, 201]
D
R
ennis L. Kasper, M , MA D
D
Professor of Medicine, Harvard Medical School, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts [155]
Minoru . H. Ko, M , Ph
T
Adolf W. Karchmer, M
D
Chairman, Leukemia Department; Professor of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [133]
ob Knight, Ph
Professor, Howard Hughes Medical Institute; Departments of Chemistry and Biochemistry and Computer Science, Biofrontiers Institute, University of Colorado, Boulder, Colorado [86e]
T
Hagop Kantarjian, M
D
San Francisco, California [33e]
Elaine . Kaye, M
Professor of Pediatrics, Division Chief, Medical Genetics, Duke University Medical Center, Durham, North Carolina [433e]
R
D
D
Gail Kang, M
D
Professor, Departments of Internal Medicine (Infectious Diseases) and Epidemiology, University of Iowa; Staff Physician, Department of Veterans Affairs Medical Center, Iowa City, Iowa [252]
D
Professor of Pediatrics, Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts [424] Gilbert H. Marquardt Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [53, 347]
b
Professor, Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York [253] D
Professor of Medicine, University of Minnesota, Minneapolis, Minnesota [186]
Kami Kim, M
S
D
R
James . Johnson, M
Professor, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota [480e]
Contri utors
Donald W. Seldin Distinguished Chair in Internal Medicine; Professor and Chairman, Department of Internal Medicine, University of Texas Southwestern School of Medicine, Dallas, Texas [107]
D
D
D
avid H. Johnson, M
D
Harriet Ryan Albee Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [214e] D
Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, State University of New York Upstate Medical University, Syracuse, New York [58]
xxvii
D
Professor of Medicine and Physiology, College of Medicine, Mayo Clinic, Rochester, Minnesota [65] D
D
S
avio John, M
undeep Khosla, M
D
S
CP
FR
D
S
R
oy M. John, MBB , Ph ,
Assistant Professor of Medicine, Harvard Medical School; Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [277]
Professor of Medicine, University of Toronto, Toronto, Ontario, Canada [149]
HPIM19_VOlI_FM.indd 27
1/30/15 2:35 PM
Clinical Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [226, 261e] Harold C. Schott Endowed Chair; Director, Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, Ohio [385, 386e, 389, 397, 398]
FR
D
D
D
D
D
D
D
ichard W. Light, M
D
Mallinckrodt Professor of Medicine, Harvard Medical School; Chief, Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [265e, 291e, 292e] Professor of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee [316, 317]
Julie Lin, M , MPH
Lecturer on Medicine, Harvard Medical School; Associate Physician, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, Boston, Massachusetts [61]
Yusen E. Lin, Ph , MBA
obert Lindsay, M , Ph
D
Professor and Director, Center for Environmental Laboratory Services; National Kaohsiung Normal University, Kaohsiung, Taiwan [184] Chief, Internal Medicine; Professor of Clinical Medicine, Helen Hayes Hospital, West Haverstraw, New York [425]
CP
FR
D
Marc E. Lippman, M , MACP,
Kathleen and Stanley Glaser Professor, Department of Medicine, Deputy Director, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida [108]
Peter E. Lipsky, M
Kathleen . Liu, M , Ph , MA
S
Charlottesville, Virginia [377e] Associate Professor, Division of Nephrology, Department of Medicine, Division of Critical Care Medicine, Department of Anesthesiology, University of California, San Francisco, San Francisco, California [336]
Bernard Lo, M
President, The Greenwall Foundation, New York; Professor of Medicine Emeritus and Director Emeritus of the Program in Medical Ethics, University of California, San Francisco, San Francisco, California [17e]
F
D
Wei C. Lau, M , AHA
Emeritus Associate Professor, Department of Anesthesiology, Section Cardiovascular Anesthesiology, University of Michigan Health System Cardiovascular Center, Ann Arbor, Michigan [9]
an L. Longo, M
D
Assistant Professor of Medicine, Harvard Medical School; Assistant Physician, Massachusetts General Hospital, Boston, Massachusetts [160]
D
D
egina C. La ocque, M , MPH R
R
Peter Libby, M
S
D
Carol A. Langford, M , MH
HPIM19_VOlI_FM.indd 28
Professor, Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee [338]
D
D
Professor and Vice Chair for Research; Director, Division of Otology, Neurotology and Skull Base Surgery; Director, Columbia Cochlear Implant Center, Columbia University College of Physicians and Surgeons, New York, New York [43]
H. Clifford Lane, M
Julia B. Lewis, M
D
D
Instructor in Medicine, Harvard Medical School; Associate Physician, Cardiovascular Medicine, Brigham and Women’s Hospital; Boston VA Healthcare; Boston, Massachusetts [287]
Anil K. Lalwani, M
Associate Professor of Medicine, Harvard Medical School; Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [322]
R D
N
Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut [57]
eil K. Lakdawala, M
Bruce . Levy, M
D
D
Associate Professor of Medicine, Harvard Medical School; Director of Cardiac Magnetic Resonance Imaging, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [270e, 271e]
elson Leung, M
Associate Professor of Medicine, Division of Nephrology and Hypertension, Division of Hematology, Mayo Clinic Rochester, Rochester, Minnesota [341]
D
aymond Y. Kwong, M , MPH D
R
Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [416]
Loren Laine, M
Associate Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [272, 297e]
S
D
obert . Kushner, M , M F
R
Principal, Tunnell Government Services (TGS), Inc.; Lead Virologist, Integrated Research Facility at Fort Detrick (IRF-Frederick); TGS IRFFrederick Team Leader, NIH/NIAID/DCR, Fort Detrick, Frederick, Maryland [233, 234]
Jane A. Leopold, M
D
D
D
Jens H. Kuhn, M , Ph , M
S
Professor of Medicine, Harvard Medical School; Chief, Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts [423]
Assistant Professor, Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee [474]
D
Henry M. Kronenberg, M
D
Associate Professor, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington [48, 305, 308e]
Charles Lei, M
D
D
Patricia A. Kritek, M , EdM
Professor of Internal Medicine; Meredith Mosle Chair in Liver Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas [361]
D
Assistant Professor, Department of Neurology; Director, Neurology Residency Program, Icahn School of Medicine at Mount Sinai; Attending Physician, The Corinne Goldsmith Dickinson Center for MS, New York, New York [486e]
ACP
D
tephen Krieger, M
D
Professor of Medicine, Director, Medical Intensive Care Unit, University of Chicago, Chicago, Illinois [321]
William M. Lee, M
R
John P. Kress, M
D
Senior Research Scientist, Yale School of Public Health; Yale School of Medicine, New Haven, Connecticut [249]
avid G. Le Couteur, M , Ph ,
Professor of Geriatric Medicine, Director of the Centre for Education and Research on Ageing, University of Sydney and Sydney Research, Sydney, Australia [94e]
D
D
Peter J. Krause, M
S
b
Contri utors
Associate Professor of Clinical Pathology and Cell Biology, Columbia University College of Physicians and Surgeons; Director, Core Laboratory, Columbia University Medical Center and the New York Presbyterian Hospital; Director, the Allen Hospital Laboratory, New York, New York [Appendix]
William P. Timmie Professor of Dermatology, Dean, Emory University School of Medicine, Atlanta, Georgia [70, 71, 73, 76e]
D
D
Alexander Kratz, M , MPH, Ph
D
Persis, Cyrus and Marlow B. Harrison Distinguished Professor of Medicine, Harvard Medical School; Massachusetts General Hospital, Boston, Massachusetts [423]
homas J. Lawley, M
D
Assistant Professor, Department of Dermatology, School of Medicine, Emory University, Atlanta, Georgia [71]
N
D
S
tephen M. Krane, M
D
Leslie P. Lawley, M
T
Professor of Neuropsychology in Neurology; Director of Neuropsychology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [37e]
D
Joel Kramer, Psy
D
xxviii
Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts [1, 77, 79, 81e, 89e, 99, 102e, 103e, 121, 123e, 124e, 125, 134, 135e, 136, 225e]
1/30/15 2:35 PM
ouglas L. Mann, M
D
D
Eleftheria Maratos- lier, M
CP(Hon)
FR
ACP,
FR
D
Phillip A. Low, M ,
D
Guido Marcucci, M
Professor of Medicine; John B. and Jane T. McCoy Chair in Cancer Research; Associate Director of Translational Research, Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio [132] D
aniel H. Lowenstein, M
D
D
Robert D. and Patricia E. Kern Professor of Neurology, Mayo Clinic, College of Medicine, Rochester, Minnesota [454]
Professor of Medicine, Harvard Medical School; Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts [415e]
aniel B. Mark, M , MPH
Professor of Medicine, Duke University Medical Center; Director, Outcomes Research, Duke Clinical Research Institute, Durham, North Carolina [3]
Elyse E. Lower, M
Assistant Professor, Department of Dermatology, Harvard Medical School; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts [75]
D
D
Alexander G. Marneros, M , Ph
D
Jeanne M. Marrazzo, M , MPH
Professor of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington [163] T
heila A. Lukehart, Ph
D
S
Professor of Medicine and Pathology, Columbia University College of Physicians and Surgeons, New York, New York [172]
homas Marrie, M
D
D
ranklin . Lowy, M D
F
Medical Oncology and Hematology, University of Cincinnati, Oncology Hematology Care, Inc., Cincinnati, Ohio [390]
D
Dr. Robert B. and Mrs. Ellinor Aird Professor of Neurology; Director, Epilepsy Center, University of California, San Francisco, San Francisco, California [437, 438e, 445]
Lucio Luzzatto, M ,
Gary J. Martin, M
CPath
FR
FR
CP,
Lawrence C. Madoff, M
Raymond J. Langenbach, MD Professor of Medicine; Vice Chairman for Faculty Affairs, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [4]
D
Professor of Hematology, University of Genova, Genova; Scientific Director, Istituto Toscano Tumori, Florence, Italy [129]
D
Dean, Faculty of Medicine; Professor, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada [211]
D
Professor, Departments of Medicine and Global Health, University of Washington, Seattle, Washington [206, 207e]
Adel A. . Mahmoud, M , Ph
Enteric Diseases Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, Georgia [178]
D
CPC
Professor of Medicine, McMaster University, Hamilton, Ontario, Canada [153]
HPIM19_VOlI_FM.indd 29
D
D
D
D
D
D
Calvin . McCall, M
John . McConville, M
D
Associate Professor, Department of Dermatology, Virginia Commonwealth University Medical Center, Richmond, Virginia; Chief, Dermatology Section, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia [71, 76e] Associate Professor of Medicine and Director, Internal Medicine Residency Program, University of Chicago, Chicago, Illinois [318]
Corey A. McGraw, M
Assistant Professor, The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, New York, New York [486e]
Kevin . Mc ary, M , AC
S
Lionel A. Mandell, M ,
FR
Professor and Chairman of Medicine, Cleveland Clinic Lerner College of Medicine, Department of Rheumatic and Immunologic Disease, Cleveland Clinic, Cleveland, Ohio [397]
Associate Professor of Pathology, Harvard Medical School; Medical Director, Infectious Diseases Diagnostic Laboratory, Children’s Hospital of Boston, Boston, Massachusetts [150e]
F
D
D
F
Brian . Mandell, M , Ph
Alexander J. McAdam, M , Ph
D
Professor of Medicine; Associate Chief, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [405]
obert J. Mayer, M
Faculty Vice President for Academic Affairs, Dana-Farber Cancer Institute; Stephen B. Kay Family Professor of Medicine, Harvard Medical School, Boston, Massachusetts [109, 110]
D
usan J. Mandel, M , MPH D
S
Associate Professor of Surgery and Chief, Division of Transplant and Assist Devices; Lester and Sue Smith Endowed Chair in Surgery, Baylor College of Medicine, Houston, Texas [281]
Fellow, Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York [485e, 486e]
V
R
Hari . Mallidi, M
D
Associate Professor of Surgery, Johns Hopkins University; Director of Endovascular Surgery; Director of The Vascular and Endovascular Clinical Research Center, Johns Hopkins Bayview Medical Center, Baltimore, Maryland [354]
Jeremy Matloff, M
O
F
S
D
Mahmoud Malas, M , MH , AC
S
Frederick F. Paustian Professor; Chief, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska College of Medicine, Omaha, Nebraska [363]
Chief, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland [244]
F
D
Mark E. Mailliard, M
Henry Masur, M
T
D
Jane and Donald D. Trunkey Professor and Vice-Chair, Surgery, University of Washington; Surgeon-in-Chief, Harborview Medical Center, Seattle, Washington [324]
usan Maslanka, Ph
D
S
Edward R. and Anne G. Lefler Professor, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts [437]
R
D
D
F
V
R
Professor in Molecular Biology and Public Policy, Princeton University, Princeton, New Jersey [259]
D
Joseph B. Martin, M , Ph D
Professor of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; Director, Division of Epidemiology and Immunization, Massachusetts Department of Public Health, Jamaica Plain, Massachusetts [157, 166e, 167e]
onald . Maier, M
Contri utors
Academic, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee [107]
D
D
D
Christine M. Lovly, M , Ph
D
Professor of Medicine and the Elizabeth Fay Brigham Professor of Women’s Health, Harvard Medical School; Chief, Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [413] F
Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston, Massachusetts [1, 49-52, 87e, 142, 264, 265e, 267, 283-287, 293, 295, 301-304]
xxix
D
D
JoAnn E. Manson, M , rPH
D
Joseph Loscalzo, M , Ph D
Lewin Chair and Chief, Cardiovascular Division; Professor of Medicine, Cell Biology and Physiology, Washington University School of Medicine, Cardiologist-in-Chief, Barnes Jewish Hospital, St. Louis, Missouri [279]
b
D
D
N
icola Longo, M , Ph
Professor and Chief, Division of Medical Genetics, Departments of Pediatrics and Pathology; Medical Co-Director, Biochemical Genetics Laboratory, ARUP Laboratories, University of Utah, Salt Lake City, Utah [434e, 435e]
Professor and Chairman, Division of Urology, Southern Illinois University School of Medicine, Springfield, Illinois [67]
1/30/15 2:35 PM
D
William J. Moss, M , MPH
D
Professor of Psychology (Neuroscience), Harvard Medical School, Boston, Massachusetts; Director, Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, Massachusetts [469e]
hlomo Melmed, M
avid B. Mount, M
FR
D
D
R
obert . Munford, M
ikhil C. Munshi, M
D
Senior Clinician, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [325] N
M.-Marsel Mesulam, M
D
Professor, Division of Pharmacology and Toxicology, College of Pharmacy; Associate Director, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas [465e]
CP(hc), Master AC
Professor and Director, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece [379, 383, 387] S
D
O
obert . Messing, M
D
Professor of Psychiatry (Neuroscience), Harvard Medical School, Belmont, Massachusetts [469e]
F
Haralampos M. Moutsopoulos, M , ACP,
D
Jack H. Mendelson,† M
S
Senior Vice President and Dean of the Medical Faculty, Cedars-Sinai Medical Center, Los Angeles, California [401e-403]
Assistant Professor of Medicine, Harvard Medical School; Renal Division, Brigham and Women’s Hospital, Renal Division, Boston VA Healthcare System, Boston, Massachusetts [63, 64e]
R
Instructor in Medicine, Harvard Medical School; Staff Physician, Brigham and Women’s Hospital, Boston, Massachusetts [482e, 484e] D
D
avid A. Morrow, M , MPH
Associate Professor of Medicine, Harvard Medical School; Director, Levine Cardiac Intensive Care Unit; Senior Investigator, TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts [19]
D
F
D
D
D
D
Eric G. eilson, M
D
Lewis Landsberg Dean, and Vice President, Medical Affairs, Feinberg School of Medicine, Northwestern University, Chicago, Illinois [62e, 332e, 338]
Emily Page elson, M
Clinical Instructor, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [484e]
Gerald . epom, M , Ph
D
D
Charles A. Morris, M , MPH
Professor of Medicine, and Director, Pulmonary Function Laboratory, and Adult Cystic Fibrosis Laboratory, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois [306e]
D
Associate Professor, Departments of Medicine and Immunology; Director, University of Pittsburgh HIV Lung Research Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania [244]
Edward . aureckas, M
D
D
Alison Morris, M , M
S
Senior Director, Scientific Review and Grants Administration, American Association for Cancer Research, Philadelphia, Pennsylvania [101e]
Chief, Section of Infections of the Nervous System; Clinical Director, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland [165]
N
D
Chairman, Department of Infectious Diseases, Ochsner Health System, New Orleans, Louisiana [246e]
Avindra ath, M N
A
obert J. Myerburg, M
Professor, Departments of Medicine and Physiology, Division of Cardiology; AHA Chair in Cardiovascular Research, University of Miami Miller School of Medicine, Miami, Florida [327]
T
F
D
T
FIDS
Professor of Medicine, Department of Medicine, Section of Pulmonary and Critical Care; Director, Sleep Disorders Center and Sleep Fellowship Program, University of Chicago, Chicago, Illinois [318]
homas A. Moore, M , ACP,
Associate Professor, Department of Emergency Medicine, Northwestern University Feinberg School of Medicine; Associate Professor, Department of Emergency Medicine, Rush University School of Medicine; Research Director, Toxikon Consortium; Attending Physician, Department of Emergency Medicine, Cook County Hospital, Chicago, Illinois [473e] R
S
D
Babak Mokhlesi, M , M c
Mark B. Mycyk, M
D
N
HM, A ZCA F
FU
D
S
imon J. Mitchell, MB ChB, Ph ,
Associate Professor, Department of Anaesthesiology, University of Auckland and Auckland City Hospital, Auckland, New Zealand [477e]
Professor of Medicine, Departments of Internal Medicine and Immunology, Mayo Clinic, Rochester, Minnesota [55]
N
D
I
S
amuel . Miller, M
Professor, Departments of Microbiology, Medicine and Genome Sciences, University of Washington, Seattle, Washington [190]
Joseph A. Murray, M
N
A. W. and Mary Margaret Clausen Distinguished Professor of Neurology, University of California, San Francisco School of Medicine, San Francisco, California [34, 35, 37e, 448, 453e]
Pat J. Morin, Ph
J. Ralph Meadows Professor and Director, Division of Infectious Diseases, University of Texas Medical School, Houston, Texas [174]
N
Bruce L. Miller, M
Barbara E. Murray, M
D
Associate Professor of Medicine, Harvard Medical School; Director, Tissue Typing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts [337]
imothy . Murphy, M
SUNY Distinguished Professor; Director, Clinical and Translational Research Center, University at Buffalo, the State University of New York, Buffalo, New York [182] D
Edgar L. Milford, M
D
Medical Oncology, Medical Director, Cancer Risk and Prevention Clinic, Maine Medical Center, Scarborough, Maine [84]
T
S
usan Miesfeldt, M
Professor of Medicine and Microbiology; Director ad interim, National Emerging Infectious Diseases Laboratories Institute, Boston University School of Medicine, Boston, Massachusetts [175]
D
Assistant Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [276]
D
John . Murphy, Ph R
Gregory . Michaud, M
D
Professor of Medicine, Harvard Medical School; Boston VA Healthcare System; Director of Basic and Correlative Sciences; Associate Director, Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts [136]
F
Professor of Neurology, Psychiatry and Psychology, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois [36]
T
Contri utors b
obert J. Motzer, M
Professor of Medicine, Joan and Sanford Weill College of Medicine of Cornell University D. Attending Physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York [114, 116]
R
D
N
ancy K. Mello,† Ph
D
Professor, Departments of Epidemiology, International Health, and Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland [229] R
Professor of Medicine, Harvard Medical School; Executive Director, Center for Advanced Heart Disease, Brigham and Women’s Hospital; Co-Director, Brigham and Women’s Hospital Heart and Vascular Center, Boston, Massachusetts [280]
D
F
F
D
Mandeep . Mehra, M , ACC, ACP R
xxx
Professor (Affiliate), University of Washington School of Medicine; Director, Benaroya Research Institute at Virginia Mason; Director, Immune Tolerance Network, Seattle, Washington [373e]
Deceased
†
HPIM19_VOlI_FM.indd 30
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D
avid L. Paterson, M , Ph
Gustav Paumgartner, M
O
D
Head, Helminth Immunology Section, Head, Clinical Parasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [257, 258] Professor of Neurology and Director, CIINAC, Hospital de Madrid; Medical School, CEU-San Pablo, Madrid, Spain [449]
FR
D
b
D
D
D
John Sealy Distinguished University Chair in Tropical and Emerging Virology; Professor, Department of Microbiology and Immunology; Department of Pathology; Director for Biodefense, Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas [233]
Chung wyang, M
D
Professor of Pathology, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [150e] H. Marvin Pollard Professor of Internal Medicine; Chief, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan [344, 352] S
mesh . Parashar, MBB , MPH
Lead, Viral Gastroenteritis Epidemiology Team, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia [227]
D
D
D
CPCH
FR
D
Andrew J. Pollard, Ph ,
Professor of Paediatric Infection and Immunity, Department of Paediatrics, University of Oxford, Oxford, United Kingdom [180]
euven Porat, M
Professor of Medicine, Department of Internal Medicine, Tel Aviv Souarsky Medical Center; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel [23]
aniel A. Portnoy, Ph
Professor, Department of Molecular and Cell Biology and the School of Public Health, University of California, Berkeley, Berkeley, California [176]
John . Potts, Jr., M
Jackson Distinguished Professor of Clinical Medicine, Harvard Medical School; Physician-in-Chief and Director of Research Emeritus, Massachusetts General Hospital, Boston, Massachusetts [424]
Lawrie W. Powell, M , Ph
D
D
O
Andrew B. nderdonk, Ph
Professor of Medicine, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, Massachusetts [339]
D
CP(hon)
Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology; Professor, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York [449]
Martin . Pollak, M
D
CPC,
FR
D
O
C. Warren lanow, M ,
FR
Professor of Medicine, Harvard Medical School; Director, Clinical Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [51e, 267, 283-286]
ichard J. Pollack, Ph
Instructor, Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts; Senior Environmental Public Health Officer, Department of Environmental Health and Safety, Harvard University, Cambridge, Massachusetts; President and Chief Scientific Officer, IdentifyUS LLC, Newton, Massachusetts [475]
D
D
O
Patrick . ’Gara, M
Professor of Medicine (Microbiology and Immunobiology), Harvard Medical School; Brigham and Women’s Hospital, Division of Infectious Diseases, Boston, Massachusetts [145e]
D
Speech-Language Pathologist, Memory and Aging Center, University of California, San Francisco, San Francisco, California [37e]
Gerald B. Pier, Ph
R
S
S
Jennifer gar, M CCC- LP O
Clarence J. Peters, M
T
CP
FR
S
D
F
O
igel ’ arrell, M , M c,
Ealing Hospital, London, United Kingdom [198e]
T
Professor Emeritus of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons; Director, Biochemical Genetics Laboratory, Columbia University Medical Center, New York Presbyterian Hospital, New York, New York [Appendix]
R
Assistant Professor of Medicine and Epidemiology, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, New York [205e]
O
Michael A. Pesce, Ph
R
D
D
O
R
Max . ’ onnell, M , MPH
D
lorencia Pereyra, M
Instructor in Medicine, Harvard Medical School; Associate Physician, Infectious Disease Division, Brigham and Women’s Hospital, Boston, Massachusetts [166e, 167e]
D
Professor, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland [171]
N
ACP
Associate Professor, Department of Infectious Diseases and Microbiology, The Alfred Hospital and Monash University, Melbourne, Victoria, Australia [187]
D
O
Katherine L. ’Brien, M , MPH
U
D
S
D
homas B. utman, M N
T
Chief of Dermatology, Children’s National Health Systems, Washington, DC [475]
HPIM19_VOlI_FM.indd 31
Anton Y. Peleg, MBB , Ph , MPH,
D
S
D
cott A. orton, M , MPH, M c N
S
Professor, Department of Surgery; Chief, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, California [474]
Jose A. beso, M
avid A. Pegues, M
Professor of Medicine, Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [190]
F D
N
R
Professor, Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi [238]
obert L. orris, M
Professor of Medicine, Autonomous University of Barcelona; Infectious Diseases Section (Senior Consultant), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain [184]
D
D
III
,M
M. Luisa Pedro-Botet, M , Ph
D
D
N
athel L. olan, N
R
Colonel, Medical Corps, U.S. Army; Deputy Joint Program Executive Officer, Medical Systems, Joint Program Executive Office for Chemical/Biological Defense, U.S. Department of Defense, Falls Church, Virginia; Adjunct Professor of Neurology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland [262e]
Professor Emeritus of Medicine, University of Munich, Munich, Germany [369]
Contri utors
Jonathan ewmark, M
D
Joseph P. ewhouse, Ph
D
Professor of Medicine, University of Queensland Centre for Clinical Research; Royal Brisbane and Women’s Hospital, Brisbane, Australia [187]
N
Universitaet Freiburg, Medizinische Universitaetsklinik, Freiburg im Breisgau, Germany [407] John D. MacArthur Professor of Health Policy and Management, Department of Health Care Policy, Harvard Medical School; Faculty, John F. Kennedy School of Government, Harvard School of Public Health, Faculty of Arts and Sciences, Harvard University, Boston, Massachusetts [15e]
xxxi
D
D
D
N
Hartmut P. H. eumann, M
hreyaskumar . Patel, M
Robert R. Herring Distinguished Professor of Medicine; Center Medical Director, Sarcoma Center, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [119e] D
Nash Family Professor and Chair, Department of Neuroscience; Director, Friedman Brain Institute, Ichan School of Medicine at Mount Sinai, New York, New York [465e]
R
S
D
D
N
Eric J. estler, M , Ph
Professor of Medicine, The University of Queensland; Director, Centre for the Advancement of Clinical Research, Royal Brisbane and Women’s Hospital, Brisbane, Australia [428]
1/30/15 2:35 PM
Research Fellow, Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland [229]
D
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D
D
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O
F
D
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R
I
V
ictor . eus, M
Department of Psychiatry, University of California, San Francisco School of Medicine; Langley Porter Neuropsychiatric Institute, San Francisco, California [466] D
R
Joseph J. hatigan, M
Peter A. ice, M
D
Assistant Professor, Harvard Medical School, Harvard School of Public Health; Associate Chief, Division of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts [2]
Elizabeth obbins, M
D
Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts [181] Clinical Professor of Pediatrics, University of California, San Francisco, San Francisco, California [443e]
Medical Officer, Division of Foodborne, Waterborne, and Environmental Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia [178]
D
R
William Stokes Professor of Experimental Therapeutics; Professor of Medicine and Pharmacology, Assistant Vice-Chancellor for Personalized Medicine, Director, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, Tennessee [5]
D
T
D
D
D
F
FR
D
R
Jonathan E. osenberg, M
S
Faculty, Department of Medicine, Pulmonary Division, Albert Einstein College of Medicine; Montefiore Medical Center, Bronx, New York [205e]
D
R
N
Myrna . osenfeld, M , Ph
D
ivya eddy, MBB , MPH
oger . osenberg, M
Zale Distinguished Chair and Professor of Neurology, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas [450, 451e] D
Director, Global TB Programme, World Health Organization, Geneva, Switzerland [202]
Associate Attending; Section Chief, Non-Prostate Program, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York [114]
R
R
Mario C. aviglione, M
D
Henry Knowles Beecher Professor of Anesthesiology, Harvard Medical School; Executive Vice Chair and Chief, Division of Pain Medicine, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts [18]
R
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R
James P. athmell, M
CP, ACP
Professor of Neurology, Harvard Medical School; Raymond D. Adams Master Clinician; Executive Vice Chair, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [328, 456, 457e] R
Scientific Director, Anis Rassi Hospital, Goiânia, Brazil [252]
Allan H. opper, M ,
D
F
F
F
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D
R
Anis assi, Jr., M , Ph , ACC, ACP, AHA
R
John and Nancy Nelson Professor of Neurology; Professor of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana [164]
R
R
Department of Neurology, University of California, San Francisco, San Francisco, California [21, 447]
HPIM19_VOlI_FM.indd 32
Karen L. oos, M
D
Technical Officer, Department of Ethics, Equity, Trade, and Human Rights, World Health Organization, Geneva, Switzerland [13e]
eil H. askin, M
Principal Senior Life Scientist Advisor, Tunnell Government Services, Inc., Rockville, Maryland [262e]
F
F
R
Kumanan asanathan, MBChB, MPH, A PHM
James A. omano, Jr., Ph , AB R
Attending Physician, Elmhurst Hospital Center, Mount Sinai Medical Affiliate, Elmhurst, New York [486e]
R
R
Beth apaport, M
an M. oden, M R
D D
R
Agam K. ao, M
ussell G. obertson, M
D
Emeritus Professor of Medicine, Northwestern University School of Medicine, Chicago, Illinois [404] R
D
R
Adjunct Professor of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida College of Medicine, Gainesville, Florida [189]
D
Professor of Family Medicine, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, Illinois [56]
R
euben amphal, M
S
Gary L. obertson, M
R
anjay am, MBB
Associate Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts [181] R
R
University Professor and Chairman, Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine; ObstetricianGynecologist In-Chief, The Milton S. Hershey Medical Center, Hershey, Pennsylvania [8]
R
D
R
Kaitlin ainwater-Lovett, Ph , MPH
N
R
R
D
R
aniel J. ader, M
Seymour Gray Professor of Molecular Medicine; Chair, Department of Genetics; Chief, Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania [421]
D
R
John . epke, M , AC G
R
R
D
Associate Professor in Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [37e]
S
Jack D. Myers Professor of Medicine and Chair, Department of Medicine; Vice Chair for Clinical Affairs, University of Pittsburgh, Pittsburgh, Pennsylvania [308e, 314]
D
Professor of Medicine, Johns Hopkins University, Baltimore, Maryland; Senior Investigator, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [213]
Gil abinovici, M
John J. eilly, Jr., M
D
T
Director, Institute for Neurodegenerative Diseases; Professor, Department of Neurology, University of California, San Francisco, San Francisco, California [444e, 453e]
homas C. Quinn, M
usan E. eef, M
Medical Epidemiologist, Centers for Disease Control and Prevention, Atlanta, Georgia [230e]
T
D
Director and Professor, Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, Texas [427]
tanley B. Prusiner, M
S
I
D
D
D
arwin J. Prockop, M , Ph
P CP R
FF
U
R
D
CPath,
Professor of Medical Microbiology, Departments of Microbiology and Pathology, University College Cork, Cork, Ireland [196]
S
Contri utors b
FR
Assistant Professor of Medicine, Harvard Medical Center; Massachusetts General Hospital, Boston, Massachusetts [58, 358]
Michael B. Prentice, MB ChB, Ph , M CP( K),
haron L. eed, M , M C M, (ABMM)
Professor of Pathology and Medicine; Director, Microbiology Laboratory, University of California, San Diego School of Medicine, La Jolla, California [245e, 247]
D
S
D
aniel . Pratt, M
usan edline, M , MPH
Peter C. Farrell Professor of Sleep Medicine, Harvard Medical School; Brigham and Women’s Hospital; Beth Israel Deaconess Medical Center, Boston, Massachusetts [319] S
Joe C. Davis Chair in Biomedical Science; Professor of Medicine, Molecular Physiology and Biophysics; Director, Vanderbilt Diabetes Center; Chief, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee [417-419]
R
S
Alvin C. Powers, M
D
xxxii
Department of Neurology, Hospital Clínic/IDIBAPS, Barcelona, Spain [122]
1/30/15 2:35 PM
S
CP, Med ci F
c,
FR
DS
D
S
V
Anthony H. . chapira, M ,
Chair and Professor of Clinical Neurosciences, UCL Institute of Neurology, London, United Kingdom [449]
F
b
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D
D
D
D
Instructor in Medicine, Harvard Medical School; Assistant Chief, Infection Control Unit, Massachusetts General Hospital, Boston, Massachusetts [170] D
D
Kanade hinkai, M , Ph
Assistant Professor, Department of Dermatology, University of California, San Francisco, San Francisco, California [74]
William ilen, M
Johnson and Johnson Professor Emeritus of Surgery, Harvard Medical School, Auburndale, Massachusetts [20] D
D
S
Edwin K. ilverman, M , Ph
Professor of Medicine, Harvard Medical School; Chief, Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts [314]
CP(C), A
SN
Karl korecki, M ,
F
D
S
Professor, Harvard Medical School; Beth Israel Deaconess Medical Center; Boston Children’s Hospital, Boston, Massachusetts [38]
HPIM19_VOlI_FM.indd 33
D
S
Erica . henoy, M , Ph
S
D
S
Gerald and Darlene Professor of Medicine; Co-Chair, Harvard Stem Cell Institute; Co-chair, Department of Stem Cell and Regenerative Biology, Harvard Medical School; Director, Center for Regenerative Medicine; Chief, Hematologic Malignancies, Cancer Center, Massachusetts General Hospital, Boston, Massachusetts [89e]
homas E. cammell, M
D
D
D
S
teven . hapiro, M
Jack D. Myers Professor and Chair, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania [314]
S
Raja N. Khuri Dean, Faculty of Medicine; Professor of Medicine and Immunology; Vice President of Medical Affairs, American University of Beirut, Beirut, Lebanon; Senior Lecturer, Harvard Medical School; Schuster Family Transplantation Center, Brigham and Women’s Hospital, Boston, Massachusetts [337]
S
D
Assistant Professor, Department of Medicine, Division of Rheumatology and Immunology, Duke University Medical Center, Durham, North Carolina [380]
D
D
Mohamed H. ayegh, M S
Ankoor hah, M
D
Professor of Medicine, University of Maryland School of Medicine; Associate Director for Clinical Research, Marlene and Stewart Greenbaum Cancer Center, Baltimore, Maryland [103e]
avid C. eldin, M , Ph
Professor, Departments of Medicine and Microbiology; Chief, Section of Hematology-Oncology; Director, Amyloidosis Center, Boston University School of Medicine; Boston Medical Center, Boston, Massachusetts [137]
S
D
D
S
Edward A. ausville, M , Ph
D
Associate Professor of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [343]
S
Associate Professor of Medicine, Section of Pulmonary, Allergy, and Critical Care Medicine, Boston University School of Medicine, Boston, Massachusetts [205e]
avid . cadden, M
D
S
S
Julian L. eifter, M
S
S
D
James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School; Chairman, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts [38]
Jussi J. aukkonen, M
S
Chief Medical Officer, McKesson Specialty Health, The Woodlands, Texas [117]
D
Clifford B. aper, M , Ph D
Michael . eiden, M , Ph
D
Professor, Collège de France; Institut Pasteur, Paris, France [191] S
Associate Professor of Neurology and Pathology, Memory and Aging Center, University of California, San Francisco, San Francisco, California [35, 448]
S
D
S
Philippe J. ansonetti, M
William W. eeley, M
D
Professor of Neurology, Harvard Medical School; Chair, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts [439e, 463e]
ichard M. chwartzstein, M
Ellen and Melvin Gordon Professor of Medicine and Medical Education, Harvard Medical School; Associate Division Chief, Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts [47e]
FR
D
S
Martin A. amuels, M
Professor of Pediatrics; Vice-Chairman for Educational Affairs; Martin I. Lorin, MD Chair in Medical Education, Department of Pediatrics, Section of Retrovirology, Vice President, Baylor International Pediatric AIDS Initiative at Texas Children’s Hospital, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas [195]
S
D
S
avid J. alant, M
Professor of Medicine, Boston University School of Medicine; Chief, Section of Nephrology, Boston Medical Center, Boston, Massachusetts [340]
Gordon E. chutze, M , AAP
S
D
S
ean adikot, M
Department of Internal Medicine, Critical Care and Pulmonary Disease, Hackensack University Medical Center, Hackensack, New Jersey [485e, 486e]
T
D
Professor of Medicine, Division of Rheumatology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania [395]
V
MH
Professor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Director, Global Infectious Diseases, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [160, 193]
D
D
H. alph chumacher, Jr., M
R
F
A, A
FIDS
F
D
R
T
Edward . yan, M , ACP,
ST
Assistant Professor, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts [483e]
T
D
S
S
Distinguished Professor of Psychiatry, University of California, San Diego School of Medicine, La Jolla, California [467]
D
Anna E. utherford, M , MPH R
Marc A. chuckit, M
S
Staff Physician, Western New York VA Healthcare System; Professor of Medicine and Microbiology and Immunology; Vice Chair of Medicine; Head, Division of Infectious Disease, University at Buffalo, State University of New York, Buffalo, New York [186, 200]
S
RADM, U.S. Public Health Service; Assistant Surgeon General, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia [148]
R
D
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homas A. usso, M , CM
xxxiii
Contri utors
T
Professor Emeritus of Medicine and Nutrition, Tufts University, Boston, Massachusetts; Office of Dietary Supplements, National Institutes of Health, Bethesda, Maryland [96e]
D
Anne chuchat, M S
D
R
R
Acting Principal Investigator, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland [231e]
Professor of Medicine, Joan and Sanford Weill College of Medicine of Cornell University; D. Wayne Calloway Chair in Urologic Oncology; Attending Physician and Chief, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York [114, 115]
D
D
teven A. ubin, Ph R
S
Assistant Professor of Medicine, University of Utah School of Medicine, Salt Lake City, Utah [44]
obert M. ussell, M
Howard . cher, M I
D
D
R
Michael A. ubin, M , Ph
Annie Chutick Professor in Medicine (Nephrology); Director, Rappaport Research Institute, Technion-Israel Institute of Technology; Director of Medical and Research Development, Rambam Health Care Campus, Haifa, Israel [85e, 335]
1/30/15 2:35 PM
Professor of Medicine, Harvard Medical School; Director, Clinical Rheumatology, Massachusetts General Hospital, Boston, Massachusetts [391e] D
S
S
D
D
D
Homayoun abandeh, M
Retina-Vitreous Associates Medical Group, Los Angeles, California [40e] D
Geoffrey abin, M
John and Marva Warnock Presidential Professor, University of Utah School of Medicine; Director, International Ophthalmology Division, John A. Moran Eye Center; Director, Himalayan Cataract Project, Salt Lake City, Utah [476e]
Maria Carmela artaglia, M
D
S
William G. tevenson, M
Brigham and Women’s Hospital; Cardiovascular Division, Department of Medicine, Harvard Medical School, Boston, Massachusetts [276, 277]
HPIM19_VOlI_FM.indd 34
D
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FR
S
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S
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Zelig A. ochner, M
D
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam [177] Professor of Radiation Oncology, University of Pennsylvania School of Medicine; Medical Director, Proton Therapy Center, Philadelphia, Pennsylvania [263e] D
T
Gordon . omaselli, M
Michel Mirowski, MD Professor of Cardiology; Professor of Medicine and Cellular and Molecular Medicine; Chief, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland [273e-275] S
Karina A. op, M , M D
Professor of Medicine, Harvard Medical School; Director, Heart Failure Program, Brigham and Women’s Hospital, Boston, Massachusetts [287]
C. Louise hwaites, M , MBB
Assistant Professor of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada [185]
Mark opazian, M
D
S
Lynne Warner tevenson, M
D
Professor of Medicine, University of Washington School of Medicine, Seattle, Washington [156, 179]
ajesh . hakker, M , Med ci,
May Professor of Medicine, Academic Endocrine Unit, University of Oxford; O.C.D.E.M., Churchill Hospital, Headington, Oxford, United Kingdom [408]
F
D
D
ennis L. tevens, M , Ph S
D
Carl J. Herzog Professor of Dermatology, Harvard Medical School; Chair, Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts [74]
tephen C. extor, M
Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota [299, 341]
T
D
S
S
R
Professor of Medicine, Harvard Medical School; Massachusetts General Hospital, Boston, Massachusetts [210]
obert . tern, M
Professor of Medicine and Hematology, Mayo Clinic, Rochester, Minnesota [135e]
T
S
D
Professor of Medicine and Immunology, Department of Medicine, Duke University Medical Center, Durham, North Carolina [380]
Allen C. teere, M
Ayalew efferi, M
T
S
E. William t. Clair, M
Professor of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas [384]
D
Associate Professor, Department of Medicine, Johns Hopkins University; Director, Electrophysiology Laboratory, Johns Hopkins Bayview Medical Center, Baltimore, Maryland [273e-275]
Joel . aurog, M
V
D
S
avid . pragg, M D
D
Professor of Medicine and Oncology, Hematology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland [131]
Assistant Professor, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada [37e]
R
S
Jerry L. pivak, M
D
Professor of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; Chief, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania [83e]
S
F
D
ancy B. pinner, Ph , ACMG S
N
T
Professor of Medicine; Associate Medical Director for Inpatient Services, Harbor–UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California [242]
D
D
D
S
obert A. werlick, M
Alicia Leizman Stonecipher Professor and Chair of Dermatology, Emory University School of Medicine, Atlanta, Georgia [76e]
D
D
S
Brad pellberg, M
FN
D
S
ichard M. uzman, Ph
Director, Behavioral and Social Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland [93e]
T
E. H. Kass Distinguished Professor of Medicine, Harvard Medical School; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital; Professor of Environmental Science, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts [311]
S
N
Professor, Clinic and Policlinic of Internal Medicine, University Hospital, Zurich, Switzerland [96e]
R D
rank E. peizer, M S
F
Professor, Departments of Medicine and Genetics, Gwaltney Chair for Medical Research; Director, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama [313]
eeraj K. urana, M , Ph
T
S
Eric J. orscher, M
A
Paolo M. uter, M , M
D
Robert L. Grissom Professor of Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska [363]
CP,
Instructor in Pediatrics, Harvard Medical School; Assistant in Medicine, Boston Children’s Hospital, Boston, Massachusetts [144] S
S
F
Michael . orrell, M
D
Walter L. Palmer Distinguished Service Professor of Medicine and Pediatrics; Associate Dean for Translational Medicine, Biological Sciences Division; Vice Chair for Research, Department of Medicine; Chair, Committee on Molecular Medicine, University of Chicago, Chicago, Illinois [306e, 318]
hyam undar, M ,
Professor of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India [251]
R
S
Julian olway, M
D
S
Professor, Harvard Medical School; Director, Noninvasive Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts [270e, 271e]
onna C. ullivan, Ph
Professor, Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical School, Jackson, Mississippi [238]
S
D
S
D
cott . olomon, M
D
Associate Professor of Neurology, Harvard Medical School; Director of Movement Disorders, Brigham and Women’s Hospital, Boston, Massachusetts [32] D
Associate Director, Duke Center for HIV/AIDS Vaccine ImmunologyImmunogen Discovery, Duke Human Vaccine Institute, Duke University, Durham, North Carolina [372e] S
Contri utors b
D
S
Kelly A. oderberg, Ph , MPH
D
S
Lewis udarsky, M S
Department of Gastrointestinal Oncology, Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom [112]
tephanie tudenski, M , MPH
FR
S
O
S
S
Professor of Neurology, Daryl R. Gress Endowed Chair of Neurocritical Care and Stroke; Director, University of California, San Francisco Neurovascular Service, San Francisco, California [330, 446]
D
S
Director, Longitudinal Studies Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland [11]
D
Elizabeth myth, MB BA , M c
D
John H. tone, M , MPH
S
Wade . mith, M , Ph S
xxxiv
Professor of Medicine, Mayo Clinic, Rochester, Minnesota [345, 346e]
1/30/15 2:35 PM
Barbara W. Trautner, MD, PhD
Assistant Professor, Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine; Houston VA Health Services Research and Development Center of Excellence, Houston, Texas [162]
Jeffrey M. Trent, PhD, FACMG
David H. Walker, MD
The Carmage and Martha Walls Distinguished University Chair in Tropical Diseases; Professor and Chairman, Department of Pathology; Executive Director, Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas [211]
President and Research Director, Translational Genomics Research Institute, Phoenix, Arizona; Van Andel Research Institute, Grand Rapids, Michigan [101e]
Mark F. Walker, MD
Elbert P. Trulock, III, MD
Fred Wang, MD
Kenneth L. Tyler, MD
John W. Warren, MD
Reuler-Lewin Family Professor and Chair of Neurology; Professor of Medicine, Immunology, and Microbiology, University of Colorado School of Medicine, Aurora, Colorado; Neurologist, Denver Veterans Affairs Medical Center, Denver, Colorado [164]
Athanasios G. Tzioufas, MD
Professor, Department of Pathophysiology, School of Medicine, National University of Athens, Athens, Greece [383]
Walter J. Urba, MD, PhD
Director of Research, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon [105]
Jos W. M. van der Meer, MD, PhD
Professor of Medicine; Head, Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [26, 464e]
Edouard G. Vannier, PharmD, PhD
Assistant Professor, Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts [249]
Gauri R. Varadhachary, MD
Professor, Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas [120e]
John Varga, MD
John Hughes Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [382]
Christy A. Varughese, PharmD
Infectious Disease Specialist, Department of Pharmacy, Massachusetts General Hospital, Boston, Massachusetts [170]
Associate Professor, Neurology, Case Western Reserve University; Cleveland VA Medical Center, Cleveland, Ohio [28] Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts [214e, 220e] Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland [60e]
Aaron B. Waxman, MD, PhD, FACP, FCCP
Associate Professor of Medicine, Harvard Medical School; Executive Director, Center for Pulmonary-Heart Diseases, Brigham and Women’s Hospital Heart and Vascular Center, Boston, Massachusetts [304]
Michael E. Wechsler, MD, MMSc
Professor of Medicine; Director, Asthma Program, National Jewish Health, Denver, Colorado [310]
Anthony P. Weetman, MD, DSc
University of Sheffield, School of Medicine Sheffield, United Kingdom [405]
Robert A. Weinstein, MD
The C. Anderson Hedberg, MD Professor of Internal Medicine, Rush Medical College; Chief Academic Officer, Cook County Health and Hospitals System, Chicago, Illinois [168]
Jeffrey I. Weitz, MD, FRCP(C), FACP
Professor of Medicine and Biochemistry, McMaster University; Executive Director, Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada [143]
Peter F. Weller, MD
Chief, Infectious Disease Division; Chief, Allergy and Inflammation Division; Beth Israel Deaconess Medical Center, Boston, Massachusetts [254-258, 260]
Andrew Wellman, MD, PhD
Assistant Professor of Medicine, Division of Sleep Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts [319]
Patrick Y. Wen, MD
Professor of Medicine-Immunology, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece [379]
Professor of Neurology, Harvard Medical School; Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of NeuroOncology, Department of Neurology, Brigham and Women’s Hospital; DanaFarber Cancer Institute, Boston, Massachusetts [118]
Bert Vogelstein, MD
Michael R. Wessels, MD
Panayiotis G. Vlachoyiannopoulos, MD
Investigator, Howard Hughes Medical Institute; Director, Ludwig Center at the Sidney Kimmel Comprehensive Cancer Center; Clayton Professor of Oncology and Pathology; Johns Hopkins Medical Institutions, Baltimore, Maryland [101e]
Everett E. Vokes, MD
John E. Ultmann Professor; Chairman, Department of Medicine; Physician-inChief, University of Chicago Medical Center, Chicago, Illinois [106]
Tamara J. Vokes, MD
John F. Enders Professor of Pediatrics; Professor of Medicine, Harvard Medical School; Chief, Division of Infectious Diseases, Boston Children’s Hospital, Boston, Massachusetts [173]
L. Joseph Wheat, MD
President and Medical Director, MiraVista Diagnostics, LLC, Indianapolis, Indiana [236]
A. Clinton White, Jr., MD
Professor, Department of Medicine, Section of Endocrinology, University of Chicago, Chicago, Illinois [426e]
Paul R. Stalnaker Distinguished Professor; Director, Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas [260]
Jiři F. P. Wagenaar, MD, PhD
Nicholas J. White, DSc, MD, FRCP, F Med Sci, FRS
Senior Scientist, WHO/FAO/OIE and National Leptospirosis Reference Centre, KIT Biomedical Research, KIT (Royal Tropical Institute), Amsterdam, The Netherlands [208]
Sushrut S. Waikar, MD, MPH
Professor of Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Mahidol-Oxford Research Unit, Bangkok, Thailand [248, 250e]
Richard J. Whitley, MD
Associate Professor, Harvard Medical School; Director, Renal Ambulatory Services, Brigham and Women’s Hospital, Boston, Massachusetts [334]
Distinguished Professor of Pediatrics; Loeb Eminent Scholar Chair in Pediatrics; Professor of Microbiology, Medicine and Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama [217]
Matthew K. Waldor, MD, PhD
Bruce U. Wintroub, MD
Edward H. Kass Professor of Medicine, Channing Laboratory, Brigham and Women’s Hospital; Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts [193]
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Contributors
Rosemary and I. Jerome Flance Professor in Pulmonary Medicine, Washington University School of Medicine, St. Louis, Missouri [320e]
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Professor and Chair, Department of Dermatology, University of California, San Francisco, San Francisco, California [74]
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Andrea S. Wolf, MD, MPH
Janet A. Yellowitz, DMD, MPH
Allan W. Wolkoff, MD
Lam Minh Yen, MD
Assistant Professor, and Director, Women’s Lung Cancer Program, Mt. Sinai Medical Center, New York, New York [482e] The Herman Lopata Chair in Liver Disease Research; Professor of Medicine and Anatomy and Structural Biology; Associate Chair of Medicine for Research; Chief, Division of Gastroenterology and Liver Diseases; Director, Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York [359]
John B. Wong, MD
Contributors
Professor of Medicine, Tufts University School of Medicine; Chief, Division of Clinical Decision Making, Department of Medicine, Tufts Medical Center, Boston, Massachusetts [3]
Louis Michel Wong Kee Song, MD
Associate Professor, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota [345, 346e]
Robert L. Wortmann, MD, FACP, MACR
Professor Emeritus, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire [431e]
Shirley H. Wray, MD, PhD, FRCP
Professor of Neurology, Harvard Medical School; Master Clinician, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts [41e]
Richard G. Wunderink, MD
Professor, Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois [153]
Kim B. Yancey, MD
Professor and Chair, Department of Dermatology, University of Texas Southwestern Medical Center in Dallas, Dallas, Texas [70, 73]
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Associate Professor; Director, Geriatric Dentistry, University of Maryland Dental School, Baltimore, Maryland [46e] Director, Tetanus Intensive Care Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam [177]
Maria A. Yialamas, MD
Assistant Professor of Medicine, Harvard Medical School; Associate Program Director, Internal Medicine Residency, Brigham and Women’s Hospital, Boston, Massachusetts [481e, 483e]
Neal S. Young, MD
Chief, Hematology Branch, National Heart, Lung and Blood Institute; Director, NIH Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, Maryland [130]
Victor L. Yu, MD
Professor of Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania [184]
Jing Zhou, MD, PhD, FASN
Director, Laboratory of Molecular Genetics and Developmental Biology of Disease, Renal Division; Director, Center for Polycystic Kidney Disease Research, Brigham and Women’s Hospital; Harvard Medical School, Boston, Massachusetts [339]
Werner Zimmerli, MD
Professor of Medicine, Basel University; Interdisciplinary Unit of Orthopaedic Infection, Kantonspital Baselland, Liestal, Switzerland [158]
Laura A. Zimmerman, MPH
Epidemiologist, Centers for Disease Control and Prevention, Atlanta, Georgia [230e]
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Preface
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focus and a comprehensive and analytical approach to pathogenesis. The updates cover the latest treatment protocols and address the issue of combination prevention modalities, making the chapter the most up-to-date and comprehensive treatise on HIV disease available. Several other chapters likewise reflect the rapid pace of advancement in the field of immune-related diseases and their treatment. In this regard, Chapter 372e, “Introduction to the Immune System,” serves as a mini-textbook of immunology for use in immunology courses. In addition, a new chapter on IgG4-mediated disease summarizes an important and newly recognized constellation of entities. Readers will find expanded coverage of the neurodegenerative diseases, highlighting advances in their classification and management and delineating the new understanding of mechanisms responsible for the deposition and spread of pathogenic protein aggregates in these disorders. The chapter on chronic hepatitis discusses in detail the dramatic new discoveries in the use of direct-acting antiviral agents for the treatment of hepatitis C virus disease; these agents are responsible for some of the most exciting therapeutic advances in medicine today. The rapidly expanding application of genetic knowledge to medicine is covered in many chapters, including a new chapter on microbial genomics and infectious diseases and substantially updated chapters on the human microbiome and chromosomal genetic disorders. Other new chapters address timely topics such as the impact of climate change on disease, infections in U.S. veterans returning from foreign wars, and advances in contraception and the treatment of infertility. Another topic of increasing interest, the impact of aging on health and disease, is addressed by several chapters, including a newly authored chapter on the biology of aging. A new chapter on men’s health complements the updated chapter on women’s health. New chapters also address diverse topics including the emerging field of tissue engineering, the examination of the comatose patient, the management of heart failure, the major characteristics of helminths and helminthic infections, specific cardiac valvular disorders, venous and lymphatic diseases of the extremities, renovascular disease, late complications of diabetes, chronic myeloid leukemia, heat-related illnesses, fatigue, polyglandular failure syndromes, and nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Supplementing new content and updates on diseases and patient care, new videos in this edition cover sleep disorders, tissue engineering, noninvasive cardiac imaging, examination of the comatose patient, and myasthenia gravis and other diseases of the neuromuscular junction. New atlases for this edition address noninvasive imaging, percutaneous revascularization, and gastrointestinal endoscopy. We have many people to thank for their efforts in producing this book. First, the authors have done a superb job of producing authoritative chapters that synthesize vast amounts of scientific and clinical data to create state-of-the-art descriptions of medical disorders encompassed by internal medicine. In today’s information-rich, rapidly evolving environment, they have ensured that this information is current. Helpful suggestions and critical input have been provided by a number of colleagues; particularly notable was the advice of Chung Owyang on the Gastroenterology Section. We are most grateful to our colleagues in each of our editorial offices who have kept track of the work in its various phases and facilitated communication with the authors, with the McGraw-Hill Education staff, and among the editors: Patricia Conrad, Patricia L. Duffey, Gregory K. Folkers, Julie B. McCoy, Elizabeth Robbins, Anita Rodriguez, and Stephanie Tribuna. The staff at McGraw-Hill Education has been a constant source of support and expertise. James Shanahan, Associate Publisher for McGrawHill Education’s Professional Publishing Division, has been a superb and insightful partner to the editors, guiding the development of the book and
Preface
The Editors are pleased to present the 19th edition of Harrison’s Principles of Internal Medicine. Since the first edition was published 65 years ago, virtually every area of medicine and medical education has evolved remarkably, and many new fields have emerged. While retaining the founding goals of Harrison’s, this edition has been modified extensively in light of the varied needs of the book’s readers and the diverse methods and formats by which information is now acquired and applied. The focus of medical education worldwide is shifting from the classic structure/function/disease approach to an integrated, often case-based approach in which basic and population sciences are specifically linked to the practical diagnosis and management of disease. Many of the updates and changes described here have been undertaken with the modern educational and clinical environments in mind. This new edition offers a thoroughly updated presentation of the classic pathophysiologic basis of clinical medicine and details the cutting-edge methods and tools that are now available for the assessment of symptoms and the effective management of diseases in the modern patient-care environment. The text is supplemented by germane new photographs, radiographs, illustrations, atlases, patient-care algorithms, tables, and practical demonstrative videos. In the interest of producing the most practical format possible for the 19th edition, a new system of referencing has been used. Detailed bibliographic listings, with summaries of articles’ relevance to practice, appear in the online edition, replacing the general and limited collection of Suggested Readings that appeared in the prior print editions. The 19th edition of Harrison’s is designed for accessibility and flexibility. The print textbook is available in two volumes. Volume 1 focuses on the foundations of medicine and the understanding and assessment of cardinal disease manifestations; Volume 2 focuses on specific diseases, by system. This functional division will be helpful to students who are mastering the basis of clinical medicine and to clinicians who are more focused on gaining an advanced understanding of mechanisms and patient care in specific diseases. In terms of digital media, Harrison’s is now available as an eBook on multiple platforms, as an enhanced “app” developed especially for tablet and smartphone devices that offer high-definition resolution of multimedia content and interactive features, and as an updated online edition. All of these options provide access to our numerous e-chapters as well as to videos and atlases. Additional resources include the Harrison’s Self-Assessment and Board Review, a useful study guide based on information in the 19th edition, and the Harrison’s Manual of Medicine, a pocket version of Harrison’s Principles of Internal Medicine. A new Harrison’s collection of case vignettes emphasizing differential diagnostic considerations in the assessment of cardinal manifestations will also be available. Advances in medical science have been spectacular since Harrison’s was first published in 1949. At that time, peptic ulcer disease was thought to be caused by stress, nearly every tumor that was not resected resulted in death, rheumatic heart disease was widely prevalent, and hepatitis B and HIV infection were unknown. In the intervening years, both the infectious cause of and the cure for peptic ulcer disease were identified; advances in diagnosis and treatment made it possible to cure two-thirds of cancers; rheumatic heart disease virtually disappeared; atherosclerotic coronary artery disease waxed and then—at least in part through management of modifiable risk factors—began to wane; hepatitis B and its consequences, cirrhosis and hepatocellular carcinoma, became preventable by a vaccine; and HIV, first viewed as a uniformly fatal worldwide scourge, became a treatable chronic disease. Notably, emerging and reemerging diseases have presented significant challenges to medical research and practice, while a new understanding of systems-wide concepts such as the microbiome offers exciting new possibilities for understanding and managing health and disease in ways never before possible. Of particular note in this 19th edition are critical updates in the classic chapter on HIV/AIDS, which offers both a clinically pragmatic
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its related products in new formats. Kim Davis, as Associate Managing Editor, has adeptly ensured that the complex production of this multiauthored textbook proceeded smoothly and efficiently. Dominik Pucek oversaw the production of the new procedural videos and Priscilla Beer expertly oversaw the production of our extensive DVD content. Jeffrey Herzich ably served as production manager for this new edition.
We are privileged to have compiled this 19th edition and are enthusiastic about all that it offers our readers. We learned much in the process of editing Harrison’s and hope that you will find this edition a uniquely valuable educational resource.
The Editors
Preface HPIM19_VOlI_FM.indd 38
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Part 1: General Considerations in Clinical Medicine The Editors
The practice of medicine has changed in significant ways since the first edition of this book appeared more than 60 years ago. The advent of molecular genetics, molecular and systems biology, and molecular pathophysiology; sophisticated new imaging techniques; and advances in bioinformatics and information technology have contributed to an explosion of scientific information that has fundamentally changed the way physicians define, diagnose, treat, and attempt to prevent disease. This growth of scientific knowledge is ongoing and accelerating. The widespread use of electronic medical records and the Internet have altered the way doctors practice medicine and access and exchange information (Fig. 1-1). As today’s physicians strive to integrate copious amounts of scientific knowledge into everyday practice, it is critically important that they remember two things: first, that the ultimate goal of medicine is to prevent disease and treat patients; and second, that despite more than 60 years of scientific advances since the first edition of this text, cultivation of the intimate relationship between physician and patient still lies at the heart of successful patient care. The Science and Art of Medicine Deductive reasoning and applied technology form the foundation for the solution to many clinical problems. Spectacular advances in biochemistry, cell biology, and genomics, coupled with newly developed imaging techniques, allow access to the innermost parts of the cell and provide a window into the most remote recesses of the body. Revelations about the nature of genes and single cells have opened a portal for formulating a new molecular basis for the physiology of systems. Increasingly, physicians are learning how subtle changes in many different genes can affect the function of cells and organisms. Researchers are deciphering the complex mechanisms by which genes are regulated. Clinicians have developed a new appreciation of the role of stem cells in normal tissue function; in the development of cancer, degenerative diseases, and other disorders; and in the treatment of certain diseases. Entirely new areas of research, including studies of the human microbiome, have become important in understanding both health and disease. The knowledge gleaned from the science of medicine continues to enhance physicians’ understanding of complex disease processes and provide new approaches to treatment and prevention. Yet skill in the most sophisticated applications of laboratory technology and in the use of the latest therapeutic modality alone does not make a good physician. When a patient poses challenging clinical problems, an effective physician must be able to identify the crucial elements in a complex history and physical examination; order the appropriate laboratory, imaging, and diagnostic tests; and extract the key results from densely populated computer screens to determine whether to treat or to “watch.” As the number of tests increases, so does the likelihood that some incidental finding, completely unrelated to the clinical problem at hand, will be uncovered. Deciding whether a clinical clue is worth pursuing or should be dismissed as a “red herring” and weighing
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CLINICAL SKILLS History-Taking The written history of an illness should include all the facts of medical significance in the life of the patient. Recent events should be given the most attention. Patients should, at some early point, have the opportunity to tell their own story of the illness without frequent interruption and, when appropriate, should receive expressions of interest, encouragement, and empathy from the physician. Any event related by a patient, however trivial or seemingly irrelevant, may provide the key to solving the medical problem. In general, only patients who feel comfortable with the physician will offer complete information; thus putting the patient at ease to the greatest extent possible contributes substantially to obtaining an adequate history. An informative history is more than an orderly listing of symptoms. By listening to patients and noting the way in which they describe their symptoms, physicians can gain valuable insight. Inflections of voice, facial expression, gestures, and attitude (i.e., “body language”) may offer important clues to patients’ perception of their symptoms. Because patients vary in their medical sophistication and ability to recall facts, the reported medical history should be corroborated whenever possible. The social history also can provide important insights into the types of diseases that should be considered. The family history not only identifies rare Mendelian disorders within a family but often reveals risk factors for common disorders, such as coronary heart disease, hypertension, and asthma. A thorough family history may require input from multiple relatives to ensure completeness and accuracy; once recorded, it can be updated readily. The process of history-taking provides an opportunity to observe the patient’s behavior and to watch for features to be pursued more thoroughly during the physical examination. The very act of eliciting the history provides the physician with an opportunity to establish or enhance the unique bond that forms the basis for the ideal patient-physician relationship. This process helps the physician develop an appreciation of the patient’s view of the illness, the patient’s expectations of the physician and the health care system, and the financial and social implications of the illness for the patient. Although current health care settings may impose time constraints on patient visits, it is important not to rush the history-taking. A hurried approach may lead patients to believe that what they are relating is not of importance to the physician, and thus they may withhold relevant information. The confidentiality of the patient-physician relationship cannot be overemphasized.
The Practice of Medicine
THE PHYSICIAN IN THE TWENTY-FIRST CENTURY No greater opportunity, responsibility, or obligation can fall to the lot of a human being than to become a physician. In the care of the suffering, [the physician] needs technical skill, scientific knowledge, and human understanding.… Tact, sympathy, and understanding are expected of the physician, for the patient is no mere collection of symptoms, signs, disordered functions, damaged organs, and disturbed emotions. [The patient] is human, fearful, and hopeful, seeking relief, help, and reassurance. —Harrison’s Principles of Internal Medicine, 1950
whether a proposed test, preventive measure, or treatment entails a greater risk than the disease itself are essential judgments that a skilled clinician must make many times each day. This combination of medical knowledge, intuition, experience, and judgment defines the art of medicine, which is as necessary to the practice of medicine as is a sound scientific base.
Chapter 1
1
The Practice of Medicine
1
Physical Examination The purpose of the physical examination is to identify physical signs of disease. The significance of these objective indications of disease is enhanced when they confirm a functional or structural change already suggested by the patient’s history. At times, however, physical signs may be the only evidence of disease. The physical examination should be methodical and thorough, with consideration given to the patient’s comfort and modesty. Although attention is often directed by the history to the diseased organ or part of the body, the examination of a new patient must extend from head to toe in an objective search for abnormalities. Unless the physical examination is systematic and is performed consistently from patient to patient, important segments may be omitted inadvertently. The results of the examination, like the details of the history, should be recorded at the time they are elicited—not hours later, when they are subject to the distortions of memory. Skill in physical diagnosis is acquired with experience, but it is not merely technique that determines success in eliciting signs of disease. The detection of a few
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PART 1 General Considerations in Clinical Medicine Figure 1-1 Woodcuts from Johannes de Ketham’s Fasciculus Medicinae, the first illustrated medical text ever printed, show methods of information access and exchange in medical practice during the early Renaissance. Initially published in 1491 for use by medical students and practitioners, Fasciculus Medicinae appeared in six editions over the next 25 years. Left: Petrus de Montagnana, a well-known physician and teacher at the University of Padua and author of an anthology of instructive case studies, consults medical texts dating from antiquity up to the early Renaissance. Right: A patient with plague is attended by a physician and his attendants. (Courtesy, U.S. National Library of Medicine.) scattered petechiae, a faint diastolic murmur, or a small mass in the abdomen is not a question of keener eyes and ears or more sensitive fingers but of a mind alert to those findings. Because physical findings can change with time, the physical examination should be repeated as frequently as the clinical situation warrants. Given the many highly sensitive diagnostic tests now available (particularly imaging techniques), it may be tempting to place less emphasis on the physical examination. Indeed, many patients are seen by consultants after a series of diagnostic tests have been performed and the results are known. This fact should not deter the physician from performing a thorough physical examination since important clinical findings may have escaped detection by the barrage of prior diagnostic tests. The act of examining (touching) the patient also offers an opportunity for communication and may have reassuring effects that foster the patient-physician relationship. Diagnostic Studies Physicians rely increasingly on a wide array of laboratory tests to solve clinical problems. However, accumulated laboratory data do not relieve the physician from the responsibility of carefully observing, examining, and studying the patient. It is also essential to appreciate the limitations of diagnostic tests. By virtue of their impersonal quality, complexity, and apparent precision, they often gain an aura of certainty regardless of the fallibility of the tests themselves, the instruments used in the tests, and the individuals performing or interpreting the tests. Physicians must weigh the expense involved in laboratory procedures against the value of the information these procedures are likely to provide. Single laboratory tests are rarely ordered. Instead, physicians generally request “batteries” of multiple tests, which often prove useful.
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For example, abnormalities of hepatic function may provide the clue to nonspecific symptoms such as generalized weakness and increased fatigability, suggesting a diagnosis of chronic liver disease. Sometimes a single abnormality, such as an elevated serum calcium level, points to a particular disease, such as hyperparathyroidism or an underlying malignancy. The thoughtful use of screening tests (e.g., measurement of lowdensity lipoprotein cholesterol) may be of great value. A group of laboratory values can conveniently be obtained with a single specimen at relatively low cost. Screening tests are most informative when they are directed toward common diseases or disorders and when their results indicate whether other useful—but often costly—tests or interventions are needed. On the one hand, biochemical measurements, together with simple laboratory determinations such as blood count, urinalysis, and erythrocyte sedimentation rate, often provide a major clue to the presence of a pathologic process. On the other hand, the physician must learn to evaluate occasional screening-test abnormalities that do not necessarily connote significant disease. An in-depth workup after the report of an isolated laboratory abnormality in a person who is otherwise well is almost invariably wasteful and unproductive. Because so many tests are performed routinely for screening purposes, it is not unusual for one or two values to be slightly abnormal. Nevertheless, even if there is no reason to suspect an underlying illness, tests yielding abnormal results ordinarily are repeated to rule out laboratory error. If an abnormality is confirmed, it is important to consider its potential significance in the context of the patient’s condition and other test results. The development of technically improved imaging studies with greater sensitivity and specificity proceeds apace. These tests provide remarkably detailed anatomic information that can be a pivotal factor
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Practice Guidelines Many professional organizations and government agencies have developed formal clinical-practice guidelines to aid physicians and other caregivers in making diagnostic and therapeutic decisions that are evidence-based, cost-effective, and most appropriate to a particular patient and clinical situation. As the evidence base of medicine increases, guidelines can provide a useful framework for managing patients with particular diagnoses or symptoms. Clinical guidelines can protect patients— particularly those with inadequate health care benefits—from receiving substandard care. These guidelines also can protect conscientious caregivers from inappropriate charges of malpractice and society from the excessive costs associated with the overuse of medical resources. There are, however, caveats associated with clinical-practice guidelines since they tend to oversimplify the complexities of medicine. Furthermore, groups with different perspectives may develop divergent recommendations regarding issues as basic as the need for screening of women in their forties by mammography or of men over age 50 by serum prostate-specific antigen (PSA) assay. Finally, guidelines, as the term implies, do not—and cannot be expected to—account for the uniqueness of each individual and his or her illness. The physician’s challenge is to integrate into clinical practice the useful recommendations offered by experts without accepting them blindly or being inappropriately constrained by them. Medical Decision-Making Medical decision-making is an important responsibility of the physician and occurs at each stage of the diagnostic and therapeutic process. The decision-making process involves the ordering of additional tests, requests for consultations, and decisions about treatment and predictions concerning prognosis. This process requires an in-depth understanding of the pathophysiology and natural history of disease. As discussed above, medical decision-making should be evidence-based so that patients derive full benefit from the available scientific knowledge. Formulating a differential diagnosis requires not only a broad knowledge base but also the ability to assess the relative probabilities of various diseases. Application of the scientific method, including hypothesis formulation and data collection, is essential to the process of accepting or rejecting a particular diagnosis. Analysis of the differential diagnosis is an iterative process. As new information or test results are acquired, the group of disease processes being considered can be contracted or expanded appropriately. Despite the importance of evidence-based medicine, much medical decision-making relies on good clinical judgment, an attribute that is difficult to quantify or even to assess qualitatively. Physicians must use
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3
The Practice of Medicine
PRINCIPLES OF PATIENT CARE Evidence-Based Medicine Evidence-based medicine refers to the making of clinical decisions that are formally supported by data, preferably data derived from prospectively designed, randomized, controlled clinical trials. This approach is in sharp contrast to anecdotal experience, which is often biased. Unless they are attuned to the importance of using larger, more objective studies for making decisions, even the most experienced physicians can be influenced to an undue extent by recent encounters with selected patients. Evidence-based medicine has become an increasingly important part of routine medical practice and has led to the publication of many practice guidelines.
their knowledge and experience as a basis for weighing known factors, along with the inevitable uncertainties, and then making a sound judgment; this synthesis of information is particularly important when a relevant evidence base is not available. Several quantitative tools may be invaluable in synthesizing the available information, including diagnostic tests, Bayes’ theorem, and multivariate statistical models. Diagnostic tests serve to reduce uncertainty about an individual’s diagnosis or prognosis and help the physician decide how best to manage that individual’s condition. The battery of diagnostic tests complements the history and the physical examination. The accuracy of a particular test is ascertained by determining its sensitivity (true-positive rate) and specificity (true-negative rate) as well as the predictive value of a positive and a negative result. Bayes’ theorem uses information on a test’s sensitivity and specificity, in conjunction with the pretest probability of a diagnosis, to determine mathematically the posttest probability of the diagnosis. More complex clinical problems can be approached with multivariate statistical models, which generate highly accurate information even when multiple factors are acting individually or together to affect disease risk, progression, or response to treatment. Studies comparing the performance of statistical models with that of expert clinicians have documented equivalent accuracy, although the models tend to be more consistent. Thus, multivariate statistical models may be particularly helpful to less experienced clinicians. See Chap. 3 for a more thorough discussion of decisionmaking in clinical medicine.
Chapter 1
in medical decision-making. Ultrasonography, a variety of isotopic scans, CT, MRI, and positron emission tomography have supplanted older, more invasive approaches and opened new diagnostic vistas. In light of their capabilities and the rapidity with which they can lead to a diagnosis, it is tempting to order a battery of imaging studies. All physicians have had experiences in which imaging studies revealed findings that led to an unexpected diagnosis. Nonetheless, patients must endure each of these tests, and the added cost of unnecessary testing is substantial. Furthermore, investigation of an unexpected abnormal finding may be associated with risk and/or expense and may lead to the diagnosis of an irrelevant or incidental problem. A skilled physician must learn to use these powerful diagnostic tools judiciously, always considering whether the results will alter management and benefit the patient.
Electronic Medical Records Both the growing reliance on computers and the strength of information technology now play central roles in medicine. Laboratory data are accessed almost universally through computers. Many medical centers now have electronic medical records, computerized order entry, and bar-coded tracking of medications. Some of these systems are interactive, sending reminders or warning of potential medical errors. Electronic medical records offer rapid access to information that is invaluable in enhancing health care quality and patient safety, including relevant data, historical and clinical information, imaging studies, laboratory results, and medication records. These data can be used to monitor and reduce unnecessary variations in care and to provide real-time information about processes of care and clinical outcomes. Ideally, patient records are easily transferred across the health care system. However, technologic limitations and concerns about privacy and cost continue to limit broad-based use of electronic health records in many clinical settings. As valuable as it is, information technology is merely a tool and can never replace the clinical decisions that are best made by the physician. Clinical knowledge and an understanding of a patient’s needs, supplemented by quantitative tools, still represent the best approach to decision-making in the practice of medicine. Evaluation of Outcomes Clinicians generally use objective and readily measurable parameters to judge the outcome of a therapeutic intervention. These measures may oversimplify the complexity of a clinical condition as patients often present with a major clinical problem in the context of multiple complicating background illnesses. For example, a patient may present with chest pain and cardiac ischemia, but with a background of chronic obstructive pulmonary disease and renal insufficiency. For this reason, outcome measures such as mortality, length of hospital stay, or readmission rates are typically risk-adjusted. An important point is that patients usually seek medical attention for subjective reasons; they wish to obtain relief from pain, to preserve or regain function, and to enjoy life. The components of a patient’s health status or quality of life can include bodily comfort, capacity for physical activity, personal and professional function, sexual function, cognitive function, and overall perception of health. Each of these important areas can be assessed through structured interviews or specially designed questionnaires. Such assessments provide useful parameters by which a physician can judge patients’ subjective views of their disabilities and responses to treatment, particularly in chronic illness. The practice of medicine requires consideration and integration of both objective and subjective outcomes.
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4
PART 1
Women’s Health and Disease Although past epidemiologic studies and clinical trials have often focused predominantly on men, more recent studies have included more women, and some, like the Women’s Health Initiative, have exclusively addressed women’s health issues. Significant sex-based differences exist in diseases that afflict both men and women. Much is still to be learned in this arena, and ongoing studies should enhance physicians’ understanding of the mechanisms underlying these differences in the course and outcome of certain diseases. For a more complete discussion of women’s health, see Chap. 6e.
General Considerations in Clinical Medicine
Care of the Elderly The relative proportion of elderly individuals in the populations of developed nations has grown considerably over the past few decades and will continue to grow. The practice of medicine is greatly influenced by the health care needs of this growing demographic group. The physician must understand and appreciate the decline in physiologic reserve associated with aging; the differences in appropriate doses, clearance, and responses to medications; the diminished responses of the elderly to vaccinations such as those against influenza; the different manifestations of common diseases among the elderly; and the disorders that occur commonly with aging, such as depression, dementia, frailty, urinary incontinence, and fractures. For a more complete discussion of medical care for the elderly, see Chap. 11 and Part 5, Chaps. 93e and 94e. Errors in the Delivery of Health Care A 1999 report from the Institute of Medicine called for an ambitious agenda to reduce medical error rates and improve patient safety by designing and implementing fundamental changes in health care systems. Adverse drug reactions occur in at least 5% of hospitalized patients, and the incidence increases with the use of a large number of drugs. Whatever the clinical situation, it is the physician’s responsibility to use powerful therapeutic measures wisely, with due regard for their beneficial actions, potential dangers, and cost. It is the responsibility of hospitals and health care organizations to develop systems to reduce risk and ensure patient safety. Medication errors can be reduced through the use of ordering systems that rely on electronic processes or, when electronic options are not available, that eliminate misreading of handwriting. Implementation of infection control systems, enforcement of hand-washing protocols, and careful oversight of antibiotic use can minimize the complications of nosocomial infections. Central-line infection rates have been dramatically reduced at many centers by careful adherence of trained personnel to standardized protocols for introducing and maintaining central lines. Rates of surgical infection and wrong-site surgery can likewise be reduced by the use of standardized protocols and checklists. Falls by patients can be minimized by judicious use of sedatives and appropriate assistance with bed-to-chair and bed-to-bathroom transitions. Taken together, these and other measures are saving thousands of lives each year. The Physician’s Role in Informed Consent The fundamental principles of medical ethics require physicians to act in the patient’s best interest and to respect the patient’s autonomy. These requirements are particularly relevant to the issue of informed consent. Patients are required to sign a consent form for essentially any diagnostic or therapeutic procedure. Most patients possess only limited medical knowledge and must rely on their physicians for advice. Communicating in a clear and understandable manner, physicians must fully discuss the alternatives for care and explain the risks, benefits, and likely consequences of each alternative. In every case, the physician is responsible for ensuring that the patient thoroughly understands these risks and benefits; encouraging questions is an important part of this process. This is the very definition of informed consent. Full, clear explanation and discussion of the proposed procedures and treatment can greatly mitigate the fear of the unknown that commonly accompanies hospitalization. Excellent communication can also help alleviate misunderstandings in situations where complications of intervention occur. Often the patient’s understanding is enhanced by repeatedly discussing the issues in an unthreatening and supportive way, answering new questions that occur to the patient as they arise. Special care should be taken to ensure that a physician seeking a patient’s informed consent has no real or apparent conflict of interest involving personal gain.
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The Approach to Grave Prognoses and Death No circumstance is more distressing than the diagnosis of an incurable disease, particularly when premature death is inevitable. What should the patient and family be told? What measures should be taken to maintain life? What can be done to maintain the quality of life? Honesty is absolutely essential in the face of a terminal illness. The patient must be given an opportunity to talk with the physician and ask questions. A wise and insightful physician uses such open communication as the basis for assessing what the patient wants to know and when he or she wants to know it. On the basis of the patient’s responses, the physician can assess the right tempo for sharing information. Ultimately, the patient must understand the expected course of the disease so that appropriate plans and preparations can be made. The patient should participate in decision-making with an understanding of the goal of treatment (palliation) and its likely effects. The patient’s religious beliefs must be taken into consideration. Some patients may find it easier to share their feelings about death with their physician, who is likely to be more objective and less emotional, than with family members. The physician should provide or arrange for emotional, physical, and spiritual support and must be compassionate, unhurried, and open. In many instances, there is much to be gained by the laying on of hands. Pain should be controlled adequately, human dignity maintained, and isolation from family and close friends avoided. These aspects of care tend to be overlooked in hospitals, where the intrusion of life-sustaining equipment can detract from attention to the whole person and encourage concentration instead on the life-threatening disease, against which the battle ultimately will be lost in any case. In the face of terminal illness, the goal of medicine must shift from cure to care in the broadest sense of the term. Primum succurrere, first hasten to help, is a guiding principle. In offering care to a dying patient, a physician must be prepared to provide information to family members and deal with their grief and sometimes their feelings of guilt or even anger. It is important for the doctor to assure the family that everything reasonable has been done. A substantial problem in these discussions is that the physician often does not know how to gauge the prognosis. In addition, various members of the health care team may offer different opinions. Good communication among providers is essential so that consistent information is provided to patients. This is especially important when the best path forward is uncertain. Advice from experts in palliative and terminal care should be sought whenever necessary to ensure that clinicians are not providing patients with unrealistic expectations. For a more complete discussion of endof-life care, see Chap. 10. THE PATIENT-PHYSICIAN RELATIONSHIP The significance of the intimate personal relationship between physician and patient cannot be too strongly emphasized, for in an extraordinarily large number of cases both the diagnosis and treatment are directly dependent on it. One of the essential qualities of the clinician is interest in humanity, for the secret of the care of the patient is in caring for the patient. —Francis W. Peabody, October 21, 1925, Lecture at Harvard Medical School Physicians must never forget that patients are individual human beings with problems that all too often transcend their physical complaints. They are not “cases” or “admissions” or “diseases.” Patients do not fail treatments; treatments fail to benefit patients. This point is particularly important in this era of high technology in clinical medicine. Most patients are anxious and fearful. Physicians should instill confidence and offer reassurance but must never come across as arrogant or patronizing. A professional attitude, coupled with warmth and openness, can do much to alleviate anxiety and to encourage patients to share all aspects of their medical history. Empathy and compassion are the essential features of a caring physician. The physician needs to consider the setting in which an illness occurs—in terms not only of patients themselves but also of their familial, social, and cultural backgrounds. The ideal patient-physician relationship is based on thorough knowledge of the patient, mutual trust, and the ability to communicate.
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Trends in the Delivery of Health Care: A Challenge to the Humane Physician Many trends in the delivery of health care tend to make medical care impersonal. These trends, some of which have been mentioned already, include (1) vigorous efforts to reduce the escalating costs of health care; (2) the growing number of managed-care programs, which are intended to reduce costs but in which the patient may have little choice in selecting a physician or in seeing that physician consistently; (3) increasing reliance on technological advances and computerization for many aspects of diagnosis and treatment; and (4) the need for numerous physicians to be involved in the care of most patients who are seriously ill. In light of these changes in the medical care system, it is a major challenge for physicians to maintain the humane aspects of medical care. The American Board of Internal Medicine, working together with the American College of Physicians–American Society of Internal Medicine and the European Federation of Internal Medicine, has published a Charter on Medical Professionalism that underscores three main principles in physicians’ contract with society: (1) the primacy of patient welfare, (2) patient autonomy, and (3) social justice. While medical schools appropriately place substantial emphasis on professionalism, a physician’s personal attributes, including integrity, respect, and compassion, also are extremely important. Availability to the patient, expression of sincere concern, willingness to take the time to explain all aspects of the illness, and a nonjudgmental attitude when dealing with patients whose cultures, lifestyles, attitudes, and values differ from those of the physician are just a few of the characteristics of a humane physician. Every physician will, at times, be challenged by patients who evoke strongly negative or positive emotional responses. Physicians should be alert to their own reactions to such patients and situations and should consciously monitor and control their behavior so that the patient’s best interest remains the principal motivation for their actions at all times. An important aspect of patient care involves an appreciation of the patient’s “quality of life,” a subjective assessment of what each patient values most. This assessment requires detailed, sometimes intimate knowledge of the patient, which usually can be obtained only through deliberate, unhurried, and often repeated conversations. Time pressures will always threaten these interactions, but they should not diminish the importance of understanding and seeking to fulfill the priorities of the patient.
5
The Practice of Medicine
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Appreciation of the Patient’s Hospital Experience The hospital is an intimidating environment for most individuals. Hospitalized patients find themselves surrounded by air jets, buttons, and glaring lights; invaded by tubes and wires; and beset by the numerous members of the health care team—hospitalists, specialists, nurses, nurses’ aides, physicians’ assistants, social workers, technologists, physical therapists, medical students, house officers, attending and consulting physicians, and many others. They may be transported to special laboratories and imaging facilities replete with blinking lights, strange sounds, and unfamiliar personnel; they may be left unattended at times; and they may be obligated to share a room with other patients who have their own health problems. It is little wonder that a patient’s sense of reality may be compromised. Physicians who appreciate the hospital experience from the patient’s perspective and who make an effort to develop a strong relationship within which they can guide the patient through this experience may make a stressful situation more tolerable.
Chapter 1
The Dichotomy of Inpatient and Outpatient Internal Medicine The hospital environment has changed dramatically over the last few decades. Emergency departments and critical care units have evolved to identify and manage critically ill patients, allowing them to survive formerly fatal diseases. At the same time, there is increasing pressure to reduce the length of stay in the hospital and to manage complex disorders in the outpatient setting. This transition has been driven not only by efforts to reduce costs but also by the availability of new outpatient technologies, such as imaging and percutaneous infusion catheters for long-term antibiotics or nutrition, minimally invasive surgical procedures, and evidence that outcomes often are improved by minimizing inpatient hospitalization. In these circumstances, two important issues arise as physicians cope with the complexities of providing care for hospitalized patients. On the one hand, highly specialized health professionals are essential to the provision of optimal acute care in the hospital; on the other, these professionals—with their diverse training, skills, responsibilities, experiences, languages, and “cultures”—need to work as a team. In addition to traditional medical beds, hospitals now encompass multiple distinct levels of care, such as the emergency department, procedure rooms, overnight observation units, critical care units, and palliative care units. A consequence of this differentiation has been the emergence of new trends, including specialties (e.g., emergency medicine and end-of-life care) and the provision of in-hospital care by hospitalists and intensivists. Most hospitalists are board-certified internists who bear primary responsibility for the care of hospitalized patients and whose work is limited entirely to the hospital setting. The shortened length of hospital stay that is now standard means that most patients receive only acute care while hospitalized; the increased complexities of inpatient medicine make the presence of a generalist with specific training, skills, and experience in the hospital environment extremely beneficial. Intensivists are board-certified physicians who are further certified in critical care medicine and who direct and provide care for very ill patients in critical care units. Clearly, then, an important challenge in internal medicine today is to ensure the continuity of communication and information flow between a patient’s primary care doctor and these physicians who are in charge of the patient’s hospital care. Maintaining these channels of communication is frequently complicated by patient “handoffs”—i.e., from the outpatient to the inpatient environment, from the critical care unit to a general medicine floor, and from the hospital to the outpatient environment. The involvement of many care providers in conjunction with these transitions can threaten the traditional one-to-one relationship between patient and primary care physician. Of course, patients can benefit greatly from effective collaboration among a number of health care professionals; however, it is the duty of the patient’s principal or primary physician to provide cohesive guidance through an illness. To meet this challenge, primary care physicians must be familiar with the techniques, skills, and objectives of specialist physicians and allied health professionals who care for their patients in the hospital. In addition, primary care doctors must ensure that their patients will benefit from scientific advances and from the expertise of specialists when they are needed both in and out of the hospital. Primary care physicians can also explain the role of these specialists to reassure patients that they are in the hands of the physicians best trained to manage an acute illness. However, the primary care physician should retain ultimate responsibility for making major decisions about diagnosis and treatment and should assure patients and their families that decisions are being made in consultation with these specialists by a physician who has an overall and complete perspective on the case. A key factor in mitigating the problems associated with multiple care providers is a commitment to interprofessional teamwork. Despite the diversity in training, skills, and responsibilities among health care professionals, common values need to be reinforced if patient care is not to be adversely affected. This component of effective medical care is widely recognized, and several medical schools have integrated interprofessional teamwork into their curricula. The evolving concept of the “medical home” incorporates team-based primary care with linked subspecialty care in a cohesive environment that ensures smooth transitions of care cost-effectively.
EXPANDING FRONTIERS IN MEDICAL PRACTICE The Era of “Omics”: Genomics, Epigenomics, Proteomics, Microbiomics, Metagenomics, Metabolomics, Exposomics . . . In the spring of 2003, announcement of the complete sequencing of the human genome officially ushered in the genomic era. However, even before that landmark accomplishment, the practice of medicine had been evolving as a result of the insights into both the human genome and the genomes of a wide variety of microbes. The clinical implications of these insights are illustrated by the complete genome sequencing of H1N1 influenza virus in 2009 and the rapid identification of H1N1 influenza as a potentially fatal pandemic illness, with swift development and dissemination of an effective protective vaccine. Today, gene expression profiles are being
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PART 1 General Considerations in Clinical Medicine
used to guide therapy and inform prognosis for a number of diseases, the use of genotyping is providing a new means to assess the risk of certain diseases as well as variations in response to a number of drugs, and physicians are better understanding the role of certain genes in the causality of common conditions such as obesity and allergies. Despite these advances, the use of complex genomics in the diagnosis, prevention, and treatment of disease is still in its early stages. The task of physicians is complicated by the fact that phenotypes generally are determined not by genes alone but by the interplay of genetic and environmental factors. Indeed, researchers have just begun to scratch the surface of the potential applications of genomics in the practice of medicine. Rapid progress also is being made in other areas of molecular medicine. Epigenomics is the study of alterations in chromatin and histone proteins and methylation of DNA sequences that influence gene expression. Every cell of the body has identical DNA sequences; the diverse phenotypes a person’s cells manifest are the result of epigenetic regulation of gene expression. Epigenetic alterations are associated with a number of cancers and other diseases. Proteomics, the study of the entire library of proteins made in a cell or organ and its complex relationship to disease, is enhancing the repertoire of the 23,000 genes in the human genome through alternate splicing, posttranslational processing, and posttranslational modifications that often have unique functional consequences. The presence or absence of particular proteins in the circulation or in cells is being explored for diagnostic and disease-screening applications. Microbiomics is the study of the resident microbes in humans and other mammals. The human haploid genome has ~20,000 genes, while the microbes residing on and in the human body comprise over 3–4 million genes; the contributions of these resident microbes are likely to be of great significance with regard to health status. In fact, research is demonstrating that the microbes inhabiting human mucosal and skin surfaces play a critical role in maturation of the immune system, in metabolic balance, and in disease susceptibility. A variety of environmental factors, including the use and overuse of antibiotics, have been tied experimentally to substantial increases in disorders such as obesity, metabolic syndrome, atherosclerosis, and immune-mediated diseases in both adults and children. Metagenomics, of which microbiomics is a part, is the genomic study of environmental species that have the potential to influence human biology directly or indirectly. An example is the study of exposures to microorganisms in farm environments that may be responsible for the lower incidence of asthma among children raised on farms. Metabolomics is the study of the range of metabolites in cells or organs and the ways they are altered in disease states. The aging process itself may leave telltale metabolic footprints that allow the prediction (and possibly the prevention) of organ dysfunction and disease. It seems likely that disease-associated patterns will be sought in lipids, carbohydrates, membranes, mitochondria, and other vital components of cells and tissues. Finally, exposomics refers to efforts to catalogue and capture environmental exposures such as smoking, sunlight, diet, exercise, education, and violence, which together have an enormous impact on health. All of this new information represents a challenge to the traditional reductionist approach to medical thinking. The variability of results in different patients, together with the large number of variables that can be assessed, creates difficulties in identifying preclinical disease and defining disease states unequivocally. Accordingly, the tools of systems biology and network medicine are being applied to the enormous body of information now obtainable for every patient and may eventually provide new approaches to classifying disease. For a more complete discussion of a complex systems approach to human disease, see Chap. 87e. The rapidity of these advances may seem overwhelming to practicing physicians. However, physicians have an important role to play in ensuring that these powerful technologies and sources of new information are applied with sensitivity and intelligence to the patient. Since “omics” are evolving so rapidly, physicians and other health care professionals must continue to educate themselves so that they can apply this new knowledge to the benefit of their patients’ health and wellbeing. Genetic testing requires wise counsel based on an understanding of the value and limitations of the tests as well as the implications of
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their results for specific individuals. For a more complete discussion of genetic testing, see Chap. 84. The Globalization of Medicine Physicians should be cognizant of diseases and health care services beyond local boundaries. Global travel has implications for disease spread, and it is not uncommon for diseases endemic to certain regions to be seen in other regions after a patient has traveled to and returned from those regions. In addition, factors such as wars, the migration of refugees, and climate change are contributing to changing disease profiles worldwide. Patients have broader access to unique expertise or clinical trials at distant medical centers, and the cost of travel may be offset by the quality of care at those distant locations. As much as any other factor influencing global aspects of medicine, the Internet has transformed the transfer of medical information throughout the world. This change has been accompanied by the transfer of technological skills through telemedicine and international consultation—for example, regarding radiologic images and pathologic specimens. For a complete discussion of global issues, see Chap. 2. Medicine on the Internet On the whole, the Internet has had a very positive effect on the practice of medicine; through personal computers, a wide range of information is available to physicians and patients almost instantaneously at any time and from anywhere in the world. This medium holds enormous potential for the delivery of current information, practice guidelines, state-of-the-art conferences, journal content, textbooks (including this text), and direct communications with other physicians and specialists, expanding the depth and breadth of information available to the physician regarding the diagnosis and care of patients. Medical journals are now accessible online, providing rapid sources of new information. By bringing them into direct and timely contact with the latest developments in medical care, this medium also serves to lessen the information gap that has hampered physicians and health care providers in remote areas. Patients, too, are turning to the Internet in increasing numbers to acquire information about their illnesses and therapies and to join Internet-based support groups. Patients often arrive at a clinic visit with sophisticated information about their illnesses. In this regard, physicians are challenged in a positive way to keep abreast of the latest relevant information while serving as an “editor” as patients navigate this seemingly endless source of information, the accuracy and validity of which are not uniform. A critically important caveat is that virtually anything can be published on the Internet, with easy circumvention of the peer-review process that is an essential feature of academic publications. Both physicians and patients who search the Internet for medical information must be aware of this danger. Notwithstanding this limitation, appropriate use of the Internet is revolutionizing information access for physicians and patients and in this regard represents a remarkable resource that was not available to practitioners a generation ago. Public Expectations and Accountability The general public’s level of knowledge and sophistication regarding health issues has grown rapidly over the last few decades. As a result, expectations of the health care system in general and of physicians in particular have risen. Physicians are expected to master rapidly advancing fields (the science of medicine) while considering their patients’ unique needs (the art of medicine). Thus, physicians are held accountable not only for the technical aspects of the care they provide but also for their patients’ satisfaction with the delivery and costs of care. In many parts of the world, physicians increasingly are expected to account for the way in which they practice medicine by meeting certain standards prescribed by federal and local governments. The hospitalization of patients whose health care costs are reimbursed by the government and other third parties is subjected to utilization review. Thus, a physician must defend the cause for and duration of a patient’s hospitalization if it falls outside certain “average” standards. Authorization for reimbursement increasingly is based on documentation of the nature and complexity of an illness, as reflected by recorded elements of the history and physical examination. A growing “pay-forperformance” movement seeks to link reimbursement to quality of
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The Physician as Perpetual Student From the time doctors graduate from medical school, it becomes all too apparent that their lot is that of the “perpetual student” and that the mosaic of their knowledge and experiences is eternally unfinished. This realization is at the same time exhilarating and anxiety-provoking. It is exhilarating because doctors can apply constantly expanding knowledge to the treatment of their patients; it is anxiety-provoking because doctors realize that they will never know as much as they want or need to know. Ideally, doctors will translate the latter feeling into energy through which they can continue to improve themselves and reach their potential as physicians. It is the physician’s responsibility to pursue new knowledge continually by reading, attending conferences and courses, and consulting colleagues and the Internet. This is often a difficult task for a busy practitioner; however, a commitment to continued learning is an integral part of being a physician and must be given the highest priority. The Physician as Citizen Being a physician is a privilege. The capacity to apply one’s skills for the benefit of one’s fellow human beings is a noble calling. The doctor–patient relationship is inherently unbalanced in the distribution of power. In light of their influence, physicians must always be aware of the potential impact of what they do and say and must always strive to strip away individual biases and preferences to find what is best for the patient. To the extent possible, physicians should also act within their communities to promote health and alleviate suffering. Meeting these goals begins by setting a healthy example and continues in taking action to deliver needed care even when personal financial compensation may not be available. A goal for medicine and its practitioners is to strive to provide the means by which the poor can cease to be unwell. Learning Medicine It has been a century since the publication of the Flexner Report, a seminal study that transformed medical education and emphasized the scientific foundations of medicine as well as the acquisition of clinical skills. In an era of burgeoning information and access to medical simulation and informatics, many schools are implementing new curricula that emphasize lifelong learning and the acquisition of competencies in teamwork, communication skills, system-based practice, and professionalism. These and other features of the medical school curriculum provide the foundation for many of the themes highlighted in this chapter and are expected to allow physicians to progress, with experience and learning over time, from competency to proficiency to mastery. At a time when the amount of information that must be mastered to practice medicine continues to expand, increasing pressures both within and outside of medicine have led to the implementation of restrictions on the amount of time a physician-in-training can spend in the hospital. Because the benefits associated with continuity of medical care and observation of a patient’s progress over time were thought
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7
Global Issues in Medicine
Medical Ethics and New Technologies The rapid pace of technological advance has profound implications for medical applications that go far beyond the traditional goals of disease prevention, treatment, and cure. Cloning, genetic engineering, gene therapy, human–computer interfaces, nanotechnology, and use of designer drugs have the potential to modify inherited predispositions to disease, select desired characteristics in embryos, augment “normal” human performance, replace failing tissues, and substantially prolong life span. Given their unique training, physicians have a responsibility to help shape the debate on the appropriate uses of and limits placed on these new techniques and to consider carefully the ethical issues associated with the implementation of such interventions.
to be outstripped by the stresses imposed on trainees by long hours and by the fatigue-related errors they made in caring for patients, strict limits were set on the number of patients that trainees could be responsible for at one time, the number of new patients they could evaluate in a day on call, and the number of hours they could spend in the hospital. In 1980, residents in medicine worked in the hospital more than 90 hours per week on average. In 1989, their hours were restricted to no more than 80 per week. Resident physicians’ hours further decreased by ~10% between 1996 and 2008, and in 2010 the Accreditation Council for Graduate Medical Education further restricted (i.e., to 16 hours per shift) consecutive in-hospital duty hours for first-year residents. The impact of these changes is still being assessed, but the evidence that medical errors have decreased as a consequence is sparse. An unavoidable by-product of fewer hours at work is an increase in the number of “handoffs” of patient responsibility from one physician to another. These transfers often involve a transition from a physician who knows the patient well, having evaluated that individual on admission, to a physician who knows the patient less well. It is imperative that these transitions of responsibility be handled with care and thoroughness, with all relevant information exchanged and acknowledged.
Chapter 2
care. The goal of this movement is to improve standards of health care and contain spiraling health care costs. In many parts of the United States, managed (capitated) care contracts with insurers have replaced traditional fee-for-service care, placing the onus of managing the cost of all care directly on the providers and increasing the emphasis on preventive strategies. In addition, physicians are expected to give evidence of their current competence through mandatory continuing education, patient record audits, maintenance of certification, and relicensing.
Research, Teaching, and the Practice of Medicine The word doctor is derived from the Latin docere, “to teach.” As teachers, physicians should share information and medical knowledge with colleagues, students of medicine and related professions, and their patients. The practice of medicine is dependent on the sum total of medical knowledge, which in turn is based on an unending chain of scientific discovery, clinical observation, analysis, and interpretation. Advances in medicine depend on the acquisition of new information through research, and improved medical care requires the transmission of that information. As part of their broader societal responsibilities, physicians should encourage patients to participate in ethical and properly approved clinical investigations if these studies do not impose undue hazard, discomfort, or inconvenience. However, physicians engaged in clinical research must be alert to potential conflicts of interest between their research goals and their obligations to individual patients. The best interests of the patient must always take priority. To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and cure of disease—these are our ambitions. —William Osler, 1849–1919
2
Global Issues in Medicine Paul Farmer, Joseph Rhatigan
WHY GLOBAL HEALTH? Global health is not a discipline; it is, rather, a collection of problems. Some scholars have defined global health as the field of study and practice concerned with improving the health of all people and achieving health equity worldwide, with an emphasis on addressing transnational problems. No single review can do much more than identify the leading problems in applying evidence-based medicine in settings of great poverty or across national boundaries. However, this is a moment of opportunity: only recently, persistent epidemics, improved metrics, and growing interest have been matched by an unprecedented investment in addressing the health problems of poor people in the developing world. To ensure that this opportunity is not wasted, the facts need to be laid out for specialists and laypeople alike. This chapter introduces the major international bodies that address health problems; identifies the more significant barriers to improving the health of people who to date have not, by and large, had access
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PART 1
to modern medicine; and summarizes population-based data on the most common health problems faced by people living in poverty. Examining specific problems—notably HIV/AIDS (Chap. 226) but also tuberculosis (TB, Chap. 202), malaria (Chap. 248), and key “noncommunicable” chronic diseases (NCDs)—helps sharpen the discussion of barriers to prevention, diagnosis, and care as well as the means of overcoming them. This chapter closes by discussing global health equity, drawing on notions of social justice that once were central to international public health but had fallen out of favor during the last decades of the twentieth century.
General Considerations in Clinical Medicine
A BRIEF HISTORY OF GLOBAL HEALTH INSTITUTIONS Concern about health across national boundaries dates back many centuries, predating the Black Plague and other pandemics. One of the first organizations founded explicitly to tackle cross-border health issues was the Pan American Sanitary Bureau, which was formed in 1902 by 11 countries in the Americas. The primary goal of what later became the Pan American Health Organization was the control of infectious diseases across the Americas. Of special concern was yellow fever, which had been running a deadly course through much of South and Central America and halted the construction of the Panama Canal. In 1948, the United Nations formed the first truly global health institution: the World Health Organization (WHO). In 1958, under the aegis of the WHO and in line with a long-standing focus on communicable diseases that cross borders, leaders in global health initiated the effort that led to what some see as the greatest success in international health: the eradication of smallpox. Naysayers were surprised when the smallpox eradication campaign, which engaged public health officials throughout the world, proved successful in 1979 despite the ongoing Cold War. At the International Conference on Primary Health Care in AlmaAta (in what is now Kazakhstan) in 1978, public health officials from around the world agreed on a commitment to “Health for All by the Year 2000,” a goal to be achieved by providing universal access to primary health care worldwide. Critics argued that the attainment of this goal by the proposed date was impossible. In the ensuing years, a strategy for the provision of selective primary health care emerged that included four inexpensive interventions collectively known as GOBI: growth monitoring, oral rehydration, breast-feeding, and immunizations for diphtheria, whooping cough, tetanus, polio, TB, and measles. GOBI later was expanded to GOBI-FFF, which also included female education, food, and family planning. Some public health figures saw GOBI-FFF as an interim strategy to achieve “health for all,” but others criticized it as a retreat from the bolder commitments of Alma-Ata. The influence of the WHO waned during the 1980s. In the early 1990s, many observers argued that, with its vastly superior financial resources and its close—if unequal—relationships with the governments of poor countries, the World Bank had eclipsed the WHO as the most important multilateral institution working in the area of health. One of the stated goals of the World Bank was to help poor countries identify “cost-effective” interventions worthy of public funding and international support. At the same time, the World Bank encouraged many of those nations to reduce public expenditures in health and education in order to stimulate economic growth as part of (later discredited) structural adjustment programs whose restrictions were imposed as a condition for access to credit and assistance through international financial institutions such as the World Bank and the International Monetary Fund. There was a resurgence of many diseases, including malaria, trypanosomiasis, and schistosomiasis, in Africa. TB, an eminently curable disease, remained the world’s leading infectious killer of adults. Half a million women per year died in childbirth during the last decade of the twentieth century, and few of the world’s largest philanthropic or funding institutions focused on global health equity. HIV/AIDS, first described in 1981, precipitated a change. In the United States, the advent of this newly described infectious killer marked the culmination of a series of events that discredited talk of “closing the book” on infectious diseases. In Africa, which would emerge as the global epicenter of the pandemic, HIV disease strained TB control programs, and malaria continued to take as many lives as
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ever. At the dawn of the twenty-first century, these three diseases alone killed nearly 6 million people each year. New research, new policies, and new funding mechanisms were called for. The past decade has seen the rise of important multilateral global health financing institutions such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria; bilateral efforts such as the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR); and private philanthropic organizations such as the Bill & Melinda Gates Foundation. With its 193 member states and 147 country offices, the WHO remains important in matters relating to the cross-border spread of infectious diseases and other health threats. In the aftermath of the epidemic of severe acute respiratory syndrome in 2003, the WHO’s International Health Regulations—which provide a legal foundation for that organization’s direct investigation into a wide range of global health problems, including pandemic influenza, in any member state—were strengthened and brought into force in May 2007. Even as attention to and resources for health problems in poor countries grow, the lack of coherence in and among global health institutions may undermine efforts to forge a more comprehensive and effective response. The WHO remains underfunded despite the ever-growing need to engage a wider and more complex range of health issues. In another instance of the paradoxical impact of success, the rapid growth of the Gates Foundation, which is one of the most important developments in the history of global health, has led some foundations to question the wisdom of continuing to invest their more modest resources in this field. This indeed may be what some have called “the golden age of global health,” but leaders of major organizations such as the WHO, the Global Fund, the United Nations Children’s Fund (UNICEF), the Joint United Nations Programme on HIV/AIDS (UNAIDS), PEPFAR, and the Gates Foundation must work together to design an effective architecture that will make the most of opportunities to link new resources for and commitments to global health equity with the emerging understanding of disease burden and unmet need. To this end, new and old players in global health must invest heavily in discovery (relevant basic science), development of new tools (preventive, diagnostic, and therapeutic), and modes of delivery that will ensure the equitable provision of health products and services to all who need them.
THE ECONOMICS OF GLOBAL HEALTH Political and economic concerns have often guided global health interventions. As mentioned, early efforts to control yellow fever were tied to the completion of the Panama Canal. However, the precise nature of the link between economics and health remains a matter for debate. Some economists and demographers argue that improving the health status of populations must begin with economic development; others maintain that addressing ill health is the starting point for development in poor countries. In either case, investment in health care, especially the control of communicable diseases, should lead to increased productivity. The question is where to find the necessary resources to start the predicted “virtuous cycle.” During the past two decades, spending on health in poor countries has increased dramatically. According to a study from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, total development assistance for health worldwide grew to $28.2 billion in 2010—up from $5.6 billion in 1990. In 2010, the leading contributors included U.S. bilateral agencies such as PEPFAR, the Global Fund, nongovernmental organizations (NGOs), the WHO, the World Bank, and the Gates Foundation. It appears, however, that total development assistance for health plateaued in 2010, and it is unclear whether growth will continue in the upcoming decade. To reach the United Nations Millennium Development Goals, which include targets for poverty reduction, universal primary education, and gender equality, spending in the health sector must be increased above the 2010 levels. To determine by how much and for how long, it is imperative to improve the ability to assess the global burden of disease and to plan interventions that more precisely match need.
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MORTALITY AND THE GLOBAL BURDEN OF DISEASE
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Global Issues in Medicine
GLOBAL MORTALITY Of the 52.8 million deaths worldwide in 2010, 24.6% (13 million) were due to communicable diseases, maternal and perinatal conditions, and nutritional deficiencies—a marked decrease compared with figures for 1990, when these conditions accounted for 34% of global mortality. Among the fraction of all deaths related to communicable diseases, maternal and perinatal conditions, and nutritional deficiencies, 76% occurred in subSaharan Africa and southern Asia. While the proportion of deaths due to these conditions has decreased significantly in the past decade, there has been a dramatic rise in the number of deaths from NCDs, which constituted the top five causes of death in 2010. The leading cause of death among adults in 2010 was ischemic heart disease, accounting for 7.3 million deaths (13.8% of total deaths) worldwide. In high-income countries ischemic heart disease accounted for 17.9% of total deaths, and in developing (low- and middle-income) countries it accounted for 10.1%. It is noteworthy that ischemic heart disease was responsible for just 2.6% of total deaths in sub-Saharan Africa (Table 2-2). In second place—causing 11.1% of global mortality—was cerebrovascular disease, which accounted for 9.9% of deaths in high-income countries, 10.5% in developing countries, and 4.0% in sub-Saharan Africa. Although the third leading cause of death in high-income countries was lung cancer (accounting for 5.6% of all deaths), this condition did not figure among the top 10 causes in low- and middle-income countries. Among the 10 leading causes of death in sub-Saharan Africa, 6 were infectious diseases, with malaria and HIV/AIDS ranking as the dominant contributors to disease burden. In high-income countries, however, only one infectious disease—lower respiratory infection—ranked among the top 10 causes of death. The GBD 2010 found that the worldwide mortality figure among children 18 Women, childbearing age
Every 10 years Two doses One dose
>65 >50 Boys >21 Girls >26 >60
One dose Yearly If not done prior
Chapter 148, 149
Once
Men 45–79 Women 55–79 Women planning or capable of pregnancy Women at high risk for breast cancer >65 at increased risk for falls
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Screening Prevention Interventions to Consider for Each Specific Population • Counseling on routine seat belt use, bicycle/motorcycle/ATV helmets (1) • Counseling on diet and exercise (5) • Discuss dangers of alcohol use while driving, swimming, boating (1) • Assess and update vaccination status (tetanus, diphtheria, hepatitis B, MMR, rubella, varicella, meningitis, HPV) • Ask about gun use and/or gun possession (2,3) • Assess for substance abuse history including alcohol (2,3) • Screen for domestic violence (2,3) • Screen for depression and/or suicidal/homicidal ideation (2,3) • Pap smear for cervical cancer screening after age 21 (4) • Discuss skin, breast awareness, and testicular self-exams (4) • Recommend UV light avoidance and regular sunscreen use (4) • Measurement of blood pressure, height, weight, and body mass index (5) • Discuss health risks of tobacco use, consider emphasis on cosmetic and economic issues to improve quit rates for younger smokers (4,5) • Chlamydia and gonorrhea screening and contraceptive counseling for sexually active females, discuss STD prevention • Hepatitis B, and syphilis testing if there is high-risk sexual behavior(s) or any prior history of sexually transmitted disease • HIV testing • Continue annual influenza vaccination
5. Heart disease
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Leading Causes of Age-Specific Mortality 1. Accident 2. Homicide 3. Suicide 4. Malignancy
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to enhance adherence to routine screening. Systems that provide nurses and other staff with standing orders are effective for smoking prevention and immunizations. The Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention have developed flow sheets and electronic tools as part of their “Put Prevention into Practice” program (http://www.uspreventiveservicestaskforce.org/ tools.htm). Many of these tools use age categories to help guide implementation. Age-specific recommendations for screening and counseling are summarized in Table 4-7. Many patients see a physician for ongoing care of chronic illnesses, and this visit provides an opportunity to include a “measure of prevention” for other health problems. For example, a patient seen for management of hypertension or diabetes can have breast cancer screening incorporated into one visit and a discussion about colon cancer screening at the next visit. Other patients may respond more favorably to a clearly defined visit that addresses all relevant screening and prevention interventions. Because of age or comorbidities, it may be appropriate with some patients to abandon certain screening and prevention activities, although there are fewer data about when to “sunset” these services. For many screening tests, the benefit of screening does not accrue until 5 to 10 years of follow-up, and there are generally few data to support continuing screening for most diseases past age 75. In addition, for patients with advanced diseases and limited life expectancy, there is considerable benefit from shifting the focus from screening procedures to the conditions and interventions more likely to affect quality and length of life.
IMPLEMENTIN ISEASE PREVENTI N AN SCREENIN The implementation of disease prevention and screening strategies in practice is challenging. A number of techniques can assist physicians with the delivery of these services. An appropriately configured electronic health record can provide reminder systems that make it easier for physicians to track and meet guidelines. Some systems give patients secure access to their medical records, providing an additional means
BL 4-7
BL 4-6
Topic Alcohol and drug use Genetic counseling for BRCA1/2 testing among women at increased risk for deleterious mutations Nutrition and diet Sexually transmitted infections Sun exposure Tobacco use
C UNSELIN N HEALTHY BEHAVI RS In considering the impact of preventive services, it is important to recognize that tobacco and alcohol use, diet, and exercise constitute the vast majority of factors that influence preventable deaths in developed countries. Perhaps the single greatest preventive health care measure is to help patients quit smoking (Chap. 470). However, efforts in these areas frequently involve behavior changes (e.g., weight loss, exercise, seat belts) or the management of addictive conditions (e.g., tobacco and alcohol use) that are often recalcitrant to intervention. Although these are challenging problems, evidence strongly supports the role of counseling by health care providers (Table 4-6) in effecting health behavior change. Educational campaigns, public policy changes, and community-based interventions have also proven to be important parts of a strategy for addressing these factors in some settings. Although the USPSTF found that the evidence was conclusive to recommend a relatively small set of counseling activities, counseling in areas such as physical activity and injury prevention (including seat belts and bicycle and motorcycle helmets) has become a routine part of primary care practice. G
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shared decision-making involves the choice of techniques for colon cancer screening (Chap. 100). In controlled studies, the use of annual FOBT reduces colon cancer deaths by 15–30%. Flexible sigmoidoscopy reduces colon cancer deaths by ~60%. Colonoscopy offers the same benefit as or greater benefit than flexible sigmoidoscopy, but its use incurs additional costs and risks. These screening procedures have not been compared directly in the same population, but the estimated cost to society is similar: $10,000–25,000 per year of life saved. Thus, although one patient may prefer the ease of preparation, less time disruption, and the lower risk of flexible sigmoidoscopy, others may prefer the sedation and thoroughness of colonoscopy. O
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Suicide Heart disease Malignancy Cerebrovascular disease Chronic lower respiratory disease Alzheimer’s disease Influenza and pneumonia Diabetes mellitus Kidney disease Accidents Septicemia
As above plus consider the following: • Readdress smoking status, encourage cessation at every visit (1,2,3,4) • One-time ultrasound for AAA in men 65–75 who have ever smoked • Consider pulmonary function testing for all long-term smokers to assess for development of chronic obstructive pulmonary disease (4,6)
4.
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4. Diabetes mellitus 5. Cerebrovascular disease 6. Chronic lower respi- • Zoster vaccination at age 60 ratory disease 7. Chronic liver disease • Begin mammography screening by age 50 and cirrhosis
7. 8. 9. 10.
6. HIV 1. Malignancy
As above plus consider the following: • Readdress smoking status, encourage cessation at every visit (2,3) • Obtain detailed family history of malignancies and begin early screening/prevention program if patient is at significant increased risk (2) • Assess all cardiac risk factors (including screening for diabetes and hyperlipidemia) and consider primary prevention with aspirin for patients at >3% 5-year risk of a vascular event (3) • Assess for chronic alcohol abuse, risk factors for viral hepatitis, or other risks for development of chronic liver disease • Consider individualized breast cancer screening with mammography at age 40 (2) • Consider prostate cancer screen with annual PSA and digital rectal exam at age 50 (or possibly earlier in African Americans or patients with family history) (1) • Begin colorectal cancer screening at age 50 with fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy (1) • Reassess and update vaccination status at age 50 and vaccinate all smokers against S. pneumoniae at age 50 (6) • Consider screening for coronary disease in higher-risk patients (2,5) • Consider screening for hepatitis C in adults born between 1945 and 1965 (7)
5. Homicide
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Principles of Clinical Pharmacology
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Leading Causes of Age-Specific Mortality Screening Prevention Interventions to Consider for Each Specific Population
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• Screen all postmenopausal women (and all men with risk factors) for osteoporosis • Continue annual influenza vaccination and vaccinate against S. pneumoniae at age 65 (4, 6) • Screen for dementia and depression (5) • Screen for visual and hearing problems, home safety issues, and elder abuse (9)
Note: The numbers in parentheses refer to areas of risk in the mortality column affected by the specified intervention.
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Abbreviations: AAA, abdominal aortic aneurysm; ATV, all-terrain vehicle; HPV, human papillomavirus; MMR, measles-mumps-rubella; PSA, prostate-specific antigen; STD, sexually transmitted disease; UV, ultraviolet.
rinciples of Clinical harmacology
Dan M. Roden
Drugs are the cornerstone of modern therapeutics. Nevertheless, it is well recognized among physicians and in the lay community that the outcome of drug therapy varies widely among individuals. While this variability has been perceived as an unpredictable, and therefore inevitable, accompaniment of drug therapy, this is not the case. The goal of this chapter is to describe the principles of clinical pharmacology that can be used for the safe and optimal use of available and new drugs. Drugs interact with specific target molecules to produce their beneficial and adverse effects. The chain of events between administration of a drug and production of these effects in the body can be divided into two components, both of which contribute to variability in drug actions. The first component comprises the processes that determine drug delivery to, and removal from, molecular targets. The resulting description of the relationship between drug concentration and time
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is termed pharmacokinetics. The second component of variability in drug action comprises the processes that determine variability in drug actions despite equivalent drug delivery to effector drug sites. This description of the relationship between drug concentration and effect is termed pharmacodynamics. As discussed further below, pharmacodynamic variability can arise as a result of variability in function of the target molecule itself or of variability in the broad biologic context in which the drug-target interaction occurs to achieve drug effects. Two important goals of the discipline of clinical pharmacology are (1) to provide a description of conditions under which drug actions vary among human subjects; and (2) to determine mechanisms underlying this variability, with the goal of improving therapy with available drugs as well as pointing to new drug mechanisms that may be effective in the treatment of human disease. The first steps in the discipline were empirical descriptions of the influence of disease on drug actions and of individuals or families with unusual sensitivities to adverse drug effects. These important descriptive findings are now being replaced by an understanding of the molecular mechanisms underlying variability in drug actions. Thus, the effects of disease, drug coadministration, or familial factors in modulating drug action can now be reinterpreted as variability in expression or function of specific genes whose products
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Adverse Effects Some adverse effects are so common and so readily associated with drug therapy that they are identified very early during clinical use of a drug. By contrast, serious adverse effects may be sufficiently uncommon that they escape detection for many years after a drug begins to be widely used. The issue of how to identify rare but serious adverse effects (that can profoundly affect the benefit-risk perception in an individual patient) has not been satisfactorily resolved. Potential approaches range from an increased understanding of the molecular and genetic basis of variability in drug actions to expanded postmarketing surveillance mechanisms. None of these have been completely effective, so practitioners must be continuously vigilant to the possibility that unusual symptoms may be related to specific drugs, or combinations of drugs, that their patients receive.
Therapeutic Index Beneficial and adverse reactions to drug therapy can be described by a series of dose-response relations (Fig. 5-1). Welltolerated drugs demonstrate a wide margin, termed the therapeutic ratio, therapeutic index, or therapeutic window, between the doses required to produce a therapeutic effect and those producing toxicity. In cases where there is a similar relationship between plasma drug concentration and effects, monitoring plasma concentrations can be a highly effective aid in managing drug therapy by enabling concentrations to be maintained above the minimum required to produce an effect and below the concentration range likely to produce toxicity. Such monitoring has been widely used to guide therapy with specific agents, such as certain antiarrhythmics, anticonvulsants, and antibiotics. Many of the principles in clinical pharmacology and examples 100 50
Wide therapeutic ratio
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Fg 5-1 The concept of a therapeutic ratio. Each panel illustrates the relationship between increasing dose and cumulative probability of a desired or adverse drug effect. Top. A drug with a wide therapeutic ratio, i.e., a wide separation of the two curves. Bottom. A drug with a narrow therapeutic ratio; here, the likelihood of adverse effects at therapeutic doses is increased because the curves are not well separated. Further, a steep dose-response curve for adverse effects is especially undesirable, as it implies that even small dosage increments may sharply increase the likelihood of toxicity. When there is a definable relationship between drug concentration (usually measured in plasma) and desirable and adverse effect curves, concentration may be substituted on the abscissa. Note that not all patients necessarily demonstrate a therapeutic response (or adverse effect) at any dose, and that some effects (notably some adverse effects) may occur in a dose-independent fashion. i
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L BAL C NSI ERATI NS It is true across all cultures and diseases that factors such as compliance, genetic variants affecting pharmacokinetics or pharmacodynamics, and drug interactions contribute to drug responses. In addition, culture- or ancestry-specific factors play a role. For example, the frequency of specific genetic variants modulating drug responses often varies by ancestry, as discussed later. Cost issues or cultural factors may determine the likelihood that specific drugs, drug combinations, or over-the-counter (OTC) remedies are prescribed. The broad principles of clinical pharmacology enunciated here can be used to analyze the mechanisms underlying successful or unsuccessful therapy with any drug.
a symptom and those designed to prolong useful life. An increasing emphasis on the principles of evidence-based medicine and techniques such as large clinical trials and meta-analyses have defined benefits of drug therapy in broad patient populations. Establishing the balance between risk and benefit is not always simple. An increasing body of evidence supports the idea, with which practitioners are very familiar, that individual patients may display responses that are not expected from large population studies and often have comorbidities that typically exclude them from large clinical trials. In addition, therapies that provide symptomatic benefits but shorten life may be entertained in patients with serious and highly symptomatic diseases such as heart failure or cancer. These considerations illustrate the continuing, highly personal nature of the relationship between the prescriber and the patient.
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I ENTIFYIN RU TAR ETS Drug therapy is an ancient feature of human culture. The first treatments were plant extracts discovered empirically to be effective for indications like fever, pain, or breathlessness. This symptom-based empiric approach to drug development was supplanted in the twentieth century by identification of compounds targeting more fundamental biologic processes such as bacterial growth or elevated blood pressure; the term “magic bullet,” coined by Paul Ehrlich to describe the search for effective compounds for syphilis, captures the essence of the hope that understanding basic biologic processes will lead to highly effective new therapies. An integral step in modern drug development follows identification of a chemical lead with biologic activity with increasingly sophisticated medicinal chemistry-based structural modifications to develop compounds with specificity for the chosen target, lack of “off-target” effects, and pharmacokinetic properties suitable for human use (e.g., consistent bioavailability, long elimination half-life, no high-risk pharmacokinetic features described further below). A common starting point for contemporary drug development is basic biologic discovery that implicates potential target molecules: examples of such target molecules include HMG-CoA reductase or the BRAF V600E mutation in many malignant melanomas. The development of compounds targeting these molecules has not only revolutionized treatment for diseases such as hypercholesterolemia or malignant melanoma, but has also revealed new biologic features of disease. Thus, for example, initial spectacular successes with vemurafenib (which targets BRAF V600E) were followed by near-universal tumor relapse, strongly suggesting that inhibition of this pathway alone would be insufficient for tumor control. This reasoning, in turn, supports a view that many complex diseases will not lend themselves to cure by targeting a single magic bullet, but rather single drugs or combinations will need to attack multiple pathways whose perturbation results in disease. The use of combination therapy in settings such as hypertension, tuberculosis, HIV infection, and many cancers highlights potential for such a “systems biology” view of drug therapy. G
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determine pharmacokinetics and pharmacodynamics. Nevertheless, it is often the personal interaction of the patient with the physician or other health care provider that first identifies unusual variability in drug actions; maintained alertness to unusual drug responses continues to be a key component of improving drug safety. Unusual drug responses, segregating in families, have been recognized for decades and initially defined the field of pharmacogenetics. Now, with an increasing appreciation of common and rare polymorphisms across the human genome, comes the opportunity to reinterpret descriptive mechanisms of variability in drug action as a consequence of specific DNA variants, or sets of variants, among individuals. This approach defines the field of pharmacogenomics, which may hold the opportunity of allowing practitioners to integrate a molecular understanding of the basis of disease with an individual’s genomic makeup to prescribe personalized, highly effective, and safe therapies. D
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outlined below, which can be applied broadly to therapeutics, have been developed in these arenas.
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Principles of Clinical Pharmacology
“First-Pass” Effect When a drug is administered orally, it must traverse the intestinal epithelium, the portal venous system, and the liver prior
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Fg 5-3 Mechanism of presystemic clearance. After drug enters the enterocyte, it can undergo metabolism, excretion into the intestinal lumen, or transport into the portal vein. Similarly, the hepatocyte may accomplish metabolism and biliary excretion prior to the entry of drug and metabolites to the systemic circulation. (Adapted by permission from DM Roden, in DP Zipes, J Jalife [eds]: Cardiac Electrophysiology: From Cell to Bedside, 4th ed. Philadelphia, Saunders, 2003. Copyright 2003 with permission from Elsevier.) i
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ABS RPTI N AN BI AVAILABILITY When a drug is administered orally, subcutaneously, intramuscularly, rectally, sublingually, or directly into desired sites of action, the amount of drug actually entering the systemic circulation may be less than with the intravenous route (Fig. 5-2A). The fraction of drug available to the systemic circulation by other routes is termed bioavailability. Bioavailability may be 20 mEq/L should be avoided in all but the most exceptional and carefully monitored circumstances. This minimizes the possibility of cardiac arrest due to accidental increases in infusion rates of more concentrated solutions. Transiently high drug concentrations after rapid intravenous administration can occasionally be used to advantage. The use of midazolam for intravenous sedation, for example, depends upon its rapid uptake by the brain during the distribution phase to produce sedation quickly, with subsequent egress from the brain during the redistribution of the drug as equilibrium is achieved. Similarly, adenosine must be administered as a rapid bolus in the treatment of reentrant supraventricular tachycardias (Chap. 276) to prevent elimination by very rapid (t1/2 of seconds) uptake into erythrocytes and endothelial cells before the drug can reach its clinical site of action, the atrioventricular node.
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When drug is administered orally, the average plasma concentration within a dosing interval (Cavg,ss ) replaces Css , and the dosage (dose per unit time) must be increased if bioavailability (F) is less than 1:
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Css = dosing rate/Cl
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Clinical Implications of Altered Clearance While elimination half-life determines the time required to achieve steady-state plasma concentration (Css), the magnitude of that steady state is determined by clearance (Cl) and dose alone. For a drug administered as an intravenous infusion, this relationship is:
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Fg 5-4 Drug accumulation to steady state. In this simulation, drug was administered (arrows) at intervals = 50% of the elimination half-life. Steady state is achieved during initiation of therapy after ∼5 elimination half-lives, or 10 doses. A loading dose did not alter the eventual steady state achieved. A doubling of the dose resulted in a doubling of the steady state but the same time course of accumulation. Once steady state is achieved, a change in dose (increase, decrease, or drug discontinuation) results in a new steady state in ∼5 elimination half-lives. (Adapted by permission from DM Roden, in DP Zipes, J Jalife [eds]: Cardiac Electrophysiology: From Cell to Bedside, 4th ed. Philadelphia, Saunders, 2003. Copyright 2003 with permission from Elsevier.)
ELIMINATI N Drug elimination reduces the amount of drug in the body over time. An important approach to quantifying this reduction is to consider that drug concentrations at the beginning and end of a time period are unchanged and that a specific volume of the body has been “cleared” of the drug during that time period. This defines clearance as volume/ time. Clearance includes both drug metabolism and excretion.
Principles of Clinical Pharmacology
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Chapter 5
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response is related to the free rather than the total circulating plasma drug concentration. In chronic kidney or liver disease, protein binding may be decreased and thus drug actions increased. In some situations (myocardial infarction, infection, surgery), acute phase reactants transiently increase drug binding and thus decrease efficacy. These changes assume the greatest clinical importance for drugs that are highly protein-bound since even a small change in protein binding can result in large changes in free drug; for example, a decrease in binding from 99% to 98% doubles the free drug concentration from 1% to 2%. For some drugs (e.g., phenytoin), monitoring free rather than total drug concentrations can be useful. O
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PRINCIPLES F SE SELECTI N The desired goal of therapy with any drug is to maximize the likelihood of a beneficial effect while minimizing the risk of adverse effects. Previous experience with the drug, in controlled clinical trials or in postmarketing use, defines the relationships between dose or plasma concentration and these dual effects (Fig. 5-1) and has important implications for initiation of drug therapy:
1. The target drug effect should be defined when drug treatment is started. With some drugs, the desired effect may be difficult to measure objectively, or the onset of efficacy can be delayed for weeks or months; drugs used in the treatment of cancer and psychiatric disease are examples. Sometimes a drug is used to treat a symptom, such as pain or palpitations, and here it is the patient who will report whether the selected dose is effective. In yet other settings,
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Failure of Efficacy Assuming the diagnosis is correct and the correct drug is prescribed, explanations for failure of efficacy include drug interactions, noncompliance, or unexpectedly low drug dosage due to administration of expired or degraded drug. These are situations in which measurement of plasma drug concentrations, if available, can be especially useful. Noncompliance is an especially frequent problem in the long-term treatment of diseases such as hypertension and epilepsy, occurring in ≥25% of patients in therapeutic environments in which no special effort is made to involve patients in the responsibility for their own health. Multidrug regimens with multiple doses per day are especially prone to noncompliance. Monitoring response to therapy, by physiologic measures or by plasma concentration measurements, requires an understanding of the relationships between plasma concentration and anticipated effects. For example, measurement of QT interval is used during treatment with sotalol or dofetilide to avoid marked QT prolongation that can herald serious arrhythmias. In this setting, evaluating the electrocardiogram at the time of anticipated peak plasma concentration and effect (e.g., 1–2 h postdose at steady state) is most appropriate. Maintained high vancomycin levels carry a risk of nephrotoxicity, so dosages should be adjusted on the basis of plasma concentrations measured at trough (predose). Similarly, for dose adjustment of other drugs (e.g., anticonvulsants), concentration should be measured at its lowest during the dosing interval, just prior to a dose at steady state (Fig. 5-4), to ensure a maintained therapeutic effect.
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Concentration of rugs in Plasma as a uide to Therapy Factors such as interactions with other drugs, disease-induced alterations in elimination and distribution, and genetic variation in drug disposition combine to yield a wide range of plasma levels in patients given the same dose. Hence, if a predictable relationship can be established between plasma drug concentration and beneficial or adverse drug effect, measurement of plasma levels can provide a valuable tool to guide selection of an optimal dose, especially when there is a narrow range between the plasma levels yielding therapeutic and adverse effects. Monitoring is commonly used with certain types of drugs including many anticonvulsants, antirejection agents, antiarrhythmics, and antibiotics. By contrast, if no such relationship can be established (e.g., if drug access to important sites of action outside plasma is highly variable), monitoring plasma concentration may not provide an accurate guide to therapy (Fig. 5-5A). The common situation of first-order elimination implies that average, maximum, and minimum steady-state concentrations are related linearly to the dosing rate. Accordingly, the maintenance dose may be adjusted on the basis of the ratio between the desired and measured concentrations at steady state; for example, if a doubling of the steady-state plasma concentration is desired, the dose should be doubled. This does not apply to drugs eliminated by zero-order kinetics (fixed amount per unit time), where small dosage increases will produce disproportionate increases in plasma concentration; examples include phenytoin and theophylline. D
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rug Effects May Be isease Specific A drug may produce no action or a different spectrum of actions in unaffected individuals compared to patients with underlying disease. Further, concomitant disease can complicate interpretation of response to drug therapy, especially adverse effects. For example, high doses of anticonvulsants such as phenytoin may cause neurologic symptoms, which may be confused with the underlying neurologic disease. Similarly, increasing dyspnea in a patient with chronic lung disease receiving amiodarone therapy could be due to drug, underlying disease, or an intercurrent cardiopulmonary problem. Thus, the presence of chronic lung disease may argue against the use of amiodarone. While drugs interact with specific molecular receptors, drug effects may vary over time, even if stable drug and metabolite concentrations are maintained. The drug-receptor interaction occurs in a complex biologic milieu that can vary to modulate the drug effect. For example, ion channel blockade by drugs, an important anticonvulsant and antiarrhythmic effect, is often modulated by membrane potential, itself a function of factors such as extracellular potassium or local ischemia. Receptors may be up- or downregulated by disease or by the drug itself. For example, β-adrenergic blockers upregulate β-receptor density during chronic therapy. While this effect does not usually result in resistance to the therapeutic effect of the drugs, it may produce severe agonist-mediated effects (such as hypertension or tachycardia) if the blocking drug is abruptly withdrawn.
such as anticoagulation or hypertension, the desired response can be repeatedly and objectively assessed by simple clinical or laboratory tests. 2. The nature of anticipated toxicity often dictates the starting dose. If side effects are minor, it may be acceptable to start chronic therapy at a dose highly likely to achieve efficacy and down-titrate if side effects occur. However, this approach is rarely, if ever, justified if the anticipated toxicity is serious or life-threatening; in this circumstance, it is more appropriate to initiate therapy with the lowest dose that may produce a desired effect. In cancer chemotherapy, it is common practice to use maximum-tolerated doses. 3. The above considerations do not apply if these relationships between dose and effects cannot be defined. This is especially relevant to some adverse drug effects (discussed in further detail below) whose development are not readily related to drug dose. 4. If a drug dose does not achieve its desired effect, a dosage increase is justified only if toxicity is absent and the likelihood of serious toxicity is small.
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PRINCIPLES F PHARMAC YNAMICS The nset of rug Action For drugs used in the urgent treatment of acute symptoms, little or no delay is anticipated (or desired) between the drug-target interaction and the development of a clinical effect. Examples of such acute situations include vascular thrombosis, shock, or status epilepticus. For many conditions, however, the indication for therapy is less urgent, and a delay between the interaction of a drug with its pharmacologic target(s) and a clinical effect is clinically acceptable. Common pharmacokinetic mechanisms that can contribute to such a delay include slow elimination (resulting in slow accumulation to steady state), uptake into peripheral compartments, or accumulation of active metabolites. Another common explanation for such a delay is that the clinical effect develops as a downstream consequence of the initial molecular effect the drug produces. Thus, administration of a proton pump inhibitor or an H2-receptor blocker produces an immediate increase in gastric pH but ulcer healing that is delayed. Cancer chemotherapy similarly produces delayed therapeutic effects. D
PART 1
a single pathway. In this case, inhibition of the elimination pathway by genetic variants or by administration of inhibiting drugs leads to marked elevation of drug concentration and, for drugs with a narrow therapeutic window, an increased likelihood of dose-related toxicity. Individuals with loss-of-function alleles in CYP2C9, responsible for metabolism of the active S-enantiomer of warfarin, appear to be at increased risk for bleeding. When drugs undergo elimination by multiple-drug metabolizing or excretory pathways, absence of one pathway (due to a genetic variant or drug interaction) is much less likely to have a large impact on drug concentrations or drug actions.
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Normal P-glycoprotein function 5
Plasma 3 2 1
Brain
Concentration
0
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Time Decreased P-glycoprotein function 5 4 Plasma 3 2
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1 0 0
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50 64/min
40 30 20
84/min 10 0 0
7.5
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Figure 5-5 A. The efflux pump P-glycoprotein excludes drugs from the endothelium of capillaries in the brain and so constitutes a key element of the blood-brain barrier. Thus, reduced P-glycoprotein function (e.g., due to drug interactions or genetically determined variability in gene transcription) increases penetration of substrate drugs into the brain, even when plasma concentrations are unchanged. B. The graph shows an effect of a β1-receptor polymorphism on receptor function in vitro. Patients with the hypofunctional variant (red) may display lesser heartrate slowing or blood pressure lowering on exposure to a receptor blocking agent. An increase in dosage is usually best achieved by changing the drug dose but not the dosing interval (e.g., by giving 200 mg every 8 h instead of 100 mg every 8 h). However, this approach is acceptable only if the resulting maximum concentration is not toxic and the trough value does not fall below the minimum effective concentration for an undesirable period of time. Alternatively, the steady state may be changed by altering the frequency of intermittent dosing but not the size of each dose. In this case, the magnitude of the fluctuations around the average steady-state level will change—the shorter the dosing interval, the smaller the difference between peak and trough levels.
EFFECTS OF DISEASE ON DRUG CONCENTRATION AND RESPONSE Renal disease Renal excretion of parent drug and metabolites is generally accomplished by glomerular filtration and by specific drug transporters. If a drug or its metabolites are primarily excreted through the kidneys
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Principles of Clinical Pharmacology
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4
and increased drug levels are associated with adverse effects, drug dosages must be reduced in patients with renal dysfunction to avoid toxicity. The antiarrhythmics dofetilide and sotalol undergo predominant renal excretion and carry a risk of QT prolongation and arrhythmias if doses are not reduced in renal disease. In end-stage renal disease, sotalol has been given as 40 mg after dialysis (every second day), compared to the usual daily dose, 80–120 mg every 12 h. The narcotic analgesic meperidine undergoes extensive hepatic metabolism, so that renal failure has little effect on its plasma concentration. However, its metabolite, normeperidine, does undergo renal excretion, accumulates in renal failure, and probably accounts for the signs of CNS excitation, such as irritability, twitching, and seizures, that appear when multiple doses of meperidine are administered to patients with renal disease. Protein binding of some drugs (e.g., phenytoin) may be altered in uremia, so measuring free drug concentration may be desirable. In non-end-stage renal disease, changes in renal drug clearance are generally proportional to those in creatinine clearance, which may be measured directly or estimated from the serum creatinine (Chap. 333e). This estimate, coupled with the knowledge of how much drug is normally excreted renally versus nonrenally, allows an estimate of the dose adjustment required. In practice, most decisions involving dosing adjustment in patients with renal failure use published recommended adjustments in dosage or dosing interval based on the severity of renal dysfunction indicated by creatinine clearance. Any such modification of dose is a first approximation and should be followed by plasma concentration data (if available) and clinical observation to further optimize therapy for the individual patient.
Liver disease Standard tests of liver function are not useful in adjusting doses in diseases like hepatitis or cirrhosis. First-pass metabolism may decrease, leading to increased oral bioavailability as a consequence of disrupted hepatocyte function, altered liver architecture, and portacaval shunts. The oral bioavailability for high first-pass drugs such as morphine, meperidine, midazolam, and nifedipine is almost doubled in patients with cirrhosis, compared to those with normal liver function. Therefore, the size of the oral dose of such drugs should be reduced in this setting. Heart failure and shock Under conditions of decreased tissue perfusion, the cardiac output is redistributed to preserve blood flow to the heart and brain at the expense of other tissues (Chap. 279). As a result, drugs may be distributed into a smaller volume of distribution, higher drug concentrations will be present in the plasma, and the tissues that are best perfused (the brain and heart) will be exposed to these higher concentrations, resulting in increased CNS or cardiac effects. As well, decreased perfusion of the kidney and liver may impair drug clearance. Another consequence of severe heart failure is decreased gut perfusion, which may reduce drug absorption and, thus, lead to reduced or absent effects of orally administered therapies.
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PART 1 General Considerations in Clinical Medicine
Drug use in the elderly In the elderly, multiple pathologies and medications used to treat them result in more drug interactions and adverse effects. Aging also results in changes in organ function, especially of the organs involved in drug disposition. Initial doses should be less than the usual adult dosage and should be increased slowly. The number of medications, and doses per day, should be kept as low as possible. Even in the absence of kidney disease, renal clearance may be reduced by 35–50% in elderly patients. Dosages should be adjusted on the basis of creatinine clearance. Aging also results in a decrease in the size of, and blood flow to, the liver and possibly in the activity of hepatic drug-metabolizing enzymes; accordingly, the hepatic clearance of some drugs is impaired in the elderly. As with liver disease, these changes are not readily predicted. Elderly patients may display altered drug sensitivity. Examples include increased analgesic effects of opioids, increased sedation from benzodiazepines and other CNS depressants, and increased risk of bleeding while receiving anticoagulant therapy, even when clotting parameters are well controlled. Exaggerated responses to cardiovascular drugs are also common because of the impaired responsiveness of normal homeostatic mechanisms. Conversely, the elderly display decreased sensitivity to β-adrenergic receptor blockers. Adverse drug reactions are especially common in the elderly because of altered pharmacokinetics and pharmacodynamics, the frequent use of multidrug regimens, and concomitant disease. For example, use of long half-life benzodiazepines is linked to the occurrence of hip fractures in elderly patients, perhaps reflecting both a risk of falls from these drugs (due to increased sedation) and the increased incidence of osteoporosis in elderly patients. In population surveys of the noninstitutionalized elderly, as many as 10% had at least one adverse drug reaction in the previous year. Population frequency
Drug use in children While most drugs used to treat disease in children are the same are those in adults, there are few studies that provide solid data to guide dosing. Drug metabolism pathways mature at different rates after birth, and disease mechanisms may be different in children. In practice, doses are adjusted for size (weight or body surface area) as a first approximation unless agespecific data are available.
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Candidate Gene Studies in Pharmacogenetics Most studies to date have used an understanding of the molecular mechanisms modulating drug action to identify candidate genes in which variants could explain variable drug responses. One very common scenario is that variable drug actions can be attributed to variability in plasma drug concentrations. When plasma drug concentrations vary widely (e.g., more than an order of magnitude), especially if their distribution is non-unimodal as in Fig. 5-6, variants in single genes controlling drug concentrations often contribute. In this case, the most obvious candidate genes are those responsible for drug metabolism and elimination. Other candidate genes are those encoding the target molecules with which drugs interact to produce their effects or molecules modulating that response, including those involved in disease pathogenesis. Genome-Wide Association Studies in Pharmacogenomics The field has also had some success with “unbiased” approaches such as genome-wide association (GWA) (Chap. 82), particularly in identifying single variants associated with high risk for certain forms of drug toxicity (Table 5-2). GWA studies have identified variants in the HLA-B locus that are associated with high risk for severe skin rashes during treatment with the anticonvulsant carbamazepine and the antiretroviral abacavir. A GWA study of simvastatin-associated myopathy identified a single noncoding single nucleotide polymorphism (SNP) in SLCO1B1, encoding OATP1B1, a drug transporter known to modulate simvastatin
Lesser Enzymatic activity
Concentration
Greater
Extensive metabolizers (EMs)
Poor metabolizers (PMs)
A 2 mutant alleles
GENETIC DETERMINANTS OF THE RESPONSE TO DRUGS Principles of genetic variation and human traits (see also chaps. 82 and 84) The concept that genetically determined variations in drug metabolism might be associated with variable drug levels and hence, effect, was advanced at the end of the nineteenth century, and the examples of familial clustering of unusual drug responses were noted in the mid-twentieth century. A goal of traditional Mendelian genetics is to identify DNA variants associated with a distinct phenotype in multiple related family members (Chap. 84). However, it is unusual for a drug response phenotype to be accurately measured in more than one family member, let alone across a kindred. Thus, non-family-based approaches are generally used to
identify and validate DNA variants contributing to variable drug actions.
Ultrarapid metabolizers (UMs)
1–2 wild-type alleles
Duplication: >2 wild-type alleles
PM PM
EM EM UM
UM B
Time
Figure 5-6 A. CYP2D6 metabolic activity was assessed in 290 subjects by administration of a test dose of a probe substrate and measurement of urinary formation of the CYP2D6-generated metabolite. The heavy arrow indicates a clear antimode, separating poor metabolizer subjects (PMs, red), with two lossof-function CYP2D6 alleles, indicated by the intron-exon structures below the chart. Individuals with one or two functional alleles are grouped together as extensive metabolizers (EMs, green). Also shown are ultra-rapid metabolizers (UMs), with 2–12 functional copies of the gene (gray), displaying the greatest enzyme activity. (Adapted from M-L Dahl et al: J Pharmacol Exp Ther 274:516, 1995.) B. These simulations show the predicted effects of CYP2D6 genotype on disposition of a substrate drug. With a single dose (left), there is an inverse “gene-dose” relationship between the number of active alleles and the areas under the time-concentration curves (smallest in UM subjects; highest in PM subjects); this indicates that clearance is greatest in UM subjects. In addition, elimination half-life is longest in PM subjects. The right panel shows that these single dose differences are exaggerated during chronic therapy: steady-state concentration is much higher in PM subjects (decreased clearance), as is the time required to achieve steady state (longer elimination half-life).
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TABLE 5-2 Genetic Variants and Drug Responses
CYP2C9
Losartan Warfarin CYP2C19 Omeprazole, voriconazole Celecoxib Clopidogrel CYP2D6 Codeine, tamoxifen Codeine Tricyclic antidepressants Metoprolol, carvedilol, timolol, propafenone CYP3A5 Tacrolimus, vincristine Dihydropyrimidine dehyCapecitabine, drogenase fluorouracil NAT2 Rifampin, isoniazid, pyrazinamide, hydralazine, procainamide Thiopurine Azathioprine, S-methyltransferase (TPMT) 6-mercaptopurine Uridine diphosphate Irinotecan glucuronosyltransferase (UGT1A1) Variants in Other Genes Glucose 6-phosphate Rasburicase, dehydrogenase primaquine, (G6PD) chloroquine HLA-B*1501 Carbamazepine
Decreased bioactivation and effects (PMs) Decreased dose requirements; possible increased bleeding risk (PMs) Decreased effect in extensive metabolizers (EMs)
HLA-B*5701
Abacavir
Carriers (1 or 2 alleles) at increased risk of severe skin toxicity
IL28B IL15
Interferon Childhood leukemia therapy
Variable response in hepatitis C therapy Variability in response
SLCO1B1
Simvastatin
Encodes a drug uptake transporter; variant non-synonymous single nucleotide polymorphism increases myopathy risk
VKORC1
Warfarin
Decreased dose requirements with variant promoter haplotype
Exaggerated effect in PMs Decreased effect in PMs Decreased bioactivation and drug effects in PMs Morphine-like adverse effects in UMs Increased adverse effects in PMs; decreased therapeutic effects in UMs Increased beta blockade in PMs Decreased drug concentrations and effect Possible severe toxicity (PMs) Increased risk of toxicity in PMs
Principles of Clinical Pharmacology
Effect of Genetic Variantsa
Chapter 5
Gene Drugs Variants in Drug Metabolism Pathways
*3A/*3A (PMs): increased risk of bone marrow aplasia; wild-type homozygote: possible decreased drug action at usual dosages *28/*28 PM homozygotes: increased risk of severe adverse effects (diarrhea, bone marrow aplasia)
Increased risk of hemolytic anemia in G6PD-deficient subjects Carriers (1 or 2 alleles) at increased risk of severe skin toxicity
ITPA Ribavirin Variants in Other Genomes (Infectious Agents, Tumors) Chemokine C-C motif Maraviroc receptor (CCR5)
Variants modulate risk for hemolytic anemia
C-KIT
Imatinib
In gastrointestinal stromal tumors, drug indicated only with c-kit–positive cases
Epidermal growth factor receptor (EGFR) Her2/neu overexpression
Cetuximab
Clinical trials conducted in patients with EGFR-positive tumors
Trastuzumab, lapatinib
Drugs indicated only with tumor overexpression
K-ras mutation
Panitumumab, cetuximab
Lack of efficacy with KRAS mutation
Philadelphia chromosome
Busulfan, dasatinib, nilotinib, imatinib
Decreased efficacy in Philadelphia chromosome–negative chronic myelogenous leukemia
Drug effective only in HIV strains with CCR5 detectible
Drug effect in homozygotes unless otherwise specified.
a
Note: EM, extensive metabolizer (normal enzymatic activity); PM, poor metabolizer (homozygote for reduced or loss of function allele); UM, ultra-rapid metabolizer (enzymatic activity much greater than normal, e.g., with gene duplication, Fig. 5-6). Further data at U.S. Food and Drug Administration: http://www.fda.gov/Drugs/ ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm; or Pharmacogenetics Research Network/Knowledge Base: http://www.pharmgkb.org.
uptake into the liver, which accounts for 60% of myopathy risk. GWA approaches have also implicated interferon variants in antileukemic responses and in response to therapy in hepatitis C. Ribavirin, used as therapy in hepatitis C, causes hemolytic anemia, and this has been linked to variants in ITPA, encoding inosine triphosphatase.
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GENETIC VARIANTS AFFECTING PHARMACOKINETICS Clinically important genetic variants have been described in multiple molecular pathways of drug disposition (Table 5-2). A distinct multimodal distribution of drug disposition (as shown in Fig. 5-6) argues for a predominant effect of variants in a single gene in the metabolism of
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PART 1 General Considerations in Clinical Medicine
that substrate. Individuals with two alleles (variants) encoding for nonfunctional protein make up one group, often termed poor metabolizers (PM phenotype); for some genes, many variants can produce such a loss of function, complicating the use of genotyping in clinical practice. Individuals with one functional allele make up a second (intermediate metabolizers) and may or may not be distinguishable from those with two functional alleles (extensive metabolizers, EMs). Ultra-rapid metabolizers with especially high enzymatic activity (occasionally due to gene duplication; Fig. 5-6) have also been described for some traits. Many drugs in widespread use can inhibit specific drug disposition pathways (Table 5-1), and so EM individuals receiving such inhibitors can respond like PM patients (phenocopying). Polymorphisms in genes encoding drug uptake or drug efflux transporters may be other contributors to variability in drug delivery to target sites and, hence, in drug effects. CYP Variants Members of the CYP3A family (CYP3A4, 3A5) metabolize the greatest number of drugs in therapeutic use. CYP3A4 activity is highly variable (up to an order of magnitude) among individuals, but the underlying mechanisms are not well understood. In whites, but not African Americans, there is a common loss-of-function polymorphism in the closely related CYP3A5 gene. Decreased efficacy of the antirejection agent tacrolimus in African-American subjects has been attributed to more rapid elimination due to relatively greater CYP3A5 activity. A lower risk of vincristine-associated neuropathy has been reported in CYP3A5 “expressers.” CYP2D6 is second to CYP3A4 in the number of commonly used drugs that it metabolizes. CYP2D6 activity is polymorphically distributed, with about 7% of European- and African-derived populations (but very few Asians) displaying the PM phenotype (Fig. 5-6). Dozens of loss-of-function variants in the CYP2D6 gene have been described; the PM phenotype arises in individuals with two such alleles. In addition, ultra-rapid metabolizers with multiple functional copies of the CYP2D6 gene have been identified. Codeine is biotransformed by CYP2D6 to the potent active metabolite morphine, so its effects are blunted in PMs and exaggerated in ultra-rapid metabolizers. In the case of drugs with beta-blocking properties metabolized by CYP2D6, greater signs of beta blockade (e.g., bronchospasm, bradycardia) are seen in PM subjects than in EMs. This can be seen not only with orally administered beta blockers such as metoprolol and carvedilol, but also with ophthalmic timolol and with the sodium channel–blocking antiarrhythmic propafenone, a CYP2D6 substrate with beta-blocking properties. Ultra-rapid metabolizers may require very high dosages of tricyclic antidepressants to achieve a therapeutic effect and, with codeine, may display transient euphoria and nausea due to very rapid generation of morphine. Tamoxifen undergoes CYP2D6-mediated biotransformation to an active metabolite, so its efficacy may be in part related to this polymorphism. In addition, the widespread use of selective serotonin reuptake inhibitors (SSRIs) to treat tamoxifen-related hot flashes may also alter the drug’s effects because many SSRIs, notably fluoxetine and paroxetine, are also CYP2D6 inhibitors. The PM phenotype for CYP2C19 is common (20%) among Asians and rarer (2–3%) in European-derived populations. The impact of polymorphic CYP2C19-mediated metabolism has been demonstrated with the proton pump inhibitor omeprazole, where ulcer cure rates with “standard” dosages were much lower in EM patients (29%) than in PMs (100%). Thus, understanding the importance of this polymorphism would have been important in developing the drug, and knowing a patient’s CYP2C19 genotype should improve therapy. CYP2C19 is responsible for bioactivation of the antiplatelet drug clopidogrel, and several large studies have documented decreased efficacy (e.g., increased myocardial infarction after placement of coronary stents) among Caucasian subjects with reduction of function alleles. In addition, some studies suggest that omeprazole and possibly other proton pump inhibitors phenocopy this effect.
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There are common variants of CYP2C9 that encode proteins with loss of catalytic function. These variant alleles are associated with increased rates of neurologic complications with phenytoin, hypoglycemia with glipizide, and reduced warfarin dose required to maintain stable anticoagulation. The angiotensin-receptor blocker losartan is a prodrug that is bioactivated by CYP2C9; as a result, PMs and those receiving inhibitor drugs may display little response to therapy. Transferase Variants One of the most extensively studied phase II polymorphisms is the PM trait for thiopurine S-methyltransferase (TPMT). TPMT bioinactivates the antileukemic drug 6-mercaptopurine. Further, 6-mercaptopurine is itself an active metabolite of the immunosuppressive azathioprine. Homozygotes for alleles encoding the inactive TPMT (1 in 300 individuals) predictably exhibit severe and potentially fatal pancytopenia on standard doses of azathioprine or 6-mercaptopurine. On the other hand, homozygotes for fully functional alleles may display less anti-inflammatory or antileukemic effect with the drugs. N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT), which represents the activity of two genes, NAT-1 and NAT-2. Both enzymes transfer an acetyl group from acetyl coenzyme A to the drug; polymorphisms in NAT-2 are thought to underlie individual differences in the rate at which drugs are acetylated and thus define “rapid acetylators” and “slow acetylators.” Slow acetylators make up ∼50% of European- and African-derived populations but are less common among Asians. Slow acetylators have an increased incidence of the drug-induced lupus syndrome during procainamide and hydralazine therapy and of hepatitis with isoniazid. Induction of CYPs (e.g., by rifampin) also increases the risk of isoniazid-related hepatitis, likely reflecting generation of reactive metabolites of acetylhydrazine, itself an isoniazid metabolite. Individuals homozygous for a common promoter polymorphism that reduces transcription of uridine diphosphate glucuronosyltransferase (UGT1A1) have benign hyperbilirubinemia (Gilbert’s syndrome; Chap. 358). This variant has also been associated with diarrhea and increased bone marrow depression with the antineoplastic prodrug irinotecan, whose active metabolite is normally detoxified by UGT1A1mediated glucuronidation. The antiretroviral atazanavir is a UGT1A1 inhibitor, and individuals with the Gilbert’s variant develop higher bilirubin levels during treatment. VARIABILITY IN THE MOLECULAR TARGETS WITH WHICH DRUGS INTERACT Multiple polymorphisms identified in the β2-adrenergic receptor appear to be linked to specific phenotypes in asthma and congestive heart failure, diseases in which β2-receptor function might be expected to determine prognosis. Polymorphisms in the β2-receptor gene have also been associated with response to inhaled β2-receptor agonists, while those in the β1-adrenergic receptor gene have been associated with variability in heart rate slowing and blood pressure lowering (Fig. 5-5B). In addition, in heart failure, a common polymorphism in the β1-adrenergic receptor gene has been implicated in variable clinical outcome during therapy with the investigational beta blocker bucindolol. Response to the 5-lipoxygenase inhibitor zileuton in asthma has been linked to polymorphisms that determine the expression level of the 5-lipoxygenase gene. Drugs may also interact with genetic pathways of disease to elicit or exacerbate symptoms of the underlying conditions. In the porphyrias, CYP inducers are thought to increase the activity of enzymes proximal to the deficient enzyme, exacerbating or triggering attacks (Chap. 430). Deficiency of glucose-6-phosphate dehydrogenase (G6PD), most often in individuals of African, Mediterranean, or South Asian descent, increases the risk of hemolytic anemia in response to the antimalarial primaquine (Chap. 129) and the uric acid–lowering agent rasburicase, which do not cause hemolysis in patients with normal amounts of the enzyme. Patients with mutations in the ryanodine receptor, which controls intracellular calcium in skeletal muscle and
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PROSPECTS FOR INCORPORATING PHARMACOGENETIC INFORMATION INTO CLINICAL PRACTICE The description of genetic variants linked to variable drug responses naturally raises the question of if and how to use this information in practice. Indeed, the U.S. Food and Drug Administration (FDA) now incorporates pharmacogenetic data into information (“package inserts”) meant to guide prescribing. A decision to adopt pharmacogenetically guided dosing for a given drug depends on multiple factors. The most important are the magnitude and clinical importance of the genetic effect and the strength of evidence linking genetic variation to variable drug effects (e.g., anecdote versus post-hoc analysis of clinical trial data versus randomized prospective clinical trial). The evidence can be strengthened if statistical arguments from clinical trial data are complemented by an understanding of underlying physiologic mechanisms. Cost versus expected benefit may also be a factor. When the evidence is compelling, alternate therapies are not available, and there are clear recommendations for dosage adjustment in subjects with variants, there is a strong argument for deploying genetic testing as a guide to prescribing. The association between HLA-B*5701 and severe skin toxicity with abacavir is an example. In other situations, the arguments are less compelling: the magnitude of the genetic effect may be smaller, the consequences may be less serious, alternate therapies may be available, or the drug effect may be amenable to monitoring by other approaches. Ongoing clinical trials are addressing the utility of preprescription genotyping in large populations exposed to drugs with known pharmacogenetic variants (e.g., warfarin). Importantly, technological advances are now raising the possibility of inexpensive whole genome sequencing. Incorporating a patient’s whole genome sequence into their electronic medical record would allow the information to be accessed as needed for many genetic and pharmacogenetic applications, and the argument has been put forward that this approach would lower logistic barriers to use of pharmacogenomic variant data in prescribing. There are multiple issues (e.g., economic, technological, and ethical) that need to be addressed if such a paradigm is to be adopted (Chap. 82). While barriers to bringing genomic and pharmacogenomic information to the bedside seem daunting, the field is very young and evolving rapidly. Indeed, one major result of understanding the role of genetics in drug action has
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INTERACTIONS BETWEEN DRUGS Drug interactions can complicate therapy by increasing or decreasing the action of a drug; interactions may be based on changes in drug disposition or in drug response in the absence of changes in drug levels. Interactions must be considered in the differential diagnosis of any unusual response occurring during drug therapy. Prescribers should recognize that patients often come to them with a legacy of drugs acquired during previous medical experiences, often with multiple physicians who may not be aware of all the patient’s medications. A meticulous drug history should include examination of the patient’s medications and, if necessary, calls to the pharmacist to identify prescriptions. It should also address the use of agents not often volunteered during questioning, such as OTC drugs, health food supplements, and topical agents such as eye drops. Lists of interactions are available from a number of electronic sources. While it is unrealistic to expect the practicing physician to memorize these, certain drugs consistently run the risk of generating interactions, often by inhibiting or inducing specific drug elimination pathways. Examples are presented below and in Table 5-3. Accordingly, when these drugs are started or stopped, prescribers must be especially alert to the possibility of interactions.
41
Principles of Clinical Pharmacology
Tumor and Infectious Agent Genomes The actions of drugs used to treat infectious or neoplastic disease may be modulated by variants in these nonhuman germline genomes. Genotyping tumors is a rapidly evolving approach to target therapies to underlying mechanisms and to avoid potentially toxic therapy in patients who would derive no benefit (Chap. 101e). Trastuzumab, which potentiates anthracycline-related cardiotoxicity, is ineffective in breast cancers that do not express the herceptin receptor. Imatinib targets a specific tyrosine kinase, BCR-Abl1, that is generated by the translocation that creates the Philadelphia chromosome typical of chronic myelogenous leukemia (CML). BCR-Abl1 is not only active but may be central to the pathogenesis of CML; its use in BCR-Abl1-positive tumors has resulted in remarkable antitumor efficacy. Similarly, the anti–epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab appear especially effective in colon cancers in which K-ras, a G protein in the EGFR pathway, is not mutated. Vemurafenib does not inhibit wild-type BRAF but is active against the V600E mutant form of the kinase.
been improved screening of drugs during the development process to reduce the likelihood of highly variable metabolism or unanticipated toxicity.
Chapter 5
other tissues, may be asymptomatic until exposed to certain general anesthetics, which trigger the rare syndrome of malignant hyperthermia. Certain antiarrhythmics and other drugs can produce marked QT prolongation and torsades des pointes (Chap. 276), and in some patients, this adverse effect represents unmasking of previously subclinical congenital long QT syndrome. Up to 50% of the variability in steady-state warfarin dose requirement is attributable to polymorphisms in the promoter of VKORC1, which encodes the warfarin target, and in the coding region of CYP2C9, which mediates its elimination.
PHARMACOKINETIC INTERACTIONS CAUSING DECREASED DRUG EFFECTS Gastrointestinal absorption can be reduced if a drug interaction results in drug binding in the gut, as with aluminum-containing antacids, kaolin-pectin suspensions, or bile acid sequestrants. Drugs such as histamine H2-receptor antagonists or proton pump inhibitors that alter gastric pH may decrease the solubility and hence absorption of weak bases such as ketoconazole. Expression of some genes responsible for drug elimination, notably CYP3A and MDR1, can be markedly increased by inducing drugs, such as rifampin, carbamazepine, phenytoin, St. John’s wort, and glutethimide, and by smoking, exposure to chlorinated insecticides such as DDT (CYP1A2), and chronic alcohol ingestion. Administration of inducing agents lowers plasma levels, and thus effects, over 2–3 weeks as gene expression is increased. If a drug dose is stabilized in the presence of an inducer that is subsequently stopped, major toxicity can occur as clearance returns to preinduction levels and drug concentrations rise. Individuals vary in the extent to which drug metabolism can be induced, likely through genetic mechanisms. Interactions that inhibit the bioactivation of prodrugs will decrease drug effects (Table 5-1). Interactions that decrease drug delivery to intracellular sites of action can decrease drug effects: tricyclic antidepressants can blunt the antihypertensive effect of clonidine by decreasing its uptake into adrenergic neurons. Reduced CNS penetration of multiple HIV protease inhibitors (with the attendant risk of facilitating viral replication in a sanctuary site) appears attributable to P-glycoprotein-mediated exclusion of the drug from the CNS; indeed, inhibition of P-glycoprotein has been proposed as a therapeutic approach to enhance drug entry to the CNS (Fig. 5-5A). PHARMACOKINETIC INTERACTIONS CAUSING INCREASED DRUG EFFECTS The most common mechanism here is inhibition of drug elimination. In contrast to induction, new protein synthesis is not involved, and the effect develops as drug and any inhibitor metabolites accumulate (a function of their elimination half-lives). Since shared substrates of a single enzyme can compete for access to the active site of the protein, many CYP substrates can also be considered inhibitors. However, some drugs are especially potent as inhibitors (and occasionally may not even be substrates) of specific drug elimination pathways, and so it is in the use of these agents that clinicians must be most alert to the potential for interactions (Table 5-3). Commonly implicated interacting drugs of this type include amiodarone, cimetidine,
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TABLE 5-3 Drugs with a High Risk of Generating Pharmacokinetic Interactions
PART 1
Drug Antacids
Mechanism Reduced absorption
Examples Antacids/tetracyclines
Bile acid sequestrants Proton pump inhibitors H2-receptor blockers
Altered gastric pH
Cholestyramine/digoxin Ketoconazole absorption decreased
General Considerations in Clinical Medicine
Rifampin Carbamazepine Barbiturates Phenytoin St. John’s wort Glutethimide Nevirapine (CYP3A; CYP2B6) Tricyclic antidepressants Fluoxetine Quinidine Cimetidine
Induction of CYPs and/or P-glycoprotein
Ketoconazole, itraconazole Erythromycin, clarithromycin Calcium channel blockers
Inhibitor of CYP3A
Inhibitors of CYP2D6
Inhibitor of multiple CYPs
Ritonavir
Decreased concentration and effects of warfarin quinidine cyclosporine losartan oral contraceptives methadone, dabigatran Increased effect of many β blockers Decreased codeine effect; possible decreased tamoxifen effect Increased concentration and effects of warfarin theophylline phenytoin Increased concentration and toxicity of some HMG-CoA reductase inhibitors cyclosporine, cisapride, terfenadine (now withdrawn) Increased concentration and effects of indinavir (with ritonavir)
Allopurinol Amiodarone
Xanthine oxidase inhibitor Inhibitor of many CYPs and of P-glycoprotein
Gemfibrozil (and other fibrates) Quinidine Amiodarone Verapamil Cyclosporine Itraconazole Erythromycin Phenylbutazone Probenecid Salicylates
CYP3A inhibition P-glycoprotein inhibition
Decreased clearance and dose requirement for cyclosporine (with calcium channel blockers) Azathioprine and 6-mercaptopurine toxicity Decreased clearance (risk of toxicity) for warfarin digoxin quinidine Rhabdomyolysis when co-prescribed with some HMG-CoA reductase inhibitors Risk of toxicity with P-glycoprotein substrates (e.g., digoxin, dabigatran)
Inhibition of renal tubular transport
Increased risk of methotrexate toxicity with salicylates
erythromycin and some other macrolide antibiotics (clarithromycin but not azithromycin), ketoconazole and other azole antifungals, the antiretroviral agent ritonavir, and high concentrations of grapefruit juice (Table 5-3). The consequences of such interactions will depend on the drug whose elimination is being inhibited (see “The Concept of High-Risk Pharmacokinetics,” above). Examples include CYP3A inhibitors increasing the risk of cyclosporine toxicity or of rhabdomyolysis with some HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin, but not pravastatin), and P-glycoprotein inhibitors increasing the risk of toxicity with digoxin therapy or of bleeding with the thrombin inhibitor dabigatran. These interactions can occasionally be exploited to therapeutic benefit. The antiviral ritonavir is a very potent CYP3A4 inhibitor that is sometimes added to anti-HIV regimens, not because of its antiviral effects but because it decreases clearance, and hence increases efficacy, of other anti-HIV agents. Similarly, calcium channel blockers have been deliberately coadministered with cyclosporine to reduce its clearance and thus its maintenance dosage and cost. Phenytoin, an inducer of many systems, including CYP3A, inhibits CYP2C9. CYP2C9 metabolism of losartan to its active metabolite is inhibited by phenytoin, with potential loss of antihypertensive effect.
HPIM19_Part01_p001-p086.indd 42
Grapefruit (but not orange) juice inhibits CYP3A, especially at high doses; patients receiving drugs where even modest CYP3A inhibition may increase the risk of adverse effects (e.g., cyclosporine, some HMG-CoA reductase inhibitors) should therefore avoid grapefruit juice. CYP2D6 is markedly inhibited by quinidine, a number of neuroleptic drugs (chlorpromazine and haloperidol), and the SSRIs fluoxetine and paroxetine. The clinical consequences of fluoxetine’s interaction with CYP2D6 substrates may not be apparent for weeks after the drug is started, because of its very long half-life and slow generation of a CYP2D6-inhibiting metabolite. 6-Mercaptopurine is metabolized not only by TPMT but also by xanthine oxidase. When allopurinol, an inhibitor of xanthine oxidase, is administered with standard doses of azathioprine or 6-mercaptopurine, life-threatening toxicity (bone marrow suppression) can result. A number of drugs are secreted by the renal tubular transport systems for organic anions. Inhibition of these systems can cause excessive drug accumulation. Salicylate, for example, reduces the renal clearance of methotrexate, an interaction that may lead to methotrexate toxicity. Renal tubular secretion contributes substantially to the elimination of penicillin, which can be inhibited (to increase its therapeutic effect) by
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probenecid. Similarly, inhibition of the tubular cation transport system by cimetidine decreases the renal clearance of dofetilide.
The beneficial effects of drugs are coupled with the inescapable risk of untoward effects. The morbidity and mortality from these adverse effects often present diagnostic problems because they can involve every organ and system of the body and may be mistaken for signs of underlying disease. As well, some surveys have suggested that drug therapy for a range of chronic conditions such as psychiatric disease or hypertension does not achieve its desired goal in up to half of treated patients; thus, the most common “adverse” drug effect may be failure of efficacy. Adverse reactions can be classified in two broad groups. One type results from exaggeration of an intended pharmacologic action of the drug, such as increased bleeding with anticoagulants or bone marrow suppression with antineoplastics. The second type of adverse reaction ensues from toxic effects unrelated to the intended pharmacologic actions. The latter effects are often unanticipated (especially with new drugs) and frequently severe and may result from recognized as well as previously undescribed mechanisms. Drugs may increase the frequency of an event that is common in a general population, and this may be especially difficult to recognize; an excellent example is the increase in myocardial infarctions with the COX-2 inhibitor rofecoxib. Drugs can also cause rare and serious adverse effects, such as hematologic abnormalities, arrhythmias, severe skin reactions, or hepatic or renal dysfunction. Prior to regulatory approval and marketing, new drugs are tested in relatively few patients who tend to be less sick and to have fewer concomitant diseases than those patients who subsequently receive the drug therapeutically.
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Principles of Clinical Pharmacology
ADVERSE REACTIONS TO DRUGS
43
Chapter 5
DRUG INTERACTIONS NOT MEDIATED BY CHANGES IN DRUG DISPOSITION Drugs may act on separate components of a common process to generate effects greater than either has alone. Antithrombotic therapy with combinations of antiplatelet agents (glycoprotein IIb/IIIa inhibitors, aspirin, clopidogrel) and anticoagulants (warfarin, heparins) is often used in the treatment of vascular disease, although such combinations carry an increased risk of bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastric ulcers, and in patients treated with warfarin, the risk of upper gastrointestinal bleeding is increased almost threefold by concomitant use of an NSAID. Indomethacin, piroxicam, and probably other NSAIDs antagonize the antihypertensive effects of β-adrenergic receptor blockers, diuretics, ACE inhibitors, and other drugs. The resulting elevation in blood pressure ranges from trivial to severe. This effect is not seen with aspirin and sulindac but has been found with the cyclooxygenase 2 (COX-2) inhibitor celecoxib. Torsades des pointes ventricular tachycardia during administration of QT-prolonging antiarrhythmics (quinidine, sotalol, dofetilide) occurs much more frequently in patients receiving diuretics, probably reflecting hypokalemia. In vitro, hypokalemia not only prolongs the QT interval in the absence of drug but also potentiates drug block of ion channels that results in QT prolongation. Also, some diuretics have direct electrophysiologic actions that prolong QT. The administration of supplemental potassium leads to more frequent and more severe hyperkalemia when potassium elimination is reduced by concurrent treatment with ACE inhibitors, spironolactone, amiloride, or triamterene. The pharmacologic effects of sildenafil result from inhibition of the phosphodiesterase type 5 isoform that inactivates cyclic guanosine monophosphate (GMP) in the vasculature. Nitroglycerin and related nitrates used to treat angina produce vasodilation by elevating cyclic GMP. Thus, coadministration of these nitrates with sildenafil can cause profound hypotension, which can be catastrophic in patients with coronary disease. Sometimes, combining drugs can increase overall efficacy and/or reduce drug-specific toxicity. Such therapeutically useful interactions are described in chapters dealing with specific disease entities.
Because of the relatively small number of patients studied in clinical trials and the selected nature of these patients, rare adverse effects are generally not detected prior to a drug’s approval; indeed, if they are detected, the new drugs are generally not approved. Therefore, physicians need to be cautious in the prescription of new drugs and alert for the appearance of previously unrecognized adverse events. Elucidating mechanisms underlying adverse drug effects can assist development of safer compounds or allow a patient subset at especially high risk to be excluded from drug exposure. National adverse reaction reporting systems, such as those operated by the FDA (suspected adverse reactions can be reported online at http://www.fda.gov/safety/ medwatch/default.htm) and the Committee on Safety of Medicines in Great Britain, can prove useful. The publication or reporting of a newly recognized adverse reaction can in a short time stimulate many similar such reports of reactions that previously had gone unrecognized. Occasionally, “adverse” effects may be exploited to develop an entirely new indication for a drug. Unwanted hair growth during minoxidil treatment of severely hypertensive patients led to development of the drug for hair growth. Sildenafil was initially developed as an antianginal, but its effects to alleviate erectile dysfunction not only led to a new drug indication but also to increased understanding of the role of type 5 phosphodiesterase in erectile tissue. These examples further reinforce the concept that prescribers must remain vigilant to the possibility that unusual symptoms may reflect unappreciated drug effects. Some 25–50% of patients make errors in self-administration of prescribed medicines, and these errors can be responsible for adverse drug effects. Similarly, patients commit errors in taking OTC drugs by not reading or following the directions on the containers. Health care providers must recognize that providing directions with prescriptions does not always guarantee compliance. In hospitals, drugs are administered in a controlled setting, and patient compliance is, in general, ensured. Errors may occur nevertheless— the wrong drug or dose may be given or the drug may be given to the wrong patient—and improved drug distribution and administration systems are addressing this problem. SCOPE OF THE PROBLEM Patients receive, on average, 10 different drugs during each hospitalization. The sicker the patient, the more drugs are given, and there is a corresponding increase in the likelihood of adverse drug reactions. When 15 drugs are given, the probability is >40%. Retrospective analyses of ambulatory patients have revealed adverse drug effects in 20%. Serious adverse reactions are also well-recognized with “herbal” remedies and OTC compounds; examples include kava-associated hepatotoxicity, L-tryptophan-associated eosinophilia-myalgia, and phenylpropanolamine-associated stroke, each of which has caused fatalities. A small group of widely used drugs accounts for a disproportionate number of reactions. Aspirin and other NSAIDs, analgesics, digoxin, anticoagulants, diuretics, antimicrobials, glucocorticoids, antineoplastics, and hypoglycemic agents account for 90% of reactions. TOXICITY UNRELATED TO A DRUG’S PRIMARY PHARMACOLOGIC ACTIVITY Drugs or more commonly reactive metabolites generated by CYPs can covalently bind to tissue macromolecules (such as proteins or DNA) to cause tissue toxicity. Because of the reactive nature of these metabolites, covalent binding often occurs close to the site of production, typically the liver. The most common cause of drug-induced hepatotoxicity is acetaminophen overdosage (Chap. 361). Normally, reactive metabolites are detoxified by combining with hepatic glutathione. When glutathione becomes depleted, the metabolites bind instead to hepatic protein, with resultant hepatocyte damage. The hepatic necrosis produced by the ingestion of acetaminophen can be prevented or attenuated by the administration of substances such as N-acetylcysteine that reduce the binding of electrophilic metabolites to hepatic proteins. The risk of acetaminophen-related hepatic necrosis is increased in patients receiving drugs such as phenobarbital or phenytoin, which increase
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44
PART 1 General Considerations in Clinical Medicine
the rate of drug metabolism, or ethanol, which exhausts glutathione stores. Such toxicity has even occurred with therapeutic dosages, so patients at risk through these mechanisms should be warned. Most pharmacologic agents are small molecules with low molecular weights (85
Ca lung, trachea, bronhus DM
HIV
IHD
Figure 6e-1 Death rates per 100,000 population for 2007 by 5-year age groups in U.S. women. Note that the scale of the y axis is increased in the graph on the right compared with that on the left. Accidents and HIV/AIDS are the leading causes of death in young women 20–34 years of age. Accidents, breast cancer, and ischemic heart disease (IHD) are the leading causes of death in women 35–49 years of age. IHD becomes the leading cause of death in women beginning at age 50 years. In older women, IHD remains the leading cause of death, cerebrovascular disease becomes the second leading cause of death, and lung cancer is the leading cause of cancer-related deaths. At age 85 years and beyond, Alzheimer’s disease (AD) becomes the third leading cause of death. Ca, cancer; CLRD, chronic lower respiratory disease; DM, diabetes mellitus. (Data adapted from Centers for Disease Control and Prevention, http://www.cdc.gov/nchs/data/dvs/MortFinal2007_WorkTable210R.pdf.)
Some studies have suggested that estrogen administration improves cognitive function in nondemented postmenopausal women as well as in women with AD, and several observational studies have suggested that postmenopausal hormone therapy (HT) may decrease the risk of AD. However, HT placebo-controlled trials have found no improvement in disease progression or cognitive function in women with AD. Further, the Women’s Health Initiative Memory Study (WHIMS), an ancillary study in the Women’s Health Initiative (WHI), found no benefit compared with placebo of estrogen alone [combined continuous equine estrogen (CEE), 0.625 mg daily] or estrogen with progestin [CEE, 0.625 mg daily, and medroxyprogesterone acetate (MPA), 2.5 mg daily] on cognitive function or the development of dementia in women ≥65 years. Indeed, there was a significantly increased risk for both dementia and mild cognitive impairment in women receiving HT. However, preliminary findings from the Kronos Early Estrogen Prevention Study (KEEPS), a randomized clinical trial of early initiation of HT after menopause that compared CEE 0.45 mg daily, 50 μg of weekly transdermal estradiol (both estrogen arms included cyclic
oral micronized progesterone 200 mg daily for 12 days each month), or placebo, found no adverse effects on cognitive function. CARDIOVASCULAR DISEASE AND STROKE (See also Chap. 293) There are major sex differences in CVD, the leading cause of death in men and women in developed countries. A greater number of U.S. women than men die annually of CVD and stroke. Deaths from CVD have decreased markedly in men since 1980, whereas CVD deaths only began to decrease substantially in women beginning in 2000. However, in middle-aged women, the prevalence rates of both coronary heart disease (CHD) and stroke have increased in the 1999–2004 National Health and Nutrition Survey (NHANES) compared to the 1988–1994 NHANES, whereas prevalence rates have decreased or remained unchanged, respectively, in men. These increases were paralleled by an increasing prevalence of abdominal obesity and other components of metabolic syndrome in women. Sex steroids have major effects on the cardiovascular system and lipid metabolism. Estrogen increases high-density lipoprotein (HDL)
1997 10%
2012 11%
7%
8%
14% 30%
6%
56% 24% 35%
Breast cancer
Cancer
Heart disease
Other
Don’t know
Figure 6e-2 Changes in perceived leading causes of death among women surveyed in 1997 compared with those surveyed in 2012. In 1997, cancer was cited as the leading cause of death in women, not heart disease. In 2012, this trend had reversed. The rate of awareness that heart disease is the leading cause of death in women was significantly higher in 2012 (56% vs 30%, p 40% of women living in northern latitudes. Receptors for estrogens and androgens have been identified in bone. Estrogen deficiency is associated with increased osteoclast activity and a decreased number of bone-forming units, leading to net bone loss. The aromatase enzyme, which converts androgens to estrogens, is also present in bone. Estrogen is an important determinant of bone mass in men (derived from the aromatization of androgens) as well as in women. PHARMACOLOGY On average, women have lower body weights, smaller organs, a higher percentage of body fat, and lower total-body water than men. There are also important sex differences in drug action and metabolism that are
SLEEP DISORDERS (See also Chap. 38) There are striking sex differences in sleep and its disorders. During sleep, women have an increased amount of slowwave activity, differences in timing of delta activity, and an increase in the number of sleep spindles. Testosterone modulates neural control of breathing and upper airway mechanics. Men have a higher prevalence of sleep apnea. Testosterone administration to hypogonadal men as well as to women increases apneic episodes during sleep. Women with the hyperandrogenic disorder polycystic ovary syndrome have an increased prevalence of obstructive sleep apnea, and apneic episodes are positively correlated with their circulating testosterone levels. In contrast, progesterone accelerates breathing, and in the past, progestins were used for treatment of sleep apnea. SUBSTANCE ABUSE AND TOBACCO (See also Chaps. 467 and 470) Substance abuse is more common in men than in women. However, one-third of Americans who
VIOLENCE AGAINST WOMEN More than one in three women in the United States have experienced rape, physical violence, and/or stalking by an intimate partner. Adult women are much more likely to be raped by a spouse, ex-spouse, or acquaintance than by a stranger. Domestic or intimate partner violence is a leading cause of death among young women. Domestic violence may be an unrecognized feature of certain clinical presentations, such as chronic abdominal pain, headaches, and eating disorders, in addition to more obvious manifestations such as trauma. Intimate partner violence is an important risk factor for depression, substance abuse, and suicide in women. Screening instruments can accurately identify women experiencing intimate partner violence. Such screening by health care providers is acceptable to women in settings ensuring adequate privacy and safety.
SUMMARY Women’s health is now a mature discipline, and the importance of sex differences in biologic processes is well recognized. There has been a striking reduction in the excess mortality rate from MI in younger women. Nevertheless, ongoing misperceptions about disease risk, not only among women but also among their physicians, result in inadequate attention to modifiable risk factors. Research into the fundamental mechanisms of sex differences will provide important biologic insights. Further, those insights will have an impact on both women’s and men’s health.
6e-5
Women’s Health
PSYCHOLOGICAL DISORDERS (See also Chap. 466) Depression, anxiety, and affective and eating disorders (bulimia and anorexia nervosa) are more common in women than in men. Epidemiologic studies from both developed and developing nations consistently find major depression to be twice as common in women as in men, with the sex difference becoming evident in early adolescence. Depression occurs in 10% of women during pregnancy and in 10–15% of women during the postpartum period. There is a high likelihood of recurrence of postpartum depression with subsequent pregnancies. The incidence of major depression diminishes after age 45 years and does not increase with the onset of menopause. Depression in women appears to have a worse prognosis than does depression in men; episodes last longer, and there is a lower rate of spontaneous remission. Schizophrenia and bipolar disorders occur at equal rates in men and women, although there may be sex differences in symptoms. Both biologic and social factors account for the greater prevalence of depressive disorders in women. Men have higher levels of the neurotransmitter serotonin. Sex steroids also affect mood, and fluctuations during the menstrual cycle have been linked to symptoms of premenstrual syndrome. Sex hormones differentially affect the hypothalamic-pituitary-adrenal responses to stress. Testosterone appears to blunt cortisol responses to corticotropin-releasing hormone. Both low and high levels of estrogen can activate the hypothalamic-pituitaryadrenal axis.
suffer from alcoholism are women. Women alcoholics are less likely to be diagnosed than men. A greater proportion of men than women seek help for alcohol and drug abuse. Men are more likely to go to an alcohol or drug treatment facility, whereas women tend to approach a primary care physician or mental health professional for help under the guise of a psychosocial problem. Late-life alcoholism is more common in women than in men. On average, alcoholic women drink less than alcoholic men but exhibit the same degree of impairment. Blood alcohol levels are higher in women than in men after drinking equivalent amounts of alcohol, adjusted for body weight. This greater bioavailability of alcohol in women is due to both the smaller volume of distribution and the slower gastric metabolism of alcohol secondary to lower activity of gastric alcohol dehydrogenase than is the case in men. In addition, alcoholic women are more likely to abuse tranquilizers, sedatives, and amphetamines. Women alcoholics have a higher mortality rate than do nonalcoholic women and alcoholic men. Women also appear to develop alcoholic liver disease and other alcohol-related diseases with shorter drinking histories and lower levels of alcohol consumption. Alcohol abuse also poses special risks to a woman, adversely affecting fertility and the health of the baby (fetal alcohol syndrome). Even moderate alcohol use increases the risk of breast cancer, hypertension, and stroke in women. More men than women smoke tobacco, but this sex difference continues to decrease. Women have a much larger burden of smokingrelated disease. Smoking markedly increases the risk of CVD in premenopausal women and is also associated with a decrease in the age of menopause. Women who smoke are more likely to develop chronic obstructive pulmonary disease and lung cancer than men and at lower levels of tobacco exposure. Postmenopausal women who smoke have lower bone density than women who never smoked. Smoking during pregnancy increases the risk of preterm deliveries and low birth weight infants.
Chapter 6e
not accounted for by these differences in body size and composition. Sex steroids alter the binding and metabolism of a number of drugs. Further, menstrual cycle phase and pregnancy can alter drug action. Two-thirds of cases of drug-induced torsades des pointes, a rare, lifethreatening ventricular arrhythmia, occur in women because they have a longer, more vulnerable QT interval. These drugs, which include certain antihistamines, antibiotics, antiarrhythmics, and antipsychotics, can prolong cardiac repolarization by blocking cardiac voltage-gated potassium channels. Women require lower doses of neuroleptics to control schizophrenia. Women awaken from anesthesia faster than do men given the same doses of anesthetics. Women also take more medications than men, including over-the-counter formulations and supplements. The greater use of medications combined with these biologic differences may account for the reported higher frequency of adverse drug reactions in women than in men.
AGING-RELATED CHANGES IN MALE REPRODUCTIVE FUNCTION (SEE CHAP. 411) A number of studies have established that testosterone concentrations decrease with advancing age. This age-related decline starts in the third decade of life and progresses thereafter (Fig. 7e-1). Low total and bioavailable testosterone concentrations are associated with decreased skeletal muscle mass and strength, higher visceral fat mass, insulin resistance, and increased risk of coronary artery disease and mortality (Table 7e-1). Most studies suggest that these symptoms and signs develop with total testosterone levels below 320 ng/dL and free testosterone levels below 64 pg/mL in older men. Testing for low testosterone in older men should be limited to those with symptoms or signs attributable to androgen deficiency. Testosterone therapy of healthy older men with low testosterone increases lean body mass, grip strength, and self-reported physical function (Fig. 7e-2). Testosterone therapy also increases vertebral but not femoral bone mineral density. In men with sexual dysfunction and low testosterone levels, testosterone therapy improves libido, but effects on erectile function and response to selective phosphodiesterase inhibitors are variable (Chap. 67). As discussed in Chap. 411, there is concern that testosterone therapy may stimulate the growth of prostate cancers. Sexual Dysfunction (See Chap. 67) Various forms of sexual dysfunction are a major motivating factor for men seeking care at men’s health clinics. The landmark descriptions of the human sexual response cycle by Masters and Johnson, demonstrating that men and women display predictable physiologic responses after sexual stimulation, provided the basis for rational classification of human sexual disorders. Accordingly, sexual disorders have been classified into four categories depending on phase of sexual response cycle in which the abnormality exists: 1. 2. 3. 4.
Hypoactive sexual desire disorder Erectile dysfunction Ejaculatory and orgasmic disorders Disorders of pain
Classification of the patient’s disorder into these categories is important because the etiologic factors, diagnostic tests, and therapeutic
Total testosterone (ng/dL) vs. Age (y) FHS
EMAS
MrOS
1000 800 600 400 200 20–29
30–39
40–49
50–59 Age (y)
60–69
70–79
80+
Figure 7e-1 Age-related decline in total testosterone levels. Total testosterone levels measured using liquid chromatography tandem mass spectrometry in men of the Framingham Heart Study (FHS), the European Male Aging Study (EMAS), and the Osteoporotic Fractures in Men Study (MrOS). (Reproduced with permission from S Bhasin et al: J Clin Endocrinol Metab 96:2430, 2011.)
7e-1
Men’s Health
The emergence of men’s health as a distinct discipline within internal medicine is founded on the evidence that men and women differ across their life span in their susceptibility to disease, in the clinical manifestations of the disease, and in their response to treatment. Furthermore, men and women weigh the health consequences of illness differently and have different motivations for seeking care. Men and women experience different types of disparities in access to health care services and in the manner in which health care is delivered to them because of a complex array of socioeconomic and cultural factors. Attitudinal and institutional barriers to accessing care, fear and embarrassment due to the perception by some that it is not manly to seek medical help, and reticence on the part of patients and physicians to discuss issues related to sexuality, drug use, and aging have heightened the need for programs tailored to address the specific health needs of men. Sex differences in disease prevalence, susceptibility, and clinical manifestations of disease were discussed in Chap. 6e (“Women’s Health”). It is notable that the two leading causes of death in both men and women—heart disease and cancer—are the same. However, men have a higher prevalence of neurodevelopmental and degenerative disorders; substance abuse disorders, including the use of performanceenhancing drugs and alcohol dependence; diabetes; and cardiovascular disease; and women have a higher prevalence of autoimmune disorders, depression, rheumatologic disorders, and osteoporosis. Men are substantially more likely to die from accidents, suicides, and homicides than women. Among men 15–34 years of age, unintentional injuries, homicides, and suicides account for over three-fourths of all deaths. Among men 35–64 years of age, heart disease, cancer, and unintentional injuries are the leading causes of death. Among men 65 years of age or older, heart disease, cancer, lower respiratory tract infections, and stroke are the major causes of death. The biologic bases of sex differences in disease susceptibility, progression, and manifestation remain incompletely understood and are likely multifactorial. Undoubtedly, sex-specific differences in the genetic architecture and circulating sex hormones influence disease phenotype; additionally, epigenetic effects of sex hormones during fetal life, early childhood, and pubertal development may imprint sexual and nonsexual behaviors, body composition, and disease susceptibility. Reproductive load and physiologic changes during pregnancy, including profound hormonal and metabolic shifts and microchimerism (transfer of cells from the mother to the fetus and from the fetus to the mother), may affect disease susceptibility and disease severity in women. Sociocultural norms of child-rearing practices, societal expectations of gender roles, and the long-term economic impact of these practices and gender roles also may affect disease risk and its clinical manifestation. The trajectories of age-related changes in sex hormones during the reproductive and postreproductive years vary substantially between men and women and may influence the sex differences in the temporal evolution of age-related conditions such as osteoporosis, breast cancer, and autoimmune disease. In a reflection of the growing attention to issues related to men’s health, health clinics focused on the health problems of men are being established with increasing frequency. Although the major threats to men’s health have not changed—heart disease, cancer, and unintentional injury continue to dominate the list of major medical causes of morbidity and mortality in men—the men who attend men’s health clinics do so largely for sexual, reproductive, and urologic health concerns involving common conditions such as androgen deficiency syndromes, age-related decline in testosterone levels, sexual dysfunction, muscle dysmorphia and anabolic-androgenic steroid use, lower urinary tract symptoms, and medical complications of prostate cancer therapy, which are the focus of this chapter. Additionally, new categories of body image disorders have emerged in men that had not been recognized until the 1980s, such as body dysmorphia syndrome and
Testosterone level (ng/dL)
Shalender Bhasin, Shehzad Basaria
the use of performance-enhancing drugs to increase muscularity and lean appearance. Although menopause in women has been the subject of intense investigation for more than five decades, the issues that are specific to men’s health are just beginning to gain the attention that they deserve because of their high prevalence and impact on overall health, well-being, and quality of life.
Chapter 7e
7e
Men’s Health
7e-2
Body composition and muscle strength
Table 7e-1 Association of Testosterone Levels with Outcomes in Older Men
PART 1 General Considerations in Clinical Medicine
1. Positively associated with: • Muscle mass and muscle strength • Physical function • Sexual desire • Bone mineral density, bone geometry, and volumetric bone mineral density 2. Negatively associated with: • Coronary artery disease • Visceral fat • Diabetes mellitus • Metabolic syndrome • Mortality • Falls and fracture risk • Frailty 3. Not associated with: • Lower urinary tract symptoms • Erectile dysfunction • Dementia • Major depression
Grip strength Fat mass Lean body mass –2
A
0
2
4
6
Difference between change in testosterone and placebo (kg)
Bone health Lumbar spine Femoral neck 0 5 10 Difference between testosterone and placebo change in bone mineral density (%)
B
Sexual function Sexual thoughts Sexual satisfaction
strategies vary for each class of sexual disorder. Historically, the classification and nomenclature for sexual disorders used criteria identified in the Diagnostic and Statistical Manual of Mental Disorders (DSM), based on the erroneous belief that sexual disorders in men are largely psychogenic in their origin. However, the recognition of erectile dysfunction as a manifestation of systemic disease and the availability of easy-to-use oral selective phosphodiesterase-5 inhibitors have placed sexual disorders in men within the purview of the primary care provider. MUSCLE DYSMORPHIA SYNDROME IN MEN: A BODY IMAGE DISORDER Muscle dysmorphia is a form of body image disorder characterized by a pathologic preoccupation with muscularity and leanness. The men with muscle dysmorphia express a strong desire to be more muscular and lean. These men describe shame and embarrassment about their body size and shape and often report adverse symptoms such as dissatisfaction with appearance, preoccupation with bodybuilding and muscularity, and functional impairment. Patients with muscle dysmorphia also report higher rates of mood and anxiety disorders, as well as obsessive and compulsive behaviors. These men often experience impairment of social and occupational functioning. Patients with muscle dysmorphia syndrome—nearly all men—are almost always engaged in weightlifting and body building and are more likely to use performance-enhancing drugs, especially anabolicandrogenic steroids. Muscle dysmorphia disorder predisposes men to an increased risk of disease due to the combined interactive effects of the intensity of physical exercise, the use of performance-enhancing drugs, and other lifestyle factors associated with weightlifting and the use of performance-enhancing drugs. No randomized trials of any treatment modalities have been conducted; anecdotally, behavioral and cognitive therapies have been tried with varying degrees of success. Anabolic-Androgenic Steroid Abuse by Athletes and Recreational BodyBuilders The illicit use of anabolic-androgenic steroids (AAS) to enhance athletic performance first surfaced in the 1950s among powerlifters and spread rapidly to other sports and to professional as well as high school athletes and recreational bodybuilders. In the early 1980s, the use of AAS spread beyond the athletic community into the general population. As many as 3 million Americans, most of them men, have likely used these compounds. Most AAS users are not athletes, but rather recreational weightlifters who use these drugs to look lean and more muscular.
Morning erections Intercourse Erectile function 0
C
1 2 3 Standardized mean difference between testosterone and placebo
Figure 7e-2 The effects of testosterone therapy on body composition, muscle strength, bone mineral density, and sexual function in intervention trials. The point estimates and the associated 95% confidence intervals are shown. A. The effects of testosterone therapy on lean body mass, grip strength, and fat mass in a meta-analysis of randomized trials. (Data derived from S Bhasin et al: Nat Clin Pract Endocrinol Metab 2:146, 2006.) B. The effects of testosterone therapy on lumbar and femoral bone mineral density in a metaanalysis of randomized trials. (Data derived from a meta-analysis by MJ Tracz et al: J Clin Endocrinol Metab 91:2011, 2006.) C. The effects of testosterone therapy on measures of sexual function in men with baseline testosterone less than 10 nmol/L (290 ng/dL). (Data derived from a meta-analysis by AM Isidori et al: Clin Endocrinol (Oxf) 63:381, 2005.) (Reproduced with permission from M Spitzer et al: Nat Rev Endocrinol 9:414, 2013.)
The most commonly used AAS include testosterone esters, nandrolone, stanozolol, methandienone, and methenolone. AAS users generally use increasing doses of multiple steroids in a practice known as stacking. The adverse effects of long-term AAS abuse remain poorly understood. Most of the information about the adverse effects of AAS has emerged from case reports, uncontrolled studies, or clinical trials that used replacement doses of testosterone (Table 7e-2). Of note, AAS users may administer 10–100 times the replacement doses of testosterone over many years, making it unjustifiable to extrapolate from trials using replacement doses. A substantial fraction of AAS users also use other drugs that are perceived to be muscle-building or performance-enhancing, such as growth hormone; erythropoiesisstimulating agents; insulin; and stimulants such as amphetamine, clenbuterol, cocaine, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as human chorionic gonadotropin, aromatase inhibitors, or estrogen antagonists. The men who abuse AAS are
Table 7e-2 Potential Adverse Effects Associated with the Use of Anabolic-Androgenic Steroids (AAS)
Females Neuropsychiatric
Hematologic Hepatic
Musculoskeletal Kidney Dermatologic
Abbreviation: HPT axis, hypothalamic-pituitary-testicular axis. Source: Modified with permission from HG Pope Jr et al: Adverse health consequences of performance-enhancing drugs: an endocrine society scientific statement. Endocr Rev 35:341, 2014.
more likely to engage in other high-risk behaviors than nonusers. The adverse events associated with AAS use may be due to AAS themselves, concomitant use of other drugs, high-risk behaviors, and host characteristics that may render these individuals more susceptible to AAS use or to other high-risk behaviors. The high rates of mortality and morbidities observed in AAS users are alarming. The risk of death among elite powerlifters has been reported to be fivefold greater than in age-matched men from the general population. The causes of death among powerlifters included suicides, myocardial infarction, hepatic coma, and non-Hodgkin’s lymphoma. Numerous reports of cardiac death among young AAS users raise concerns about the adverse cardiovascular effects of AAS. High doses of AAS may induce proatherogenic dyslipidemia, increase thrombosis risk via effects on clotting factors and platelets, induce vasospasm through their effects on vascular nitric oxide, and induce myocardial hypertrophy and fibrosis. Replacement doses of testosterone, when administered parenterally, are associated with only a small decrease in high-density lipoprotein (HDL) cholesterol and little or no effect on total cholesterol, lowdensity lipoprotein (LDL) cholesterol, and triglyceride levels. In contrast, supraphysiologic doses of testosterone and orally administered, 17-α-alkylated, nonaromatizable AAS are associated with marked reductions in HDL cholesterol and increases in LDL cholesterol. Long-term AAS use may be associated with myocardial hypertrophy and fibrosis as well as shortening of QT intervals. AAS use suppresses LH and FSH secretion and inhibits endogenous testosterone production and spermatogenesis. Consequently, stopping AAS may be associated with sexual dysfunction, fatigue, infertility, and depressive symptoms.
Approach to THE Patient: AAS Use AAS users generally mistrust physicians and seek medical help infrequently; when they do seek medical help, it is often for the treatment of AAS withdrawal syndrome, infertility, gynecomastia, or other medical or psychiatric complications of AAS use. The suspicion of AAS use should be raised by increased hemoglobin and hematocrit levels; suppressed luteinizing hormone (LH), folliclestimulating hormone (FSH), and testosterone levels; low HDL cholesterol; and low testicular volume and sperm density in a person who looks highly muscular (Table 7e-3). A combination of these findings and a self-report of AAS use by the patient, which usually can be elicited by a tactful interview, are often sufficient to establish a diagnosis in clinical practice. Accredited laboratories use gas chromatography and mass spectrometry or liquid chromatography and mass spectrometry to detect AAS abuse. In recent years, the availability of high-resolution mass spectrometry and tandem mass spectrometry has further improved the sensitivity of detecting AAS abuse. Illicit testosterone use is most often detected by the urinary testosterone-toepitestosterone ratio and further confirmed by the use of the 13C:12C
Table 7e-3 Detection of the Use of Anabolic-Androgenic Steroids Clinical indicators that should raise suspicion of anabolic-androgenic steroid use Very muscular phenotype Reduced testicular volume (140/90 mmHg) and proteinuria (either a 24 hour urinary protein >300 mg/24 h, or a protein-creatinine ratio ≥0.3) after 20 weeks of gestation. Although the precise pathophysiology of preeclampsia remains unknown, recent studies show excessive placental production of antagonists to both vascular epithelial growth factor (VEGF) and transforming growth factor β (TGF-β). These antagonists to VEGF and TGF-β disrupt endothelial and renal glomerular function resulting in edema, hypertension, and proteinuria. The renal histological feature of preeclampsia is glomerular endotheliosis. Glomerular endothelial cells are swollen and encroach on the vascular lumen. Preeclampsia is associated with abnormalities of cerebral circulatory autoregulation, which increase the risk of stroke at mildly and moderately elevated blood pressures. Risk factors for the development of preeclampsia include nulliparity, diabetes mellitus, a history of renal disease or chronic hypertension, a prior history of preeclampsia, extremes of maternal age (>35 years or 160/110 mmHg), evidence of central nervous system (CNS) dysfunction (headaches, blurred vision, seizures, coma), renal dysfunction (oliguria or creatinine >1.5 mg/dL), pulmonary edema, hepatocellular injury (serum alanine aminotransferase level more than twofold the upper limit of normal), hematologic dysfunction (platelet count 160/110 mmHg reduces the risk of cerebrovascular accidents. IV labetalol or hydralazine is most commonly used to acutely manage severe hypertension in preeclampsia; labetalol is associated with fewer episodes of maternal hypotension. Oral nifedipine and labetalol are commonly used to manage hypertension in pregnancy. Elevated arterial pressure should be reduced slowly to avoid hypotension and a decrease in blood flow to the fetus. Angiotensin-converting enzyme (ACE) inhibitors as well as angiotensin-receptor blockers should be avoided in the second and third trimesters of pregnancy because of their adverse effects on fetal development. Magnesium sulfate is the preferred agent for the prevention and treatment of eclamptic seizures. Large, randomized clinical trials have demonstrated the superiority of magnesium sulfate over phenytoin and diazepam in reducing the risk of seizure and, possibly, the risk of maternal death. Magnesium may prevent seizures by interacting with N-methyl-d-aspartate (NMDA) receptors in the CNS. Given the difficulty of predicting eclamptic seizures on the basis of disease severity, once the decision to proceed with delivery is made, most patients carrying a diagnosis of preeclampsia should be treated with magnesium sulfate. Women who have had preeclampsia appear to be at increased risk of cardiovascular and renal disease later in life. CHRONIC ESSENTIAL HYPERTENSION Pregnancy complicated by chronic essential hypertension is associated with intrauterine growth restriction and increased perinatal mortality.
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Pregnant women with chronic hypertension are at increased risk for superimposed preeclampsia and abruptio placentae. Women with chronic hypertension should have a thorough prepregnancy evaluation, both to identify remediable causes of hypertension and to ensure that the prescribed antihypertensive agents (e.g., ACE inhibitors, angiotensin-receptor blockers) are not associated with an adverse outcome of pregnancy. α-Methyldopa, labetalol, and nifedipine are the most commonly used medications for the treatment of chronic hypertension in pregnancy. The target blood pressure is in the range of 130–150 mmHg systolic and 80–100 mmHg diastolic. Should hypertension worsen during pregnancy, baseline evaluation of renal function (see below) is necessary to help differentiate the effects of chronic hypertension from those of superimposed preeclampsia. There are no convincing data that the treatment of mild chronic hypertension improves perinatal outcome. GESTATIONAL HYPERTENSION The development of elevated blood pressure during pregnancy or in the first 24 h post-partum in the absence of preexisting chronic hypertension or proteinuria is referred to as gestational hypertension. Mild gestational hypertension that does not progress to preeclampsia has not been associated with adverse pregnancy outcome or adverse long-term prognosis. RENAL DISEASE (See also Chaps. 333 and 341) Normal pregnancy is characterized by an increase in glomerular filtration rate and creatinine clearance. This increase occurs secondary to a rise in renal plasma flow and increased glomerular filtration pressures. Patients with underlying renal disease and hypertension may expect a worsening of hypertension during pregnancy. If superimposed preeclampsia develops, the additional endothelial injury results in a capillary leak syndrome that may make management challenging. In general, patients with underlying renal disease and hypertension benefit from aggressive management of blood pressure. Preconception counseling is also essential for these patients so that accurate risk assessment and medication changes can occur prior to pregnancy. In general, a prepregnancy serum creatinine level 90%) in the repair of tympanic membrane perforations. Otoscopy is usually sufficient to diagnose AOM, SOM, chronic otitis media, cerumen impaction, tympanic membrane perforation, and eustachian tube dysfunction; tympanometry can be useful to confirm the clinical suspicion of these conditions.
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External acoustic meatus
Semicircular canals
Middle ear Stapes
Semicircular canals
Incus
Anterior
Membranous labyrinth (contains endolymph)
Posterior
Cochlea
Malleus
Bony labyrinth (contains perilymph)
Vestibulocochlear nerve
Inner ear
Ampulla of semicircular canal
Lateral
Utricle Saccule
Auricle or pinna
Cochlea
PART 2
Tympanic membrane
External acoustic canal
Vestibule
Oval window
Eustachian tube
Round window
Lobe
A
Cochlear duct
B
Cardinal Manifestations and Presentation of Diseases
External ear
Figure 43-1 Ear anatomy. A. Drawing of modified coronal section through external ear and temporal bone, with structures of the middle and inner ear demonstrated. B. High-resolution view of inner ear. Cholesteatoma, a benign tumor composed of stratified squamous epithelium in the middle ear or mastoid, occurs frequently in adults. This is a slowly growing lesion that destroys bone and normal ear tissue. Theories of pathogenesis include traumatic immigration and invasion of squamous epithelium through a retraction pocket, implantation of squamous epithelia in the middle ear through a perforation or surgery, and metaplasia following chronic infection and irritation.
On examination, there is often a perforation of the tympanic membrane filled with cheesy white squamous debris. The presence of an aural polyp obscuring the tympanic membrane is highly suggestive of an underlying cholesteatoma. A chronically draining ear that fails to respond to appropriate antibiotic therapy should raise suspicion of a cholesteatoma. Conductive hearing loss secondary to ossicular erosion is common. Surgery is required to remove this destructive process.
Hearing Loss Cerumen impaction TM perforation Cholesteatoma SOM AOM External auditory canal atresia/ stenosis Eustachian tube dysfunction Tympanosclerosis
History abnormal
normal Otologic examination
Conductive HL
Mixed HL
Impedance audiometry
Impedance audiometry
normal Otosclerosis Cerumen impaction Ossicular fixation Cholesteatoma* Temporal bone trauma* Inner ear dehiscence or “third window”
abnormal
normal
AOM SOM TM perforation* Eustachian tube dysfunction Cerumen impaction Cholesteatoma* Temporal bone trauma* Ossicular discontinuity* Middle ear tumor*
Stapes gusher syndrome* Inner ear malformation* Otosclerosis Temporal bone trauma* Inner ear dehiscence or “third window”
Pure tone and speech audiometry
SNHL
abnormal AOM TM perforation* Cholesteatoma* Temporal bone trauma* Middle ear tumors* glomus tympanicum glomus jugulare
Chronic
Acute Asymmetric/symmetric CNS infection† Tumors† Cerebellopontine angle CNS Stroke† Trauma*
Asymmetric
Symmetric
Inner ear malformation* Presbycusis Noise exposure Radiation therapy
MRI/BAER normal Endolymphatic hydrops Labyrinthitis* Perilymphatic fistula* Radiation therapy
abnormal Labyrinthitis* Inner ear malformations* Cerebellopontine angle tumors Arachnoid cyst; facial nerve tumor; lipoma; meningioma; vestibular schwannoma Multiple sclerosis†
Figure 43-2 An algorithm for the approach to hearing loss. AOM, acute otitis media; BAER, brainstem auditory evoked response; CNS, central nervous system; HL, hearing loss; SNHL, sensorineural hearing loss; SOM, serous otitis media; TM, tympanic membrane. *Computed tomography scan of temporal bone. †Magnetic resonance imaging (MRI) scan.
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10 20 Right Left 50 dB SRT 55 dB 64% Disc. 70%
30 dB HL
40 50 60 70 80 90 100 250
500
1000
2000
4000
8000
Frequency (Hz)
Figure 43-3 Presbyacusis or age-related hearing loss. The audiogram shows a moderate to severe downsloping sensorineural hearing loss typical of presbyacusis. The loss of high-frequency hearing is associated with a decreased speech discrimination score; consequently, patients complain of lack of clarity of hearing, especially in a noisy background. HL, hearing threshold level; SRT, speech reception threshold.
Disorders of Hearing
Sensorineural Hearing Loss Sensorineural hearing loss results from either damage to the mechanotransduction apparatus of the cochlea or disruption of the electrical conduction pathway from the inner ear to the brain. Thus, injury to hair cells, supporting cells, auditory neurons, or the central auditory pathway can cause sensorineural hearing loss. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs (e.g., salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, loop diuretics such as furosemide and ethacrynic acid, and cancer chemotherapeutic agents such as cisplatin), fractures of the temporal bone, meningitis, cochlear otosclerosis (see above), Ménière’s disease, and aging. Congenital malformations of the inner ear may be the cause of hearing loss in some adults. Genetic predisposition alone or in concert with environmental exposures may also be responsible (see below). Presbycusis (age-associated hearing loss) is the most common cause of sensorineural hearing loss in adults. In the early stages, it is characterized by symmetric, gentle to sharply sloping high-frequency hearing loss (Fig. 43-3). With progression, the hearing loss involves all frequencies. More importantly, the hearing impairment is associated with significant loss in clarity. There is a loss of discrimination for phonemes, recruitment (abnormal growth of loudness), and particular difficulty in understanding speech in noisy environments such as at restaurants and social events. Hearing aids are helpful in enhancing the signal-to-noise ratio by amplifying sounds that are close to the listener. Although hearing aids are able to amplify sounds, they cannot restore the clarity of hearing. Thus, amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove inadequate, even when hearing loss is incomplete (see below). Ménière’s disease is characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Tinnitus and/ or deafness may be absent during the initial attacks of vertigo, but it
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Conductive hearing loss with a normal ear canal and intact tympanic membrane suggests either ossicular pathology or the presence of “third window” in the inner ear (see below). Fixation of the stapes from otosclerosis is a common cause of low-frequency conductive hearing loss. It occurs equally in men and women and is inherited as an autosomal dominant trait with incomplete penetrance; in some cases, it may be a manifestation of osteogenesis imperfecta. Hearing impairment usually presents between the late teens and the forties. In women, the otosclerotic process is accelerated during pregnancy, and the hearing loss is often first noticeable at this time. A hearing aid or a simple outpatient surgical procedure (stapedectomy) can provide adequate auditory rehabilitation. Extension of otosclerosis beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis is of uncertain value. Disorders that lead to the formation of a pathologic “third window” in the inner ear can be associated with conductive hearing loss. There are normally two major openings, or windows, that connect the inner ear with the middle ear and serve as conduits for transmission of sound; these are, respectively, the oval and round windows. A third window is formed where the normally hard otic bone surrounding the inner ear is eroded; dissipation of the acoustic energy at the third window is responsible for the “inner ear conductive hearing loss.” The superior semicircular canal dehiscence syndrome resulting from erosion of the otic bone over the superior circular canal can present with conductive hearing loss that mimics otosclerosis. A common symptom is vertigo evoked by loud sounds (Tullio phenomenon), by Valsalva maneuvers that change middle ear pressure, or by applying positive pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this syndrome also complain of being able to hear the movement of their eyes and neck. A large jugular bulb or jugular bulb diverticulum can create a “third window” by eroding into the vestibular aqueduct or posterior semicircular canal; the symptoms are similar to those of the superior semicircular canal dehiscence syndrome.
invariably appears as the disease progresses and increases in severity during acute attacks. The annual incidence of Ménière’s disease is 0.5– 7.5 per 1000; onset is most frequently in the fifth decade of life but may also occur in young adults or the elderly. Histologically, there is distention of the endolymphatic system (endolymphatic hydrops) leading to degeneration of vestibular and cochlear hair cells. This may result from endolymphatic sac dysfunction secondary to infection, trauma, autoimmune disease, inflammatory causes, or tumor; an idiopathic etiology constitutes the largest category and is most accurately referred to as Ménière’s disease. Although any pattern of hearing loss can be observed, typically, low-frequency, unilateral sensorineural hearing impairment is present. Magnetic resonance imaging (MRI) should be obtained to exclude retrocochlear pathology such as a cerebellopontine angle tumor or demyelinating disorder. Therapy is directed toward the control of vertigo. A 2-g/d low-salt diet is the mainstay of treatment for control of rotatory vertigo. Diuretics, a short course of glucocorticoids, and intratympanic gentamicin may also be useful adjuncts in recalcitrant cases. Surgical therapy of vertigo is reserved for unresponsive cases and includes endolymphatic sac decompression, labyrinthectomy, and vestibular nerve section. Both labyrinthectomy and vestibular nerve section abolish rotatory vertigo in >90% of cases. Unfortunately, there is no effective therapy for hearing loss, tinnitus, or aural fullness from Ménière’s disease. Sensorineural hearing loss may also result from any neoplastic, vascular, demyelinating, infectious, or degenerative disease or trauma affecting the central auditory pathways. HIV leads to both peripheral and central auditory system pathology and is associated with sensorineural hearing impairment. Primary diseases of the central nervous system can also present with hearing impairment. Characteristically, a reduction in clarity of hearing and speech comprehension is much greater than the loss of the ability to hear pure tone. Auditory testing is consistent with an auditory neuropathy; normal otoacoustic emissions (OAE) and an abnormal auditory brainstem response (ABR) is typical (see below). Hearing loss can accompany hereditary sensorimotor neuropathies and inherited disorders of myelin. Tumors of the cerebellopontine angle such as vestibular schwannoma and meningioma usually present with asymmetric sensorineural hearing loss with greater deterioration of speech understanding than pure tone hearing. Multiple sclerosis may present with acute unilateral or bilateral hearing loss; typically, pure tone testing remains relatively stable while speech understanding
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PART 2 Cardinal Manifestations and Presentation of Diseases
fluctuates. Isolated labyrinthine infarction can present with acute hearing loss and vertigo due to a cerebrovascular accident involving the posterior circulation, usually the anterior inferior cerebellar artery; it may also be the heralding sign of impending catastrophic basilar artery infarction (Chap. 446). A finding of conductive and sensory hearing loss in combination is termed mixed hearing loss. Mixed hearing losses are due to pathology of both the middle and inner ear, as can occur in otosclerosis involving the ossicles and the cochlea, head trauma, chronic otitis media, cholesteatoma, middle ear tumors, and some inner ear malformations. Trauma resulting in temporal bone fractures may be associated with conductive, sensorineural, or mixed hearing loss. If the fracture spares the inner ear, there may simply be conductive hearing loss due to rupture of the tympanic membrane or disruption of the ossicular chain. These abnormalities can be surgically corrected. Profound hearing loss and severe vertigo are associated with temporal bone fractures involving the inner ear. A perilymphatic fistula associated with leakage of inner ear fluid into the middle ear can occur and may require surgical repair. An associated facial nerve injury is not uncommon. Computed tomography (CT) is best suited to assess fracture of the traumatized temporal bone, evaluate the ear canal, and determine the integrity of the ossicular chain and the involvement of the inner ear. Cerebrospinal fluid leaks that accompany temporal bone fractures are usually selflimited; the value of prophylactic antibiotics is uncertain. Tinnitus is defined as the perception of a sound when there is no sound in the environment. It may have a buzzing, roaring, or ringing quality and may be pulsatile (synchronous with the heartbeat). Tinnitus is often associated with either a conductive or sensorineural hearing loss. The pathophysiology of tinnitus is not well understood. The cause of the tinnitus can usually be determined by finding the cause of the associated hearing loss. Tinnitus may be the first symptom of a serious condition such as a vestibular schwannoma. Pulsatile tinnitus requires evaluation of the vascular system of the head to exclude vascular tumors such as glomus jugulare tumors, aneurysms, dural arteriovenous fistulas, and stenotic arterial lesions; it may also occur with SOM. It is most commonly associated with some abnormality of the jugular bulb such as a large jugular bulb or jugular bulb diverticulum. GENETIC CAUSES OF HEARING LOSS More than half of childhood hearing impairment is thought to be hereditary; hereditary hearing impairment (HHI) can also manifest later in life. HHI may be classified as either nonsyndromic, when hearing loss is the only clinical abnormality, or syndromic, when hearing loss is associated with anomalies in other organ systems. Nearly two-thirds of HHIs are nonsyndromic, and the remaining onethird are syndromic. Between 70 and 80% of nonsyndromic HHI is inherited in an autosomal recessive manner and designated DFNB; another 15–20% is autosomal dominant (DFNA). Less than 5% is X-linked (DFNX) or maternally inherited via the mitochondria. More than 150 loci harboring genes for nonsyndromic HHI have been mapped, with recessive loci outnumbering dominant; numerous genes have now been identified (Table 43-1). The hearing genes fall into the categories of structural proteins (MYH9, MYO7A, MYO15, TECTA, DIAPH1), transcription factors (POU3F4, POU4F3), ion channels (KCNQ4, SLC26A4), and gap junction proteins (GJB2, GJB3, GJB6). Several of these genes, including GJB2, TECTA, and TMC1, cause both autosomal dominant and recessive forms of nonsyndromic HHI. In general, the hearing loss associated with dominant genes has its onset in adolescence or adulthood, varies in severity, and progresses with age, whereas the hearing loss associated with recessive inheritance is congenital and profound. Connexin 26, product of the GJB2 gene, is particularly important because it is responsible for nearly 20% of all cases of childhood deafness; half of genetic deafness in children is GJB2-related. Two frameshift mutations, 35delG and 167delT, account for >50% of the cases; however, screening for these two mutations alone is insufficient, and sequencing of the entire gene is required to diagnose GJB2-related recessive deafness. The 167delT mutation is highly prevalent in Ashkenazi Jews; ~1 in 1765 individuals in this
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population are homozygous and affected. The hearing loss can also vary among the members of the same family, suggesting that other genes or factors influence the auditory phenotype. In addition to GJB2, several other nonsyndromic genes are associated with hearing loss that progresses with age. The contribution of genetics to presbycusis is also becoming better understood. Sensitivity to aminoglycoside ototoxicity can be maternally transmitted through a mitochondrial mutation. Susceptibility to noise-induced hearing loss may also be genetically determined. There are >400 syndromic forms of hearing loss. These include Usher’s syndrome (retinitis pigmentosa and hearing loss), Waardenburg’s syndrome (pigmentary abnormality and hearing loss), Pendred’s syndrome (thyroid organification defect and hearing loss), Alport’s syndrome (renal disease and hearing loss), Jervell and Lange-Nielsen syndrome (prolonged QT interval and hearing loss), neurofibromatosis type 2 (bilateral acoustic schwannoma), and mitochondrial disorders (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS]; myoclonic epilepsy and ragged red fibers [MERRF]; progressive external ophthalmoplegia [PEO]) (Table 43-2).
APPROACH TO THE PATIENT: Disorders of the Sense of Hearing The goal in the evaluation of a patient with auditory complaints is to determine (1) the nature of the hearing impairment (conductive vs sensorineural vs mixed), (2) the severity of the impairment (mild, moderate, severe, or profound), (3) the anatomy of the impairment (external ear, middle ear, inner ear, or central auditory pathway), and (4) the etiology. The history should elicit characteristics of the hearing loss, including the duration of deafness, unilateral versus bilateral involvement, nature of onset (sudden vs insidious), and rate of progression (rapid vs slow). Symptoms of tinnitus, vertigo, imbalance, aural fullness, otorrhea, headache, facial nerve dysfunction, and head and neck paresthesias should be noted. Information regarding head trauma, exposure to ototoxins, occupational or recreational noise exposure, and family history of hearing impairment may also be important. A sudden onset of unilateral hearing loss, with or without tinnitus, may represent a viral infection of the inner ear, vestibular schwannoma, or a stroke. Patients with unilateral hearing loss (sensory or conductive) usually complain of reduced hearing, poor sound localization, and difficulty hearing clearly with background noise. Gradual progression of a hearing deficit is common with otosclerosis, noise-induced hearing loss, vestibular schwannoma, or Ménière’s disease. Small vestibular schwannomas typically present with asymmetric hearing impairment, tinnitus, and imbalance (rarely vertigo); cranial neuropathy, in particular of the trigeminal or facial nerve, may accompany larger tumors. In addition to hearing loss, Ménière’s disease may be associated with episodic vertigo, tinnitus, and aural fullness. Hearing loss with otorrhea is most likely due to chronic otitis media or cholesteatoma. Examination should include the auricle, external ear canal, and tympanic membrane. The external ear canal of the elderly is often dry and fragile; it is preferable to clean cerumen with wall-mounted suction or cerumen loops and to avoid irrigation. In examining the eardrum, the topography of the tympanic membrane is more important than the presence or absence of the light reflex. In addition to the pars tensa (the lower two-thirds of the tympanic membrane), the pars flaccida (upper one-third of the tympanic membrane) above the short process of the malleus should also be examined for retraction pockets that may be evidence of chronic eustachian tube dysfunction or cholesteatoma. Insufflation of the ear canal is necessary to assess tympanic membrane mobility and compliance. Careful inspection of the nose, nasopharynx, and upper respiratory tract is indicated. Unilateral serous effusion should prompt a fiberoptic examination of the nasopharynx to exclude neoplasms. Cranial nerves should be evaluated with special attention to facial and trigeminal nerves, which are commonly affected with tumors involving the cerebellopontine angle.
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Gap junction Gap junction Cytoskeletal protein Cytoskeletal protein Chloride/iodide transporter Transmembrane protein Transmembrane protein Trafficking of membrane vesicles Transmembrane serine protease
Gene CDH23 GIPC3 STRC
Function Intercellular adherence protein PDZ domain containing protein Stereocilia protein
DFNB18 DFNB21 DFNB22 DFNB23 DFNB24 DFNB25
USH1C TECTA OTOA PCDH15 RDX GRXCR1
DFNB28 DFNB29 DFNB30 DFNB31 DFNB35 DFNB36 DFNB37 DFNB39 DFNB42 DFNB48 DFNB49 DFNB53 DFNB59 DFNB61 DFNB63 DFNB66/67 DFNB70 DFNB74 DFNB77 DFNB79 DFNB82 DFNB84
TRIOBP CLDN14 MYO3A WHRN ESRRB ESPN MYO6 HFG ILDR1 CIB2 MARVELD2 COL11A2 PJVK SLC26A5 LRTOMT/COMT2 LHFPL5 PNPT1 MSRB3 LOXHD1 TPRN GPSM2 PTPRQ
DFNB86 DFNB88 DFNB89 DFNB91 DFNB93 DFNB98
TBC1D24 ELMOD3 KARS GJB3 CABP2 TSPEAR
Unknown Tectorial membrane protein Gel attachment to nonsensory cell Morphogenesis and cohesion Cytoskeletal protein Reversible S-glutathionylation of proteins Cytoskeletal-organizing protein Tight junctions Hybrid motor-signaling myosin PDZ domain–containing protein Estrogen-related receptor beta protein Ca-insensitive actin-bundling protein Unconventional myosin Hepatocyte growth factor Ig-like domain-containing receptor Calcium and integrin binding protein Tight junction protein Collagen protein Zn-binding protein Motor protein Putative methyltransferase Tetraspan protein Mitochondrial-RNA-import protein Methionine sulfoxide reductase Stereociliary protein Unknown G protein signaling modulator Type III receptor-like protein-tyrosine phosphatase family GTPase-activating protein GTPase-activating protein Lysyl-tRNA synthetase Gap junction Calcium binding protein Epilepsy-associated repeats containing protein Protease inhibitor
SERPINB6
the head in the midline and the patient is asked whether the tone is heard in both ears or better in one ear than in the other. With a unilateral conductive hearing loss, the tone is perceived in the affected ear. With a unilateral sensorineural hearing loss, the tone is perceived in the unaffected ear. A 5-dB difference in hearing between the two ears is required for lateralization.
LABORATORY ASSESSMENT OF HEARIN Audiologic Assessment The minimum audiologic assessment for hearing loss should include the measurement of pure tone air-conduction and bone-conduction thresholds, speech reception threshold, word recognition score, tympanometry, acoustic reflexes, and acousticreflex decay. This test battery provides a screening evaluation of the entire auditory system and allows one to determine whether further G
Thyroid hormone–binding protein Cytoskeletal protein Potassium channel Gap junction Gap junction Gap junction Class II nonmuscle myosin Cell adhesion molecule Unknown Transmembrane protein Tectorial membrane protein Unknown Developmental gene Cytoskeletal protein Cytoskeletal protein Transcription factor Cytoskeletal protein Cytoskeletal protein Unconventional myosin Developmental gene Vesicular glutamate transporter Transcription factor Transmembrane protein Purinergic receptor Effector of epidermal growth factor– mediated signaling Unconventional myosin MicroRNA Tight junction protein Extracellular matrix protein Mitochondrial proapoptotic protein
Designation DFNB12 DFNB15/72/95 DFNB16
Function
The Rinne and Weber tuning fork tests, with a 512-Hz tuning fork, are used to screen for hearing loss, differentiate conductive from sensorineural hearing losses, and confirm the findings of audiologic evaluation. The Rinne test compares the ability to hear by air conduction with the ability to hear by bone conduction. The tines of a vibrating tuning fork are held near the opening of the external auditory canal, and then the stem is placed on the mastoid process; for direct contact, it may be placed on teeth or dentures. The patient is asked to indicate whether the tone is louder by air conduction or bone conduction. Normally, and in the presence of sensorineural hearing loss, a tone is heard louder by air conduction than by bone conduction; however, with conductive hearing loss of ≥30 dB (see “Audiologic Assessment,” below), the bone-conduction stimulus is perceived as louder than the air-conduction stimulus. For the Weber test, the stem of a vibrating tuning fork is placed on
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es
Ge
t
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Disorders of Hearing
DFNA48 MYO1A DFNA50 MIRN96 DFNA51 TJP2 DFNA56 TNC DFNA64 SMAC/DIABLO Autosomal Recessive DFNB1A GJB2 (CX26) DFNB1B GJB6 (CX30) DFNB2 MYO7A DFNB3 MYO15 DFNB4 PDS (SLC26A4) DFNB6 TMIE DFNB7/B11 TMC1 DFNB9 OTOF DFNB8/10 TMPRSS3
n
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Designation Gene Autosomal Dominant CRYM DFNA1 DIAPH1 DFNA2A KCNQ4 DFNA2B GJB3 (Cx31) DFNA3A GJB2 (Cx26) DFNA3B GJB6 (Cx30) DFNA4 MYH14 CEACAM16 DFNA5 DFNA5 DFNA6/14/38 WFS1 DFNA8/12 TECTA DFNA9 COCH DFNA10 EYA4 DFNA11 MYO7A DFNA13 COL11A2 DFNA15 POU4F3 DFNA17 MYH9 DFNA20/26 ACTG1 DFNA22 MYO6 DFNA23 SIX1 DFNA25 SLC17AB DFNA28 TFCP2L3 DFNA36 TMC1 DFNA41 P2RX2 DFNA44 CCDC50
i
rme
ing
Impa
yH
ear
i
tar
ered
TABLE 43-1 H
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Syndrome Alport’s syndrome BOR syndrome
n
es
Ge
n
t
i
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ing
Impa
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ear
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tar
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c
o i H m
dr
TABLE 43-2 Syn
222
Gene COL4A3-5 EYA1 SIX5 SIX1 KCNQ1
Function Cytoskeletal protein Developmental gene Developmental gene Developmental gene Delayed rectifier K+ channel
Norrie’s disease Pendred’s syndrome
KCNE1 NDP SLC26A4 FOXI1
Treacher Collins syndrome
KCNJ10 TCOF1 POLR1D POLR1C
Delayed rectifier K+ channel Cell-cell interactions Chloride/iodide transporter Transcriptional activator of SLC26A4 Inwardly rectifying K+ channel Nucleolar-cytoplasmic transport Subunit of RNA polymerases I and III Subunit of RNA polymerases I and III Cytoskeletal protein Unknown Intercellular adherence protein Cell adhesion molecule Harmonin-associated protein Calcium and integrin binding protein Cell adhesion molecule G protein–coupled receptor PDZ domain–containing protein Cellular synapse protein? PDZ domain containing protein Transcription factor Transcription factor Transcription factor Endothelin B receptor Endothelin B receptor ligand Transcription factor
Jervell and LangeNielsen syndrome
PART 2 Cardinal Manifestations and Presentation of Diseases
Usher’s syndrome
WS type I, III WS type II WS type IV
MYO7A USH1C CDH23 PCDH15 SANS CIB2 USH2A VLGR1 WHRN CLRN1 PDZD7 PAX3 MITF SNAI2 EDNRB EDN3 SOX10
Abbreviations: BOR, branchio-oto-renal syndrome; WS, Waardenburg’s syndrome.
differentiation of a sensory (cochlear) from a neural (retrocochlear) hearing loss is indicated. Pure tone audiometry assesses hearing acuity for pure tones. The test is administered by an audiologist and is performed in a soundattenuated chamber. The pure tone stimulus is delivered with an audiometer, an electronic device that allows the presentation of specific frequencies (generally between 250 and 8000 Hz) at specific intensities. Air- and bone-conduction thresholds are established for each ear. Air-conduction thresholds are determined by presenting the stimulus in air with the use of headphones. Bone-conduction thresholds are determined by placing the stem of a vibrating tuning fork or an oscillator of an audiometer in contact with the head. In the presence of a hearing loss, broad-spectrum noise is presented to the nontest ear for masking purposes so that responses are based on perception from the ear under test. The responses are measured in decibels. An audiogram is a plot of intensity in decibels of hearing threshold versus frequency. A decibel (dB) is equal to 20 times the logarithm of the ratio of the sound pressure required to achieve threshold in the patient to the sound pressure required to achieve threshold in a normal-hearing person. Therefore, a change of 6 dB represents doubling of sound pressure, and a change of 20 dB represents a tenfold change in sound pressure. Loudness, which depends on the frequency, intensity, and duration of a sound, doubles with approximately each 10-dB increase in sound pressure level. Pitch,
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on the other hand, does not directly correlate with frequency. The perception of pitch changes slowly in the low and high frequencies. In the middle tones, which are important for human speech, pitch varies more rapidly with changes in frequency. Pure tone audiometry establishes the presence and severity of hearing impairment, unilateral versus bilateral involvement, and the type of hearing loss. Conductive hearing losses with a large mass component, as is often seen in middle ear effusions, produce elevation of thresholds that predominate in the higher frequencies. Conductive hearing losses with a large stiffness component, as in fixation of the footplate of the stapes in early otosclerosis, produce threshold elevations in the lower frequencies. Often, the conductive hearing loss involves all frequencies, suggesting involvement of both stiffness and mass. In general, sensorineural hearing losses such as presbycusis affect higher frequencies more than lower frequencies (Fig. 43-3). An exception is Ménière’s disease, which is characteristically associated with low-frequency sensorineural hearing loss. Noise-induced hearing loss has an unusual pattern of hearing impairment in which the loss at 4000 Hz is greater than at higher frequencies. Vestibular schwannomas characteristically affect the higher frequencies, but any pattern of hearing loss can be observed. Speech recognition requires greater synchronous neural firing than is necessary for appreciation of pure tones. Speech audiometry tests the clarity with which one hears. The speech reception threshold (SRT) is defined as the intensity at which speech is recognized as a meaningful symbol and is obtained by presenting two-syllable words with an equal accent on each syllable. The intensity at which the patient can repeat 50% of the words correctly is the SRT. Once the SRT is determined, discrimination or word recognition ability is tested by presenting one-syllable words at 25–40 dB above the SRT. The words are phonetically balanced in that the phonemes (speech sounds) occur in the list of words at the same frequency that they occur in ordinary conversational English. An individual with normal hearing or conductive hearing loss can repeat 88–100% of the phonetically balanced words correctly. Patients with a sensorineural hearing loss have variable loss of discrimination. As a general rule, neural lesions produce greater deficits in discrimination than do cochlear lesions. For example, in a patient with mild asymmetric sensorineural hearing loss, a clue to the diagnosis of vestibular schwannoma is the presence of greater than expected deterioration in discrimination ability. Deterioration in discrimination ability at higher intensities above the SRT also suggests a lesion in the eighth nerve or central auditory pathways. Tympanometry measures the impedance of the middle ear to sound and is useful in diagnosis of middle ear effusions. A tympanogram is the graphic representation of change in impedance or compliance as the pressure in the ear canal is changed. Normally, the middle ear is most compliant at atmospheric pressure, and the compliance decreases as the pressure is increased or decreased (type A); this pattern is seen with normal hearing or in the presence of sensorineural hearing loss. Compliance that does not change with change in pressure suggests middle ear effusion (type B). With a negative pressure in the middle ear, as with eustachian tube obstruction, the point of maximal compliance occurs with negative pressure in the ear canal (type C). A tympanogram in which no point of maximal compliance can be obtained is most commonly seen with discontinuity of the ossicular chain (type Ad). A reduction in the maximal compliance peak can be seen in otosclerosis (type As). During tympanometry, an intense tone elicits contraction of the stapedius muscle. The change in compliance of the middle ear with contraction of the stapedius muscle can be detected. The presence or absence of this acoustic reflex is important in determining the etiology of hearing loss as well as in the anatomic localization of facial nerve paralysis. The acoustic reflex can help differentiate between conductive hearing loss due to otosclerosis and that caused by an inner ear “third window”: it is absent in otosclerosis and present in inner ear conductive hearing loss. Normal or elevated acoustic reflex thresholds in an individual with sensorineural hearing impairment suggest a cochlear hearing loss. An absent acoustic reflex in the setting of sensorineural
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hearing loss is not helpful in localizing the site of lesion. Assessment of acoustic reflex decay helps differentiate sensory from neural hearing losses. In neural hearing loss, such as with vestibular schwannoma, the reflex adapts or decays with time. OAEs generated by outer hair cells only can be measured with microphones inserted into the external auditory canal. The emissions may be spontaneous or evoked with sound stimulation. The presence of OAEs indicates that the outer hair cells of the organ of Corti are intact and can be used to assess auditory thresholds and to distinguish sensory from neural hearing losses.
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In general, conductive hearing losses are amenable to surgical correction, whereas sensorineural hearing losses are usually managed medically. Atresia of the ear canal can be surgically repaired, often with significant improvement in hearing. Tympanic membrane perforations due to chronic otitis media or trauma can be repaired with an outpatient tympanoplasty. Likewise, conductive hearing loss associated with otosclerosis can be treated by stapedectomy, which is successful in >95% of cases. Tympanostomy tubes allow
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Disorders of Hearing
Imaging Studies The choice of radiologic tests is largely determined by whether the goal is to evaluate the bony anatomy of the external, middle, and inner ear or to image the auditory nerve and brain. Axial and coronal CT of the temporal bone with fine 0.3- to 0.6-mm cuts is ideal for determining the caliber of the external auditory canal, integrity of the ossicular chain, and presence of middle ear or mastoid disease; it can also detect inner ear malformations. CT is also ideal for the detection of bone erosion with chronic otitis media and cholesteatoma. Pöschl reformatting in the plane of the superior semicircular canal is required for the identification of dehiscence or absence of bone over the superior semicircular canal. MRI is superior to CT for imaging of retrocochlear pathology such as vestibular schwannoma, meningioma, other lesions of the cerebellopontine angle, demyelinating lesions of the brainstem, and brain tumors. Both CT and MRI are equally capable of identifying inner ear malformations and assessing cochlear patency for preoperative evaluation of patients for cochlear implantation.
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Evoked Responses Electrocochleography measures the earliest evoked potentials generated in the cochlea and the auditory nerve. Receptor potentials recorded include the cochlear microphonic, generated by the outer hair cells of the organ of Corti, and the summating potential, generated by the inner hair cells in response to sound. The whole nerve action potential representing the composite firing of the first-order neurons can also be recorded during electrocochleography. Clinically, the test is useful in the diagnosis of Ménière’s disease, where an elevation of the ratio of summating potential to action potential is seen. Brainstem auditory evoked responses (BAERs), also known as auditory brainstem responses (ABRs), are useful in differentiating the site of sensorineural hearing loss. In response to sound, five distinct electrical potentials arising from different stations along the peripheral and central auditory pathway can be identified using computer averaging from scalp surface electrodes. BAERs are valuable in situations in which patients cannot or will not give reliable voluntary thresholds. They are also used to assess the integrity of the auditory nerve and brainstem in various clinical situations, including intraoperative monitoring, and in determination of brain death. The vestibular-evoked myogenic potential (VEMP) test elicits a vestibulocolic reflex whose afferent limb arises from acoustically sensitive cells in the saccule, with signals conducted via the inferior vestibular nerve. VEMP is a biphasic, short-latency response recorded from the tonically contracted sternocleidomastoid muscle in response to loud auditory clicks or tones. VEMPs may be diminished or absent in patients with early and late Ménière’s disease, vestibular neuritis, benign paroxysmal positional vertigo, and vestibular schwannoma. On the other hand, the threshold for VEMPs may be lower in cases of superior canal dehiscence, other inner ear dehiscence, and perilymphatic fistula.
the prompt return of normal hearing in individuals with middle ear effusions. Hearing aids are effective and well tolerated in patients with conductive hearing losses. Patients with mild, moderate, and severe sensorineural hearing losses are regularly rehabilitated with hearing aids of varying configuration and strength. Hearing aids have been improved to provide greater fidelity and have been miniaturized. The current generation of hearing aids can be placed entirely within the ear canal, thus reducing any stigma associated with their use. In general, the more severe the hearing impairment, the larger the hearing aid required for auditory rehabilitation. Digital hearing aids lend themselves to individual programming, and multiple and directional microphones at the ear level may be helpful in noisy surroundings. Because all hearing aids amplify noise as well as speech, the only absolute solution to the problem of noise is to place the microphone closer to the speaker than the noise source. This arrangement is not possible with a self-contained, cosmetically acceptable device. A significant limitation of rehabilitation with a hearing aid is that although it is able to enhance detection of sound with amplification, it cannot restore clarity of hearing that is lost with presbycusis. Patients with unilateral deafness have difficulty with sound localization and reduced clarity of hearing in background noise. They may benefit from a CROS (contralateral routing of signal) hearing aid in which a microphone is placed on the hearing-impaired side and the sound is transmitted to the receiver placed on the contralateral ear. The same result may be obtained with a bone-anchored hearing aid (BAHA), in which a hearing aid clamps to a screw integrated into the skull on the hearing-impaired side. Like the CROS hearing aid, the BAHA transfers the acoustic signal to the contralateral hearing ear, but it does so by vibrating the skull. Patients with profound deafness on one side and some hearing loss in the better ear are candidates for a BICROS hearing aid; it differs from the CROS hearing aid in that the patient wears a hearing aid, and not simply a receiver, in the better ear. Unfortunately, while CROS and BAHA devices provide benefit, they do not restore hearing in the deaf ear. Only cochlear implants can restore hearing (see below). Increasingly, cochlear implants are being investigated for the treatment of patients with single-sided deafness; early reports show great promise in not only restoring hearing but also improving sound localization and performance in background noise. In many situations, including lectures and the theater, hearingimpaired persons benefit from assistive devices that are based on the principle of having the speaker closer to the microphone than any source of noise. Assistive devices include infrared and frequency-modulated (FM) transmission as well as an electromagnetic loop around the room for transmission to the individual’s hearing aid. Hearing aids with telecoils can also be used with properly equipped telephones in the same way. In the event that the hearing aid provides inadequate rehabilitation, cochlear implants may be appropriate (Fig. 43-4). Criteria for implantation include severe to profound hearing loss with openset sentence cognition of ≤40% under best aided conditions. Worldwide, more than 300,000 hearing-impaired individuals have received cochlear implants. Cochlear implants are neural prostheses that convert sound energy to electrical energy and can be used to stimulate the auditory division of the eighth nerve directly. In most cases of profound hearing impairment, the auditory hair cells are lost but the ganglionic cells of the auditory division of the eighth nerve are preserved. Cochlear implants consist of electrodes that are inserted into the cochlea through the round window, speech processors that extract acoustical elements of speech for conversion to electrical currents, and a means of transmitting the electrical energy through the skin. Patients with implants experience sound that helps with speech reading, allows open-set word recognition, and helps in modulating the person’s own voice. Usually, within the first 3–6 months after implantation, adult patients can understand speech without visual cues. With the current generation of multichannel cochlear implants, nearly 75% of patients are able to converse on the telephone.
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224 1 Headpiece microphone Magnetic headpiece Back microphone
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4 Hearing nerve
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F gu 43-4 A cochlear implant is composed of an external microphone and speech processor worn on the ear and a receiver implanted underneath the temporalis muscle. The internal receiver is attached to an electrode that is placed surgically in the cochlea. i
Cardinal Manifestations and Presentation of Diseases
1 T-MicTM 2 microphone
The U.S. Food and Drug Administration recently approved the first hybrid cochlear implant for the treatment of high-frequency hearing loss. Patients with presbyacusis typically have normal lowfrequency hearing, while suffering from high-frequency hearing loss associated with loss of clarity that cannot always be adequately rehabilitated with a hearing aid. However, these patients are not candidates for conventional cochlear implants because they have too much residual hearing. The hybrid implant has been specifically designed for this patient population; it has a shorter electrode than a conventional cochlear implant and can be introduced into the cochlea atraumatically, thus preserving low-frequency hearing. Individuals with a hybrid implant use their own natural lowfrequency “acoustic” hearing and rely on the implant for providing “electrical” high-frequency hearing. Patients who have received the hybrid implant perform better on speech testing in both quiet and noisy backgrounds. For individuals who have had both eighth nerves destroyed by trauma or bilateral vestibular schwannomas (e.g., neurofibromatosis type 2), brainstem auditory implants placed near the cochlear nucleus may provide auditory rehabilitation. Tinnitus often accompanies hearing loss. As for background noise, tinnitus can degrade speech comprehension in individuals with hearing impairment. Therapy for tinnitus is usually directed toward minimizing the appreciation of tinnitus. Relief of the tinnitus may be obtained by masking it with background music. Hearing aids are also helpful in tinnitus suppression, as are tinnitus maskers, devices that present a sound to the affected ear that is more pleasant to listen to than the tinnitus. The use of a tinnitus
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masker is often followed by several hours of inhibition of the tinnitus. Antidepressants have been shown to be beneficial in helping patients cope with tinnitus. Hard-of-hearing individuals often benefit from a reduction in unnecessary noise in the environment (e.g., radio or television) to enhance the signal-to-noise ratio. Speech comprehension is aided by lip reading; therefore, the impaired listener should be seated so that the face of the speaker is well illuminated and easily seen. Although speech should be in a loud, clear voice, one should be aware that in sensorineural hearing losses in general and in hard-ofhearing elderly in particular, recruitment (abnormal perception of loud sounds) may be troublesome. Above all, optimal communication cannot take place without both parties giving it their full and undivided attention. PREVENTION Conductive hearing losses may be prevented by prompt antibiotic therapy of adequate duration for AOM and by ventilation of the middle ear with tympanostomy tubes in middle ear effusions lasting ≥12 weeks. Loss of vestibular function and deafness due to aminoglycoside antibiotics can largely be prevented by careful monitoring of serum peak and trough levels. Some 10 million Americans have noise-induced hearing loss, and 20 million are exposed to hazardous noise in their employment. Noiseinduced hearing loss can be prevented by avoidance of exposure to loud noise or by regular use of ear plugs or fluid-filled ear muffs to attenuate intense sound. Table 43-3 lists loudness levels for a variety of
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Abbreviation: OSHA, Occupational Safety and Health Administration.
Sound Level (dB) 90 92 95 97 100 102 105 110 115
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Duration per Day (h) 8 6 4 3 2 1.5 1 0.5 ≤0.25
Note: Exposure to impulsive or impact noise should not exceed 140-dB peak sound pressure level. Source: From https://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table= standards&p_id=9735.
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Sore Throat, Earache, and pper Respiratory Symptoms
225
Michael A. Rubin, Larry C. Ford, Ralph Gonzales
Infections of the upper respiratory tract (URIs) have a tremendous impact on public health. They are among the most common reasons for visits to primary care providers, and although the illnesses are typically mild, their high incidence and transmission rates place them among the leading causes of time lost from work or school. Even though a minority (~25%) of cases are caused by bacteria, URIs are the leading diagnoses for which antibiotics are prescribed on an outpatient basis in the United States. The enormous consumption of antibiotics for these illnesses has contributed to the rise in antibiotic resistance among common community-acquired pathogens such as Streptococcus pneumoniae—a trend that in itself has an enormous influence on public health. Although most URIs are caused by viruses, distinguishing patients with primary viral infection from those with primary bacterial infection is difficult. Signs and symptoms of bacterial and viral URIs are typically indistinguishable. Until consistent, inexpensive, and rapid testing becomes available and is used widely, acute infections will be diagnosed largely on clinical grounds. The judicious use and potential for misuse of antibiotics in this setting pose definite challenges.
NONSPECIFIC INFECTIONS OF THE PPER RESPIRATORY TRACT Nonspecific URIs are a broadly defined group of disorders that collectively constitute the leading cause of ambulatory care visits in the United States. By definition, nonspecific URIs have no prominent localizing features. They are identified by a variety of descriptive names, including acute infective rhinitis, acute rhinopharyngitis/ nasopharyngitis, acute coryza, and acute nasal catarrh, as well as by the inclusive label common cold. ETIOLO Y The large assortment of URI classifications reflects the wide variety of causative infectious agents and the varied manifestations of common pathogens. Nearly all nonspecific URIs are caused by viruses spanning multiple virus families and many antigenic types. For instance, there are at least 100 immunotypes of rhinovirus (Chap. 223), the most common cause of URI (~30–40% of cases); other causes include influenza virus (three immunotypes; Chap. 224) as well as parainfluenza virus (four immunotypes), coronavirus (at least three immunotypes), and adenovirus (47 immunotypes) (Chap. 223). Respiratory syncytial virus (RSV), a well-established pathogen in pediatric populations, is also a recognized cause of significant disease in elderly and immunocompromised individuals. A host of additional viruses, including some viruses not typically associated with URIs (e.g., enteroviruses, rubella virus, and varicella-zoster virus), account for a small percentage of cases in adults each year. Although new diagnostic modalities (e.g., nasopharyngeal swab for polymerase chain reaction [PCR]) can assign a viral etiology, there are few specific treatment options, and no pathogen is identified in a substantial proportion of cases. A specific diagnostic workup beyond a clinical diagnosis is generally unnecessary in an otherwise healthy adult.
Sore Throat, Earache, and Upper Respiratory Symptoms
environmental sounds. High-risk activities for noise-induced hearing loss include use of electrical equipment for wood and metal working and target practice or hunting with small firearms. All internalcombustion and electric engines, including snow and leaf blowers, snowmobiles, outboard motors, and chainsaws, require protection of the user with hearing protectors. Virtually all noise-induced hearing loss is preventable through education, which should begin before the teenage years. Programs for conservation of hearing in the workplace are required by the Occupational Safety and Health Administration (OSHA) whenever the exposure over an 8-h period averages 85 dB. OSHA mandates that workers in such noisy environments have hearing monitoring and protection programs that include a preemployment screen, an annual audiologic assessment, and the mandatory use of hearing protectors. Exposure to loud sounds above 85 dB in the work environment is restricted by OSHA, with halving of allowed exposure time for each increment of 5 dB above this threshold; for example, exposure to 90 dB is permitted for 8 h; 95 dB for 4 h, and 100 dB for 2 h (Table 43-4).
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Decibel (dB) 0 30 55–65 85 90 95 95 107 110 125 140 165 194
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Source Weakest sound heard Whisper Normal conversation City traffic inside car OSHA monitoring requirement begins Jackhammer Subway train at 200 ft Power mower Power saw Painful sound Jet engine at 100 feet 12-gauge shotgun blast Loudest sound that can occur
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CLINICAL MANIFESTATIONS The signs and symptoms of nonspecific URI are similar to those of other URIs but lack a pronounced localization to one particular anatomic location, such as the sinuses, pharynx, or lower airway. Nonspecific URI commonly presents as an acute, mild, and selflimited catarrhal syndrome with a median duration of ~1 week (range, 2–10 days). Signs and symptoms are diverse and frequently variable across patients, even when caused by the same virus. The principal
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Antibiotics have no role in the treatment of uncomplicated nonspecific URI, and their misuse facilitates the emergence of antimicrobial resistance; in healthy volunteers, a single course of a commonly prescribed antibiotic like azithromycin can result in macrolide resistance in oral streptococci many months later. In the absence of clinical evidence of bacterial infection, treatment remains entirely symptom based, with use of decongestants and nonsteroidal antiinflammatory drugs. Clinical trials of zinc, vitamin C, echinacea, and other alternative remedies have revealed no consistent benefit in the treatment of nonspecific URI.
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INFECTIONS OF THE SIN S Rhinosinusitis refers to an inflammatory condition involving the nasal sinuses. Although most cases of sinusitis involve more than one sinus, the maxillary sinus is most commonly involved; next, in order of frequency, are the ethmoid, frontal, and sphenoid sinuses. Each sinus is lined with a respiratory epithelium that produces mucus, which is transported out by ciliary action through the sinus ostium and into the nasal cavity. Normally, mucus does not accumulate in the sinuses, which remain mostly sterile despite their adjacency to the bacteriumfilled nasal passages. When the sinus ostia are obstructed or when ciliary clearance is impaired or absent, the secretions can be retained, producing the typical signs and symptoms of sinusitis. As these secretions accumulate with obstruction, they become more susceptible to infection with a variety of pathogens, including viruses, bacteria, and fungi. Sinusitis affects a tremendous proportion of the population, accounts for millions of visits to primary care physicians each year, and is the fifth leading diagnosis for which antibiotics are prescribed. It typically is classified by duration of illness (acute vs. chronic); by etiology (infectious vs. noninfectious); and, when infectious, by the offending pathogen type (viral, bacterial, or fungal). U
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AC TE RHINOSIN SITIS Acute rhinosinusitis—defined as sinusitis of 30% prevalence of penicillin-resistant Streptococcus pneumoniae: Amoxicillin/clavulanate (extended release), 2000/125 mg PO bid; or An antipneumococcal fluoroquinolone (e.g., moxifloxacin, 400 mg PO daily) Recent treatment failure: Amoxicillin/clavulanate (extended release), 2000 mg PO bid; or An antipneumococcal fluoroquinolone (e.g., moxifloxacin, 400 mg PO daily)
The duration of therapy is generally 7–10 days (with consideration of a 5-day course), with appropriate follow-up. Severe disease may warrant IV antibiotics and consideration of hospital admission. bAlthough the evidence is not as strong, amoxicillin/clavulanate may be considered for initial use, particularly if local rates of penicillin resistance or β-lactamase production are high.
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Most patients with a clinical diagnosis of acute rhinosinusitis improve without antibiotic therapy. The preferred initial approach in patients with mild to moderate symptoms of short duration is therapy aimed at symptom relief and facilitation of sinus drainage, such as with oral and topical decongestants, nasal saline lavage, and—at least in patients with a history of chronic sinusitis or allergies—nasal glucocorticoids. Newer studies have cast doubt on the role of antibiotics and nasal glucocorticoids in acute rhinosinusitis. In one notable double-blind, randomized, placebo-controlled trial, neither antibiotics nor topical glucocorticoids had a significant impact on cure in the study population of patients, the majority of whom had had symptoms for 12 weeks. This illness is most commonly associated with either bacteria or fungi, and clinical cure in most cases is very difficult. Many patients have undergone treatment with repeated courses of antibacterial agents and multiple sinus surgeries, increasing their risk of colonization with antibiotic-resistant pathogens and of surgical complications. These patients often have high rates of morbidity, sometimes over many years. In chronic bacterial sinusitis, infection is thought to be due to the impairment of mucociliary clearance from repeated infections rather than to persistent bacterial infection. The pathogenesis of this U
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Diagnostic Criteria Moderate symptoms (e.g., nasal purulence/ congestion or cough) for >10 d or Severe symptoms of any duration, including unilateral/focal facial swelling or tooth pain
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Diagnosis Distinguishing viral from bacterial rhinosinusitis in the ambulatory setting is usually difficult because of the relatively low sensitivity and specificity of the common clinical features. One clinical feature that has been used to help guide diagnostic and therapeutic decision-making is illness duration. Because acute bacterial sinusitis is uncommon in patients whose symptoms have lasted 10 days in adults or >10–14 days in children) accompanied by the three cardinal signs of purulent nasal discharge, nasal obstruction, and facial pain (Table 44-1). Even among patients who meet these criteria, only 40–50% have true bacterial sinusitis. The use of CT or sinus radiography is not recommended for acute disease, particularly early in the course of illness (i.e., at 2 yrs or 6 mo to 2 yrs without middle-ear effusion Observation alone (deferring antibiotic therapy for 48–72 h and limiting management to symptom relief ) 2 yrs with bilateral disease, TM perforation, high Exposure to antibiotics within 30 d or recent treatment failurea,b: fever, immunocompromise, emesis Amoxicillin, 90 mg/kg qd (up to 2 g) PO in divided doses (bid), plus clavulanate,
As above, with temperature ≥39.0°C (102°F); or Moderate to severe otalgia
6.4 mg/kg qd PO in divided doses (bid); or Ceftriaxone, 50 mg/kg IV/IM qd for 3 d; or Clindamycin, 30–40 mg/kg qd PO in divided doses (tid) Initial therapya Amoxicillin, 90 mg/kg qd (up to 2 g) PO in divided doses (bid), plus clavulanate, 6.4 mg/kg qd PO in divided doses (bid); or Ceftriaxone, 50 mg/kg IV/IM qd for 3 d Exposure to antibiotics within 30 d or recent treatment failurea,b Ceftriaxone, 50 mg/kg IV/IM qd for 3 d; or Clindamycin, 30–40 mg/kg qd PO in divided doses (tid); or Consider tympanocentesis with culture
Duration (unless otherwise specified): 10 days for patients 85% of the predicted maximum, if the anaerobic threshold occurs early, if the blood pressure becomes excessively high or decreases during exercise, if the O2 pulse (O2 consumption/heart rate, an indicator of stroke volume) falls, or if there are ischemic changes on the electrocardiogram, an abnormality of the cardiovascular system is likely the explanation for the breathing discomfort. TREATMENT
Dyspnea
The first goal is to correct the underlying problem responsible for the symptom. If this is not possible, an effort is made to lessen the intensity of the symptom and its effect on the patient’s quality of life. Supplemental O2 should be administered if the resting O2 saturation is ≤89% or if the patient’s saturation drops to these levels with activity. For patients with COPD, pulmonary rehabilitation programs have demonstrated positive effects on dyspnea, exercise capacity, and rates of hospitalization. Studies of anxiolytics and antidepressants have not documented consistent benefit. Experimental interventions—e.g., cold air on the face, chest wall vibration, and inhaled furosemide—aimed at modulating the afferent information from receptors throughout the respiratory system are being studied. Morphine has been shown to reduce dyspnea out of proportion to the change in ventilation in laboratory models.
PULMONARY EDEMA MECHANISMS OF FLUID ACCUMULATION The extent to which fluid accumulates in the interstitium of the lung depends on the balance of hydrostatic and oncotic forces within the pulmonary capillaries and in the surrounding tissue. Hydrostatic pressure favors movement of fluid from the capillary into the interstitium. The oncotic pressure, which is determined by the protein concentration in the blood, favors movement of fluid into the vessel. Levels of albumin, the primary protein in the plasma, may be low in conditions such as cirrhosis and nephrotic syndrome. While hypoalbuminemia favors movement of fluid into the tissue for any given hydrostatic pressure in the capillary, it is usually not sufficient by itself to cause interstitial edema. In a healthy individual, the tight junctions of the capillary endothelium are impermeable to proteins, and the lymphatics in the tissue carry away the small amounts of protein that may leak out; together, these factors result in an oncotic force that maintains fluid in the capillary. Disruption of the endothelial barrier, however, allows protein to escape the capillary bed and enhances the movement of fluid into the tissue of the lung. CARDIOGENIC PULMONARY EDEMA (See also Chap. 326) Cardiac abnormalities that lead to an increase in pulmonary venous pressure shift the balance of forces between the capillary and the interstitium. Hydrostatic pressure is increased and fluid exits the capillary at an increased rate, resulting in interstitial and, in more severe cases, alveolar edema. The development of pleural effusions may further compromise respiratory system function and contribute to breathing discomfort. Early signs of pulmonary edema include exertional dyspnea and orthopnea. Chest radiographs show peribronchial thickening, prominent vascular markings in the upper lung zones, and Kerley B lines. As the pulmonary edema worsens, alveoli fill with fluid; the chest radiograph shows patchy alveolar filling, typically in a perihilar distribution, which then progresses to diffuse alveolar infiltrates. Increasing airway edema is associated with rhonchi and wheezes. NONCARDIOGENIC PULMONARY EDEMA In noncardiogenic pulmonary edema, lung water increases due to damage of the pulmonary capillary lining with consequent leakage of proteins and other macromolecules into the tissue; fluid follows the protein as oncotic forces are shifted from the vessel to the surrounding lung tissue. This process is associated with dysfunction of the surfactant lining the alveoli, increased surface forces, and a propensity for the alveoli to collapse at low lung volumes. Physiologically, noncardiogenic pulmonary edema is characterized by intrapulmonary shunt with hypoxemia and decreased pulmonary compliance leading to lower functional residual capacity. On pathologic examination, hyaline membranes are evident in the alveoli, and inflammation leading to pulmonary fibrosis may be seen. Clinically, the picture ranges from mild dyspnea to respiratory failure. Auscultation of the lungs may be relatively normal despite chest radiographs that show diffuse alveolar infiltrates. CT scans demonstrate that the distribution of alveolar edema is more heterogeneous than was once thought. Although normal intracardiac pressures are considered by many to be part of the definition of noncardiogenic pulmonary edema, the pathology of the process, as described above, is distinctly different, and a combination of cardiogenic and noncardiogenic pulmonary edema is observed in some patients. It is useful to categorize the causes of noncardiogenic pulmonary edema in terms of whether the injury to the lung is likely to result from direct, indirect, or pulmonary vascular causes (Table 47e-3). Direct injuries are mediated via the airways (e.g., aspiration) or as the consequence of blunt chest trauma. Indirect injury is the consequence of mediators that reach the lung via the bloodstream. The third category includes conditions that may result from acute changes in pulmonary vascular pressures, possibly due to sudden autonomic discharge (in the case of neurogenic and high-altitude pulmonary edema) or sudden swings of pleural pressure as well as transient damage to the pulmonary capillaries (in the case of reexpansion pulmonary edema).
Table 47e-3 Common Causes of Noncardiogenic Pulmonary Edema
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CHAPTER 47e Dyspnea
Direct Injury to Lung Chest trauma, pulmonary contusion Aspiration Smoke inhalation Pneumonia Oxygen toxicity Pulmonary embolism, reperfusion Hematogenous Injury to Lung Sepsis Pancreatitis Nonthoracic trauma Leukoagglutination reactions Multiple transfusions Intravenous drug use (e.g., heroin) Cardiopulmonary bypass Possible Lung Injury Plus Elevated Hydrostatic Pressures High-altitude pulmonary edema Neurogenic pulmonary edema Reexpansion pulmonary edema
DISTINGUISHING CARDIOGENIC FROM NONCARDIOGENIC PULMONARY EDEMA The history is essential for assessing the likelihood of underlying cardiac disease as well as for identification of one of the conditions associated with noncardiogenic pulmonary edema. The physical examination in cardiogenic pulmonary edema is notable for evidence of increased intracardiac pressures (S3 gallop, elevated jugular venous pulse, peripheral edema) and rales and/or wheezes on auscultation of the chest. In contrast, the physical examination in noncardiogenic pulmonary edema is dominated by the findings of the precipitating condition; pulmonary findings may be relatively normal in the early stages. The chest radiograph in cardiogenic pulmonary edema typically shows an enlarged cardiac silhouette, vascular redistribution, interstitial thickening, and perihilar alveolar infiltrates; pleural effusions are common. In noncardiogenic pulmonary edema, heart size is normal, alveolar infiltrates are distributed more uniformly throughout the lungs, and pleural effusions are uncommon. Finally, . the hypoxemia of cardiogenic pulmonary edema is due largely to V/Q to mismatch and responds to the administration of supplemental oxygen. In contrast, hypoxemia in noncardiogenic pulmonary edema is due primarily to intrapulmonary shunting and typically persists despite high concentrations of inhaled oxygen.
Section 5 Alterations in Circulatory and Respiratory Functions 12
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Patient’s Predicted
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CHAPTER 48
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Figure 48-1 Flow-volume curve shows spikes of high expiratory flow achieved with cough. FEV1, forced expiratory volume in 1 s.
48
Cough and Hemoptysis Patricia A. Kritek, Christopher H. Fanta
COUGH Cough performs an essential protective function for human airways and lungs. Without an effective cough reflex, we are at risk for retained airway secretions and aspirated material predisposing to infection, atelectasis, and respiratory compromise. At the other extreme, excessive coughing can be exhausting; can be complicated by emesis, syncope, muscular pain, or rib fractures; and can aggravate abdominal or inguinal hernias and urinary incontinence. Cough is often a clue to the presence of respiratory disease. In many instances, cough is an expected and accepted manifestation of disease, as in acute respiratory tract infection. However, persistent cough in the absence of other respiratory symptoms commonly causes patients to seek medical attention. COUGH MECHANISM Spontaneous cough is triggered by stimulation of sensory nerve endings that are thought to be primarily rapidly adapting receptors and C fibers. Both chemical (e.g., capsaicin) and mechanical (e.g., particulates in air pollution) stimuli may initiate the cough reflex. A cationic ion channel—the type 1 vanilloid receptor—found on rapidly adapting receptors and C fibers is the receptor for capsaicin, and its expression is increased in patients with chronic cough. Afferent nerve endings richly innervate the pharynx, larynx, and airways to the level of the terminal bronchioles and extend into the lung parenchyma. They may also be located in the external auditory meatus (the auricular branch of the vagus nerve, or the Arnold nerve) and in the esophagus. Sensory signals travel via the vagus and superior laryngeal nerves to a region of the brainstem in the nucleus tractus solitarius vaguely identified as the “cough center.” The cough reflex involves a highly orchestrated series of involuntary muscular actions, with the potential for input from cortical pathways as well. The vocal cords adduct, leading to transient upper-airway occlusion. Expiratory muscles contract, generating positive intrathoracic pressures as high as 300 mmHg. With sudden release of the laryngeal contraction, rapid expiratory flows are generated,
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exceeding the normal “envelope” of maximal expiratory flow seen on the flow-volume curve (Fig. 48-1). Bronchial smooth-muscle contraction together with dynamic compression of airways narrows airway lumens and maximizes the velocity of exhalation. The kinetic energy available to dislodge mucus from the inside of airway walls is directly proportional to the square of the velocity of expiratory airflow. A deep breath preceding a cough optimizes the function of the expiratory muscles; a series of repetitive coughs at successively lower lung volumes sweeps the point of maximal expiratory velocity progressively further into the lung periphery.
Cough and Hemoptysis
–8
IMPAIRED COUGH Weak or ineffective cough compromises the ability to clear lower respiratory tract infections, predisposing to more serious infections and their sequelae. Weakness, paralysis, or pain of the expiratory (abdominal and intercostal) muscles is foremost on the list of causes of impaired cough (Table 48-1). Cough strength is generally assessed qualitatively; peak expiratory flow or maximal expiratory pressure at the mouth can be used as a surrogate marker for cough strength. A variety of assistive devices and techniques have been developed to improve cough strength, running the gamut from simple (splinting of the abdominal muscles with a tightly-held pillow to reduce postoperative pain while coughing) to complex (a mechanical cough-assist device supplied via face mask or tracheal tube that applies a cycle of positive pressure followed rapidly by negative pressure). Cough may fail to clear secretions despite a preserved ability to generate normal expiratory velocities; such failure may be due to either abnormal airway secretions (e.g., bronchiectasis due to cystic fibrosis) or structural abnormalities of the airways (e.g., tracheomalacia with expiratory collapse during cough). SYMPTOMATIC COUGH The cough of chronic bronchitis in long-term cigarette smokers rarely leads the patient to seek medical advice. It lasts for only seconds to a Table 48-1 Causes of Impaired Cough Decreased expiratory-muscle strength Decreased inspiratory-muscle strength Chest wall deformity Impaired glottic closure or tracheostomy Tracheomalacia Abnormal airway secretions Central respiratory depression (e.g., anesthesia, sedation, or coma)
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few minutes, is productive of benign-appearing mucoid sputum, and generally does not cause discomfort. Cough may occur in the context of other respiratory symptoms that together point to a diagnosis; for example, cough accompanied by wheezing, shortness of breath, and chest tightness after exposure to a cat or other sources of allergens suggests asthma. At times, however, cough is the dominant or sole symptom of disease, and it may be of sufficient duration and severity that relief is sought. The duration of cough is a clue to its etiology. Acute cough (8 weeks) may be caused by a wide variety of cardiopulmonary diseases, including those of inflammatory, infectious, neoplastic, and cardiovascular etiologies. When initial assessment with chest examination and radiography is normal, cough-variant asthma, gastroesophageal reflux, nasopharyngeal drainage, and medications (angiotensin-converting enzyme [ACE] inhibitors) are the most common causes of chronic cough. ASSESSMENT OF CHRONIC COUGH Details as to the sound, the time of occurrence during the day, and the pattern of coughing infrequently provide useful etiologic clues. Regardless of cause, cough often worsens upon first lying down at night, with talking, or with the hyperpnea of exercise; it frequently improves with sleep. An exception may involve the cough that occurs only with certain allergic exposures or exercise in cold air, as in asthma. Useful historical questions include what circumstances surround the onset of cough, what makes the cough better or worse, and whether or not the cough produces sputum. The physical examination seeks clues suggesting the presence of cardiopulmonary disease, including findings such as wheezing or crackles on chest examination. Examination of the auditory canals and tympanic membranes (for irritation of the latter resulting in stimulation of Arnold’s nerve), the nasal passageways (for rhinitis or polyps), and the nails (for clubbing) may also provide etiologic clues. Because cough can be a manifestation of a systemic disease such as sarcoidosis or vasculitis, a thorough general examination is equally important. In virtually all instances, evaluation of chronic cough merits a chest radiograph. The list of diseases that can cause persistent cough without other symptoms and without detectable abnormalities on physical examination is long. It includes serious illnesses such as sarcoidosis or Hodgkin’s disease in young adults, lung cancer in older patients, and (worldwide) pulmonary tuberculosis. An abnormal chest film prompts an evaluation aimed at explaining the cough. In a patient with chronic productive cough, examination of expectorated sputum is warranted. Purulent-appearing sputum should be sent for routine bacterial culture and, in certain circumstances, mycobacterial culture as well. Cytologic examination of mucoid sputum may be useful to assess for malignancy and to distinguish neutrophilic from eosinophilic bronchitis. Expectoration of blood—whether streaks of blood, blood mixed with airway secretions, or pure blood—deserves a special approach to assessment and management (see “Hemoptysis,” below). CHRONIC COUGH WITH A NORMAL CHEST RADIOGRAPH It is commonly held that (alone or in combination) the use of an ACE inhibitor; postnasal drainage; gastroesophageal reflux; and asthma account for more than 90% of cases of chronic cough with a normal or noncontributory chest radiograph. However, clinical experience does not support this contention, and strict adherence to this concept discourages the search for alternative explanations by both clinicians and researchers. ACE inhibitor–induced cough occurs in 5–30% of patients taking these agents and is not dose dependent. ACE metabolizes bradykinin and other tachykinins, such as substance P. The mechanism of ACE inhibitor–associated cough may involve sensitization of sensory nerve endings due to accumulation of bradykinin. In support of this hypothesis, polymorphisms in the neurokinin-2 receptor gene are associated with ACE inhibitor–induced cough. Any patient with
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chronic unexplained cough who is taking an ACE inhibitor should have a trial period off the medication, regardless of the timing of the onset of cough relative to the initiation of ACE inhibitor therapy. In most instances, a safe alternative is available; angiotensin-receptor blockers do not cause cough. Failure to observe a decrease in cough after 1 month off medication argues strongly against this etiology. Postnasal drainage of any etiology can cause cough as a response to stimulation of sensory receptors of the cough-reflex pathway in the hypopharynx or aspiration of draining secretions into the trachea. Clues suggesting this etiology include postnasal drip, frequent throat clearing, and sneezing and rhinorrhea. On speculum examination of the nose, excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, and/or polyps may be seen; in addition, secretions or a cobblestoned appearance of the mucosa along the posterior pharyngeal wall may be noted. Unfortunately, there is no means by which to quantitate postnasal drainage. In many instances, this diagnosis must rely on subjective information provided by the patient. This assessment must also be counterbalanced by the fact that many people who have chronic postnasal drainage do not experience cough. Linking gastroesophageal reflux to chronic cough poses similar challenges. It is thought that reflux of gastric contents into the lower esophagus may trigger cough via reflex pathways initiated in the esophageal mucosa. Reflux to the level of the pharynx (laryngopharyngeal reflux), with consequent aspiration of gastric contents, causes a chemical bronchitis and possibly pneumonitis that can elicit cough for days afterward. Retrosternal burning after meals or on recumbency, frequent eructation, hoarseness, and throat pain may be indicative of gastroesophageal reflux. Nevertheless, reflux may also elicit minimal or no symptoms. Glottic inflammation detected on laryngoscopy may be a manifestation of recurrent reflux to the level of the throat, but it is a nonspecific finding. Quantification of the frequency and level of reflux requires a somewhat invasive procedure to measure esophageal pH directly (either nasopharyngeal placement of a catheter with a pH probe into the esophagus for 24 h or endoscopic placement of a radiotransmitter capsule into the esophagus). The precise interpretation of test results that permits an etiologic linking of reflux events and cough remains debated. Again, assigning the cause of cough to gastroesophageal reflux must be weighed against the observation that many people with symptomatic reflux do not experience chronic cough. Cough alone as a manifestation of asthma is common among children but not among adults. Cough due to asthma in the absence of wheezing, shortness of breath, and chest tightness is referred to as “cough-variant asthma.” A history suggestive of cough-variant asthma ties the onset of cough to exposure to typical triggers for asthma and the resolution of cough to discontinuation of exposure. Objective testing can establish the diagnosis of asthma (airflow obstruction on spirometry that varies over time or reverses in response to a bronchodilator) or exclude it with certainty (a negative response to a bronchoprovocation challenge—e.g., with methacholine). In a patient capable of taking reliable measurements, home expiratory peak flow monitoring can be a cost-effective method to support or discount a diagnosis of asthma. Chronic eosinophilic bronchitis causes chronic cough with a normal chest radiograph. This condition is characterized by sputum eosinophilia in excess of 3% without airflow obstruction or bronchial hyperresponsiveness and is successfully treated with inhaled glucocorticoids. Treatment of chronic cough in a patient with a normal chest radiograph is often empirical and is targeted at the most likely cause(s) of cough as determined by history, physical examination, and possibly pulmonary-function testing. Therapy for postnasal drainage depends on the presumed etiology (infection, allergy, or vasomotor rhinitis) and may include systemic antihistamines; antibiotics; nasal saline irrigation; and nasal pump sprays with glucocorticoids, antihistamines, or anticholinergics. Antacids, histamine type 2 (H2) receptor antagonists, and proton-pump inhibitors are used to neutralize or decrease the production of gastric acid in gastroesophageal reflux disease; dietary changes, elevation of the head and torso during sleep, and medications to improve gastric emptying are additional therapeutic measures.
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Cough-variant asthma typically responds well to inhaled glucocorticoids and intermittent use of inhaled β-agonist bronchodilators. Patients who fail to respond to treatment targeting the common causes of chronic cough or who have had these causes excluded by appropriate diagnostic testing should undergo chest CT. Diseases causing cough that may be missed on chest x-ray include tumors, early interstitial lung disease, bronchiectasis, and atypical mycobacterial pulmonary infection. On the other hand, patients with chronic cough who have normal findings on chest examination, lung function testing, oxygenation assessment, and chest CT can be reassured as to the absence of serious pulmonary pathology.
Hemoptysis, the expectoration of blood from the respiratory tract, can arise at any location from the alveoli to the glottis. It is important to distinguish hemoptysis from epistaxis (bleeding from the nasopharynx) and hematemesis (bleeding from the upper gastrointestinal tract). Hemoptysis can range from the expectoration of blood-tinged sputum to that of life-threatening large volumes of bright red blood. For most patients, any degree of hemoptysis can cause anxiety and often prompts medical evaluation. While precise epidemiologic data are lacking, the most common etiology of hemoptysis is infection of the medium-sized airways. In the United States, the cause is usually viral or bacterial bronchitis. Hemoptysis can arise in the setting of acute bronchitis or during an exacerbation of chronic bronchitis. Worldwide, the most common cause of hemoptysis is infection with Mycobacterium tuberculosis, presumably because of the high prevalence of tuberculosis and its predilection for cavity formation. While these are the most common causes, the differential diagnosis for hemoptysis is extensive, and a step-wise approach to evaluation is appropriate.
ETIOLOGY One way to approach the source of hemoptysis is to search systematically for potential sites of bleeding from the alveolus to the mouth. Diffuse bleeding in the alveolar space, often referred to as diffuse alveolar hemorrhage (DAH), may present as hemoptysis. Causes of DAH can be inflammatory or noninflammatory. Inflammatory DAH is due to smallvessel vasculitis/capillaritis from a variety of diseases, including granulomatosis with polyangiitis and microscopic polyangiitis. Similarly,
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Cough and Hemoptysis
HEMOPTYSIS
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SYMPTOM-BASED TREATMENT OF COUGH Chronic idiopathic cough, also called cough hypersensitivity syndrome, is distressingly common. It is often experienced as a tickle or sensitivity in the throat, occurs more often in women, and is typically “dry” or at most productive of scant amounts of mucoid sputum. It can be exhausting, interfere with work, and cause social embarrassment. Once serious underlying cardiopulmonary pathology has been excluded, an attempt at cough suppression is appropriate. Most effective are narcotic cough suppressants, such as codeine or hydrocodone, which are thought to act in the “cough center” in the brainstem. The tendency of narcotic cough suppressants to cause drowsiness and constipation and their potential for addictive dependence limit their appeal for longterm use. Dextromethorphan is an over-the-counter, centrally acting cough suppressant with fewer side effects and less efficacy than the narcotic cough suppressants. Dextromethorphan is thought to have a different site of action than narcotic cough suppressants and can be used in combination with them if necessary. Benzonatate is thought to inhibit neural activity of sensory nerves in the cough-reflex pathway. It is generally free of side effects; however, its effectiveness in suppressing cough is variable and unpredictable. Case series have reported benefit from off-label use of gabapentin or amitriptyline for chronic idiopathic cough. Novel cough suppressants without the limitations of currently available agents are greatly needed. Approaches that are being explored include the development of neurokinin receptor antagonists, type 1 vanilloid receptor antagonists, and novel opioid and opioid-like receptor agonists.
systemic autoimmune diseases such as systemic lupus erythematosus can manifest as pulmonary capillaritis. Antibodies to the alveolar basement membrane, as are seen in Goodpasture’s disease, can also result in alveolar hemorrhage. In the early period after bone marrow transplantation, patients can develop a form of inflammatory DAH that can be catastrophic and life-threatening. The exact pathophysiology of this process is not well understood, but DAH should be suspected in patients with sudden-onset dyspnea and hypoxemia in the first 100 days after bone marrow transplantation. Alveoli can also bleed due to direct inhalational injury, including thermal injury from fires, inhalation of illicit substances (e.g., cocaine), and inhalation of toxic chemicals. If alveoli are irritated from any process, patients with thrombocytopenia, coagulopathy, or antiplatelet or anticoagulant use will be at increased risk of hemoptysis. Bleeding in hemoptysis most commonly arises from the small- to medium-sized airways. Irritation and injury of the bronchial mucosa can lead to small-volume bleeding. More significant hemoptysis can result from the proximity of the bronchial artery and vein to the airway, with these vessels and the bronchus running together in what is often referred to as the bronchovascular bundle. In the smaller airways, these blood vessels are close to the airspace, and lesser degrees of inflammation or injury can therefore result in their rupture into the airways. While alveolar hemorrhage arises from capillaries that are part of the low-pressure pulmonary circulation, bronchial bleeding generally originates from bronchial arteries, which are under systemic pressure and thus are predisposed to larger-volume bleeding. Any infection of the airways can result in hemoptysis, although acute bronchitis is most commonly caused by viral infection. In patients with a history of chronic bronchitis, bacterial superinfection with organisms such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis can also result in hemoptysis. Patients with bronchiectasis (a permanent dilation of the airways with loss of mucosal integrity) are particularly prone to hemoptysis due to chronic inflammation and anatomic abnormalities that bring the bronchial arteries closer to the mucosal surface. One common presentation of patients with advanced cystic fibrosis—the prototypical bronchiectatic lung disease—is hemoptysis, which can be life-threatening. Pneumonias of any sort can cause hemoptysis. Tuberculous infection, which can lead to bronchiectasis or cavitary pneumonia, is a very common cause of hemoptysis worldwide. Patients may present with a chronic cough productive of blood-streaked sputum or with largervolume bleeding. Rasmussen’s aneurysm (the dilation of a pulmonary artery in a cavity formed by previous tuberculous infection) remains a source of massive, life-threatening hemoptysis in the developing world. Community-acquired pneumonia and lung abscess can also result in bleeding. Once again, if the infection results in cavitation, there is a greater likelihood of bleeding due to erosion into blood vessels. Infections with Staphylococcus aureus and gram-negative rods (e.g., Klebsiella pneumoniae) are especially likely to cause necrotizing lung infections and thus to be associated with hemoptysis. While not common in North America, pulmonary paragonimiasis (i.e., infection with the lung fluke Paragonimus westermani) often presents as fever, cough, and hemoptysis. This infection is a public health issue in Southeast Asia and China and is frequently confused with active tuberculosis, in which the clinical picture can be similar. Paragonimiasis should be considered in recent immigrants from endemic areas who have new or recurrent hemoptysis. In addition, pulmonary paragonimiasis has been reported secondary to ingestion of crayfish or small crabs in the United States. Other causes of airway irritation resulting in hemoptysis include inhalation of toxic chemicals, thermal injury, and direct trauma from suctioning of the airways (particularly in intubated patients). All of these etiologies should be considered in light of the individual patient’s history and exposures. Perhaps the most feared cause of hemoptysis is bronchogenic lung cancer, although hemoptysis is a presenting symptom in only ∼10% of patients. Cancers arising in the proximal airways are much more likely to cause hemoptysis, but any malignancy in the chest can do so. Because both squamous cell carcinomas and small-cell carcinomas are
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more commonly in or adjacent to the proximal airways, and large at presentation, they are more often a cause of hemoptysis. These cancers can present with large-volume and life-threatening hemoptysis because of erosion into the hilar vessels. Carcinoid tumors, which are found almost exclusively as endobronchial lesions with friable mucosa, can also present with hemoptysis. In addition to cancers arising in the lung, metastatic disease in the pulmonary parenchyma can bleed. Malignancies that commonly metastasize to the lungs include renal cell, breast, colon, testicular, and thyroid cancers as well as melanoma. While hemoptysis is not a common manifestation of pulmonary metastases, the combination of multiple pulmonary nodules and hemoptysis should raise suspicion of this etiology. Finally, disease of the pulmonary vasculature can cause hemoptysis. Perhaps most frequently, congestive heart failure with transmission of elevated left atrial pressures can lead to rupture of small alveolar capillaries. These patients rarely present with bright red blood but more commonly have pink, frothy sputum or bloodtinged secretions. Patients with a focal jet of mitral regurgitation can present with an upper-lobe opacity on chest radiography together with hemoptysis. This finding is thought to be due to focal increases in pulmonary capillary pressure due to the regurgitant jet. Pulmonary arteriovenous malformations are prone to bleeding. Pulmonary embolism can also lead to the development of hemoptysis, which is generally associated with pulmonary infarction. Pulmonary arterial hypertension from other causes rarely results in hemoptysis. EVALUATION As with most signs of possible illness, the initial step in the evaluation of hemoptysis is a thorough history and physical examination (Fig. 48-2). As already mentioned, initial questioning should focus on ascertaining whether the bleeding is truly from the respiratory tract and not the nasopharynx or gastrointestinal tract; bleeding from the latter sources requires different approaches to evaluation and treatment.
of the bleeding (e.g., recent inhalation exposures) as well as any previous episodes of hemoptysis should be elicited during history-taking. Monthly hemoptysis in a woman suggests catamenial hemoptysis from pulmonary endometriosis. Moreover, the volume of blood expectorated is important not only in determining the cause but also in gauging the urgency for further diagnostic and therapeutic maneuvers. Patients rarely exsanguinate from hemoptysis but can effectively “drown” in aspirated blood. Large-volume hemoptysis, referred to as massive hemoptysis, is variably defined as hemoptysis of >200–600 mL in 24 h. Massive hemoptysis should be considered a medical emergency. All patients should be asked about current or former cigarette smoking; this behavior predisposes to chronic bronchitis and increases the likelihood of bronchogenic cancer. Practitioners should inquire about symptoms and signs suggestive of respiratory tract infection (including fever, chills, and dyspnea), recent inhalation exposures, recent use of illicit substances, and risk factors for venous thromboembolism. A medical history of malignancy or treatment thereof, rheumatologic disease, vascular disease, or underlying lung disease (e.g., bronchiectasis) may be relevant to the cause of hemoptysis. Because many causes of DAH can be part of a pulmonary-renal syndrome, specific inquiry into a history of renal insufficiency is important. The physical examination begins with an assessment of vital signs and oxygen saturation to gauge whether there is evidence of lifethreatening bleeding. Tachycardia, hypotension, and decreased oxygen saturation mandate a more expedited evaluation of hemoptysis. A specific focus on respiratory and cardiac examinations is important; these examinations should include inspection of the nares, auscultation of the lungs and heart, assessment of the lower extremities for symmetric or asymmetric edema, and evaluation for jugular venous distention. Clubbing of the digits may suggest underlying lung diseases such as bronchogenic carcinoma or bronchiectasis, which predispose to hemoptysis. Similarly, mucocutaneous telangiectasias should raise the specter of pulmonary arterial-venous malformations.
History and Physical Examination The specific characteristics of hemoptysis may be helpful in determining an etiology, such as whether the expectorated material consists of blood-tinged, purulent secretions; pink, frothy sputum; or pure blood. Information on specific triggers
Diagnostic Evaluation For most patients, the next step in evaluation of hemoptysis should be a standard chest radiograph. If a source of bleeding is not identified on plain film, CT of the chest should be performed. CT allows better delineation of bronchiectasis, alveolar filling, cavitary
Patient with hemoptysis Rule out other sources: • Oropharynx • Gastrointestinal tract
Mild
History and physical exam Quantify amount of bleeding Moderate
Massive
Secure airway
No risk factors*
Risk factors* or recurrent bleeding
CXR, CBC, coagulation studies, UA, creatinine
Treat underlying disease (usually infection)
CT scan if unrevealing, bronchoscopy
CT scan
Treat underlying disease
Bronchoscopy
Bleeding stops
Bleeding continues Embolization or resection
Treat underlying disease *Risk Factors: smoking, age >40
Persistent bleeding
Figure 48-2 Decision tree for evaluation of hemoptysis. CBC, complete blood count; CT, computed tomography; CXR, chest x-ray; UA, urinalysis.
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Hemoptysis
For the most part, the treatment of hemoptysis varies with its etiology. However, large-volume, life-threatening hemoptysis generally requires immediate intervention regardless of the cause. The first step is to establish a patent airway, usually by endotracheal intubation and subsequent mechanical ventilation. As large-volume hemoptysis usually arises from an airway lesion, it is ideal to identify the site of bleeding by either chest imaging or bronchoscopy (more commonly rigid rather than flexible). The goals are then to isolate the bleeding to one lung and not to allow the preserved airspaces in the other lung to be filled with blood so that gas exchange is further impaired. Patients should be placed with the bleeding lung in a dependent position (i.e., bleeding-side down), and, if possible, duallumen endotracheal tubes or an airway blocker should be placed in the proximal airway of the bleeding lung. These interventions generally require the assistance of anesthesiologists, interventional pulmonologists, or thoracic surgeons. If the bleeding does not stop with treatment of the underlying cause and the passage of time, severe hemoptysis from bronchial arteries can be treated with angiographic embolization of the responsible bronchial artery. This intervention should be entertained only in the most severe and life-threatening cases of hemoptysis because of the risk of unintentional spinal-artery embolization and consequent paraplegia. Endobronchial lesions can be treated with a variety of bronchoscopically directed interventions, including cauterization and laser therapy. In extreme circumstances, surgical resection of the affected region of the lung is considered. Most cases of hemoptysis resolve with treatment of the infection or inflammatory process or with removal of the offending stimulus.
49
Hypoxia and Cyanosis Joseph Loscalzo
HYPOXIA The fundamental purpose of the cardiorespiratory system is to deliver O2 and nutrients to cells and to remove CO2 and other metabolic products from them. Proper maintenance of this function depends not only on intact cardiovascular and respiratory systems, but also on an adequate number of red blood cells and hemoglobin and a supply of inspired gas containing adequate O2.
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TREATMENT
RESPONSES TO HYPOXIA Decreased O2 availability to cells results in an inhibition of oxidative phosphorylation and increased anaerobic glycolysis. This switch from aerobic to anaerobic metabolism, the Pasteur effect, maintains some, albeit reduced, adenosine 5′-triphosphate (ATP) production. In severe hypoxia, when ATP production is inadequate to meet the energy requirements of ionic and osmotic equilibrium, cell membrane depolarization leads to uncontrolled Ca2+ influx and activation of Ca2+-dependent phospholipases and proteases. These events, in turn, cause cell swelling, activation of apoptotic pathways, and, ultimately, cell death. The adaptations to hypoxia are mediated, in part, by the upregulation of genes encoding a variety of proteins, including glycolytic enzymes, such as phosphoglycerate kinase and phosphofructokinase, as well as the glucose transporters Glut-1 and Glut-2; and by growth factors, such as vascular endothelial growth factor (VEGF) and erythropoietin, which enhance erythrocyte production. The hypoxiainduced increase in expression of these key proteins is governed by the hypoxia-sensitive transcription factor, hypoxia-inducible factor-1 (HIF-1). During hypoxia, systemic arterioles dilate, at least in part, by opening of KATP channels in vascular smooth-muscle cells due to the hypoxia-induced reduction in ATP concentration. By contrast, in pulmonary vascular smooth-muscle cells, inhibition of K+ channels causes depolarization which, in turn, activates voltage-gated Ca2+ channels raising the cytosolic [Ca2+] and causing smooth-muscle cell contraction. Hypoxia-induced pulmonary arterial constriction shunts blood away from poorly ventilated portions toward better ventilated portions of the lung; however, it also increases pulmonary vascular resistance and right ventricular afterload.
CHAPTER 49
infiltrates, and masses than does chest radiograph. The practitioner should consider a CT protocol to assess for pulmonary embolism if the history or examination suggests venous thromboembolism as a cause of bleeding. Laboratory studies should include a complete blood count to assess both the hematocrit and the platelet count as well as coagulation studies. Renal function should be evaluated and urinalysis conducted because of the possibility of pulmonary-renal syndromes presenting with hemoptysis. The documentation of acute renal insufficiency or the detection of red blood cells or their casts on urinalysis should elevate suspicion of small-vessel vasculitis, and studies such as antineutrophil cytoplasmic antibody, antiglomerular basement membrane antibody, and antinuclear antibody should be considered. If a patient is producing sputum, Gram’s and acid-fast staining as well as culture should be undertaken. If all of these studies are unrevealing, bronchoscopy should be considered. In any patient with a history of cigarette smoking, airway inspection should be part of the evaluation of new-onset hemoptysis as endobronchial lesions are not reliably visualized on CT.
Effects on the Central Nervous System Changes in the central nervous system (CNS), particularly the higher centers, are especially important consequences of hypoxia. Acute hypoxia causes impaired judgment, motor incoordination, and a clinical picture resembling acute alcohol intoxication. High-altitude illness is characterized by headache secondary to cerebral vasodilation, gastrointestinal symptoms, dizziness, insomnia, fatigue, or somnolence. Pulmonary arterial and sometimes venous constriction causes capillary leakage and high-altitude pulmonary edema (HAPE) (Chap. 47e), which intensifies hypoxia, further promoting vasoconstriction. Rarely, high-altitude cerebral edema (HACE) develops, which is manifest by severe headache and papilledema and can cause coma. As hypoxia becomes more severe, the regulatory centers of the brainstem are affected, and death usually results from respiratory failure. Effects on the Cardiovascular System Acute hypoxia stimulates the chemoreceptor reflex arc to induce venoconstriction and systemic arterial vasodilation. These acute changes are accompanied by transiently increased myocardial contractility, which is followed by depressed myocardial contractility with prolonged hypoxia. CAUSES OF HYPOXIA Respiratory Hypoxia When hypoxia occurs from respiratory failure, Pao2 declines, and when respiratory failure is persistent, the hemoglobin-oxygen (Hb-O2) dissociation curve (see Fig. 127-2) is displaced to the right, with greater quantities of O2 released at any level of tissue Po2. Arterial hypoxemia, i.e., a reduction of O2 saturation of arterial blood (Sao2), and consequent cyanosis are likely to be more marked when such depression of Pao2 results from pulmonary disease than when the depression occurs as the result of a decline in the fraction of oxygen in inspired air (Fio2). In this latter situation, Paco2 falls secondary to anoxia-induced hyperventilation and the Hb-O2 dissociation curve is displaced to the left, limiting the decline in Sao2 at any level of Pao2. The most common cause of respiratory hypoxia is ventilationperfusion mismatch resulting from perfusion of poorly ventilated alveoli. Respiratory hypoxemia may also be caused by hypoventilation, in which case it is associated with an elevation of Paco2 (Chap. 306e). These two forms of respiratory hypoxia are usually correctable by
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inspiring 100% O2 for several minutes. A third cause of respiratory hypoxia is shunting of blood across the lung from the pulmonary arterial to the venous bed (intrapulmonary right-to-left shunting) by perfusion of nonventilated portions of the lung, as in pulmonary atelectasis or through pulmonary arteriovenous connections. The low Pao2 in this situation is only partially corrected by an Fio2 of 100%.
PART 2
Hypoxia Secondary to High Altitude As one ascends rapidly to 3000 m (~10,000 ft), the reduction of the O2 content of inspired air (Fio2) leads to a decrease in alveolar Po2 to approximately 60 mmHg, and a condition termed high-altitude illness develops (see above). At higher altitudes, arterial saturation declines rapidly and symptoms become more serious; and at 5000 m, unacclimated individuals usually cease to be able to function normally owing to the changes in CNS function described above.
Cardinal Manifestations and Presentation of Diseases
Hypoxia Secondary to Right-to-Left Extrapulmonary Shunting From a physiologic viewpoint, this cause of hypoxia resembles intrapulmonary right-to-left shunting but is caused by congenital cardiac malformations, such as tetralogy of Fallot, transposition of the great arteries, and Eisenmenger’s syndrome (Chap. 282). As in pulmonary right-toleft shunting, the Pao2 cannot be restored to normal with inspiration of 100% O2. Anemic Hypoxia A reduction in hemoglobin concentration of the blood is accompanied by a corresponding decline in the O2-carrying capacity of the blood. Although the Pao2 is normal in anemic hypoxia, the absolute quantity of O2 transported per unit volume of blood is diminished. As the anemic blood passes through the capillaries and the usual quantity of O2 is removed from it, the Po2 and saturation in the venous blood decline to a greater extent than normal. Carbon Monoxide (CO) Intoxication (See also Chap. 472e) Hemoglobin that binds with CO (carboxy-hemoglobin, COHb) is unavailable for O2 transport. In addition, the presence of COHb shifts the Hb-O2 dissociation curve to the left (see Fig. 127-2) so that O2 is unloaded only at lower tensions, further contributing to tissue hypoxia. Circulatory Hypoxia As in anemic hypoxia, the Pao2 is usually normal, but venous and tissue Po2 values are reduced as a consequence of reduced tissue perfusion and greater tissue O2 extraction. This pathophysiology leads to an increased arterial-mixed venous O2 difference (a-v-O2 difference), or gradient. Generalized circulatory hypoxia occurs in heart failure (Chap. 279) and in most forms of shock (Chap. 324). Specific Organ Hypoxia Localized circulatory hypoxia may occur as a result of decreased perfusion secondary to arterial obstruction, as in localized atherosclerosis in any vascular bed, or as a consequence of vasoconstriction, as observed in Raynaud’s phenomenon (Chap. 302). Localized hypoxia may also result from venous obstruction and the resultant expansion of interstitial fluid causing arteriolar compression and, thereby, reduction of arterial inflow. Edema, which increases the distance through which O2 must diffuse before it reaches cells, can also cause localized hypoxia. In an attempt to maintain adequate perfusion to more vital organs in patients with reduced cardiac output secondary to heart failure or hypovolemic shock, vasoconstriction may reduce perfusion in the limbs and skin, causing hypoxia of these regions. Increased O2 Requirements If the O2 consumption of tissues is elevated without a corresponding increase in perfusion, tissue hypoxia ensues and the Po2 in venous blood declines. Ordinarily, the clinical picture of patients with hypoxia due to an elevated metabolic rate, as in fever or thyrotoxicosis, is quite different from that in other types of hypoxia: the skin is warm and flushed owing to increased cutaneous blood flow that dissipates the excessive heat produced, and cyanosis is usually absent. Exercise is a classic example of increased tissue O2 requirements. These increased demands are normally met by several mechanisms operating simultaneously: (1) increase in the cardiac output and ventilation and, thus, O2 delivery to the tissues; (2) a preferential shift in blood flow to the exercising muscles by changing vascular resistances
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in the circulatory beds of exercising tissues, directly and/or reflexly; (3) an increase in O2 extraction from the delivered blood and a widening of the arteriovenous O2 difference; and (4) a reduction in the pH of the tissues and capillary blood, shifting the Hb-O2 curve to the right (see Fig. 127-2), and unloading more O2 from hemoglobin. If the capacity of these mechanisms is exceeded, then hypoxia, especially of the exercising muscles, will result. Improper Oxygen Utilization Cyanide (Chap. 473e) and several other similarly acting poisons cause cellular hypoxia. The tissues are unable to use O2, and, as a consequence, the venous blood tends to have a high O2 tension. This condition has been termed histotoxic hypoxia. ADAPTATION TO HYPOXIA An important component of the respiratory response to hypoxia originates in special chemosensitive cells in the carotid and aortic bodies and in the respiratory center in the brainstem. The stimulation of these cells by hypoxia increases ventilation, with a loss of CO2, and can lead to respiratory alkalosis. When combined with the metabolic acidosis resulting from the production of lactic acid, the serum bicarbonate level declines (Chap. 66). With the reduction of Pao2, cerebrovascular resistance decreases and cerebral blood flow increases in an attempt to maintain O2 delivery to the brain. However, when the reduction of Pao2 is accompanied by hyperventilation and a reduction of Paco2, cerebrovascular resistance rises, cerebral blood flow falls, and tissue hypoxia intensifies. The diffuse, systemic vasodilation that occurs in generalized hypoxia increases the cardiac output. In patients with underlying heart disease, the requirements of peripheral tissues for an increase of cardiac output with hypoxia may precipitate congestive heart failure. In patients with ischemic heart disease, a reduced Pao2 may intensify myocardial ischemia and further impair left ventricular function. One of the important compensatory mechanisms for chronic hypoxia is an increase in the hemoglobin concentration and in the number of red blood cells in the circulating blood, i.e., the development of polycythemia secondary to erythropoietin production (Chap. 131). In persons with chronic hypoxemia secondary to prolonged residence at a high altitude (>13,000 ft, 4200 m), a condition termed chronic mountain sickness develops. This disorder is characterized by a blunted respiratory drive, reduced ventilation, erythrocytosis, cyanosis, weakness, right ventricular enlargement secondary to pulmonary hypertension, and even stupor.
CYANOSIS Cyanosis refers to a bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin (i.e., deoxygenated hemoglobin) or of hemoglobin derivatives (e.g., methemoglobin or sulfhemoglobin) in the small blood vessels of those tissues. It is usually most marked in the lips, nail beds, ears, and malar eminences. Cyanosis, especially if developed recently, is more commonly detected by a family member than the patient. The florid skin characteristic of polycythemia vera (Chap. 131) must be distinguished from the true cyanosis discussed here. A cherry-colored flush, rather than cyanosis, is caused by COHb (Chap. 473e). The degree of cyanosis is modified by the color of the cutaneous pigment and the thickness of the skin, as well as by the state of the cutaneous capillaries. The accurate clinical detection of the presence and degree of cyanosis is difficult, as proved by oximetric studies. In some instances, central cyanosis can be detected reliably when the Sao2 has fallen to 85%; in others, particularly in dark-skinned persons, it may not be detected until it has declined to 75%. In the latter case, examination of the mucous membranes in the oral cavity and the conjunctivae rather than examination of the skin is more helpful in the detection of cyanosis. The increase in the quantity of reduced hemoglobin in the mucocutaneous vessels that produces cyanosis may be brought about either by an increase in the quantity of venous blood as a result of dilation of the venules (including precapillary venules) or by a reduction in the Sao2 in the capillary blood. In general, cyanosis becomes apparent when
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TABLE 49-1 Causes of Cyanosis Central Cyanosis Decreased arterial oxygen saturation Decreased atmospheric pressure—high altitude Impaired pulmonary function Alveolar hypoventilation Inhomogeneity in pulmonary ventilation and perfusion (perfusion of hypoventilated alveoli) Impaired oxygen diffusion Anatomic shunts Certain types of congenital heart disease Pulmonary arteriovenous fistulas Multiple small intrapulmonary shunts Hemoglobin with low affinity for oxygen Hemoglobin abnormalities Methemoglobinemia—hereditary, acquired Sulfhemoglobinemia—acquired Carboxyhemoglobinemia (not true cyanosis) Peripheral Cyanosis Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction
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Hypoxia and Cyanosis
DIFFERENTIAL DIAGNOSIS Central Cyanosis (Table 49-1) Decreased Sao2 results from a marked reduction in the Pao2. This reduction may be brought about by a decline in the Fio2 without sufficient compensatory alveolar hyperventilation to maintain alveolar Po2. Cyanosis usually becomes manifest in an ascent to an altitude of 4000 m (13,000 ft). Seriously impaired pulmonary function, through perfusion of unventilated or poorly ventilated areas of the lung or alveolar hypoventilation, is a common cause of central cyanosis (Chap. 306e).
This condition may occur acutely, as in extensive pneumonia or pulmonary edema, or chronically, with chronic pulmonary diseases (e.g., emphysema). In the latter situation, secondary polycythemia is generally present and clubbing of the fingers (see below) may occur. Another cause of reduced Sao2 is shunting of systemic venous blood into the arterial circuit. Certain forms of congenital heart disease are associated with cyanosis on this basis (see above and Chap. 282). Pulmonary arteriovenous fistulae may be congenital or acquired, solitary or multiple, microscopic or massive. The severity of cyanosis produced by these fistulae depends on their size and number. They occur with some frequency in hereditary hemorrhagic telangiectasia. Sao2 reduction and cyanosis may also occur in some patients with cirrhosis, presumably as a consequence of pulmonary arteriovenous fistulae or portal vein–pulmonary vein anastomoses. In patients with cardiac or pulmonary right-to-left shunts, the presence and severity of cyanosis depend on the size of the shunt relative to the systemic flow as well as on the Hb-O2 saturation of the venous blood. With increased extraction of O2 from the blood by the exercising muscles, the venous blood returning to the right side of the heart is more unsaturated than at rest, and shunting of this blood intensifies the cyanosis. Secondary polycythemia occurs frequently in patients in this setting and contributes to the cyanosis. Cyanosis can be caused by small quantities of circulating methemoglobin (Hb Fe3+) and by even smaller quantities of sulfhemoglobin (Chap. 127); both of these hemoglobin derivatives impair oxygen delivery to the tissues. Although they are uncommon causes of cyanosis, these abnormal hemoglobin species should be sought by spectroscopy when cyanosis is not readily explained by malfunction of the circulatory or respiratory systems. Generally, digital clubbing does not occur with them.
CHAPTER 49
the concentration of reduced hemoglobin in capillary blood exceeds 40 g/L (4 g/dL). It is the absolute, rather than the relative, quantity of reduced hemoglobin that is important in producing cyanosis. Thus, in a patient with severe anemia, the relative quantity of reduced hemoglobin in the venous blood may be very large when considered in relation to the total quantity of hemoglobin in the blood. However, since the concentration of the latter is markedly reduced, the absolute quantity of reduced hemoglobin may still be low, and, therefore, patients with severe anemia and even marked arterial desaturation may not display cyanosis. Conversely, the higher the total hemoglobin content, the greater the tendency toward cyanosis; thus, patients with marked polycythemia tend to be cyanotic at higher levels of Sao2 than patients with normal hematocrit values. Likewise, local passive congestion, which causes an increase in the total quantity of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin, such as methemoglobin (consequential or acquired) or sulfhemoglobin (Chap. 127), is present in blood. Cyanosis may be subdivided into central and peripheral types. In central cyanosis, the Sao2 is reduced or an abnormal hemoglobin derivative is present, and the mucous membranes and skin are both affected. Peripheral cyanosis is due to a slowing of blood flow and abnormally great extraction of O2 from normally saturated arterial blood; it results from vasoconstriction and diminished peripheral blood flow, such as occurs in cold exposure, shock, congestive failure, and peripheral vascular disease. Often in these conditions, the mucous membranes of the oral cavity or those beneath the tongue may be spared. Clinical differentiation between central and peripheral cyanosis may not always be simple, and in conditions such as cardiogenic shock with pulmonary edema, there may be a mixture of both types.
Peripheral Cyanosis Probably the most common cause of peripheral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vasoconstriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the CNS and heart, and cyanosis of the extremities may result even though the arterial blood is normally saturated. Arterial obstruction to an extremity, as with an embolus, or arteriolar constriction, as in cold-induced vasospasm (Raynaud’s phenomenon) (Chap. 302), generally results in pallor and coldness, and there may be associated cyanosis. Venous obstruction, as in thrombophlebitis or deep venous thrombosis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis.
APPROACH TO THE PATIENT: Cyanosis Certain features are important in arriving at the cause of cyanosis: 1. It is important to ascertain the time of onset of cyanosis. Cyanosis present since birth or infancy is usually due to congenital heart disease. 2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems is helpful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis. 3. The presence or absence of clubbing of the digits (see below) should be ascertained. The combination of cyanosis and clubbing is frequent in patients with congenital heart disease and right-to-left shunting and is seen occasionally in patients with pulmonary disease, such as lung abscess or pulmonary arteriovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits. 4. Pao2 and Sao2 should be determined, and, in patients with cyanosis in whom the mechanism is obscure, spectroscopic examination of the blood should be performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis).
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CLUBBING
PART 2
The selective bulbous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is termed clubbing; there is also increased sponginess of the soft tissue at the base of the clubbed nail. Clubbing may be hereditary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease (see above), infective endocarditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, asbestosis, sarcoidosis, lung abscess, cystic fibrosis, tuberculosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). In some instances, it is occupational, e.g., in jackhammer operators. Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, or hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperiosteal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritis-like changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of hypertrophic osteoarthropathy may be confirmed by bone radiograph or magnetic resonance imaging (MRI). Although the mechanism of clubbing is unclear, it appears to be secondary to humoral substances that cause dilation of the vessels of the distal digits as well as growth factors released from platelet precursors in the digital circulation. In certain circumstances, clubbing is reversible, such as following lung transplantation for cystic fibrosis.
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50
Edema Eugene Braunwald, Joseph Loscalzo
STARLING FORCES AND FLUID EXCHANGE About one-third of total-body water is confined to the extracellular space. Approximately 75% of the latter is interstitial fluid, and the remainder is the plasma. The forces that regulate the disposition of fluid between these two components of the extracellular compartment frequently are referred to as the Starling forces. The hydrostatic pressure within the capillaries and the colloid oncotic pressure in the interstitial fluid tend to promote movement of fluid from the vascular to the extravascular space. By contrast, the colloid oncotic pressure contributed by plasma proteins and the hydrostatic pressure within the interstitial fluid promote the movement of fluid into the vascular compartment. As a consequence, there is movement of water and diffusible solutes from the vascular space at the arteriolar end of the capillaries. Fluid is returned from the interstitial space into the vascular system at the venous end of the capillaries and by way of the lymphatics. These movements are usually balanced so that there is a steady state in the sizes of the intravascular and interstitial compartments, yet a large exchange between them occurs. However, if either the capillary hydrostatic pressure is increased and/or the oncotic pressure is reduced, a further net movement of fluid from intravascular to the interstitial spaces will take place. Edema is defined as a clinically apparent increase in the interstitial fluid volume, which develops when Starling forces are altered so that there is increased flow of fluid from the vascular system into the interstitium. Edema due to an increase in capillary pressure may result from an elevation of venous pressure caused by obstruction to venous and/ or lymphatic drainage. An increase in capillary pressure may be generalized, as occurs in heart failure, or it may be localized to one extremity when venous pressure is elevated due to unilateral thrombophlebitis (see below). The Starling forces also may be imbalanced when the colloid oncotic pressure of the plasma is reduced owing to any factor
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that may induce hypoalbuminemia, as when large quantities of protein are lost in the urine such as in the nephrotic syndrome (see below), or when synthesis is reduced in a severe catabolic state. CAPILLARY DAMAGE Edema may also result from damage to the capillary endothelium, which increases its permeability and permits the transfer of proteins into the interstitial compartment. Injury to the capillary wall can result from drugs (see below), viral or bacterial agents, and thermal or mechanical trauma. Increased capillary permeability also may be a consequence of a hypersensitivity reaction and of immune injury. Damage to the capillary endothelium is presumably responsible for inflammatory edema, which is usually nonpitting, localized, and accompanied by other signs of inflammation—i.e., erythema, heat, and tenderness. REDUCTION OF EFFECTIVE ARTERIAL VOLUME In many forms of edema, despite the increase in extracellular fluid volume, the effective arterial blood volume, a parameter that represents the filling of the arterial tree and that effectively perfuses the tissues, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance, by pooling of blood in the splanchnic veins (as in cirrhosis), and by hypoalbuminemia (Fig. 50-1A). As a consequence of underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the renal retention of sodium and, therefore, water, thereby restoring effective arterial volume, but sometimes also leading to or intensifying edema. RENAL FACTORS AND THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its substrate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties, particularly on the renal efferent arterioles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration fraction raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle. The renin-angiotensin-aldosterone system (RAAS) operates as both a hormonal and paracrine system. Its activation causes sodium and water retention and thereby contributes to edema formation. Blockade of the conversion of angiotensin I to AII and blockade of the AII receptor enhance sodium and water excretion and reduce many forms of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone in turn enhances sodium reabsorption (and potassium excretion) by the collecting tubule, further favoring edema formation. In patients with heart failure, not only is aldosterone secretion elevated but the biologic half-life of the hormone is prolonged secondary to the depression of hepatic blood flow, which reduces its hepatic catabolism and increases further the plasma level of the hormone. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial sodium channels) often induces a moderate diuresis in edematous states. ARGININE VASOPRESSIN (See also Chap. 404) The secretion of arginine vasopressin (AVP) occurs in response to increased intracellular osmolar concentration, and, by stimulating V2 receptors, AVP increases the reabsorption of free water in the distal tubules and collecting ducts of the kidneys, thereby increasing total-body water. Circulating AVP is elevated in many patients with heart failure secondary to a nonosmotic stimulus associated with decreased effective arterial volume and reduced compliance of the left atrium. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia.
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↓Extracellular fluid volume
Low output heart failure, Pericardial tamponade Constructive pericarditis
↓Oncotic pressure and/or ↑capillary permeability
↓Cardiac output Effective arterial volume
Activation of RAAS
SNS stimulation ↑Systemic and renal arterial vascular resistance
Renal H2O retention
Renal Na+ retention
A High-output cardiac failure
Sepsis
Cirrhosis
Arteriovenous fistula
Pregnancy
Arterial vasodilators
↓Systemic vascular resistance Effective arterial volume
Activation of arterial baroreceptors Nonosmotic AVP stimulation ↑Cardiac output
Renal H2O retention
SNS stimulation
Activation of RAAS
↑Systemic arterial, vascular, and renal resistance
Renal Na+ retention
Maintenance of arterial circulatory integrity B
Figure 50-1 Clinical conditions in which a decrease in cardiac output (A) and systemic vascular resistance (B) cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nervous system. (Modified from RW Schrier: Ann Intern Med 113:155, 1990.)
ENDOTHELIN-1 This potent peptide vasoconstrictor is released by endothelial cells. Its concentration in the plasma is elevated in patients with severe heart failure and contributes to renal vasoconstriction, sodium retention, and edema. NATRIURETIC PEPTIDES Atrial distention causes release into the circulation of atrial natriuretic peptide (ANP), a polypeptide; a high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. The closely
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Edema
Restoration of effective arterial volume
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Activation of ventricular and arterial receptors
Nonosmotic vasopressin stimulation
related brain natriuretic peptide (pre-prohormone BNP) is stored primarily in ventricular myocytes and is released when ventricular diastolic pressure rises. Released ANP and BNP (which is derived from its precursor) bind to the natriuretic receptor-A, which causes: (1) excretion of sodium and water by augmenting glomerular filtration rate, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone; and (2) dilation of arterioles and venules by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, elevated levels of natriuretic peptides have the capacity to oppose sodium retention in hypervolemic and edematous states. Although circulating levels of ANP and BNP are elevated in heart failure and in cirrhosis with ascites, the natriuretic peptides are not sufficiently potent to prevent edema formation. Indeed, in edematous states, resistance to the actions of natriuretic peptides may be increased, further reducing their effectiveness. Further discussion of the control of sodium and water balance is found in Chap. 64e. CLINICAL CAUSES OF EDEMA A weight gain of several kilograms usually precedes overt manifestations of generalized edema, and a similar weight loss from diuresis can be induced in a slightly edematous patient before “dry weight” is achieved. Anasarca refers to gross, generalized edema. Ascites (Chap. 59) and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema. Edema is recognized by the persistence of an indentation of the skin after pressure; this is known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. Edema may be present when the ring on a finger fits more snugly than in the past or when a patient complains of difficulty putting on shoes, particularly in the evening. Edema may also be recognized by puffiness of the face, which is most readily apparent in the periorbital areas.
GENERALIZED EDEMA The differences among the major causes of generalized edema are shown in Table 50-1. Cardiac, renal, hepatic, or nutritional disorders are responsible for a majority of patients with generalized edema. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions. Heart Failure (See also Chap. 279) In heart failure, the impaired systolic emptying of the ventricle(s) and/or the impairment of ventricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume. In addition, the heightened tone of the sympathetic nervous system causes renal vasoconstriction and reduction of glomerular filtration. In mild heart failure, a small increment of total blood volume may repair the deficit of
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TABLE 50-1 Principal Causes of Generalized Edema: History, Physical Examination, and Laboratory Findings Organ System Cardiac
Hepatic
PART 2
Renal (CRF)
Cardinal Manifestations and Presentation of Diseases
Renal (NS)
History Dyspnea with exertion prominent— often associated with orthopnea—or paroxysmal nocturnal dyspnea
Physical Examination Elevated jugular venous pressure, ventricular (S3) gallop; occasionally with displaced or dyskinetic apical pulse; peripheral cyanosis, cool extremities, small pulse pressure when severe Dyspnea uncommon, except if associ- Frequently associated with ascites; jugular ated with significant degree of ascites; venous pressure normal or low; blood presmost often a history of ethanol abuse sure lower than in renal or cardiac disease; one or more additional signs of chronic liver disease (jaundice, palmar erythema, Dupuytren’s contracture, spider angiomata, male gynecomastia; asterixis and other signs of encephalopathy) may be present Usually chronic: may be associated Elevated blood pressure; hypertensive retiwith uremic signs and symptoms, nopathy; nitrogenous fetor; pericardial friction including decreased appetite, altered rub in advanced cases with uremia (metallic or fishy) taste, altered sleep pattern, difficulty concentrating, restless legs, or myoclonus; dyspnea can be present, but generally less prominent than in heart failure Childhood diabetes mellitus; plasma Periorbital edema; hypertension cell dyscrasias
Laboratory Findings Elevated urea nitrogen-to-creatinine ratio common; serum sodium often diminished; elevated natriuretic peptides If severe, reductions in serum albumin, cholesterol, other hepatic proteins (transferrin, fibrinogen); liver enzymes elevated, depending on the cause and acuity of liver injury; tendency toward hypokalemia, respiratory alkalosis; macrocytosis from folate deficiency
Elevation of serum creatinine and cystatin C; albuminuria; hyperkalemia, metabolic acidosis, hyperphosphatemia, hypocalcemia, anemia (usually normocytic)
Proteinuria (≥3.5 g/d); hypoalbuminemia; hypercholesterolemia; microscopic hematuria
Abbreviations: CRF, chronic renal failure; NS, nephrotic syndrome. Source: Modified from GM Chertow: Approach to the patient with edema, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman (eds). Philadelphia, Saunders, 2003, pp 117–128.
effective arterial volume through the operation of Starling’s law of the heart, in which an increase in ventricular diastolic volume promotes a more forceful contraction and may thereby maintain the cardiac output. However, if the cardiac disorder is more severe, sodium and water retention continue, and the increment in blood volume accumulates in the venous circulation, raising venous pressure and causing edema (Fig. 50-1). The presence of heart disease, as manifested by cardiac enlargement and/or ventricular hypertrophy, together with evidence of cardiac failure, such as dyspnea, basilar rales, venous distention, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as echocardiography may be helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body. Edema of Renal Disease (See also Chap. 338) The edema that occurs during the acute phase of glomerulonephritis is characteristically associated with hematuria, proteinuria, and hypertension. Although some evidence supports the view that the fluid retention is due to increased capillary permeability, in most instances, the edema results from primary retention of sodium and water by the kidneys owing to renal insufficiency. This state differs from most forms of heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output. Patients with edema due to acute renal failure commonly have arterial hypertension as well as pulmonary congestion on chest roentgenogram, often without considerable cardiac enlargement, but they may not develop orthopnea. Patients with chronic renal failure may also develop edema due to primary renal retention of sodium and water. Nephrotic Syndrome and other Hypoalbuminemic States The primary alteration in the nephrotic syndrome is a diminished colloid oncotic pressure due to losses of large quantities (≥3.5 g/d) of protein into the urine. With severe hypoalbuminemia (50 years old, endoscopy is advocated to screen for Barrett’s metaplasia. The benefits and cost-effectiveness of this approach have not been validated in controlled studies. Ambulatory esophageal pH testing using a catheter method or a wireless capsule endoscopically attached to the esophageal wall is considered for drug-refractory symptoms and atypical symptoms like unexplained chest pain. High-resolution esophageal manometry is ordered when surgical treatment of GERD is considered. A low LES pressure predicts failure of drug therapy and provides a rationale to proceed to surgery. Poor esophageal body peristalsis raises concern about postoperative dysphagia and directs the choice of surgical technique. Nonacidic reflux may be detected by combined esophageal impedance-pH testing in medication-unresponsive patients. Upper endoscopy is recommended as the initial test in patients with unexplained dyspepsia who are >55 years old or who have alarm factors because of the purported elevated risks of malignancy and ulcer in these groups. However, endoscopic findings in unexplained dyspepsia include erosive esophagitis in 13%, peptic ulcer in 8%, and gastric or esophageal malignancy in only 0.3%. Management of patients 1 billion individuals suffer one or more episodes of acute diarrhea each year. Among the 100 million persons affected annually by acute diarrhea in the United States, nearly half must restrict activities, 10% consult physicians, ∼250,000 require hospitalization, and ∼5000 die (primarily the elderly). The annual economic burden to society may exceed $20 billion. Acute infectious diarrhea remains one of the most common causes of mortality in developing countries, particularly among impoverished infants, accounting for 1.8 million deaths per year. Recurrent, acute diarrhea in children in tropical countries results in environmental enteropathy with longterm impacts on physical and intellectual development. Constipation, by contrast, is rarely associated with mortality and is exceedingly common in developed countries, leading to frequent selfmedication and, in a third of those, to medical consultation. Population statistics on chronic diarrhea and constipation are more uncertain, perhaps due to variable definitions and reporting, but the frequency of these conditions is also high. United States population surveys put prevalence rates for chronic diarrhea at 2–7% and for chronic constipation at 12–19%, with women being affected twice as often as men. Diarrhea and constipation are among the most common patient complaints presenting to internists and primary care physicians, and they account for nearly 50% of referrals to gastroenterologists. Although diarrhea and constipation may present as mere nuisance symptoms at one extreme, they can be severe or life-threatening at the other. Even mild symptoms may signal a serious underlying gastrointestinal lesion, such as colorectal cancer, or systemic disorder, such as thyroid disease. Given the heterogeneous causes and potential severity of these common complaints, it is imperative for clinicians to appreciate the pathophysiology, etiologic classification, diagnostic strategies, and principles of management of diarrhea and constipation, so that rational and cost-effective care can be delivered.
NORMAL PHYSIOLOGY While the primary function of the small intestine is the digestion and assimilation of nutrients from food, the small intestine and colon together perform important functions that regulate the secretion and absorption of water and electrolytes, the storage and subsequent transport of intraluminal contents aborally, and the salvage of some nutrients that are not absorbed in the small intestine after bacterial metabolism of carbohydrate allows salvage of short-chain fatty acids. The main motor functions are summarized in Table 55-1. Alterations in fluid and electrolyte handling contribute significantly to diarrhea. Alterations in motor and sensory functions of the colon result in
Table 55-1 Normal Gastrointestinal Motility: Functions at Different Anatomic Levels Stomach and Small Bowel Synchronized MMC in fasting Accommodation, trituration, mixing, transit Stomach ∼3 h Small bowel ∼3 h Ileal reservoir empties boluses Colon: Irregular Mixing, Fermentation, Absorption, Transit Ascending, transverse: reservoirs Descending: conduit Sigmoid/rectum: volitional reservoir Abbreviation: MMC, migrating motor complex.
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highly prevalent syndromes such as irritable bowel syndrome (IBS), chronic diarrhea, and chronic constipation. NEURAL CONTROL The small intestine and colon have intrinsic and extrinsic innervation. The intrinsic innervation, also called the enteric nervous system, comprises myenteric, submucosal, and mucosal neuronal layers. The function of these layers is modulated by interneurons through the actions of neurotransmitter amines or peptides, including acetylcholine, vasoactive intestinal peptide (VIP), opioids, norepinephrine, serotonin, adenosine triphosphate (ATP), and nitric oxide (NO). The myenteric plexus regulates smooth-muscle function through intermediary pacemaker-like cells called the interstitial cells of Cajal, and the submucosal plexus affects secretion, absorption, and mucosal blood flow. The enteric nervous system receives input from the extrinsic nerves, but it is capable of independent control of these functions. The extrinsic innervations of the small intestine and colon are part of the autonomic nervous system and also modulate motor and secretory functions. The parasympathetic nerves convey visceral sensory pathways from and excitatory pathways to the small intestine and colon. Parasympathetic fibers via the vagus nerve reach the small intestine and proximal colon along the branches of the superior mesenteric artery. The distal colon is supplied by sacral parasympathetic nerves (S2–4) via the pelvic plexus; these fibers course through the wall of the colon as ascending intracolonic fibers as far as, and in some instances including, the proximal colon. The chief excitatory neurotransmitters controlling motor function are acetylcholine and the tachykinins, such as substance P. The sympathetic nerve supply modulates motor functions and reaches the small intestine and colon alongside their arterial vessels. Sympathetic input to the gut is generally excitatory to sphincters and inhibitory to non-sphincteric muscle. Visceral afferents convey sensation from the gut to the central nervous system (CNS); initially, they course along sympathetic fibers, but as they approach the spinal cord they separate, have cell bodies in the dorsal root ganglion, and enter the dorsal horn of the spinal cord. Afferent signals are conveyed to the brain along the lateral spinothalamic tract and the nociceptive dorsal column pathway and are then projected beyond the thalamus and brainstem to the insula and cerebral cortex to be perceived. Other afferent fibers synapse in the prevertebral ganglia and reflexly modulate intestinal motility, blood flow, and secretion. INTESTINAL FLUID ABSORPTION AND SECRETION On an average day, 9 L of fluid enter the gastrointestinal (GI) tract, ∼1 L of residual fluid reaches the colon, and the stool excretion of fluid constitutes about 0.2 L/d. The colon has a large capacitance and functional reserve and may recover up to four times its usual volume of 0.8 L/d, provided the rate of flow permits reabsorption to occur. Thus, the colon can partially compensate for excess fluid delivery to the colon that may result from intestinal absorptive or secretory disorders. In the small intestine and colon, sodium absorption is predominantly electrogenic (i.e., it can be measured as an ionic current across the membrane because there is not an equivalent loss of a cation from the cell), and uptake takes place at the apical membrane; it is compensated for by the export functions of the basolateral sodium pump. There are several active transport proteins at the apical membrane, especially in the small intestine, whereby sodium ion entry is coupled to monosaccharides (e.g., glucose through the transporter SGLT1, or fructose through GLUT-5). Glucose then exits the basal membrane through a specific transport protein, GLUT-5, creating a glucose concentration gradient between the lumen and the intercellular space, drawing water and electrolytes passively from the lumen. A variety of neural and nonneural mediators regulate colonic fluid and electrolyte balance, including cholinergic, adrenergic, and serotonergic mediators. Angiotensin and aldosterone also influence colonic absorption, reflecting the common embryologic development of the distal colonic epithelium and the renal tubules. SMALL-INTESTINAL MOTILITY During the fasting period, the motility of the small intestine is characterized by a cyclical event called the migrating motor complex (MMC),
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which serves to clear nondigestible residue from the small intestine (the intestinal “housekeeper”). This organized, propagated series of contractions lasts, on average, 4 min, occurs every 60–90 min, and usually involves the entire small intestine. After food ingestion, the small intestine produces irregular, mixing contractions of relatively low amplitude, except in the distal ileum where more powerful contractions occur intermittently and empty the ileum by bolus transfers.
COLONIC MOTILITY AFTER MEAL INGESTION After meal ingestion, colonic phasic and tonic contractility increase for a period of ∼2 h. The initial phase (∼10 min) is mediated by the vagus nerve in response to mechanical distention of the stomach. The subsequent response of the colon requires caloric stimulation (e.g., intake of at least 500 kcal) and is mediated, at least in part, by hormones (e.g., gastrin and serotonin). DEFECATION Tonic contraction of the puborectalis muscle, which forms a sling around the rectoanal junction, is important to maintain continence; during defecation, sacral parasympathetic nerves relax this muscle, facilitating the straightening of the rectoanal angle (Fig. 55-1). Distention of the rectum results in transient relaxation of the internal anal sphincter via intrinsic and
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DIARRHEA DEFINITION Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, stool weight >200 g/d can generally be considered diarrheal. Diarrhea may be further defined as acute if 4 weeks in duration. Two common conditions, usually associated with the passage of stool totaling 75 mmHg) propagated contractions (HAPCs) are sometimes associated with mass movements through the colon and normally occur approximately five times per day, usually on awakening in the morning and postprandially. Increased frequency of HAPCs may result in diarrhea or urgency. The predominant phasic contractions in the colon are irregular and non-propagated and serve a “mixing” function. Colonic tone refers to the background contractility upon which phasic contractile activity (typically contractions lasting 15°. Voluntary relaxation of the external anal sphincter (striated muscle innervated by the pudendal nerve) in response to the sensation produced by distention permits the evacuation of feces. Defecation can also be delayed voluntarily by contraction of the external anal sphincter.
ACUTE DIARRHEA More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medications, toxic ingestions, ischemia, food indiscretions, and other conditions. Infectious Agents Most infectious diarrheas are acquired by fecaloral transmission or, more commonly, via ingestion of food or water contaminated with pathogens from human or animal feces. In the immunocompetent person, the resident fecal microflora, containing >500 taxonomically distinct species, are rarely the source of diarrhea
At rest
During straining
Pubis
Puborectalis
A
External anal sphincter Internal anal sphincter
Coccyx Anorectal angle
Anorectal angle B
Descent of the pelvic floor
Figure 55-1 Sagittal view of the anorectum (A) at rest and (B) during straining to defecate. Continence is maintained by normal rectal sensation and tonic contraction of the internal anal sphincter and the puborectalis muscle, which wraps around the anorectum, maintaining an anorectal angle between 80° and 110°. During defecation, the pelvic floor muscles (including the puborectalis) relax, allowing the anorectal angle to straighten by at least 15°, and the perineum descends by 1–3.5 cm. The external anal sphincter also relaxes and reduces pressure on the anal canal. (Reproduced with permission from A Lembo, M Camilleri: N Engl J Med 349:1360, 2003.)
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and may actually play a role in suppressing the growth of ingested pathogens. Disturbances of flora by antibiotics can lead to diarrhea by reducing the digestive function or by allowing the overgrowth of pathogens, such as Clostridium difficile (Chap. 161). Acute infection or injury occurs when the ingested agent overwhelms or bypasses the host’s mucosal immune and nonimmune (gastric acid, digestive enzymes, mucus secretion, peristalsis, and suppressive resident flora) defenses. Established clinical associations with specific enteropathogens may offer diagnostic clues. In the United States, five high-risk groups are recognized:
PART 2 Cardinal Manifestations and Presentation of Diseases
1. Travelers. Nearly 40% of tourists to endemic regions of Latin America, Africa, and Asia develop so-called traveler’s diarrhea, most commonly due to enterotoxigenic or enteroaggregative Escherichia coli as well as to Campylobacter, Shigella, Aeromonas, norovirus, Coronavirus, and Salmonella. Visitors to Russia (especially St. Petersburg) may have increased risk of Giardia-associated diarrhea; visitors to Nepal may acquire Cyclospora. Campers, backpackers, and swimmers in wilderness areas may become infected with Giardia. Cruise ships may be affected by outbreaks of gastroenteritis caused by agents such as norovirus. 2. Consumers of certain foods. Diarrhea closely following food consumption at a picnic, banquet, or restaurant may suggest infection with Salmonella, Campylobacter, or Shigella from chicken; enterohemorrhagic E. coli (O157:H7) from undercooked hamburger; Bacillus cereus from fried rice or other reheated food; Staphylococcus aureus or Salmonella from mayonnaise or creams; Salmonella from eggs; Listeria from uncooked foods or soft cheeses; and Vibrio species, Salmonella, or acute hepatitis A from seafood, especially if raw. State departments of public health issue communications regarding food-related illnesses, which may have originated domestically or been imported, but ultimately cause epidemics in the United States (e.g., the Cyclospora epidemic of 2013 in midwestern states that resulted from bagged salads). 3. Immunodeficient persons. Individuals at risk for diarrhea include those with either primary immunodeficiency (e.g., IgA deficiency, common variable hypogammaglobulinemia, chronic granulomatous disease) or the much more common secondary immunodeficiency states
(e.g., AIDS, senescence, pharmacologic suppression). Common enteric pathogens often cause a more severe and protracted diarrheal illness, and, particularly in persons with AIDS, opportunistic infections, such as by Mycobacterium species, certain viruses (cytomegalovirus, adenovirus, and herpes simplex), and protozoa (Cryptosporidium, Isospora belli, Microsporida, and Blastocystis hominis) may also play a role (Chap. 226). In patients with AIDS, agents transmitted venereally per rectum (e.g., Neisseria gonorrhoeae, Treponema pallidum, Chlamydia) may contribute to proctocolitis. Persons with hemochromatosis are especially prone to invasive, even fatal, enteric infections with Vibrio species and Yersinia infections and should avoid raw fish. 4. Daycare attendees and their family members. Infections with Shigella, Giardia, Cryptosporidium, rotavirus, and other agents are very common and should be considered. 5. Institutionalized persons. Infectious diarrhea is one of the most frequent categories of nosocomial infections in many hospitals and long-term care facilities; the causes are a variety of microorganisms but most commonly C. difficile. C. difficile can affect those with no history of antibiotic use and may be acquired in the community. The pathophysiology underlying acute diarrhea by infectious agents produces specific clinical features that may also be helpful in diagnosis (Table 55-2). Profuse, watery diarrhea secondary to small-bowel hypersecretion occurs with ingestion of preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens. Diarrhea associated with marked vomiting and minimal or no fever may occur abruptly within a few hours after ingestion of the former two types; vomiting is usually less, abdominal cramping or bloating is greater, and fever is higher with the latter. Cytotoxin-producing and invasive microorganisms all cause high fever and abdominal pain. Invasive bacteria and Entamoeba histolytica often cause bloody diarrhea (referred to as dysentery). Yersinia invades the terminal ileal and proximal colon mucosa and may cause especially severe abdominal pain with tenderness mimicking acute appendicitis. Finally, infectious diarrhea may be associated with systemic manifestations. Reactive arthritis (formerly known as Reiter’s syndrome), arthritis, urethritis, and conjunctivitis may accompany or follow
Table 55-2 Association Between Pathobiology of Causative Agents and Clinical Features in Acute Infectious Diarrhea Pathobiology/Agents Toxin producers Preformed toxin Bacillus cereus, Staphylococcus aureus, Clostridium perfringens Enterotoxin Vibrio cholerae, enterotoxigenic Escherichia coli, Klebsiella pneumoniae, Aeromonas species Enteroadherent Enteropathogenic and enteroadherent E. coli, Giardia organisms, cryptosporidiosis, helminths Cytotoxin producers C. difficile Hemorrhagic E. coli Invasive organisms Minimal inflammation Rotavirus and norovirus Variable inflammation Salmonella, Campylobacter, and Aeromonas species, Vibrio parahaemolyticus, Yersinia Severe inflammation Shigella species, enteroinvasive E. coli, Entamoeba histolytica
Incubation Period
Vomiting
Abdominal Pain
Fever
Diarrhea
1–8 h 8–24 h
3–4+
1–2+
0–1+
3–4+, watery
8–72 h
2–4+
1–2+
0–1+
3–4+, watery
1–8 d
0–1+
1–3+
0–2+
1–2+, watery, mushy
1–3 d
0–1+
3–4+
1–2+
12–72 h
0–1+
3–4+
1–2+
1–3+, usually watery, occasionally bloody 1–3+, initially watery, quickly bloody
1–3 d
1–3+
2–3+
3–4+
1–3+, watery
12 h–11 d
0–3+
2–4+
3–4+
1–4+, watery or bloody
12 h–8 d
0–1+
3–4+
3–4+
1–2+, bloody
Source: Adapted from DW Powell, in T Yamada (ed): Textbook of Gastroenterology and Hepatology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003.
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infections by Salmonella, Campylobacter, Shigella, and Yersinia. Yersiniosis may also lead to an autoimmune-type thyroiditis, pericarditis, and glomerulonephritis. Both enterohemorrhagic E. coli (O157:H7) and Shigella can lead to the hemolytic-uremic syndrome with an attendant high mortality rate. The syndrome of postinfectious IBS has now been recognized as a complication of infectious diarrhea. Similarly, acute gastroenteritis may precede the diagnosis of celiac disease or Crohn’s disease. Acute diarrhea can also be a major symptom of several systemic infections including viral hepatitis, listeriosis, legionellosis, and toxic shock syndrome.
The decision to evaluate acute diarrhea depends on its severity and duration and on various host factors (Fig. 55-2). Most episodes of acute diarrhea are mild and self-limited and do not justify the cost and potential morbidity rate of diagnostic or pharmacologic interventions. Indications for evaluation include profuse diarrhea with dehydration, grossly bloody stools, fever ≥38.5°C (≥101°F), duration >48 h without improvement, recent antibiotic use, new community outbreaks, associated severe abdominal pain in patients >50 years, and elderly (≥70 years) or immunocompromised patients. In some cases of moderately severe febrile diarrhea associated with fecal leukocytes (or increased fecal levels of the leukocyte proteins, such as calprotectin) or with gross blood, a diagnostic evaluation might be avoided in favor of an empirical antibiotic trial (see below). The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool. Workup includes cultures for bacterial and viral pathogens, direct inspection for ova and parasites, and immunoassays for certain bacterial toxins (C. difficile), viral antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica). The aforementioned clinical and epidemiologic associations may assist in focusing the evaluation. If a particular pathogen or set of possible pathogens is so implicated, then either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate as for enterohemorrhagic and other types of E. coli, Vibrio species, and Yersinia. Molecular diagnosis of pathogens in stool can be made by identification of unique DNA sequences; and evolving microarray technologies have led to more rapid, sensitive, specific, and costeffective diagnosis.
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Likely noninfectious
Likely infectious
Evaluate and treat accordingly
Moderate (activities altered)
Severe (incapacitated)
Institute fluid and electrolyte replacement
Observe
Resolves
Fever ≥38.5°C, bloody stools, fecal WBCs, immunocompromised or elderly host Persists*
Stool microbiology studies
Yes†
No
Antidiarrheal agents Pathogen found Resolves
Persists* No
Empirical treatment + further evaluation
Yes†
Diarrhea and Constipation
APPROACH TO THE PATIENT: Acute Diarrhea
Mild (unrestricted)
History and physical exam
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Other Causes Side effects from medications are probably the most common noninfectious causes of acute diarrhea, and etiology may be suggested by a temporal association between use and symptom onset. Although innumerable medications may produce diarrhea, some of the more frequently incriminated include antibiotics, cardiac antidysrhythmics, antihypertensives, nonsteroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, chemotherapeutic agents, bronchodilators, antacids, and laxatives. Occlusive or nonocclusive ischemic colitis typically occurs in persons >50 years; often presents as acute lower abdominal pain preceding watery, then bloody diarrhea; and generally results in acute inflammatory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versus-host disease. Acute diarrhea, often associated with systemic compromise, can follow ingestion of toxins including organophosphate insecticides; amanita and other mushrooms; arsenic; and preformed environmental toxins in seafood, such as ciguatera and scombroid. Acute anaphylaxis to food ingestion can have a similar presentation. Conditions causing chronic diarrhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease (IBD) and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection.
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Acute Diarrhea
Select specific treatment
Figure 55-2 Algorithm for the management of acute diarrhea. Consider empirical treatment before evaluation with (*) metronidazole and with (†) quinolone. WBCs, white blood cells. Persistent diarrhea is commonly due to Giardia (Chap. 247), but additional causative organisms that should be considered include C. difficile (especially if antibiotics had been administered), E. histolytica, Cryptosporidium, Campylobacter, and others. If stool studies are unrevealing, flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated. Brainerd diarrhea is an increasingly recognized entity characterized by an abrupt-onset diarrhea that persists for at least 4 weeks, but may last 1–3 years, and is thought to be of infectious origin. It may be associated with subtle inflammation of the distal small intestine or proximal colon. Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomography (CT) scanning (or other imaging approaches) may be appropriate in patients with uncharacterized persistent diarrhea to exclude IBD or as an initial approach in patients with suspected noninfectious acute diarrhea such as might be caused by ischemic colitis, diverticulitis, or partial bowel obstruction.
TREATMENT
Acute Diarrhea
Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea. Fluid replacement alone may suffice for mild cases. Oral sugar-electrolyte solutions (iso-osmolar sport drinks or designed formulations) should be instituted promptly with severe diarrhea to limit dehydration, which is the major cause of death. Profoundly dehydrated patients, especially infants and the elderly, require IV rehydration. In moderately severe nonfebrile and nonbloody diarrhea, antimotility and antisecretory agents such as loperamide can be useful adjuncts to control symptoms. Such agents should be avoided with
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PART 2 Cardinal Manifestations and Presentation of Diseases
febrile dysentery, which may be exacerbated or prolonged by them. Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients or those with renal impairment because of the risk of bismuth encephalopathy. Judicious use of antibiotics is appropriate in selected instances of acute diarrhea and may reduce its severity and duration (Fig. 55-2). Many physicians treat moderately to severely ill patients with febrile dysentery empirically without diagnostic evaluation using a quinolone, such as ciprofloxacin (500 mg bid for 3–5 d). Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d). Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens, geographic patterns of resistance, and conditions found (Chaps. 160, 186, and 190–196). Antibiotic coverage is indicated, whether or not a causative organism is discovered, in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly. Bismuth subsalicylate may reduce the frequency of traveler’s diarrhea. Antibiotic prophylaxis is only indicated for certain patients traveling to high-risk countries in whom the likelihood or seriousness of acquired diarrhea would be especially high, including those with immunocompromise, IBD, hemochromatosis, or gastric achlorhydria. Use of ciprofloxacin, azithromycin, or rifaximin may reduce bacterial diarrhea in such travelers by 90%, though rifaximin is not suitable for invasive disease, but rather as treatment for uncomplicated traveler’s diarrhea. Finally, physicians should be vigilant to identify if an outbreak of diarrheal illness is occurring and to alert the public health authorities promptly. This may reduce the ultimate size of the affected population. CHRONIC DIARRHEA Diarrhea lasting >4 weeks warrants evaluation to exclude serious underlying pathology. In contrast to acute diarrhea, most of the causes of chronic diarrhea are noninfectious. The classification of chronic diarrhea by pathophysiologic mechanism facilitates a rational approach to management, although many diseases cause diarrhea by more than one mechanism (Table 55-3). Secretory Causes Secretory diarrheas are due to derangements in fluid and electrolyte transport across the enterocolonic mucosa. They are characterized clinically by watery, large-volume fecal outputs that are typically painless and persist with fasting. Because there is no malabsorbed solute, stool osmolality is accounted for by normal endogenous electrolytes with no fecal osmotic gap. Medications Side effects from regular ingestion of drugs and toxins are the most common secretory causes of chronic diarrhea. Hundreds of prescription and over-the-counter medications (see earlier section, “Acute Diarrhea, Other Causes”) may produce diarrhea. Surreptitious or habitual use of stimulant laxatives (e.g., senna, cascara, bisacodyl, ricinoleic acid [castor oil]) must also be considered. Chronic ethanol consumption may cause a secretory-type diarrhea due to enterocyte injury with impaired sodium and water absorption as well as rapid transit and other alterations. Inadvertent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute forms of diarrhea. Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea. Bowel resection, mucosal disease, or enterocolic fistula These conditions may result in a secretory-type diarrhea because of inadequate surface for reabsorption of secreted fluids and electrolytes. Unlike other secretory diarrheas, this subset of conditions tends to worsen with eating. With disease (e.g., Crohn’s ileitis) or resection of 50 mosmol/L): serum osmolarity (typically 290 mosmol/kg) – (2 × [fecal sodium + potassium concentration]). Measurement of fecal osmolarity is no longer recommended because, even when measured immediately after evacuation, it may be erroneous because carbohydrates are metabolized by colonic bacteria, causing an increase in osmolarity. Carbohydrate malabsorption Carbohydrate malabsorption due to acquired or congenital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low pH. One of the most common causes of chronic diarrhea in adults is lactase deficiency, which affects three-fourths of nonwhites worldwide and 5–30% of persons in the United States; the total lactose load at any one time influences the symptoms experienced. Most patients learn to avoid milk products without requiring treatment with enzyme supplements. Some sugars, such as sorbitol, lactulose, or fructose, are frequently malabsorbed, and diarrhea ensues with ingestion of medications, gum, or candies sweetened with these poorly or incompletely absorbed sugars.
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Steatorrheal Causes Fat malabsorption may lead to greasy, foulsmelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the neutral fat. Quantitatively, steatorrhea is defined as stool fat exceeding the normal 7 g/d; rapid-transit diarrhea may result in fecal fat up to 14 g/d; daily fecal fat averages 15–25 g with small-intestinal diseases and is often >32 g with pancreatic exocrine insufficiency. Intraluminal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea. Intraluminal maldigestion This condition most commonly results from pancreatic exocrine insufficiency, which occurs when >90% of pancreatic secretory function is lost. Chronic pancreatitis, usually a sequel of ethanol abuse, most frequently causes pancreatic insufficiency. Other causes include cystic fibrosis; pancreatic duct obstruction; and, rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle formation, impairing fat digestion; it occurs with stasis from a blind-loop, smallbowel diverticulum or dysmotility and is especially likely in the elderly. Finally, cirrhosis or biliary obstruction may lead to mild steatorrhea due to deficient intraluminal bile acid concentration.
269
Diarrhea and Constipation
Congenital defects in ion absorption Rarely, defects in specific carriers associated with ion absorption cause watery diarrhea from birth. These disorders include defective Cl–/HCO3– exchange (congenital chloridorrhea) with alkalosis (which results from a mutated DRA [down-regulated in adenoma] gene) and defective Na+/H+ exchange (congenital sodium diarrhea), which results from a mutation in the NHE3 (sodium-hydrogen exchanger) gene and results in acidosis. Some hormone deficiencies may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison’s disease) that may be accompanied by skin hyperpigmentation.
Wheat and FODMAP intolerance Chronic diarrhea, bloating, and abdominal pain are recognized as symptoms of nonceliac gluten intolerance (which is associated with impaired intestinal or colonic barrier function) and intolerance of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). The latter’s effects represent the interaction between the GI microbiome and the nutrients.
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carcinoid tumors or, rarely, primary bronchial carcinoids may produce watery diarrhea alone or as part of the carcinoid syndrome that comprises episodic flushing, wheezing, dyspnea, and right-sided valvular heart disease. Diarrhea is due to the release into the circulation of potent intestinal secretagogues including serotonin, histamine, prostaglandins, and various kinins. Pellagra-like skin lesions may rarely occur as the result of serotonin overproduction with niacin depletion. Gastrinoma, one of the most common neuroendocrine tumors, most typically presents with refractory peptic ulcers, but diarrhea occurs in up to one-third of cases and may be the only clinical manifestation in 10%. While other secretagogues released with gastrin may play a role, the diarrhea most often results from fat maldigestion owing to pancreatic enzyme inactivation by low intraduodenal pH. The watery diarrhea hypokalemia achlorhydria syndrome, also called pancreatic cholera, is due to a non-β cell pancreatic adenoma, referred to as a VIPoma, that secretes VIP and a host of other peptide hormones including pancreatic polypeptide, secretin, gastrin, gastrin-inhibitory polypeptide (also called glucose-dependent insulinotropic peptide), neurotensin, calcitonin, and prostaglandins. The secretory diarrhea is often massive with stool volumes >3 L/d; daily volumes as high as 20 L have been reported. Life-threatening dehydration; neuromuscular dysfunction from associated hypokalemia, hypomagnesemia, or hypercalcemia; flushing; and hyperglycemia may accompany a VIPoma. Medullary carcinoma of the thyroid may present with watery diarrhea caused by calcitonin, other secretory peptides, or prostaglandins. Prominent diarrhea is often associated with metastatic disease and poor prognosis. Systemic mastocytosis, which may be associated with the skin lesion urticaria pigmentosa, may cause diarrhea that is either secretory and mediated by histamine or inflammatory due to intestinal infiltration by mast cells. Large colorectal villous adenomas may rarely be associated with a secretory diarrhea that may cause hypokalemia, can be inhibited by NSAIDs, and are apparently mediated by prostaglandins.
Mucosal malabsorption Mucosal malabsorption occurs from a variety of enteropathies, but it most commonly occurs from celiac disease. This gluten-sensitive enteropathy affects all ages and is characterized by villous atrophy and crypt hyperplasia in the proximal small bowel and can present with fatty diarrhea associated with multiple nutritional deficiencies of varying severity. Celiac disease is much more frequent than previously thought; it affects ∼1% of the population, frequently presents without steatorrhea, can mimic IBS, and has many other GI and extraintestinal manifestations. Tropical sprue may produce a similar histologic and clinical syndrome but occurs in residents of or travelers to tropical climates; abrupt onset and response to antibiotics suggest an infectious etiology. Whipple’s disease, due to the bacillus Tropheryma whipplei and histiocytic infiltration of the smallbowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue, and it may affect the CNS and endocardium. A similar clinical and histologic picture results from Mycobacterium avium-intracellulare infection in patients with AIDS. Abetalipoproteinemia is a rare defect of chylomicron formation and fat malabsorption in children, associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause mucosal malabsorption including infections, especially with protozoa such as Giardia; numerous medications (e.g., olmesartan, mycophenolate mofetil, colchicine, cholestyramine, neomycin); amyloidosis; and chronic ischemia. Postmucosal lymphatic obstruction The pathophysiology of this condition, which is due to the rare congenital intestinal lymphangiectasia or to acquired lymphatic obstruction secondary to trauma, tumor, cardiac disease or infection, leads to the unique constellation of fat malabsorption with enteric losses of protein (often causing edema) and lymphocytopenia. Carbohydrate and amino acid absorption are preserved. Inflammatory Causes Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflammation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/ electrolyte absorption, and hypersecretion or hypermotility from
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release of cytokines and other inflammatory mediators. The unifying feature on stool analysis is the presence of leukocytes or leukocytederived proteins such as calprotectin. With severe inflammation, exudative protein loss can lead to anasarca (generalized edema). Any middle-aged or older person with chronic inflammatory-type diarrhea, especially with blood, should be carefully evaluated to exclude a colorectal tumor.
PART 2 Cardinal Manifestations and Presentation of Diseases
Idiopathic inflammatory bowel disease The illnesses in this category, which include Crohn’s disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life-threatening. They may be associated with uveitis, polyarthralgias, cholestatic liver disease (primary sclerosing cholangitis), and skin lesions (erythema nodosum, pyoderma gangrenosum). Microscopic colitis, including both lymphocytic and collagenous colitis, is an increasingly recognized cause of chronic watery diarrhea, especially in middle-aged women and those on NSAIDs, statins, proton pump inhibitors (PPIs), and selective serotonin reuptake inhibitors (SSRIs); biopsy of a normal-appearing colon is required for histologic diagnosis. It may coexist with symptoms suggesting IBS or with celiac sprue or drug-induced enteropathy. It typically responds well to anti-inflammatory drugs (e.g., bismuth), to the opioid agonist loperamide, or to budesonide. Primary or secondary forms of immunodeficiency Immunodeficiency may lead to prolonged infectious diarrhea. With selective IgA deficiency or common variable hypogammaglobulinemia, diarrhea is particularly prevalent and often the result of giardiasis, bacterial overgrowth, or sprue. Eosinophilic gastroenteritis Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the GI tract may cause diarrhea, pain, vomiting, or ascites. Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspection of stool, and peripheral eosinophilia is present in 50–75% of patients. While hypersensitivity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare. Other causes Chronic inflammatory diarrhea may be caused by radiation enterocolitis, chronic graft-versus-host disease, Behçet’s syndrome, and Cronkhite-Canada syndrome, among others. Dysmotility Causes Rapid transit may accompany many diarrheas as a secondary or contributing phenomenon, but primary dysmotility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea of up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prostaglandins, prokinetic agents) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopathies or idiopathic acquired intestinal pseudoobstruction may lead to stasis with secondary bacterial overgrowth causing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility. The exceedingly common IBS (10% point prevalence, 1–2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of stool frequency typically cease at night, alternate with periods of constipation, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss. Factitial Causes Factitial diarrhea accounts for up to 15% of unexplained diarrheas referred to tertiary care centers. Either as a form of Munchausen syndrome (deception or self-injury for secondary gain) or eating disorders, some patients covertly self-administer laxatives alone or in combination with other medications (e.g., diuretics) or surreptitiously add water or urine to stool sent for analysis. Such patients are typically women, often with histories of psychiatric illness, and disproportionately from careers in health care. Hypotension and hypokalemia are common co-presenting features. The evaluation of such patients may be difficult: contamination of the stool with water or urine is suggested by very low or high stool osmolarity, respectively.
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Such patients often deny this possibility when confronted, but they do benefit from psychiatric counseling when they acknowledge their behavior.
APPROACH TO THE PATIENT: Chronic Diarrhea The laboratory tools available to evaluate the very common problem of chronic diarrhea are extensive, and many are costly and invasive. As such, the diagnostic evaluation must be rationally directed by a careful history, including medications, and physical examination (Fig. 55-3A). When this strategy is unrevealing, simple triage tests are often warranted to direct the choice of more complex investigations (Fig. 55-3B). The history, physical examination (Table 55-4), and routine blood studies should attempt to characterize the mechanism of diarrhea, identify diagnostically helpful associations, and assess the patient’s fluid/electrolyte and nutritional status. Patients should be questioned about the onset, duration, pattern, aggravating (especially diet) and relieving factors, and stool characteristics of their diarrhea. The presence or absence of fecal incontinence, fever, weight loss, pain, certain exposures (travel, medications, contacts with diarrhea), and common extraintestinal manifestations (skin changes, arthralgias, oral aphthous ulcers) should be noted. A family history of IBD or sprue may indicate those possibilities. Physical findings may offer clues such as a thyroid mass, wheezing, heart murmurs, edema, hepatomegaly, abdominal masses, lymphadenopathy, mucocutaneous abnormalities, perianal fistulas, or anal sphincter laxity. Peripheral blood leukocytosis, elevated sedimentation rate, or C-reactive protein suggests inflammation; anemia reflects blood loss or nutritional deficiencies; or eosinophilia may occur with parasitoses, neoplasia, collagen-vascular disease, allergy, or eosinophilic gastroenteritis. Blood chemistries may demonstrate electrolyte, hepatic, or other metabolic disturbances. Measuring IgA tissue transglutaminase antibodies may help detect celiac disease. Bile acid diarrhea is confirmed by a scintigraphic radiolabeled bile acid retention test; however, this is not available in many countries. Alternative approaches are a screening blood test (serum C4 or FGF-19), measurement of fecal bile acids, or a therapeutic trial with a bile acid sequestrant (e.g., cholestyramine or colesevelam). A therapeutic trial is often appropriate, definitive, and highly cost-effective when a specific diagnosis is suggested on the initial physician encounter. For example, chronic watery diarrhea, which ceases with fasting in an otherwise healthy young adult, may justify a trial of a lactose-restricted diet; bloating and diarrhea persisting since a mountain backpacking trip may warrant a trial of metronidazole for likely giardiasis; and postprandial diarrhea persisting following resection of terminal ileum might be due to bile acid malabsorption and be treated with cholestyramine or colesevelam before further evaluation. Persistent symptoms require additional investigation. Certain diagnoses may be suggested on the initial encounter (e.g., idiopathic IBD); however, additional focused evaluations may be necessary to confirm the diagnosis and characterize the severity or extent of disease so that treatment can be best guided. Patients suspected of having IBS should be initially evaluated with flexible sigmoidoscopy with colorectal biopsies to exclude IBD, or particularly microscopic colitis, which is clinically indistinguishable from IBS with diarrhea; those with normal findings might be reassured and, as indicated, treated empirically with antispasmodics, antidiarrheals, or antidepressants (e.g., tricyclic agents). Any patient who presents with chronic diarrhea and hematochezia should be evaluated with stool microbiologic studies and colonoscopy. In an estimated two-thirds of cases, the cause for chronic diarrhea remains unclear after the initial encounter, and further testing is required. Quantitative stool collection and analyses can yield
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271 Chronic diarrhea Exclude iatrogenic problem: medication, surgery
Features, e.g., stool, suggest malabsorption
Colonoscopy + biopsy
Small bowel: Imaging, biopsy, aspirate
Pain aggravated before bm, relieved with bm, sense incomplete evacuation
No blood, features of malabsorption
Consider functional diarrhea
Suspect IBS
Limited screen for organic disease
A Chronic diarrhea Limited screen for organic disease Low Hb, Alb; abnormal MCV, MCH; excess fat in stool
Colonoscopy + biopsy
Small bowel: X-ray, biopsy, aspirate; stool 48-h fat
+
Low K
Stool vol, OSM, pH; Laxative screen; Hormonal screen
Screening tests all normal
Diarrhea and Constipation
Dietary exclusion, e.g., lactose, sorbitol
CHAPTER 55
Blood pr
Opioid Rx + follow-up
Persistent chronic diarrhea Stool fat >20 g/day Pancreatic function
Normal and stool fat 200 g/d, additional stool analyses should be performed that might include electrolyte concentration,
Table 55-4 Physical Examination in Patients With Chronic Diarrhea 1. Are there general features to suggest malabsorption or inflammatory bowel disease (IBD) such as anemia, dermatitis herpetiformis, edema, or clubbing? 2. Are there features to suggest underlying autonomic neuropathy or collagen-vascular disease in the pupils, orthostasis, skin, hands, or joints? 3. Is there an abdominal mass or tenderness? 4. Are there any abnormalities of rectal mucosa, rectal defects, or altered anal sphincter functions? 5. Are there any mucocutaneous manifestations of systemic disease such as dermatitis herpetiformis (celiac disease), erythema nodosum (ulcerative colitis), flushing (carcinoid), or oral ulcers for IBD or celiac disease?
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pH, occult blood testing, leukocyte inspection (or leukocyte protein assay), fat quantitation, and laxative screens. For secretory diarrheas (watery, normal osmotic gap), possible medication-related side effects or surreptitious laxative use should be reconsidered. Microbiologic studies should be done including fecal bacterial cultures (including media for Aeromonas and Plesiomonas), inspection for ova and parasites, and Giardia antigen assay (the most sensitive test for giardiasis). Small-bowel bacterial overgrowth can be excluded by intestinal aspirates with quantitative cultures or with glucose or lactulose breath tests involving measurement of breath hydrogen, methane, or other metabolite. However, interpretation of these breath tests may be confounded by disturbances of intestinal transit. Upper endoscopy and colonoscopy with biopsies and small-bowel x-rays (formerly barium, but increasingly CT with enterography or magnetic resonance with enteroclysis) are helpful to rule out structural or occult inflammatory disease. When suggested by history or other findings, screens for peptide hormones should
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be pursued (e.g., serum gastrin, VIP, calcitonin, and thyroid hormone/thyroid-stimulating hormone, urinary 5-hydroxyindolacetic acid, histamine). Further evaluation of osmotic diarrhea should include tests for lactose intolerance and magnesium ingestion, the two most common causes. Low fecal pH suggests carbohydrate malabsorption; lactose malabsorption can be confirmed by lactose breath testing or by a therapeutic trial with lactose exclusion and observation of the effect of lactose challenge (e.g., a liter of milk). Lactase determination on small-bowel biopsy is not generally available. If fecal magnesium or laxative levels are elevated, inadvertent or surreptitious ingestion should be considered and psychiatric help should be sought. For those with proven fatty diarrhea, endoscopy with smallbowel biopsy (including aspiration for Giardia and quantitative cultures) should be performed; if this procedure is unrevealing, a small-bowel radiograph is often an appropriate next step. If smallbowel studies are negative or if pancreatic disease is suspected, pancreatic exocrine insufficiency should be excluded with direct tests, such as the secretin-cholecystokinin stimulation test or a variation that could be performed endoscopically. In general, indirect tests such as assay of fecal elastase or chymotrypsin activity or a bentiromide test have fallen out of favor because of low sensitivity and specificity. Chronic inflammatory-type diarrheas should be suspected by the presence of blood or leukocytes in the stool. Such findings warrant stool cultures; inspection for ova and parasites; C. difficile toxin assay; colonoscopy with biopsies; and, if indicated, small-bowel contrast studies. TREATMENT
Chronic Diarrhea
Treatment of chronic diarrhea depends on the specific etiology and may be curative, suppressive, or empirical. If the cause can be eradicated, treatment is curative as with resection of a colorectal cancer, antibiotic administration for Whipple’s disease or tropical sprue, or discontinuation of a drug. For many chronic conditions, diarrhea can be controlled by suppression of the underlying mechanism. Examples include elimination of dietary lactose for lactase deficiency or gluten for celiac sprue, use of glucocorticoids or other anti-inflammatory agents for idiopathic IBDs, bile acid sequestrants for bile acid malabsorption, PPIs for the gastric hypersecretion of gastrinomas, somatostatin analogues such as octreotide for malignant carcinoid syndrome, prostaglandin inhibitors such as indomethacin for medullary carcinoma of the thyroid, and pancreatic enzyme replacement for pancreatic insufficiency. When the specific cause or mechanism of chronic diarrhea evades diagnosis, empirical therapy may be beneficial. Mild opiates, such as diphenoxylate or loperamide, are often helpful in mild or moderate watery diarrhea. For those with more severe diarrhea, codeine or tincture of opium may be beneficial. Such antimotility agents should be avoided with severe IBD, because toxic megacolon may be precipitated. Clonidine, an α2-adrenergic agonist, may allow control of diabetic diarrhea, although the medication may be poorly tolerated because it causes postural hypotension. The 5-HT3 receptor antagonists (e.g., alosetron) may relieve diarrhea and urgency in patients with IBS diarrhea. For all patients with chronic diarrhea, fluid and electrolyte repletion is an important component of management (see “Acute Diarrhea,” earlier). Replacement of fat-soluble vitamins may also be necessary in patients with chronic steatorrhea.
CONSTIPATION DEFINITION Constipation is a common complaint in clinical practice and usually refers to persistent, difficult, infrequent, or seemingly incomplete
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defecation. Because of the wide range of normal bowel habits, constipation is difficult to define precisely. Most persons have at least three bowel movements per week; however, low stool frequency alone is not the sole criterion for the diagnosis of constipation. Many constipated patients have a normal frequency of defecation but complain of excessive straining, hard stools, lower abdominal fullness, or a sense of incomplete evacuation. The individual patient’s symptoms must be analyzed in detail to ascertain what is meant by “constipation” or “difficulty” with defecation. Stool form and consistency are well correlated with the time elapsed from the preceding defecation. Hard, pellety stools occur with slow transit, whereas loose, watery stools are associated with rapid transit. Both small pellety or very large stools are more difficult to expel than normal stools. The perception of hard stools or excessive straining is more difficult to assess objectively, and the need for enemas or digital disimpaction is a clinically useful way to corroborate the patient’s perceptions of difficult defecation. Psychosocial or cultural factors may also be important. A person whose parents attached great importance to daily defecation will become greatly concerned when he or she misses a daily bowel movement; some children withhold stool to gain attention or because of fear of pain from anal irritation; and some adults habitually ignore or delay the call to have a bowel movement. CAUSES Pathophysiologically, chronic constipation generally results from inadequate fiber or fluid intake or from disordered colonic transit or anorectal function. These result from neurogastroenterologic disturbance, certain drugs, advancing age, or in association with a large number of systemic diseases that affect the GI tract (Table 55-5). Constipation of recent onset may be a symptom of significant organic disease such as tumor or stricture. In idiopathic constipation, a subset of patients exhibit delayed emptying of the ascending and transverse colon with prolongation of transit (often in the proximal colon) and a reduced frequency of propulsive HAPCs. Outlet obstruction to defecation (also called evacuation disorders) accounts for about a quarter of cases presenting with constipation in tertiary care and may cause delayed colonic transit, which is usually corrected by biofeedback retraining of the disordered defecation. Constipation of any cause may be exacerbated by hospitalization or chronic illnesses that lead to physical or mental impairment and result in inactivity or physical immobility. Table 55-5 Causes of Constipation in Adults Types of Constipation and Causes Recent Onset Colonic obstruction Anal sphincter spasm Medications Chronic Irritable bowel syndrome Medications Colonic pseudoobstruction Disorders of rectal evacuation
Endocrinopathies Psychiatric disorders Neurologic disease Generalized muscle disease
Examples Neoplasm; stricture: ischemic, diverticular, inflammatory Anal fissure, painful hemorrhoids
Constipation-predominant, alternating Ca2+ blockers, antidepressants Slow-transit constipation, megacolon (rare Hirschsprung’s, Chagas’ diseases) Pelvic floor dysfunction; anismus; descending perineum syndrome; rectal mucosal prolapse; rectocele Hypothyroidism, hypercalcemia, pregnancy Depression, eating disorders, drugs Parkinsonism, multiple sclerosis, spinal cord injury Progressive systemic sclerosis
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APPROACH TO THE PATIENT: Constipation
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Normal
Colonic transit
Consider functional bowel disease
Abnormal Slow colonic transit
No known underlying disorder
Known disorder
Anorectal manometry and balloon expulsion
Normal
Rx
Rectoanal angle measurement, defecation proctography?
Appropriate Rx: Rehabilitation program, surgery, or other
Figure 55-4 Algorithm for the management of constipation. abd, abdominal.
Diarrhea and Constipation
INVESTIGATION OF SEVERE CONSTIPATION A small minority (probably 90%), there is no underlying cause (e.g., cancer, depression, or hypothyroidism), and constipation responds to ample hydration, exercise, and supplementation of dietary fiber (15–25 g/d). A good diet and medication history and attention to psychosocial issues are key. Physical examination and, particularly, a rectal examination should exclude fecal impaction and most of the important diseases that present with constipation and possibly indicate features suggesting an evacuation disorder (e.g., high anal sphincter tone, failure of perineal descent, or paradoxical puborectalis contraction during straining to simulate stool evacuation). The presence of weight loss, rectal bleeding, or anemia with constipation mandates either flexible sigmoidoscopy plus barium enema or colonoscopy alone, particularly in patients >40 years, to exclude structural diseases such as cancer or strictures. Colonoscopy alone is most cost-effective in this setting because it provides an opportunity to biopsy mucosal lesions, perform polypectomy, or dilate strictures. Barium enema has advantages over colonoscopy in the patient with isolated constipation because it is less costly and identifies colonic dilation and all significant mucosal lesions or strictures that are likely to present with constipation. Melanosis coli, or pigmentation of the colon mucosa, indicates the use of anthraquinone laxatives such as cascara or senna; however, this is usually apparent from a careful history. An unexpected disorder such as megacolon or cathartic colon may also be detected by colonic radiographs. Measurement of serum calcium, potassium, and thyroid-stimulating hormone levels will identify rare patients with metabolic disorders. Patients with more troublesome constipation may not respond to fiber alone and may be helped by a bowel-training regimen, which involves taking an osmotic laxative (e.g., magnesium salts, lactulose, sorbitol, polyethylene glycol) and evacuating with enema or suppository (e.g., glycerine or bisacodyl) as needed. After breakfast, a distraction-free 15–20 min on the toilet without straining is encouraged. Excessive straining may lead to development of hemorrhoids, and, if there is weakness of the pelvic floor or injury to the pudendal nerve, may result in obstructed defecation from descending perineum syndrome several years later. Those few who do not benefit from the simple measures delineated above or require long-term treatment or fail to respond to potent laxatives should undergo further investigation (Fig. 55-4). Novel agents that induce secretion (e.g., lubiprostone, a chloride channel activator, or linaclotide, a guanylate cyclase C agonist that activates chloride secretion) are also available.
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Chronic Constipation
Measurement of Colonic Transit Radiopaque marker transit tests are easy, repeatable, generally safe, inexpensive, reliable, and highly applicable in evaluating constipated patients in clinical practice. Several validated methods are very simple. For example, radiopaque markers are ingested; an abdominal flat film taken 5 days later should indicate passage of 80% of the markers out of the colon without the use of laxatives or enemas. This test does not provide useful information about the transit profile of the stomach and small bowel. Radioscintigraphy with a delayed-release capsule containing radiolabeled particles has been used to noninvasively characterize normal, accelerated, or delayed colonic function over 24–48 h with low radiation exposure. This approach simultaneously assesses gastric, small bowel (which may be important in ∼20% of patients with delayed colonic transit because they reflect a more generalized GI motility disorder), and colonic transit. The disadvantages are the greater cost and the need for specific materials prepared in a nuclear medicine laboratory. Anorectal and Pelvic Floor Tests Pelvic floor dysfunction is suggested by the inability to evacuate the rectum, a feeling of persistent rectal fullness, rectal pain, the need to extract stool from the rectum digitally, application of pressure on the posterior wall of the vagina, support of the perineum during straining, and excessive straining. These significant symptoms should be contrasted with the simple sense of incomplete rectal evacuation, which is common in IBS. Formal psychological evaluation may identify eating disorders, “control issues,” depression, or post-traumatic stress disorders that may respond to cognitive or other intervention and may be important in restoring quality of life to patients who might present with chronic constipation. A simple clinical test in the office to document a non-relaxing puborectalis muscle is to have the patient strain to expel the index finger during a digital rectal examination. Motion of the puborectalis posteriorly during straining indicates proper coordination of the pelvic floor muscles. Motion anteriorly with paradoxical contraction during simulated evacuation indicates pelvic floor dysfunction. Measurement of perineal descent is relatively easy to gauge clinically by placing the patient in the left decubitus position and watching
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the perineum to detect inadequate descent (4 cm, suggesting excessive perineal descent). A useful overall test of evacuation is the balloon expulsion test. A balloon-tipped urinary catheter is placed and inflated with 50 mL of water. Normally, a patient can expel it while seated on a toilet or in the left lateral decubitus position. In the lateral position, the weight needed to facilitate expulsion of the balloon is determined; normally, expulsion occurs with 80 mmHg) or squeeze anal sphincter tone, suggesting anismus (anal sphincter spasm). This test also identifies rare syndromes, such as adult Hirschsprung’s disease, by the absence of the rectoanal inhibitory reflex. Defecography (a dynamic barium enema including lateral views obtained during barium expulsion or a magnetic resonance defecogram) reveals “soft abnormalities” in many patients; the most relevant findings are the measured changes in rectoanal angle, anatomic defects of the rectum such as internal mucosal prolapse, and enteroceles or rectoceles. Surgically remediable conditions are identified in only a few patients. These include severe, whole-thickness intussusception with complete outlet obstruction due to funnel-shaped plugging at the anal canal or an extremely large rectocele that fills preferentially during attempts at defecation instead of expulsion of the barium through the anus. In summary, defecography requires an interested and experienced radiologist, and abnormalities are not pathognomonic for pelvic floor dysfunction. The most common cause of outlet obstruction is failure of the puborectalis muscle to relax; this is not identified by barium defecography, but can be demonstrated by magnetic resonance defecography, which provides more information about the structure and function of the pelvic floor, distal colorectum, and anal sphincters. Neurologic testing (electromyography) is more helpful in the evaluation of patients with incontinence than of those with symptoms suggesting obstructed defecation. The absence of neurologic signs in the lower extremities suggests that any documented denervation of the puborectalis results from pelvic (e.g., obstetric) injury or from stretching of the pudendal nerve by chronic, long-standing straining. Constipation is common among patients with spinal cord injuries, neurologic diseases such as Parkinson’s disease, multiple sclerosis, and diabetic neuropathy. Spinal-evoked responses during electrical rectal stimulation or stimulation of external anal sphincter contraction by applying magnetic stimulation over the lumbosacral cord identify patients with limited sacral neuropathies with sufficient residual nerve conduction to attempt biofeedback training. In summary, a balloon expulsion test is an important screening test for anorectal dysfunction. Rarely, an anatomic evaluation of the rectum or anal sphincters and an assessment of pelvic floor relaxation are the tools for evaluating patients in whom obstructed defecation is suspected and is associated with symptoms of rectal mucosal prolapse, pressure of the posterior wall of the vagina to facilitate defecation (suggestive of anterior rectocele), or prior pelvic surgery that may be complicated by enterocele. TREATMENT
Constipation
After the cause of constipation is characterized, a treatment decision can be made. Slow-transit constipation requires aggressive medical or surgical treatment; anismus or pelvic floor dysfunction usually responds to biofeedback management (Fig. 40-4). The remaining ∼60% of patients with constipation has normal colonic transit and can be treated symptomatically. Patients with spinal cord injuries or other neurologic disorders require a dedicated bowel regimen that often includes rectal stimulation, enema therapy, and carefully timed laxative therapy. Patients with constipation are treated with bulk, osmotic, prokinetic, secretory, and stimulant laxatives including fiber, psyllium, milk of magnesia, lactulose, polyethylene glycol (colonic lavage
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solution), lubiprostone, linaclotide, and bisacodyl, or, in some countries, prucalopride, a 5-HT4 agonist. If a 3-to 6-month trial of medical therapy fails, unassociated with obstructed defecation, the patients should be considered for laparoscopic colectomy with ileorectostomy; however, this should not be undertaken if there is continued evidence of an evacuation disorder or a generalized GI dysmotility. Referral to a specialized center for further tests of colonic motor function is warranted. The decision to resort to surgery is facilitated in the presence of megacolon and megarectum. The complications after surgery include small-bowel obstruction (11%) and fecal soiling, particularly at night during the first postoperative year. Frequency of defecation is 3–8 per day during the first year, dropping to 1–3 per day from the second year after surgery. Patients who have a combined (evacuation and transit/motility) disorder should pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological counseling, and dietetic advice first. If symptoms are intractable despite biofeedback and optimized medical therapy, colectomy and ileorectostomy could be considered as long as the evacuation disorder is resolved and optimized medical therapy is unsuccessful. In patients with pelvic floor dysfunction alone, biofeedback training has a 70–80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) or injections with botulinum toxin have achieved only mediocre success and have been largely abandoned.
56
Involuntary Weight Loss Russell G. Robertson, J. Larry Jameson
Involuntary weight loss (IWL) is frequently insidious and can have important implications, often serving as a harbinger of serious underlying disease. Clinically important weight loss is defined as the loss of 10 pounds (4.5 kg) or >5% of one’s body weight over a period of 6–12 months. IWL is encountered in up to 8% of all adult outpatients and 27% of frail persons age 65 years and older. There is no identifiable cause in up to one-quarter of patients despite extensive investigation. Conversely, up to half of people who claim to have lost weight have no documented evidence of weight loss. People with no known cause of weight loss generally have a better prognosis than do those with known causes, particularly when the source is neoplastic. Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, impaired immune function, and decreased functional status. Not surprisingly, significant weight loss is associated with increased mortality, which can range from 9% to as high as 38% within 1 to 2.5 years in the absence of clinical awareness and attention. PHYSIOLOGY OF WEIGHT REGULATION WITH AGING (See also Chaps. 94e and 415e) Among healthy aging people, total body weight peaks in the sixth decade of life and generally remains stable until the ninth decade, after which it gradually falls. In contrast, lean body mass (fat-free mass) begins to decline at a rate of 0.3 kg per year in the third decade, and the rate of decline increases further beginning at age 60 in men and age 65 in women. These changes in lean body mass largely reflect the age-dependent decline in growth hormone secretion and, consequently, circulating levels of insulinlike growth factor type I (IGF-I) that occur with normal aging. Loss of sex steroids, at menopause in women and more gradually with aging in men, also contributes to these changes in body composition. In the healthy elderly, an increase in fat tissue balances the loss in lean body mass until very old age, when loss of both fat and skeletal muscle occurs. Age-dependent changes also occur at the cellular level. Telomeres shorten, and body cell mass—the fat-free portion of cells— declines steadily with aging.
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Table 56-1 Causes of Involuntary Weight Loss Cancer Colon Hepatobiliary Hematologic Lung Breast Genitourinary Ovarian Prostate Gastrointestinal disorders Malabsorption Peptic ulcer Inflammatory bowel disease Pancreatitis Obstruction/constipation Pernicious anemia Endocrine and metabolic Hyperthyroidism Diabetes mellitus Pheochromocytoma Adrenal insufficiency Cardiac disorders Chronic ischemia Chronic congestive heart failure Respiratory disorders Emphysema Chronic obstructive pulmonary disease Renal insufficiency Rheumatologic disease Infections HIV Tuberculosis Parasitic infection Subacute bacterial endocarditis
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Medications Sedatives Antibiotics Nonsteroidal anti-inflammatory drugs Serotonin reuptake inhibitors Metformin Levodopa Angiotensin-converting enzyme inhibitors Other drugs Disorders of the mouth and teeth Caries Dysgeusia Age-related factors Physiologic changes Visual impairment Decreased taste and smell Functional disabilities Neurologic Stroke Parkinson’s disease Neuromuscular disorders Dementia Social Isolation Economic hardship Psychiatric and behavioral Depression Anxiety Paranoia Bereavement Alcoholism Eating disorders Increased activity or exercise Idiopathic
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Involuntary Weight Loss
CAUSES OF INVOLUNTARY WEIGHT LOSS Most causes of IWL belong to one of four categories: (1) malignant neoplasms, (2) chronic inflammatory or infectious diseases, (3) metabolic disorders (e.g., hyperthyroidism and diabetes), or (4) psychiatric disorders (Table 56-1). Not infrequently, more than one of these causes can be responsible for IWL. In most series, IWL is caused by malignant disease in a quarter of patients and by organic disease in one-third, with the remainder due to psychiatric disease, medications, or uncertain causes. The most common malignant causes of IWL are gastrointestinal, hepatobiliary, hematologic, lung, breast, genitourinary, ovarian, and prostate. Half of all patients with cancer lose some body weight;
one-third lose more than 5% of their original body weight, and up to 20% of all cancer deaths are caused directly by cachexia (through immobility and/or cardiac/respiratory failure). The greatest incidence of weight loss is seen among patients with solid tumors. Malignancy that reveals itself through significant weight loss usually has a very poor prognosis. In addition to malignancies, gastrointestinal causes are among the most prominent causes of IWL. Peptic ulcer disease, inflammatory bowel disease, dysmotility syndromes, chronic pancreatitis, celiac disease, constipation, and atrophic gastritis are some of the more common entities. Oral and dental problems are easily overlooked and may manifest with halitosis, poor oral hygiene, xerostomia, inability to chew, reduced masticatory force, nonocclusion, temporomandibular joint syndrome, edentulousness, and pain due to caries or abscesses. Tuberculosis, fungal diseases, parasites, subacute bacterial endocarditis, and HIV are well-documented causes of IWL. Cardiovascular and pulmonary diseases cause unintentional weight loss through increased metabolic demand and decreased appetite and caloric intake. Uremia produces nausea, anorexia, and vomiting. Connective tissue diseases may increase metabolic demand and disrupt nutritional balance. As the incidence of diabetes mellitus increases with aging, the associated glucosuria can contribute to weight loss. Hyperthyroidism in the elderly may have less prominent sympathomimetic features and may present as “apathetic hyperthyroidism” or T3 toxicosis (Chap. 405). Neurologic injuries such as stroke, quadriplegia, and multiple sclerosis may lead to visceral and autonomic dysfunction that can impair caloric intake. Dysphagia from these neurologic insults is a common mechanism. Functional disability that compromises activities of daily living (ADLs) is a common cause of undernutrition in the elderly. Visual impairment from ophthalmic or central nervous system disorders such as a tremor can limit the ability of people to prepare and eat meals. IWL may be one of the earliest manifestations of Alzheimer’s dementia. Isolation and depression are significant causes of IWL that may manifest as an inability to care for oneself, including nutritional needs. A cytokine-mediated inflammatory metabolic cascade can be both a cause of and a manifestation of depression. Bereavement can be a cause of IWL and, when present, is more pronounced in men. More intense forms of mental illness such as paranoid disorders may lead to delusions about food and cause weight loss. Alcoholism can be a significant source of weight loss and malnutrition. Elderly persons living in poverty may have to choose whether to purchase food or use the money for other expenses, including medications. Institutionalization is an independent risk factor, as up to 30–50% of nursing home patients have inadequate food intake. Medications can cause anorexia, nausea, vomiting, gastrointestinal distress, diarrhea, dry mouth, and changes in taste. This is particularly an issue in the elderly, many of whom take five or more medications.
CHAPTER 56
Between ages 20 and 80, mean energy intake is reduced by up to 1200 kcal/d in men and 800 kcal/d in women. Decreased hunger is a reflection of reduced physical activity and loss of lean body mass, producing lower demand for calories and food intake. Several important age-associated physiologic changes also predispose elderly persons to weight loss, such as declining chemosensory function (smell and taste), reduced efficiency of chewing, slowed gastric emptying, and alterations in the neuroendocrine axis, including changes in levels of leptin, cholecystokinin, neuropeptide Y, and other hormones and peptides. These changes are associated with early satiety and a decline in both appetite and the hedonistic appreciation of food. Collectively, they contribute to the “anorexia of aging.”
ASSESSMENT The four major manifestations of IWL are (1) anorexia (loss of appetite), (2) sarcopenia (loss of muscle mass), (3) cachexia (a syndrome that combines weight loss, loss of muscle and adipose tissue, anorexia, and weakness), and (4) dehydration. The current obesity epidemic adds complexity, as excess adipose tissue can mask the development of sarcopenia and delay awareness of the development of cachexia. If it is not possible to measure weight directly, a change in clothing size, corroboration of weight loss by a relative or friend, and a numeric estimate of weight loss provided by the patient are suggestive of true weight loss. Initial assessment includes a comprehensive history and physical, a complete blood count, tests of liver enzyme levels, C-reactive protein, erythrocyte sedimentation rate, renal function studies, thyroid function tests, chest radiography, and an abdominal ultrasound (Table 56-2). Age, sex, and risk factor–specific cancer screening tests, such as mammography and colonoscopy, should be performed (Chap. 100). Patients at risk should have HIV testing. All elderly patients with weight loss should undergo screening for dementia and depression by using instruments such as the
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Table 56-2 Assessment and Testing for Involuntary Weight Loss Indications 5% weight loss in 30 d 10% weight loss in 180 d
PART 2
Body mass index 90% of those with other organic diseases have at least one laboratory abnormality. In patients presenting with substantial IWL, major organic and malignant diseases are unlikely when a baseline evaluation is completely normal. Careful followup rather than undirected testing is advised since the prognosis of weight loss of undetermined cause is generally favorable. TREATMENT
Unintentional Weight Loss
The first priority in managing weight loss is to identify and treat the underlying causes systematically. Treatment of underlying metabolic, psychiatric, infectious, or other systemic disorders may be sufficient to restore weight and functional status gradually. Medications that cause nausea or anorexia should be withdrawn or changed, if possible. For those with unexplained IWL, oral nutritional supplements such as high-energy drinks sometimes reverse weight loss. Advising patients to consume supplements between meals rather than with a meal may help minimize appetite suppression and facilitate increased overall intake. Orexigenic, anabolic, and anticytokine agents are under investigation. In selected patients, the antidepressant mirtazapine results in a significant increase in body weight, body fat mass, and leptin concentration. Patients with wasting conditions who can comply with an appropriate exercise program gain muscle protein mass, strength, and endurance and may be more capable of performing ADLs.
57
Gastrointestinal Bleeding Loren Laine
Gastrointestinal bleeding (GIB) accounts for ~150 hospitalizations per 100,000 population annually in the United States, with upper GIB (UGIB) ~1.5–2 times more common than lower GIB (LGIB) The incidence of GIB has decreased in recent decades, primarily due to a reduction in UGIB, and the mortality has also decreased to 6 and enhance clot stability, decreases further bleeding and mortality in patients with high-risk ulcers (active bleeding, nonbleeding visible vessel, adherent clot) when given after endoscopic therapy. Patients with lower-risk findings (flat pigmented spot or clean base) do not require endoscopic TABLE 57-1 Sources of Bleeding in Patients Hospitalized for Upper Gastrointestinal Bleeding Sources of Bleeding Ulcers Varices Mallory-Weiss tears Gastroduodenal erosions Erosive esophagitis Neoplasm Vascular ectasias No source identified
Proportion of Patients, % 31–67 6–39 2–8 2–18 1–13 2–8 0–6 5–14
Source: Data on hospitalizations from year 2000 onward from Am J Gastroenterol 98:1494, 2003; Gastrointest Endosc 57:AB147, 2003; 60;875, 2004; Eur J Gastroenterol Hepatol 16:177, 2004; 17:641, 2005; J Clin Gastroenterol 42:128, 2008; World J Gastroenterol 14:5046, 2008; Dig Dis Sci 54:333, 2009; Gut 60:1327, 2011; Endoscopy 44:998, 2012; J Clin Gastroenterol 48:113, 2014.
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Esophageal varices Patients with variceal hemorrhage have poorer outcomes than patients with other sources of UGIB. Urgent endoscopy within 12 h is recommended in cirrhotics with UGIB, and if esophageal varices are present, endoscopic ligation is performed and an IV vasoactive medication (e.g., octreotide 50 μg bolus and 50 μg/h infusion) is given for 2–5 days. Combination endoscopic and medical therapy appears to be superior to either therapy alone in decreasing rebleeding. In patients with advanced liver disease (e.g., Child-Pugh class C with score 10–13), a transjugular intrahepatic portosystemic shunt (TIPS) should be strongly considered within the first 1–2 days of hospitalization because randomized trials show significant decreases in rebleeding and mortality compared with standard endoscopic and medical therapy. Over the long term, treatment with nonselective beta blockers plus endoscopic ligation is recommended because the combination of endoscopic and medical therapy is more effective than either alone in reduction of recurrent esophageal variceal bleeding. In patients who have persistent or recurrent bleeding despite endoscopic and medical therapy, TIPS is recommended. Decompressive surgery (e.g., distal splenorenal shunt) may be considered instead of TIPS in patients with well-compensated cirrhosis. Portal hypertension is also responsible for bleeding from gastric varices, varices in the small and large intestine, and portal hypertensive gastropathy and enterocolopathy. Bleeding gastric varices due to cirrhosis are treated with endoscopic injection of tissue adhesive (e.g., n-butyl cyanoacrylate), if available; if not, TIPS is performed. Hemorrhagic and erosive gastropathy (“gastritis”) Hemorrhagic and erosive gastropathy, often labeled gastritis, refers to endoscopically visualized subepithelial hemorrhages and erosions. These are mucosal lesions and do not cause major bleeding due to the absence of arteries and veins in the mucosa. Erosions develop in various clinical settings, the most important of which are NSAID use, alcohol intake, and stress. Half of patients who chronically ingest NSAIDs have erosions, whereas up to 20% of actively drinking alcoholic patients with symptoms of UGIB have evidence of subepithelial hemorrhages or erosions. Stress-related gastric mucosal injury occurs only in extremely sick patients, such as those who have experienced serious trauma, major
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Other causes Other less frequent causes of UGIB include erosive duodenitis, neoplasms, aortoenteric fistulas, vascular lesions (including hereditary hemorrhagic telangiectasias [Osler-Weber-Rendu] and gastric antral vascular ectasia [“watermelon stomach”]), Dieulafoy’s lesion (in which an aberrant vessel in the mucosa bleeds from a pinpoint mucosal defect), prolapse gastropathy (prolapse of proximal stomach into esophagus with retching, especially in alcoholics), and hemobilia or hemosuccus pancreaticus (bleeding from the bile duct or pancreatic duct). Small-Intestinal Sources of Bleeding Small-intestinal sources of bleeding (bleeding from sites beyond the reach of the standard upper endoscope) are often difficult to diagnose and are responsible for the majority of cases of obscure GIB. Fortunately, small-intestinal bleeding is uncommon. The most common causes in adults are vascular ectasias, tumors (e.g., GI stromal tumor, carcinoid, adenocarcinoma, lymphoma, metastases), and NSAID-induced erosions and ulcers. Other less common causes in adults include Crohn’s disease, infection, ischemia, vasculitis, small-bowel varices, diverticula, Meckel’s diverticulum, duplication cysts, and intussusception. Meckel’s diverticulum is the most common cause of significant LGIB in children, decreasing in frequency as a cause of bleeding with age. In adults 50–60 years, vascular ectasias and NSAIDinduced lesions are more commonly responsible. Vascular ectasias should be treated with endoscopic therapy if possible. Although estrogen/progesterone compounds have been used for vascular ectasias, a large double-blind trial found no benefit in prevention of recurrent bleeding. Octreotide is also used, based on case series but no randomized trials. A randomized trial reported significant benefit of thalidomide and awaits further confirmation. Other isolated lesions, such as tumors, are generally treated with surgical resection.
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Gastrointestinal Bleeding
Mallory-Weiss tears The classic history is vomiting, retching, or coughing preceding hematemesis, especially in an alcoholic patient. Bleeding from these tears, which are usually on the gastric side of the gastroesophageal junction, stops spontaneously in 80–90% of patients and recurs in only 0–10%. Endoscopic therapy is indicated for actively bleeding Mallory-Weiss tears. Angiographic therapy with embolization and operative therapy with oversewing of the tear are rarely required. Mallory-Weiss tears are discussed in Chap. 347.
surgery, burns covering more than one-third of the body surface area, major intracranial disease, or severe medical illness (i.e., ventilator dependence, coagulopathy). Severe bleeding should not develop unless ulceration occurs. The mortality rate in these patients is quite high because of their serious underlying illnesses. The incidence of bleeding from stress-related gastric mucosal injury has decreased dramatically in recent years, most likely due to better care of critically ill patients. Pharmacologic prophylaxis for bleeding may be considered in the high-risk patients mentioned above. Metaanalyses of randomized trials indicate that PPIs are more effective than H2 receptor antagonists in reduction of overt and clinically important UGIB without differences in mortality or nosocomial pneumonia.
CHAPTER 57
therapy and receive standard doses of oral PPI. Approximately onethird of patients with bleeding ulcers will rebleed within the next 1–2 years if no preventive strategies are employed. Prevention of recurrent bleeding focuses on the three main factors in ulcer pathogenesis, Helicobacter pylori, NSAIDs, and acid. Eradication of H. pylori in patients with bleeding ulcers decreases rates of rebleeding to 70 years), neoplasms (primarily adenocarcinoma), colitis (ischemic, infectious, idiopathic inflammatory bowel disease), and postpolypectomy bleeding. Less common causes include NSAID-induced ulcers or colitis, radiation proctopathy, solitary rectal ulcer syndrome, trauma, varices (most commonly rectal), lymphoid nodular hyperplasia, vasculitis, and aortocolic fistulas. In children and adolescents, the most common colonic causes of significant GIB are inflammatory bowel disease and juvenile polyps. Diverticular bleeding is abrupt in onset, usually painless, sometimes massive, and often from the right colon; chronic or occult bleeding is not characteristic. Clinical reports suggest that bleeding colonic diverticula stop bleeding spontaneously in ~80% of patients and, on long-term follow-up, rebleed in ~15–25% of patients. Case series suggest endoscopic therapy may decrease recurrent bleeding in the uncommon case when colonoscopy identifies the specific bleeding diverticulum. When diverticular bleeding is found at angiography, transcatheter arterial embolization by superselective technique stops bleeding in a majority of patients. If bleeding persists or recurs, segmental surgical resection is indicated.
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278
Bleeding from right colonic vascular ectasias in the elderly may be overt or occult; it tends to be chronic and only occasionally is hemodynamically significant. Endoscopic hemostatic therapy may be useful in the treatment of vascular ectasias, as well as discrete bleeding ulcers and postpolypectomy bleeding. Surgical therapy is generally required for major, persistent, or recurrent bleeding from the wide variety of colonic sources of GIB that cannot be treated medically, angiographically, or endoscopically.
APPROACH TO THE PATIENT: Gastrointestinal Bleeding PART 2 Cardinal Manifestations and Presentation of Diseases
INITIAL ASSESSMENT Measurement of the heart rate and blood pressure is the best way to initially assess a patient with GIB. Clinically significant bleeding leads to postural changes in heart rate or blood pressure, tachycardia, and, finally, recumbent hypotension. In contrast, the hemoglobin does not fall immediately with acute GIB, due to proportionate reductions in plasma and red cell volumes (i.e., “people bleed whole blood”). Thus, hemoglobin may be normal or only minimally decreased at the initial presentation of a severe bleeding episode. As extravascular fluid enters the vascular space to restore volume, the hemoglobin falls, but this process may take up to 72 h. Transfusion is recommended when the hemoglobin drops below 7 g/dL, based on a large randomized trial showing this restrictive transfusion strategy decreases rebleeding and death in acute UGIB compared with a transfusion threshold of 9 g/dL. Patients with slow, chronic GIB may have very low hemoglobin values despite normal blood pressure and heart rate. With the development of iron-deficiency anemia, the mean corpuscular volume will be low and red blood cell distribution width will increase. DIFFERENTIATION OF UGIB FROM LGIB Hematemesis indicates an upper GI source of bleeding (above the ligament of Treitz). Melena indicates blood has been present in the GI tract for at least 14 h, and as long as 3–5 days. The more proximal the bleeding site, the more likely melena will occur. Hematochezia usually represents a lower GI source of bleeding, although an upper GI lesion may bleed so briskly that blood transits the bowel before melena develops. When hematochezia is the presenting symptom of UGIB, it is associated with hemodynamic instability and dropping hemoglobin. Bleeding lesions of the small bowel may present as melena or hematochezia. Other clues to UGIB include hyperactive bowel sounds and an elevated blood urea nitrogen (due to volume depletion and blood proteins absorbed in the small intestine).
A nonbloody nasogastric aspirate may be seen in up to ~18% of patients with UGIB, usually from a duodenal source. Even a bilestained appearance does not exclude a bleeding postpyloric lesion because reports of bile in the aspirate are incorrect in ~50% of cases. Testing of aspirates that are not grossly bloody for occult blood is not useful. EVALUATION AND MANAGEMENT OF UGIB (Fig. 57-1) At presentation, patients are generally stratified as higher or lower risk for further bleeding and death. Baseline characteristics predictive of rebleeding and death include hemodynamic compromise (tachycardia or hypotension), increasing age, and comorbidities. PPI infusion may be considered at presentation: it decreases highrisk ulcer stigmata (e.g., active bleeding) and need for endoscopic therapy but does not improve clinical outcomes such as further bleeding, surgery, or death. Treatment to improve endoscopic visualization with the promotility agent erythromycin, 250 mg intravenously ~30 min before endoscopy, also may be considered: it provides a small but significant increase in diagnostic yield and decrease in second endoscopies but is not documented to decrease further bleeding or death. Cirrhotic patients presenting with UGIB should be placed on antibiotics (e.g., quinolone, ceftriaxone) and started on a vasoactive medication (octreotide, terlipressin, somatostatin, vapreotide) upon presentation, even before endoscopy. Antibiotics decrease bacterial infections, rebleeding, and mortality in this population, and vasoactive medications appear to improve control of bleeding in the first 12 h after presentation. Upper endoscopy should be performed within 24 h in most patients with UGIB. Patients at higher risk (e.g., hemodynamic instability, cirrhosis) may benefit from more urgent endoscopy within 12 h. Early endoscopy is also beneficial in low-risk patients for management decisions. Patients with major bleeding and highrisk endoscopic findings (e.g., varices, ulcers with active bleeding or a visible vessel) benefit from endoscopic hemostatic therapy, whereas patients with low-risk lesions (e.g., clean-based ulcers, nonbleeding Mallory-Weiss tears, erosive or hemorrhagic gastropathy) who have stable vital signs and hemoglobin and no other medical problems can be discharged home. EVALUATION AND MANAGEMENT OF LGIB (Fig. 57-2) Patients with hematochezia and hemodynamic instability should have upper endoscopy to rule out an upper GI source before evaluation of the lower GI tract. Colonoscopy after an oral lavage solution is the procedure of choice in most patients admitted with LGIB unless bleeding is too massive,
Acute upper GI bleeding
Ulcer
Esophageal varices
Active bleeding or visible vessel
Adherent clot
Flat, pigmented spot
Clean base
IV PPI therapy + endoscopic therapy
IV PPI therapy +/– endoscopic therapy
No IV PPI or endoscopic therapy
No IV PPI or endoscopic therapy
ICU for 1 day; ward for 2 days
Ward for 3 days
Ward for 2–3 days
Discharge
Mallory-Weiss tear
Ligation + IV vasoactive drug (e.g., octreotide)
Active bleeding
No active bleeding
ICU for 1–2 days; ward for 2–3 days
Endoscopic therapy
No endoscopic therapy
Ward for 1–2 days
Discharge
Figure 57-1 Suggested algorithm for patients with acute upper gastrointestinal (GI) bleeding. Recommendations on level of care and time of discharge assume patient is stabilized without further bleeding or other concomitant medical problems. ICU, intensive care unit; PPI, proton pump inhibitor.
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Acute lower GI bleeding
Hemodynamic instability
No hemodynamic instability
Age ≥40 yrs
Upper endoscopy^
Flexible sigmoidoscopy (colonoscopy if iron-deficiency anemia, familial colon cancer, or copious bleeding)*
Colonoscopy
Colonoscopy†
Site identified; bleeding persists
Site not identified; bleeding persists
Angiography
Obscure bleeding work-up
Bleeding persists
Jaundice
Site identified; bleeding stops
POSITIVE FECAL OCCULT BLOOD TEST Fecal occult blood testing is recommended only for colorectal cancer screening and may be used beginning at age 50 in average-risk adults and beginning at age 40 in adults with a first-degree relative with colorectal neoplasm at ≥60 years or two second-degree relatives with colorectal cancer. A positive test necessitates colonoscopy. If evaluation of the colon is negative, further workup is not recommended unless iron-deficiency anemia or GI symptoms are present.
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Age 300 mosmol/L, a solute diuresis is clearly present and a search for the responsible solute(s) is mandatory. Excessive filtration of a poorly reabsorbed solute such as glucose or mannitol can depress reabsorption of NaCl and water in the proximal tubule and lead to enhanced excretion in the urine. Poorly controlled diabetes mellitus with glucosuria is the most common cause of a solute diuresis, leading to volume depletion and serum hypertonicity. Since the urine sodium concentration is less than that of blood, more water than sodium is lost, causing hypernatremia and hypertonicity. Common iatrogenic solute diuresis occurs in association with mannitol administration, radiocontrast media, and high-protein feedings (enteral or parenteral), leading to increased urea production and excretion. Less commonly, excessive sodium loss may result from cystic renal diseases or Bartter’s syndrome or may develop during a tubulointerstitial process (such as resolving ATN). In these so-called salt-wasting disorders, the tubule damage results in direct impairment of sodium reabsorption and indirectly reduces the responsiveness of the tubule to aldosterone. Usually, the sodium losses are mild, and the obligatory urine output is 20 mM and urine pH of >7.0, due to the increase in filtered HCO3–; the urine Cl– concentration in this setting is a more accurate indicator of volume status, with a level 20 mM in patients with renal causes
of hypovolemia, such as acute tubular necrosis; similarly, patients with diabetes insipidus will have an inappropriately dilute urine.
U
PART 2
concentration), whereas biliary, pancreatic, and intestinal secretions are alkaline (high HCO3– concentration), vomiting and diarrhea are often accompanied by metabolic alkalosis and acidosis, respectively. Evaporation of water from the skin and respiratory tract (so-called “insensible losses”) constitutes the major route for loss of solute-free water, which is typically 500–650 mL/d in healthy adults. This evaporative loss can increase during febrile illness or prolonged heat exposure. Hyperventilation can also increase insensible losses via the respiratory tract, particularly in ventilated patients; the humidity of inspired air is another determining factor. In addition, increased exertion and/or ambient temperature will increase insensible losses via sweat, which is hypotonic to plasma. Profuse sweating without adequate repletion of water and Na+-Cl– can thus lead to both hypovolemia and hypertonicity. Alternatively, replacement of these insensible losses with a surfeit of free water, without adequate replacement of electrolytes, may lead to hypovolemic hyponatremia. Excessive fluid accumulation in interstitial and/or peritoneal spaces can also cause intravascular hypovolemia. Increases in vascular permeability and/or a reduction in oncotic pressure (hypoalbuminemia) alter Starling forces, resulting in excessive “third spacing” of the ECFV. This occurs in sepsis syndrome, burns, pancreatitis, nutritional hypoalbuminemia, and peritonitis. Alternatively, distributive hypovolemia can occur due to accumulation of fluid within specific compartments, for example within the bowel lumen in gastrointestinal obstruction or ileus. Hypovolemia can also occur after extracorporeal hemorrhage or after significant hemorrhage into an expandable space, for example, the retroperitoneum.
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299 Assessment of volume status
Euvolemia (no edema) • Total body water ↑ • Total body sodium ←→
Hypovolemia • Total body water ↓ • Total body sodium ↓↓
UNa >20
Renal losses Diuretic excess Mineral corticoid deficiency Salt-losing deficiency Bicarbonaturia with renal tubal acidosis and metabolic alkalosis Ketonuria Osmotic diuresis Cerebral salt wasting syndrome
Extrarenal losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis Trauma
Glucocorticoid deficiency Hypothyroidism Stress Drugs Syndrome of inappropriate antidiuretic hormone secretion
UNa >20
Acute or chronic renal failure
UNa 400 mg/dL.
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Pyroglutamic acid Acetaminophen-induced high-AG metabolic acidosis is uncommon but is being recognized more often in either patients with acetaminophen overdose or malnourished or critically ill patients receiving acetaminophen in typical dosage. 5-Oxoproline accumulation after acetaminophen should be suspected in the setting of an unexplained high-AG acidosis without elevation of the osmolar gap in patients receiving acetaminophen. The first step in treatment is to immediately discontinue the drug. Additionally, sodium bicarbonate IV should be given. Although N-acetylcysteine has been suggested, it is not known if it hastens the metabolism of 5-oxoproline by increasing intracellular glutathione concentrations in this setting.
PART 2 Cardinal Manifestations and Presentation of Diseases
Renal Failure (See also Chap. 335) The hyperchloremic acidosis of moderate renal insufficiency is eventually converted to the high-AG acidosis of advanced renal failure. Poor filtration and reabsorption of organic anions contribute to the pathogenesis. As renal disease progresses, the number of functioning nephrons eventually becomes insufficient to keep pace with net acid production. Uremic acidosis is characterized, therefore, by a reduced rate of NH4+ production and excretion. The acid retained in chronic renal disease is buffered by alkaline salts from bone. Despite significant retention of acid (up to 20 mmol/d), the serum [HCO3-] does not decrease further, indicating participation of buffers outside the extracellular compartment. Chronic metabolic acidosis results in significant loss of bone mass due to reduction in bone calcium carbonate. Chronic acidosis also increases urinary calcium excretion, proportional to cumulative acid retention. TREATMENT
Renal Failure
Because of the association of renal failure acidosis with muscle catabolism and bone disease, both uremic acidosis and the hyperchloremic acidosis of renal failure require oral alkali replacement to maintain the [HCO3-] >22 mmol/L. This can be accomplished with relatively modest amounts of alkali (1.0–1.5 mmol/kg body weight per day). Sodium citrate (Shohl’s solution) or NaHCO3 tablets (650-mg tablets contain 7.8 meq) are equally effective alkalinizing salts. Citrate enhances the absorption of aluminum from the gastrointestinal tract and should never be given together with aluminum-containing antacids because of the risk of aluminum intoxication. NON–ANION GAP METABOLIC ACIDOSES Alkali can be lost from the gastrointestinal tract from diarrhea or from the kidneys (renal tubular acidosis, RTA). In these disorders (Table 66-5), reciprocal changes in [Cl-] and [HCO3-] result in a normal AG. In pure non–AG acidosis, therefore, the increase in [Cl-] above the normal value approximates the decrease in [HCO3-]. The absence of such a relationship suggests a mixed disturbance. TREATMENT
Non–Anion Gap Metabolic Acidoses
In diarrhea, stools contain a higher [HCO3-] and decomposed HCO3than plasma so that metabolic acidosis develops along with volume depletion. Instead of an acid urine pH (as anticipated with systemic acidosis), urine pH is usually >6 because metabolic acidosis and hypokalemia increase renal synthesis and excretion of NH4+, thus providing a urinary buffer that increases urine pH. Metabolic acidosis due to gastrointestinal losses with a high urine pH can be differentiated from RTA because urinary NH4+ excretion is typically low in RTA and high with diarrhea. Urinary NH4+ levels can be estimated by calculating the urine anion gap (UAG): UAG = [Na+ + K+]u – [Cl-]u. When [Cl-]u > [Na+ + K+]u, the UAG is negative by definition. This indicates that the urine ammonium level is appropriately increased, suggesting an extrarenal cause of the acidosis. Conversely, when the UAG is positive, the urine ammonium level is low, suggesting a renal cause of the acidosis.
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TABLE 66-5 Causes of Non–Anion Gap Acidosis 1. Gastrointestinal bicarbonate loss A. Diarrhea B. External pancreatic or small-bowel drainage C. Ureterosigmoidostomy, jejunal loop, ileal loop D. Drugs 1. Calcium chloride (acidifying agent) 2. Magnesium sulfate (diarrhea) 3. Cholestyramine (bile acid diarrhea) II. Renal acidosis A. Hypokalemia 1. Proximal RTA (type 2) Drug-induced: acetazolamide, topiramate 2. Distal (classic) RTA (type 1) Drug induced: amphotericin B, ifosfamide B. Hyperkalemia 1. Generalized distal nephron dysfunction (type 4 RTA) a. Mineralocorticoid deficiency b. Mineralocorticoid resistance (PHA I, autosomal dominant) c. Voltage defect (PHA I, autosomal recessive, and PHA II) d. Tubulointerstitial disease C. Normokalemia 1. Chronic progressive kidney disease III. Drug-induced hyperkalemia (with renal insufficiency) A. Potassium-sparing diuretics (amiloride, triamterene, spironolactone, eplerenone) B. Trimethoprim C. Pentamidine D. ACE-Is and ARBs E. Nonsteroidal anti-inflammatory drugs F. Calcineurin inhibitors IV. Other A. Acid loads (ammonium chloride, hyperalimentation) B. Loss of potential bicarbonate: ketosis with ketone excretion C. Expansion acidosis (rapid saline administration) D. Hippurate E. Cation exchange resins Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; PHA, pseudohypoaldosteronism; RTA, renal tubular acidosis.
Proximal RTA (type 2 RTA) (Chap. 339) is most often due to generalized proximal tubular dysfunction manifested by glycosuria, generalized aminoaciduria, and phosphaturia (Fanconi syndrome). With a low plasma [HCO3-], the urine pH is acid (pH 20 mmol/L. Because HCO3- is not reabsorbed normally in the proximal tubule, therapy with NaHCO3 will enhance renal potassium wasting and hypokalemia. The typical findings in acquired or inherited forms of classic distal RTA (type 1 RTA) include hypokalemia, non-AG metabolic acidosis, low urinary NH4+ excretion (positive UAG, low urine [NH4+]), and inappropriately high urine pH (pH > 5.5). Most patients have hypocitraturia and hypercalciuria, so nephrolithiasis, nephrocalcinosis, and bone disease are common. In generalized distal RTA (type 4 RTA), hyperkalemia is disproportionate to the reduction in glomerular filtration rate (GFR) because of coexisting dysfunction of potassium and acid secretion. Urinary ammonium excretion is invariably depressed, and renal function may be compromised, for example, due to diabetic nephropathy, obstructive uropathy, or chronic tubulointerstitial disease. Hyporeninemic hypoaldosteronism typically causes non-AG metabolic acidosis, most commonly in older adults with diabetes mellitus or tubulointerstitial disease and renal insufficiency. Patients usually
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have mild to moderate CKD (GFR, 20–50 mL/min) and acidosis, with elevation in serum [K+] (5.2–6.0 mmol/L), concurrent hypertension, and congestive heart failure. Both the metabolic acidosis and the hyperkalemia are out of proportion to impairment in GFR. Nonsteroidal anti-inflammatory drugs, trimethoprim, pentamidine, and angiotensin-converting enzyme (ACE) inhibitors can also cause non-AG metabolic acidosis in patients with renal insufficiency (Table 66-5).
METABOLIC ALKALOSIS
DIFFERENTIAL DIAGNOSIS To establish the cause of metabolic alkalosis (Table 66-6), it is necessary to assess the status of the extracellular fluid volume (ECFV), the recumbent and upright blood pressure, the serum [K+], and the renin-aldosterone system. For example, the presence of chronic hypertension and chronic hypokalemia in an alkalotic patient suggests either mineralocorticoid excess or that the hypertensive patient is receiving diuretics. Low plasma renin activity and normal urine [Na+] and [Cl-] in a patient who is not taking diuretics indicate a primary mineralocorticoid excess syndrome. The combination of hypokalemia and alkalosis in a normotensive, nonedematous patient can be due to Bartter’s or Gitelman’s syndrome, magnesium deficiency, vomiting, exogenous alkali, or diuretic ingestion. Determination of urine electrolytes (especially the urine [Cl-]) and screening of the urine for diuretics may be helpful. If the urine is alkaline, with an elevated [Na+] and [K+] but low [Cl-], the diagnosis is usually either vomiting (overt or surreptitious) or alkali ingestion. If the urine is relatively acid and has low concentrations of Na+, K+, and Cl-, the most likely possibilities are prior vomiting, the posthypercapnic state, or prior diuretic ingestion. If, on the other hand, neither the urine sodium, potassium, nor chloride concentrations are depressed, magnesium deficiency, Bartter’s or Gitelman’s syndrome, or current diuretic ingestion should be considered. Bartter’s syndrome is distinguished from Gitelman’s syndrome because of hypocalciuria and hypomagnesemia in the latter disorder. Alkali Administration Chronic administration of alkali to individuals with normal renal function rarely causes alkalosis. However, in patients with coexistent hemodynamic disturbances, alkalosis can develop because the normal capacity to excrete HCO3- may be exceeded or there may be enhanced reabsorption of HCO3-. Such patients include those who receive HCO3- (PO or IV), acetate loads
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Acidosis and Alkalosis
PATHOGENESIS Metabolic alkalosis occurs as a result of net gain of [HCO3-] or loss of nonvolatile acid (usually HCl by vomiting) from the extracellular fluid. For HCO3- to be added to the extracellular fluid, it must be administered exogenously or synthesized endogenously, in part or entirely by the kidneys. Because it is unusual for alkali to be added to the body, the disorder involves a generative stage, in which the loss of acid usually causes alkalosis, and a maintenance stage, in which the kidneys fail to compensate by excreting HCO3-. Maintenance of metabolic alkalosis represents a failure of the kidneys to eliminate HCO3- in the usual manner. The kidneys will retain, rather than excrete, the excess alkali and maintain the alkalosis if (1) volume deficiency, chloride deficiency, and K+ deficiency exist in combination with a reduced GFR; or (2) hypokalemia exists because of autonomous hyperaldosteronism. In the first example, alkalosis is corrected by administration of NaCl and KCl, whereas, in the latter, it may be necessary to repair the alkalosis by pharmacologic or surgical intervention, not with saline administration.
I. Exogenous HCO3- loads A. Acute alkali administration B. Milk-alkali syndrome II. Effective ECFV contraction, normotension, K+ deficiency, and secondary hyperreninemic hyperaldosteronism A. Gastrointestinal origin 1. Vomiting 2. Gastric aspiration 3. Congenital chloridorrhea 4. Villous adenoma B. Renal origin 1. Diuretics 2. Posthypercapnic state 3. Hypercalcemia/hypoparathyroidism 4. Recovery from lactic acidosis or ketoacidosis 5. Nonreabsorbable anions including penicillin, carbenicillin 6. Mg2+ deficiency 7. K+ depletion 8. Bartter’s syndrome (loss of function mutations of transporters and ion channels in TALH) 9. Gitelman’s syndrome (loss of function mutation in Na+-Cl- cotransporter in DCT) III. ECFV expansion, hypertension, K+ deficiency, and mineralocorticoid excess A. High renin 1. Renal artery stenosis 2. Accelerated hypertension 3. Renin-secreting tumor 4. Estrogen therapy B. Low renin 1. Primary aldosteronism a. Adenoma b. Hyperplasia c. Carcinoma 2. Adrenal enzyme defects a. 11β-Hydroxylase deficiency b. 17α-Hydroxylase deficiency 3. Cushing’s syndrome or disease 4. Other a. Licorice b. Carbenoxolone c. Chewer’s tobacco IV. Gain-of-function mutation of renal sodium channel with ECFV expansion, hypertension, K+ deficiency, and hyporeninemic-hypoaldosteronism A. Liddle’s syndrome
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Metabolic alkalosis is manifested by an elevated arterial pH, an increase in the serum [HCO3-], and an increase in Paco2 as a result of compensatory alveolar hypoventilation (Table 66-1). It is often accompanied by hypochloremia and hypokalemia. The arterial pH establishes the diagnosis, because it is increased in metabolic alkalosis and decreased or normal in respiratory acidosis. Metabolic alkalosis frequently occurs in association with other disorders such as respiratory acidosis or alkalosis or metabolic acidosis.
TABLE 66-6 Causes of Metabolic Alkalosis
Abbreviations: DCT, distal convoluted tubule; ECFV, extracellular fluid volume; TALH, thick ascending limb of Henle’s loop.
(parenteral hyperalimentation solutions), citrate loads (transfusions), or antacids plus cation-exchange resins (aluminum hydroxide and sodium polystyrene sulfonate). Nursing home patients receiving tube feedings have a higher incidence of metabolic alkalosis than nursing home patients receiving oral feedings. METABOLIC ALKALOSIS ASSOCIATED WITH ECFV CONTRACTION, K+ DEPLETION, AND SECONDARY HYPERRENINEMIC HYPERALDOSTERONISM Gastrointestinal Origin Gastrointestinal loss of H+ from vomiting or gastric aspiration results in retention of HCO3-. During active vomiting, the filtered load of bicarbonate is acutely increased to exceed the reabsorptive capacity of the proximal tubule for HCO3- so that the urine becomes alkaline and high in potassium. When vomiting ceases, the persistence of volume, potassium, and chloride depletion causes
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maintenance of the alkalosis because of an enhanced capacity of the nephron to reabsorb HCO3-. Correction of the contracted ECFV with NaCl and repair of K+ deficits corrects the acid-base disorder by restoring the ability of the kidney to excrete the excess bicarbonate.
PART 2
Renal Origin • Diuretics (See also Chap. 279) Drugs that induce chloruresis, such as thiazides and loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid), acutely diminish the ECFV without altering the total body bicarbonate content. The serum [HCO3-] increases because the reduced ECFV “contracts” the [HCO3-] in the plasma (contraction alkalosis). The chronic administration of diuretics tends to generate an alkalosis by increasing distal salt delivery, so that K+ and H+ secretion are stimulated. The alkalosis is maintained by persistence of the contraction of the ECFV, secondary hyperaldosteronism, K+ deficiency, and the direct effect of the diuretic (as long as diuretic administration continues). Repair of the alkalosis is achieved by providing isotonic saline to correct the ECFV deficit.
Cardinal Manifestations and Presentation of Diseases
Solute losing disorders: Bartter’s syndrome and Gitelman’s syndrome See Chap. 339. Nonreabsorbable anions and magnesium deficiency Administration of large quantities of nonreabsorbable anions, such as penicillin or carbenicillin, can enhance distal acidification and K+ secretion by increasing the transepithelial potential difference. Mg2+ deficiency results in hypokalemic alkalosis by enhancing distal acidification through stimulation of renin and hence aldosterone secretion. Potassium depletion Chronic K+ depletion may cause metabolic alkalosis by increasing urinary acid excretion. Both NH4+ production and absorption are enhanced and HCO3- reabsorption is stimulated. Chronic K+ deficiency upregulates the renal H+, K+-ATPase to increase K+ absorption at the expense of enhanced H+ secretion. Alkalosis associated with severe K+ depletion is resistant to salt administration, but repair of the K+ deficiency corrects the alkalosis. After treatment of lactic acidosis or ketoacidosis When an underlying stimulus for the generation of lactic acid or ketoacid is removed rapidly, as with repair of circulatory insufficiency or with insulin therapy, the lactate or ketones are metabolized to yield an equivalent amount of HCO3-. Other sources of new HCO3- are additive with the original amount generated by organic anion metabolism to create a surfeit of HCO3-. Such sources include (1) new HCO3- added to the blood by the kidneys as a result of enhanced acid excretion during the preexisting period of acidosis, and (2) alkali therapy during the treatment phase of the acidosis. Acidosis-induced contraction of the ECFV and K+ deficiency act to sustain the alkalosis. Posthypercapnia Prolonged CO2 retention with chronic respiratory acidosis enhances renal HCO3- absorption and the generation of new HCO3- (increased net acid excretion). Metabolic alkalosis results from the effect of the persistently elevated [HCO3-] when the elevated Paco2 is abruptly returned toward normal. METABOLIC ALKALOSIS ASSOCIATED WITH ECFV EXPANSION, HYPERTENSION, AND HYPERALDOSTERONISM Increased aldosterone levels may be the result of autonomous primary adrenal overproduction or of secondary aldosterone release due to renal overproduction of renin. Mineralocorticoid excess increases net acid excretion and may result in metabolic alkalosis, which may be worsened by associated K+ deficiency. ECFV expansion from salt retention causes hypertension. The kaliuresis persists because of mineralocorticoid excess and distal Na+ absorption causing enhanced K+ excretion, continued K+ depletion with polydipsia, inability to concentrate the urine, and polyuria. Liddle’s syndrome (Chap. 339) results from increased activity of the collecting duct Na+ channel (ENaC) and is a rare monogenic form of hypertension due to volume expansion manifested as hypokalemic alkalosis and normal aldosterone levels. Symptoms With metabolic alkalosis, changes in CNS and peripheral nervous system function are similar to those of hypocalcemia (Chap. 423); symptoms include mental confusion; obtundation; and
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a predisposition to seizures, paresthesia, muscular cramping, tetany, aggravation of arrhythmias, and hypoxemia in chronic obstructive pulmonary disease. Related electrolyte abnormalities include hypokalemia and hypophosphatemia. TREATMENT
Metabolic Alkalosis
This is primarily directed at correcting the underlying stimulus for HCO3- generation. If primary aldosteronism, renal artery stenosis, or Cushing’s syndrome is present, correction of the underlying cause will reverse the alkalosis. [H+] loss by the stomach or kidneys can be mitigated by the use of proton pump inhibitors or the discontinuation of diuretics. The second aspect of treatment is to remove the factors that sustain the inappropriate increase in HCO3- reabsorption, such as ECFV contraction or K+ deficiency. K+ deficits should always be repaired. Isotonic saline is usually sufficient to reverse the alkalosis if ECFV contraction is present. If associated conditions preclude infusion of saline, renal HCO3loss can be accelerated by administration of acetazolamide, a carbonic anhydrase inhibitor, which is usually effective in patients with adequate renal function but can worsen K+ losses. Dilute hydrochloric acid (0.1 N HCl) is also effective but can cause hemolysis, and must be delivered slowly in a central vein.
RESPIRATORY ACIDOSIS Respiratory acidosis can be due to severe pulmonary disease, respiratory muscle fatigue, or abnormalities in ventilatory control and is recognized by an increase in Paco2 and decrease in pH (Table 66-7). In acute respiratory acidosis, there is an immediate compensatory elevation (due to cellular buffering mechanisms) in HCO3-, which increases 1 mmol/L for every 10-mmHg increase in Paco2. In chronic respiratory acidosis (>24 h), renal adaptation increases the [HCO3-] by 4 mmol/L for every 10-mmHg increase in Paco2. The serum HCO3usually does not increase above 38 mmol/L. The clinical features vary according to the severity and duration of the respiratory acidosis, the underlying disease, and whether there is accompanying hypoxemia. A rapid increase in Paco2 may cause anxiety, dyspnea, confusion, psychosis, and hallucinations and may progress to coma. Lesser degrees of dysfunction in chronic hypercapnia include sleep disturbances; loss of memory; daytime somnolence; personality changes; impairment of coordination; and motor disturbances such as tremor, myoclonic jerks, and asterixis. Headaches and other signs that mimic raised intracranial pressure, such as papilledema, abnormal reflexes, and focal muscle weakness, are due to vasoconstriction secondary to loss of the vasodilator effects of CO2. Depression of the respiratory center by a variety of drugs, injury, or disease can produce respiratory acidosis. This may occur acutely with general anesthetics, sedatives, and head trauma or chronically with sedatives, alcohol, intracranial tumors, and the syndromes of sleep-disordered breathing including the primary alveolar and obesityhypoventilation syndromes (Chaps. 318 and 319). Abnormalities or disease in the motor neurons, neuromuscular junction, and skeletal muscle can cause hypoventilation via respiratory muscle fatigue. Mechanical ventilation, when not properly adjusted and supervised, may result in respiratory acidosis, particularly if CO2 production suddenly rises (because of fever, agitation, sepsis, or overfeeding) or alveolar ventilation falls because of worsening pulmonary function. High levels of positive end-expiratory pressure in the presence of reduced cardiac output may cause hypercapnia as a result of large increases in alveolar dead space (Chap. 306e). Permissive hypercapnia is being used with increasing frequency because of studies suggesting lower mortality rates than with conventional mechanical ventilation, especially with severe CNS or heart disease. The respiratory acidosis associated with permissive hypercapnia may require administration of NaHCO3 to increase the arterial pH to 7.25, but overcorrection of the acidemia may be deleterious. Acute hypercapnia follows sudden occlusion of the upper airway or generalized bronchospasm as in severe asthma, anaphylaxis,
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TABLE 66-7 Respiratory Acid-Base Disorders
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Respiratory Acidosis
The management of respiratory acidosis depends on its severity and rate of onset. Acute respiratory acidosis can be life-threatening, and measures to reverse the underlying cause should be undertaken simultaneously with restoration of adequate alveolar ventilation. This may necessitate tracheal intubation and assisted mechanical ventilation. Oxygen administration should be titrated carefully in patients with severe obstructive pulmonary disease and chronic CO2 retention who are breathing spontaneously (Chap. 314). When oxygen is used injudiciously, these patients may experience progression of the respiratory acidosis. Aggressive and rapid correction of hypercapnia should be avoided, because the falling Paco2 may provoke the same complications noted with acute respiratory alkalosis (i.e., cardiac arrhythmias, reduced cerebral perfusion, and seizures). The Paco2 should be lowered gradually in chronic respiratory acidosis, aiming to restore the Paco2 to baseline levels and to provide sufficient Cl- and K+ to enhance the renal excretion of HCO3-. Chronic respiratory acidosis is frequently difficult to correct, but measures aimed at improving lung function (Chap. 314) can help some patients and forestall further deterioration in most.
Acidosis and Alkalosis
inhalational burn, or toxin injury. Chronic hypercapnia and respiratory acidosis occur in end-stage obstructive lung disease. Restrictive disorders involving both the chest wall and the lungs can cause respiratory acidosis because the high metabolic cost of respiration causes ventilatory muscle fatigue. Advanced stages of intrapulmonary and extrapulmonary restrictive defects present as chronic respiratory acidosis.
TREATMENT
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CHAPTER 66
I. Alkalosis A. Central nervous system stimulation 1. Pain 2. Anxiety, psychosis 3. Fever 4. Cerebrovascular accident 5. Meningitis, encephalitis 6. Tumor 7. Trauma B. Hypoxemia or tissue hypoxia 1. High altitude 2. Pneumonia, pulmonary edema 3. Aspiration 4. Severe anemia C. Drugs or hormones 1. Pregnancy, progesterone 2. Salicylates 3. Cardiac failure D. Stimulation of chest receptors 1. Hemothorax 2. Flail chest 3. Cardiac failure 4. Pulmonary embolism E. Miscellaneous 1. Septicemia 2. Hepatic failure 3. Mechanical hyperventilation 4. Heat exposure 5. Recovery from metabolic acidosis II. Acidosis A. Central 1. Drugs (anesthetics, morphine, sedatives) 2. Stroke 3. Infection B. Airway 1. Obstruction 2. Asthma C. Parenchyma 1. Emphysema 2. Pneumoconiosis 3. Bronchitis 4. Adult respiratory distress syndrome 5. Barotrauma D. Neuromuscular 1. Poliomyelitis 2. Kyphoscoliosis 3. Myasthenia 4. Muscular dystrophies E. Miscellaneous 1. Obesity 2. Hypoventilation 3. Permissive hypercapnia
The diagnosis of respiratory acidosis requires the measurement of Paco2 and arterial pH. A detailed history and physical examination often indicate the cause. Pulmonary function studies (Chap. 306e), including spirometry, diffusion capacity for carbon monoxide, lung volumes, and arterial Paco2 and O2 saturation, usually make it possible to determine if respiratory acidosis is secondary to lung disease. The workup for nonpulmonary causes should include a detailed drug history, measurement of hematocrit, and assessment of upper airway, chest wall, pleura, and neuromuscular function.
RESPIRATORY ALKALOSIS Alveolar hyperventilation decreases Paco2 and increases the HCO3-/ Paco2 ratio, thus increasing pH (Table 66-7). Nonbicarbonate cellular buffers respond by consuming HCO3-. Hypocapnia develops when a sufficiently strong ventilatory stimulus causes CO2 output in the lungs to exceed its metabolic production by tissues. Plasma pH and [HCO3-] appear to vary proportionately with Paco2 over a range from 40–15 mmHg. The relationship between arterial [H+] concentration and Paco2 is ∼0.7 mmol/L per mmHg (or 0.01 pH unit/mmHg), and that for plasma [HCO3-] is 0.2 mmol/L per mmHg. Hypocapnia sustained for >2–6 h is further compensated by a decrease in renal ammonium and titratable acid excretion and a reduction in filtered HCO3- reabsorption. Full renal adaptation to respiratory alkalosis may take several days and requires normal volume status and renal function. The kidneys appear to respond directly to the lowered Paco2 rather than to alkalosis per se. In chronic respiratory alkalosis a 1-mmHg decrease in Paco2 causes a 0.4-to 0.5-mmol/L drop in [HCO3-] and a 0.3-mmol/L decrease (or 0.003 increase in pH) in [H+]. The effects of respiratory alkalosis vary according to duration and severity but are primarily those of the underlying disease. Reduced cerebral blood flow as a consequence of a rapid decline in Paco2 may cause dizziness, mental confusion, and seizures, even in the absence of hypoxemia. The cardiovascular effects of acute hypocapnia in the conscious human are generally minimal, but in the anesthetized or mechanically ventilated patient, cardiac output and blood pressure may fall because of the depressant effects of anesthesia and positivepressure ventilation on heart rate, systemic resistance, and venous return. Cardiac arrhythmias may occur in patients with heart disease as a result of changes in oxygen unloading by blood from a left shift in the hemoglobin-oxygen dissociation curve (Bohr effect). Acute respiratory alkalosis causes intracellular shifts of Na+, K+, and PO42and reduces free [Ca2+] by increasing the protein-bound fraction. Hypocapnia-induced hypokalemia is usually minor. Chronic respiratory alkalosis is the most common acid-base disturbance in critically ill patients and, when severe, portends a poor prognosis. Many cardiopulmonary disorders manifest respiratory alkalosis
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in their early to intermediate stages, and the finding of normocapnia and hypoxemia in a patient with hyperventilation may herald the onset of rapid respiratory failure and should prompt an assessment to determine if the patient is becoming fatigued. Respiratory alkalosis is common during mechanical ventilation. The hyperventilation syndrome may be disabling. Paresthesia; circumoral numbness; chest wall tightness or pain; dizziness; inability to take an adequate breath; and, rarely, tetany may be sufficiently stressful to perpetuate the disorder. Arterial blood-gas analysis demonstrates an acute or chronic respiratory alkalosis, often with hypocapnia in the range of 15–30 mmHg and no hypoxemia. CNS diseases or injury can produce several patterns of hyperventilation and sustained Paco2 levels of 20–30 mmHg. Hyperthyroidism, high caloric loads, and exercise raise the basal metabolic rate, but ventilation usually rises in proportion so that arterial blood gases are unchanged and respiratory alkalosis does not develop. Salicylates are the most common cause of drug-induced respiratory alkalosis as a result of direct stimulation of the medullary chemoreceptor (Chap. 472e). The methylxanthines, theophylline, and aminophylline stimulate ventilation and increase the ventilatory response to CO2. Progesterone increases ventilation and lowers arterial Paco2 by as much as 5–10 mmHg. Therefore, chronic respiratory alkalosis is a common feature of pregnancy. Respiratory alkalosis is also prominent in liver failure, and the severity correlates with the degree of hepatic insufficiency. Respiratory alkalosis is often an early finding in gram-negative septicemia, before fever, hypoxemia, or hypotension develops.
The diagnosis of respiratory alkalosis depends on measurement of arterial pH and Paco2. The plasma [K+] is often reduced and the [Cl-] increased. In the acute phase, respiratory alkalosis is not associated with increased renal HCO3- excretion, but within hours net acid excretion is reduced. In general, the HCO3- concentration falls by 2.0 mmol/L for each 10-mmHg decrease in Paco2. Chronic hypocapnia reduces the serum [HCO3-] by 4.0 mmol/L for each 10-mmHg decrease in Paco2. It is unusual to observe a plasma HCO3- 80% of cases of ED in older men. Vasculogenic The most common organic cause of ED is a disturbance of blood flow to and from the penis. Atherosclerotic or traumatic arterial disease can decrease flow to the lacunar spaces, resulting in decreased rigidity and an increased time to full erection. Excessive outflow through the veins despite adequate inflow also may contribute to ED. Structural alterations to the fibroelastic components of the corpora may cause a loss of compliance and inability to compress the tunical veins. This condition may result from aging, increased cross-linking of collagen fibers induced by nonenzymatic glycosylation, hypoxemia, or altered synthesis of collagen associated with hypercholesterolemia. Neurogenic Disorders that affect the sacral spinal cord or the autonomic fibers to the penis preclude nervous system relaxation of penile smooth muscle, thus leading to ED. In patients with spinal cord injury, the degree of ED depends on the completeness and level of the lesion. Patients with incomplete lesions or injuries to the upper part of the spinal cord are more likely to retain erectile capabilities than are those with complete lesions or injuries to the lower part. Although 75% of patients with spinal cord injuries have some erectile capability, only 25% have erections sufficient for penetration. Other neurologic disorders commonly associated with ED include multiple sclerosis and peripheral neuropathy. The latter is often due to either diabetes or alcoholism. Pelvic surgery may cause ED through disruption of the autonomic nerve supply. Endocrinologic Androgens increase libido, but their exact role in erectile function is unclear. Individuals with castrate levels of testosterone can achieve erections from visual or sexual stimuli. Nonetheless, normal levels of testosterone appear to be important for erectile function, particularly in older males. Androgen replacement therapy can improve depressed erectile function when it is secondary to hypogonadism; however, it is not useful for ED when endogenous testosterone levels are normal. Increased prolactin may decrease libido by suppressing gonadotropin-releasing hormone (GnRH), and it also leads to decreased testosterone levels. Treatment of hyperprolactinemia with dopamine agonists can restore libido and testosterone. Diabetic ED occurs in 35–75% of men with diabetes mellitus. Pathologic mechanisms are related primarily to diabetes-associated vascular and neurologic complications. Diabetic macrovascular complications are related mainly to age, whereas microvascular complications correlate with the duration of diabetes and the degree of glycemic control (Chap. 417). Individuals with diabetes also have reduced amounts of nitric oxide synthase in both endothelial and neural tissues. Psychogenic Two mechanisms contribute to the inhibition of erections in psychogenic ED. First, psychogenic stimuli to the sacral cord may inhibit reflexogenic responses, thereby blocking activation of vasodilator outflow to the penis. Second, excess sympathetic stimulation in an anxious man may increase penile smooth-muscle tone. The most common causes of psychogenic ED are performance anxiety, depression, relationship conflict, loss of attraction, sexual inhibition, conflicts over sexual preference, sexual abuse in childhood, and fear of pregnancy or sexually transmitted disease. Almost all patients with ED, even when it has a clear-cut organic basis, develop a psychogenic component as a reaction to ED. Medication-related Medication-induced ED (Table 67-1) is estimated to occur in 25% of men seen in general medical outpatient clinics. The adverse effects related to drug therapy are additive, especially in older men. In addition to the drug itself, the disease being treated is likely to contribute to sexual dysfunction. Among the antihypertensive agents, the thiazide diuretics and beta blockers have been implicated most frequently. Calcium channel blockers and angiotensin converting-enzyme inhibitors are cited less frequently. These drugs may act directly at the corporal level (e.g., calcium channel blockers) or indirectly by reducing pelvic blood pressure, which is important in the development of penile rigidity. α-Adrenergic blockers are less likely to
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TABLE 67-1 Drugs Associated with Erectile Dysfunction Classification Diuretics Antihypertensives
Antidepressants
H2 antagonists Hormones
Cytotoxic agents
Anticholinergics Recreational
Abbreviation: GnRH, gonadotropin-releasing hormone.
cause ED. Estrogens, GnRH agonists, H2 antagonists, and spironolactone cause ED by suppressing gonadotropin production or by blocking androgen action. Antidepressant and antipsychotic agents—particularly neuroleptics, tricyclics, and SSRIs—are associated with erectile, ejaculatory, orgasmic, and sexual desire difficulties. If there is a strong association between the institution of a drug and the onset of ED, alternative medications should be considered. Otherwise, it is often practical to treat the ED without attempting multiple changes in medications, as it may be difficult to establish a causal role for a drug.
APPROACH TO THE PATIENT: Erectile Dysfunction A good physician-patient relationship helps unravel the possible causes of ED, many of which require discussion of personal and sometimes embarrassing topics. For this reason, a primary care provider is often ideally suited to initiate the evaluation. However, a significant percentage of men experience ED and remain undiagnosed unless specifically questioned about this issue. By far the two most common reasons for underreporting of ED are patient embarrassment and perceptions of physicians’ inattention to the disease. Once the topic is initiated by the physician, patients are more willing to discuss their potency issues. A complete medical and sexual
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Problem resolved
Problem persists Patient/partner education Goal-directed therapy planning
Sex therapy Special testing
Oral PDE-inhibitors
Treatment success
Intraurethral or injection therapy
Treatment success
Vacuum device
Implantation/ vascular surgery
Figure 67-3 Algorithm for the evaluation and management of patients with erectile dysfunction. PDE, phosphodiesterase.
history should be taken in an effort to assess whether the cause of ED is organic, psychogenic, or multifactorial (Fig. 67-3). Both the patient and his sexual partner should be interviewed regarding sexual history. ED should be distinguished from other sexual problems, such as premature ejaculation. Lifestyle factors such as sexual orientation, the patient’s distress from ED, performance anxiety, and details of sexual techniques should be addressed. Standardized questionnaires are available to assess ED, including the International Index of Erectile Function (IIEF) and the more easily administered Sexual Health Inventory for Men (SHIM), a validated abridged version of the IIEF. The initial evaluation of ED begins with a review of the patient’s medical, surgical, sexual, and psychosocial histories. The history should note whether the patient has experienced pelvic trauma, surgery, or radiation. In light of the increasing recognition of the relationship between lower urinary tract symptoms and ED, it is advisable to evaluate for the presence of symptoms of bladder outlet obstruction. Questions should focus on the onset of symptoms, the presence and duration of partial erections, and the progression of ED. A history of nocturnal or early morning erections is useful for distinguishing physiologic ED from psychogenic ED. Nocturnal erections occur during rapid eye movement (REM) sleep and require intact neurologic and circulatory systems. Organic causes of ED generally are characterized by a gradual and persistent change in rigidity or the inability to sustain nocturnal, coital, or self-stimulated erections. The patient should be questioned about the presence of penile curvature or pain with coitus. It is also important to address libido, as decreased sexual drive and ED are sometimes the earliest signs of endocrine abnormalities (e.g., increased prolactin, decreased testosterone levels). It is useful to ask whether the problem is confined to coitus with one partner or also involves other partners; ED not uncommonly arises in association with new or extramarital sexual relationships. Situational ED, as opposed to consistent ED, suggests psychogenic causes. Ejaculation is much less commonly affected than erection, but questions should be asked about whether ejaculation is normal, premature, delayed, or absent. Relevant risk factors should be identified, such as diabetes mellitus, coronary artery disease (CAD), and neurologic disorders. The patient’s surgical history should be explored with an emphasis on bowel, bladder, prostate, and vascular procedures. A complete drug history is also important. Social changes that may precipitate ED are also crucial to the evaluation, including health worries, spousal death, divorce, relationship difficulties, and financial concerns.
Sexual Dysfunction
Tranquilizers
History: Medical, sexual, and psychosocial Physical examination Serum: Testosterone and prolactin levels Lifestyle risk management Medication review
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Cardiac/antihyperlipidemics
Drugs Thiazides Spironolactone Calcium channel blockers Methyldopa Clonidine Reserpine Beta blockers Guanethidine Digoxin Gemfibrozil Clofibrate Selective serotonin reuptake inhibitors Tricyclic antidepressants Lithium Monoamine oxidase inhibitors Butyrophenones Phenothiazines Ranitidine Cimetidine Progesterone Estrogens Corticosteroids GnRH agonists 5α-Reductase inhibitors Cyproterone acetate Cyclophosphamide Methotrexate Roferon-A Disopyramide Anticonvulsants Ethanol Cocaine Marijuana
PATIENT EVALUATION AND MANAGEMENT
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Because ED commonly involves a host of endothelial cell risk factors, men with ED report higher rates of overt and silent myocardial infarction. Therefore, ED in an otherwise asymptomatic male warrants consideration of other vascular disorders, including CAD. The physical examination is an essential element in the assessment of ED. Signs of hypertension as well as evidence of thyroid, hepatic, hematologic, cardiovascular, or renal diseases should be sought. An assessment should be made of the endocrine and vascular systems, the external genitalia, and the prostate gland. The penis should be palpated carefully along the corpora to detect fibrotic plaques. Reduced testicular size and loss of secondary sexual characteristics are suggestive of hypogonadism. Neurologic examination should include assessment of anal sphincter tone, investigation of the bulbocavernosus reflex, and testing for peripheral neuropathy. Although hyperprolactinemia is uncommon, a serum prolactin level should be measured, as decreased libido and/or ED may be the presenting symptoms of a prolactinoma or another mass lesion of the sella (Chap. 403). The serum testosterone level should be measured, and if it is low, gonadotropins should be measured to determine whether hypogonadism is primary (testicular) or secondary (hypothalamic-pituitary) in origin (Chap. 411). If not performed recently, serum chemistries, complete blood count (CBC), and lipid profiles may be of value, as they can yield evidence of anemia, diabetes, hyperlipidemia, or other systemic diseases associated with ED. Determination of serum prostate-specific antigen (PSA) should be conducted according to recommended clinical guidelines (Chap. 115). Additional diagnostic testing is rarely necessary in the evaluation of ED. However, in selected patients, specialized testing may provide insight into pathologic mechanisms of ED and aid in the selection of treatment options. Optional specialized testing includes (1) studies of nocturnal penile tumescence and rigidity, (2) vascular testing (in-office injection of vasoactive substances, penile Doppler ultrasound, penile angiography, dynamic infusion cavernosography/ cavernosometry), (3) neurologic testing (biothesiometry-graded vibratory perception, somatosensory evoked potentials), and (4) psychological diagnostic tests. The information potentially gained from these procedures must be balanced against their invasiveness and cost. TREATMENT
Male Sexual Dysfunction
PATIENT EDUCATION Patient and partner education is essential in the treatment of ED. In goal-directed therapy, education facilitates understanding of the disease, the results of the tests, and the selection of treatment. Discussion of treatment options helps clarify how treatment is best offered and stratify first- and second-line therapies. Patients with high-risk lifestyle issues such as obesity, smoking, alcohol abuse, and recreational drug use should be counseled on the role those factors play in the development of ED. Therapies currently employed for the treatment of ED include oral PDE-5 inhibitor therapy (most commonly used), injection therapies, testosterone therapy, penile devices, and psychological therapy. In addition, limited data suggest that treatments for underlying risk factors and comorbidities—for example, weight loss, exercise, stress reduction, and smoking cessation—may improve erectile function. Decisions regarding therapy should take into account the preferences and expectations of patients and their partners. ORAL AGENTS Sildenafil, tadalafil, vardenafil, and avanafil are the only approved and effective oral agents for the treatment of ED. These four medications have markedly improved the management of ED because they are effective for the treatment of a broad range of causes, including psychogenic, diabetic, vasculogenic, postradical prostatectomy (nerve-sparing procedures), and spinal cord injury. They belong to a class of medications that are selective and potent inhibitors of PDE-5, the predominant phosphodiesterase
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isoform found in the penis. They are administered in graduated doses and enhance erections after sexual stimulation. The onset of action is approximately 30–120 min, depending on the medication used and other factors, such as recent food intake. Reduced initial doses should be considered for patients who are elderly, are taking concomitant alpha blockers, have renal insufficiency, or are taking medications that inhibit the CYP3A4 metabolic pathway in the liver (e.g., erythromycin, cimetidine, ketoconazole, and possibly itraconazole and mibefradil), as they may increase the serum concentration of the PDE-5 inhibitors (PDE-5i) or promote hypotension. Initially, there were concerns about the cardiovascular safety of PDE-5i drugs. These agents can act as a mild vasodilator, and warnings exist about orthostatic hypotension with concomitant use of alpha blockers. The use of PDE-5i is not contraindicated in men who are also receiving alpha blockers, but they must be stabilized on this blood pressure medication prior to initiating therapy. Concerns also existed that use of PDE-5i would increase cardiovascular events. However, the safety of these drugs has been confirmed in several controlled trials with no increase in myocardial ischemic events or overall mortality compared to the general population. Several randomized trials have demonstrated the efficacy of this class of medications. There are no compelling data to support the superiority of one PDE-5i over another. Subtle differences between agents have variable clinical relevance (Table 67-2). Patients may fail to respond to a PDE-5i for several reasons (Table 67-3). Some patients may not tolerate PDE-5i secondary to adverse events from vasodilation in nonpenile tissues expressing PDE-5 or from the inhibition of homologous nonpenile isozymes (i.e., PDE-6 found in the retina). Abnormal vision attributed to the effects of PDE-5i on retinal PDE-6 is of short duration, reported only with sildenafil and not thought to be clinically significant. A more serious concern is the possibility that PDE-5i may cause nonarteritic anterior ischemic optic neuropathy; although data to support that association are limited, it is prudent to avoid the use of these agents in men with a prior history of nonarteritic anterior ischemic optic neuropathy. Testosterone supplementation combined with a PDE-5i may be beneficial in improving erectile function in hypogonadal men with ED who are unresponsive to PDE-5i alone. These drugs do not affect ejaculation, orgasm, or sexual drive. Side effects associated with PDE-5i include headaches (19%), facial flushing (9%), dyspepsia (6%), and nasal congestion (4%). Approximately 7% of men using sildenafil may experience transient altered color vision (blue halo effect), and 6% of men taking tadalafil may experience loin pain. PDE-5i is contraindicated in men receiving nitrate therapy for cardiovascular disease, including agents delivered by the oral, sublingual, transnasal, and topical routes. These agents can potentiate its hypotensive effect and may result in profound shock. Likewise, amyl/butyl nitrate “poppers” may have a fatal synergistic effect on blood pressure. PDE-5i also should be avoided in patients with congestive heart failure and cardiomyopathy because of the risk of vascular collapse. Because sexual activity leads to an increase in physiologic expenditure (5–6 metabolic equivalents [METS]), physicians have been advised to exercise caution in prescribing any drug for sexual activity to those with active coronary disease, heart failure, borderline hypotension, or hypovolemia and to those on complex antihypertensive regimens. Although the various forms of PDE-5i have a common mechanism of action, there are a few differences among the four agents (Table 67-2). Tadalafil is unique in its longer half-life, whereas avanafil appears to have the most rapid onset of action. All four drugs are effective for patients with ED of all ages, severities, and etiologies. Although there are pharmacokinetic and pharmacodynamic differences among these agents, clinically relevant differences are not clear. ANDROGEN THERAPY Testosterone replacement is used to treat both primary and secondary causes of hypogonadism (Chap. 411). Androgen supplementation
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TABLE 67-2 Characteristics of PDE-5i Medications Half-Life 2–5 h
Dose 25–100 mg Starting dose, 50 mg
Adverse Effects Headache, flushing, dyspepsia, nasal congestion, altered vision
Vardenafil
Tmax, 30–120 min Duration, 4–5 h High-fat meal decreases absorption ETOH may affect efficacy
4.5 h
5–10 mg
Headache, flushing, rhinitis, dyspepsia
Tadalafil
Tmax, 30–60 min Duration, 12–36 h Plasma concentration Not affected by food or ETOH Tmax, 30 min Duration, 2 h Plasma concentration not affected by food
17.5 h
10 mg, 20 mg; 2.5 or 5 mg for daily dose
Headache, dyspepsia, back pain, nasal congestion, myalgia
3–5 h
50, 100, and 200 mg
Headache, flushing, nasal congestion, nasopharyngitis, back pain
Avanafil
Contraindications Nitrates Hypotension Cardiovascular risk factors Retinitis pigmentosa Change dose with some antiretrovirals Should be on stable dose of alpha blockers Same as sildenafil May have minor prolongation of QT interval Concomitant use of Class I antiarrhythmic Same as sildenafil
Same as sildenafil
Abbreviations: ETOH, alcohol; Tmax, time to maximum plasma concentration.
in the setting of normal testosterone is rarely efficacious in the treatment of ED and is discouraged. Methods of androgen replacement include transdermal patches and gels, parenteral administration of long-acting testosterone esters (enanthate and cypionate), and oral preparations (17 α-alkylated derivatives) (Chap. 411). Oral androgen preparations have the potential for hepatotoxicity and should be avoided. Men who receive testosterone should be reevaluated after 1–3 months and at least annually thereafter for testosterone levels, erectile function, and adverse effects, which may include gynecomastia, sleep apnea, development or exacerbation of lower urinary tract symptoms or BPH, prostate cancer, lowering of HDL, erythrocytosis, elevations of liver function tests, and reduced fertility. Periodic reevaluation should include measurement of CBC and PSA and digital rectal exam. Therapy should be discontinued in patients who do not respond within 3 months. VACUUM CONSTRICTION DEVICES Vacuum constriction devices (VCDs) are a well-established noninvasive therapy. They are a reasonable treatment alternative for select patients who cannot take sildenafil or do not desire other interventions. VCDs draw venous blood into the penis and use a constriction ring to restrict venous return and maintain tumescence. Adverse events with VCD include pain, numbness, bruising, and altered ejaculation. Additionally, many patients complain that the devices are cumbersome and that the induced erections have a nonphysiologic appearance and feel. INTRAURETHRAL ALPROSTADIL If a patient fails to respond to oral agents, a reasonable next choice is intraurethral or self-injection of vasoactive substances. TABLE 67-3 Issues to Consider if Patients Report Failure of PDE-5i to Improve Erectile Dysfunction • A trial of medication on at least 6 different days at the maximal dose should be made before declaring patient nonresponsive to PDE-5i use • Confirm that patient did not take medication after a high-fat meal • Failure to include physical and psychic stimulation at the time of foreplay to induce endogenous NO • Unrecognized hypogonadism Abbreviations: NO, nitric oxide; PDE-5i, phosphodiesterase type 5 inhibitor.
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Sexual Dysfunction
Onset of Action Tmax, 30-120 min Duration, 4 h High-fat meal decreases absorption ETOH may affect efficacy
CHAPTER 67
Drug Sildenafil
Intraurethral prostaglandin E1 (alprostadil), in the form of a semisolid pellet (doses of 125–1000 μg), is delivered with an applicator. Approximately 65% of men receiving intraurethral alprostadil respond with an erection when tested in the office, but only 50% achieve successful coitus at home. Intraurethral insertion is associated with a markedly reduced incidence of priapism in comparison to intracavernosal injection. INTRACAVERNOSAL SELF-INJECTION Injection of synthetic formulations of alprostadil is effective in 70–80% of patients with ED, but discontinuation rates are high because of the invasive nature of administration. Doses range between 1 and 40 μg. Injection therapy is contraindicated in men with a history of hypersensitivity to the drug and men at risk for priapism (hypercoagulable states, sickle cell disease). Side effects include local adverse events, prolonged erections, pain, and fibrosis with chronic use. Various combinations of alprostadil, phentolamine, and/or papaverine sometimes are used. SURGERY A less frequently used form of therapy for ED involves the surgical implantation of a semirigid or inflatable penile prosthesis. The choice of prosthesis is dependent on patient preference and should take into account body habitus and manual dexterity, which may affect the ability of the patient to manipulate the device. Because of the permanence of prosthetic devices, patients should be advised to first consider less invasive options for treatment. These surgical treatments are invasive, are associated with potential complications, and generally are reserved for treatment of refractory ED. Despite their high cost and invasiveness, penile prostheses are associated with high rates of patient and partner satisfaction. SEX THERAPY A course of sex therapy may be useful for addressing specific interpersonal factors that may affect sexual functioning. Sex therapy generally consists of in-session discussion and at-home exercises specific to the person and the relationship. Psychosexual therapy involves techniques such as sensate focus (nongenital massage), sensory awareness exercises, correction of misconceptions about sexuality, and interpersonal difficulties therapy (e.g., open communication about sexual issues, physical intimacy scheduling, and
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behavioral interventions). These approaches may be useful in patients who have psychogenic or social components to their ED, although data from randomized trials are scanty and inconsistent. It is preferable if therapy includes both partners if the patient is involved in an ongoing relationship.
FEMALE SEXUAL DYSFUNCTION
PART 2
Female sexual dysfunction (FSD) has traditionally included disorders of desire, arousal, pain, and muted orgasm. The associated risk factors for FSD are similar to those in males: cardiovascular disease, endocrine disorders, hypertension, neurologic disorders, and smoking (Table 67-4).
Cardinal Manifestations and Presentation of Diseases
EPIDEMIOLOGY Epidemiologic data are limited, but the available estimates suggest that as many as 43% of women complain of at least one sexual problem. Despite the recent interest in organic causes of FSD, desire and arousal phase disorders (including lubrication complaints) remain the most common presenting problems when surveyed in a community-based population. PHYSIOLOGY OF THE FEMALE SEXUAL RESPONSE The female sexual response requires the presence of estrogens. A role for androgens is also likely but less well established. In the CNS, estrogens and androgens work synergistically to enhance sexual arousal and response. A number of studies report enhanced libido in women during preovulatory phases of the menstrual cycle, suggesting that hormones involved in the ovulatory surge (e.g., estrogens) increase desire. Sexual motivation is heavily influenced by context, including the environment and partner factors. Once sufficient sexual desire is reached, sexual arousal is mediated by the central and autonomic nervous systems. Cerebral sympathetic outflow is thought to increase desire, and peripheral parasympathetic activity results in clitoral vasocongestion and vaginal secretion (lubrication). The neurotransmitters for clitoral corporal engorgement are similar to those in the male, with a prominent role for neural, smooth-muscle, and endothelial released nitric oxide (NO). A fine network of vaginal nerves and arterioles promotes a vaginal transudate. The major transmitters of this complex vaginal response are not certain, but roles for NO and vasointestinal polypeptide (VIP) are suspected. Investigators studying the normal female sexual response have challenged the long-held construct of a linear and unmitigated relationship between initial desire, arousal, vasocongestion, lubrication, and eventual orgasm. Caregivers
TABLE 67-4 Risk Factors for Female Sexual Dysfunction Neurologic disease: stroke, spinal cord injury, parkinsonism Trauma, genital surgery, radiation Endocrinopathies: diabetes, hyperprolactinemia Liver and/or renal failure Cardiovascular disease Psychological factors and interpersonal relationship disorders: sexual abuse, life stressors Medications Antiandrogens: cimetidine, spironolactone Antidepressants, alcohol, hypnotics, sedatives Antiestrogens or GnRH antagonists Antihistamines, sympathomimetic amines Antihypertensives: diuretics, calcium channel blockers Alkylating agents Anticholinergics Abbreviation: GnRH, gonadotropin-releasing hormone.
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should consider a paradigm of a positive emotional and physical outcome with one, many, or no orgasmic peak and release. Although there are anatomic differences as well as variation in the density of vascular and neural beds in males and females, the primary effectors of sexual response are strikingly similar. Intact sensation is important for arousal. Thus, reduced levels of sexual functioning are more common in women with peripheral neuropathies (e.g., diabetes). Vaginal lubrication is a transudate of serum that results from the increased pelvic blood flow associated with arousal. Vascular insufficiency from a variety of causes may compromise adequate lubrication and result in dyspareunia. Cavernosal and arteriole smooth-muscle relaxation occurs via increased nitric oxide synthase (NOS) activity and produces engorgement in the clitoris and the surrounding vestibule. Orgasm requires an intact sympathetic outflow tract; hence, orgasmic disorders are common in female patients with spinal cord injuries.
APPROACH TO THE PATIENT: Female Sexual Dysfunction Many women do not volunteer information about their sexual response. Open-ended questions in a supportive atmosphere are helpful in initiating a discussion of sexual fitness in women who are reluctant to discuss such issues. Once a complaint has been voiced, a comprehensive evaluation should be performed, including a medical history, a psychosocial history, a physical examination, and limited laboratory testing. The history should include the usual medical, surgical, obstetric, psychological, gynecologic, sexual, and social information. Past experiences, intimacy, knowledge, and partner availability should also be ascertained. Medical disorders that may affect sexual health should be delineated. They include diabetes, cardiovascular disease, gynecologic conditions, obstetric history, depression, anxiety disorders, and neurologic disease. Medications should be reviewed as they may affect arousal, libido, and orgasm. The need for counseling and recognizing life stresses should be identified. The physical examination should assess the genitalia, including the clitoris. Pelvic floor examination may identify prolapse or other disorders. Laboratory studies are needed, especially if menopausal status is uncertain. Estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are usually obtained, and dehydroepiandrosterone (DHEA) should be considered as it reflects adrenal androgen secretion. A CBC, liver function assessment, and lipid studies may be useful, if not otherwise obtained. Complicated diagnostic evaluations such as clitoral Doppler ultrasonography and biothesiometry require expensive equipment and are of uncertain utility. It is important for the patient to identify which symptoms are most distressing. The evaluation of FSD previously occurred mainly in a psychosocial context. However, inconsistencies between diagnostic categories based only on psychosocial considerations and the emerging recognition of organic etiologies have led to a new classification of FSD. This diagnostic scheme is based on four components that are not mutually exclusive: (1) hypoactive sexual desire—the persistent or recurrent lack of sexual thoughts and/or receptivity to sexual activity, which causes personal distress; hypoactive sexual desire may result from endocrine failure or may be associated with psychological or emotional disorders; (2) sexual arousal disorder—the persistent or recurrent inability to attain or maintain sexual excitement, which causes personal distress; (3) orgasmic disorder—the persistent or recurrent loss of orgasmic potential after sufficient sexual stimulation and arousal, which causes personal distress; and (4) sexual pain disorder—persistent or recurrent genital pain associated with noncoital sexual stimulation, which causes personal distress. This newer classification emphasizes “personal distress” as a requirement for dysfunction and provides clinicians with an organized framework for evaluation before or in conjunction with more traditional counseling methods.
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TREATMENT
Female Sexual Dysfunction
ORAL AGENTS The efficacy of PDE-5i in FDS has been a marked disappointment in light of the proposed role of nitric oxide–dependent physiology in the normal female sexual response. The use of PDE-5i for FSD should be discouraged pending proof that it is effective. CLITORAL VACUUM DEVICE In patients with arousal and orgasmic difficulties, the option of using a clitoral vacuum device may be explored. This handheld batteryoperated device has a small soft plastic cup that applies a vacuum over the stimulated clitoris. This causes increased cavernosal blood flow, engorgement, and vaginal lubrication.
68
Hirsutism David A. Ehrmann
Hirsutism, which is defined as androgen-dependent excessive malepattern hair growth, affects approximately 10% of women. Hirsutism is most often idiopathic or the consequence of androgen excess associated with the polycystic ovarian syndrome (PCOS). Less frequently, it may result from adrenal androgen overproduction as occurs in nonclassic congenital adrenal hyperplasia (CAH) (Table 68-1). Rarely, it is a sign of a serious underlying condition. Cutaneous manifestations commonly associated with hirsutism include acne and male-pattern balding (androgenic alopecia). Virilization refers to a condition in which androgen levels are sufficiently high to cause additional signs and symptoms, such as deepening of the voice, breast atrophy,
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Hirsutism
HORMONAL THERAPY In postmenopausal women, estrogen replacement therapy may be helpful in treating vaginal atrophy, decreasing coital pain, and improving clitoral sensitivity (Chap. 413). Estrogen replacement in the form of local cream is the preferred method, as it avoids systemic side effects. Androgen levels in women decline substantially before menopause. However, low levels of testosterone or DHEA are not effective predictors of a positive therapeutic outcome with androgen therapy. The widespread use of exogenous androgens is not supported by the literature except in select circumstances (premature ovarian failure or menopausal states) and in secondary arousal disorders.
Gonadal hyperandrogenism Ovarian hyperandrogenism Polycystic ovary syndrome/functional ovarian hyperandrogenism Ovarian steroidogenic blocks Syndromes of extreme insulin resistance (e.g., lipodystrophy) Ovarian neoplasms Adrenal hyperandrogenism Premature adrenarche Functional adrenal hyperandrogenism Congenital adrenal hyperplasia (nonclassic and classic) Abnormal cortisol action/metabolism Adrenal neoplasms Other endocrine disorders Cushing’s syndrome Hyperprolactinemia Acromegaly Peripheral androgen overproduction Obesity Idiopathic Pregnancy-related hyperandrogenism Hyperreactio luteinalis Thecoma of pregnancy Drugs Androgens Oral contraceptives containing androgenic progestins Minoxidil Phenytoin Diazoxide Cyclosporine True hermaphroditism
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GENERAL An open discussion with the patient is important as couples may need to be educated about normal anatomy and physiologic responses, including the role of orgasm, in sexual encounters. Physiologic changes associated with aging and/or disease should be explained. Couples may need to be reminded that clitoral stimulation rather than coital intromission may be more beneficial. Behavioral modification and nonpharmacologic therapies should be a first step. Patient and partner counseling may improve communication and relationship strains. Lifestyle changes involving known risk factors can be an important part of the treatment process. Emphasis on maximizing physical health and avoiding lifestyles (e.g., smoking, alcohol abuse) and medications likely to produce FSD is important (Table 67-4). The use of topical lubricants may address complaints of dyspareunia and dryness. Contributing medications such as antidepressants may need to be altered, including the use of medications with less impact on sexual function, dose reduction, medication switching, or drug holidays.
TABLE 68-1 Causes of Hirsutism
increased muscle bulk, clitoromegaly, and increased libido; virilization is an ominous sign that suggests the possibility of an ovarian or adrenal neoplasm. HAIR FOLLICLE GROWTH AND DIFFERENTIATION Hair can be categorized as either vellus (fine, soft, and not pigmented) or terminal (long, coarse, and pigmented). The number of hair follicles does not change over an individual’s lifetime, but the follicle size and type of hair can change in response to numerous factors, particularly androgens. Androgens are necessary for terminal hair and sebaceous gland development and mediate differentiation of pilosebaceous units (PSUs) into either a terminal hair follicle or a sebaceous gland. In the former case, androgens transform the vellus hair into a terminal hair; in the latter case, the sebaceous component proliferates and the hair remains vellus. There are three phases in the cycle of hair growth: (1) anagen (growth phase), (2) catagen (involution phase), and (3) telogen (rest phase). Depending on the body site, hormonal regulation may play an important role in the hair growth cycle. For example, the eyebrows, eyelashes, and vellus hairs are androgen-insensitive, whereas the axillary and pubic areas are sensitive to low levels of androgens. Hair growth on the face, chest, upper abdomen, and back requires higher levels of androgens and is therefore more characteristic of the pattern typically seen in men. Androgen excess in women leads to increased hair growth in most androgen-sensitive sites except in the scalp region, where hair loss occurs because androgens cause scalp hairs to spend less time in the anagen phase. Although androgen excess underlies most cases of hirsutism, there is only a modest correlation between androgen levels and the quantity of hair growth. This is due to the fact that hair growth from the follicle also
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depends on local growth factors, and there is variability in end organ (PSU) sensitivity. Genetic factors and ethnic background also influence hair growth. In general, dark-haired individuals tend to be more hirsute than blond or fair individuals. Asians and Native Americans have relatively sparse hair in regions sensitive to high androgen levels, whereas people of Mediterranean descent are more hirsute.
PART 2 Cardinal Manifestations and Presentation of Diseases
CLINICAL ASSESSMENT Historic elements relevant to the assessment of hirsutism include the age at onset and rate of progression of hair growth and associated symptoms or signs (e.g., acne). Depending on the cause, excess hair growth typically is first noted during the second and third decades of life. The growth is usually slow but progressive. Sudden development and rapid progression of hirsutism suggest the possibility of an androgensecreting neoplasm, in which case virilization also may be present. The age at onset of menstrual cycles (menarche) and the pattern of the menstrual cycle should be ascertained; irregular cycles from the time of menarche onward are more likely to result from ovarian rather than adrenal androgen excess. Associated symptoms such as galactorrhea should prompt evaluation for hyperprolactinemia (Chap. 403) and possibly hypothyroidism (Chap. 405). Hypertension, striae, easy bruising, centripetal weight gain, and weakness suggest hypercortisolism (Cushing’s syndrome; Chap. 406). Rarely, patients with growth hormone excess (i.e., acromegaly) present with hirsutism. Use of medications such as phenytoin, minoxidil, and cyclosporine may be associated with androgen-independent excess hair growth (i.e., hypertrichosis). A family history of infertility and/or hirsutism may indicate disorders such as nonclassic CAH (Chap. 406). Lipodystrophy is often associated with increased ovarian androgen production that occurs as a consequence of insulin resistance. Patients with lipodystrophy have a preponderance of central fat distribution together with scant subcutaneous adipose tissue in the upper and lower extremities. Physical examination should include measurement of height and weight and calculation of body mass index (BMI). A BMI >25 kg/m2 is indicative of excess weight for height, and values >30 kg/m2 are often seen in association with hirsutism, probably the result of increased conversion of androgen precursors to testosterone. Notation should be made of blood pressure, as adrenal causes may be associated with hypertension. Cutaneous signs sometimes associated with androgen excess and insulin resistance include acanthosis nigricans and skin tags. Body fat distribution should also be noted. An objective clinical assessment of hair distribution and quantity is central to the evaluation in any woman presenting with hirsutism. This assessment permits the distinction between hirsutism and hypertrichosis and provides a baseline reference point to gauge the response to treatment. A simple and commonly used method to grade hair growth is the modified scale of Ferriman and Gallwey (Fig. 68-1), in which each of nine androgen-sensitive sites is graded from 0 to 4. Approximately 95% of white women have a score below 8 on this scale; thus, it is normal for most women to have some hair growth in androgensensitive sites. Scores above 8 suggest excess androgen-mediated hair growth, a finding that should be assessed further by means of hormonal evaluation (see below). In racial/ethnic groups that are less likely to manifest hirsutism (e.g., Asian women), additional cutaneous evidence of androgen excess should be sought, including pustular acne and thinning scalp hair. HORMONAL EVALUATION Androgens are secreted by the ovaries and adrenal glands in response to their respective tropic hormones: luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH). The principal circulating steroids involved in the etiology of hirsutism are testosterone, androstenedione, and dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS). The ovaries and adrenal glands normally contribute about equally to testosterone production. Approximately half of the total testosterone originates from direct glandular secretion, and the remainder is derived from the peripheral conversion of androstenedione and DHEA (Chap. 411).
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Although it is the most important circulating androgen, testosterone is in effect the penultimate androgen in mediating hirsutism; it is converted to the more potent dihydrotestosterone (DHT) by the enzyme 5α-reductase, which is located in the PSU. DHT has a higher affinity for, and slower dissociation from, the androgen receptor. The local production of DHT allows it to serve as the primary mediator of androgen action at the level of the pilosebaceous unit. There are two isoenzymes of 5α-reductase: Type 2 is found in the prostate gland and in hair follicles, and type 1 is found primarily in sebaceous glands. One approach to the evaluation of hirsutism is depicted in Fig. 68-2. In addition to measuring blood levels of testosterone and DHEAS, it is important to measure the level of free (or unbound) testosterone. The fraction of testosterone that is not bound to its carrier protein, sex hormone–binding globulin (SHBG), is biologically available for conversion to DHT and binding to androgen receptors. Hyperinsulinemia and/or androgen excess decrease hepatic production of SHBG, resulting in levels of total testosterone within the high-normal range, whereas the unbound hormone is elevated more substantially. Although there is a decline in ovarian testosterone production after menopause, ovarian estrogen production decreases to an even greater extent, and the concentration of SHBG is reduced. Consequently, there is an increase in the relative proportion of unbound testosterone, and it may exacerbate hirsutism after menopause. A baseline plasma total testosterone level >12 nmol/L (>3.5 ng/mL) usually indicates a virilizing tumor, whereas a level >7 nmol/L (>2 ng/ mL) is suggestive. A basal DHEAS level >18.5 μmol/L (>7000 μg/L) suggests an adrenal tumor. Although DHEAS has been proposed as a “marker” of predominant adrenal androgen excess, it is not unusual to find modest elevations in DHEAS among women with PCOS. Computed tomography (CT) or magnetic resonance imaging (MRI) should be used to localize an adrenal mass, and transvaginal ultrasound usually suffices to identify an ovarian mass if clinical evaluation and hormonal levels suggest these possibilities. PCOS is the most common cause of ovarian androgen excess (Chap. 412). An increased ratio of LH to follicle-stimulating hormone (FSH) is characteristic in carefully studied patients with PCOS. However, because of the pulsatile nature of gonadotropin secretion, this finding may be absent in up to half of women with PCOS. Therefore, measurement of plasma LH and FSH is not needed to make a diagnosis of PCOS. Transvaginal ultrasound classically shows enlarged ovaries and increased stroma in women with PCOS. However, cystic ovaries also may be found in women without clinical or laboratory features of PCOS. It has been suggested that the measurement of circulating levels of antimüllerian hormone (AMH) may help in making the diagnosis of PCOS; however, this remains controversial. AMH levels reflect ovarian reserve and correlate with follicular number. Measurement of AMH can be useful when considering premature ovarian insufficiency in a patient who presents with oligomenorrhea, in which case a subnormal level of AMH will be present. Because adrenal androgens are readily suppressed by low doses of glucocorticoids, the dexamethasone androgen-suppression test may broadly distinguish ovarian from adrenal androgen overproduction. A blood sample is obtained before and after the administration of dexamethasone (0.5 mg orally every 6 h for 4 days). An adrenal source is suggested by suppression of unbound testosterone into the normal range; incomplete suppression suggests ovarian androgen excess. An overnight 1-mg dexamethasone suppression test, with measurement of 8:00 a.m. serum cortisol, is useful when there is clinical suspicion of Cushing’s syndrome (Chap. 406). Nonclassic CAH is most commonly due to 21-hydroxylase deficiency but also can be caused by autosomal recessive defects in other steroidogenic enzymes necessary for adrenal corticosteroid synthesis (Chap. 406). Because of the enzyme defect, the adrenal gland cannot secrete glucocorticoids (especially cortisol) efficiently. This results in diminished negative feedback inhibition of ACTH, leading to compensatory adrenal hyperplasia and the accumulation of steroid precursors that subsequently are converted to androgen. Deficiency
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333 Upper lip
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Chest
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Figure 68-1 Hirsutism scoring scale of Ferriman and Gallwey. The nine body areas that have androgen-sensitive areas are graded from 0 (no terminal hair) to 4 (frankly virile) to obtain a total score. A normal hirsutism score is 18.5 μmol/L (>7000 μg/L)
Treat empirically or Consider further testing • Dexamethasone suppression → adrenal vs ovarian causes; R/O Cushing’s • ACTH stimulation → assess nonclassic CAH
Cardinal Manifestations and Presentation of Diseases
Final diagnosis Idiopathic Other causes see Table 68-1
• Nonclassic CAH • Functional adrenal hyperandrogenism
• PCOS • Functional ovarian hyperandrogenism
Figure 68-2 Algorithm for the evaluation and differential diagnosis of hirsutism. ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyperplasia; DHEAS, sulfated form of dehydroepiandrosterone; PCOS, polycystic ovarian syndrome.
Nonpharmacologic treatments include (1) bleaching; (2) depilatory (removal from the skin surface), such as shaving and chemical treatments; and (3) epilatory (removal of the hair including the root), such as plucking, waxing, electrolysis, and laser therapy. Despite perceptions to the contrary, shaving does not increase the rate or density of hair growth. Chemical depilatory treatments may be useful for mild hirsutism that affects only limited skin areas, though they can cause skin irritation. Wax treatment removes hair temporarily but is uncomfortable. Electrolysis is effective for more permanent hair removal, particularly in the hands of a skilled electrologist. Laser phototherapy appears to be efficacious for hair removal. It delays hair regrowth and causes permanent hair removal in most patients. The long-term effects and complications associated with laser treatment are being evaluated. Pharmacologic therapy is directed at interrupting one or more of the steps in the pathway of androgen synthesis and action: (1) suppression of adrenal and/or ovarian androgen production; (2) enhancement of androgen-binding to plasma-binding proteins, particularly SHBG; (3) impairment of the peripheral conversion of androgen precursors to active androgen; and (4) inhibition of androgen action at the target tissue level. Attenuation of hair growth is typically not evident until 4–6 months after initiation of medical treatment and in most cases leads to only a modest reduction in hair growth. Combination estrogen-progestin therapy in the form of an oral contraceptive is usually the first-line endocrine treatment for hirsutism and acne, after cosmetic and dermatologic management. The estrogenic component of most oral contraceptives currently in use is either ethinyl estradiol or mestranol. The suppression of LH leads to reduced production of ovarian androgens. The reduced androgen levels also result in a dose-related increase in SHBG, thus lowering the fraction of unbound plasma testosterone. Combination therapy also has been demonstrated to decrease DHEAS, perhaps by reducing ACTH levels. Estrogens also have a direct, dose-dependent suppressive effect on sebaceous cell function. The choice of a specific oral contraceptive should be predicated on the progestational component, as progestins vary in their suppressive effect on SHBG levels and in their androgenic
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potential. Ethynodiol diacetate has relatively low androgenic potential, whereas progestins such as norgestrel and levonorgestrel are particularly androgenic, as judged from their attenuation of the estrogen-induced increase in SHBG. Norgestimate exemplifies the newer generation of progestins that are virtually nonandrogenic. Drospirenone, an analogue of spironolactone that has both antimineralocorticoid and antiandrogenic activities, has been approved for use as a progestational agent in combination with ethinyl estradiol. Oral contraceptives are contraindicated in women with a history of thromboembolic disease and women with increased risk of breast or other estrogen-dependent cancers (Chap. 413). There is a relative contraindication to the use of oral contraceptives in smokers and those with hypertension or a history of migraine headaches. In most trials, estrogen-progestin therapy alone improves the extent of acne by a maximum of 50–70%. The effect on hair growth may not be evident for 6 months, and the maximum effect may require 9–12 months owing to the length of the hair growth cycle. Improvements in hirsutism are typically in the range of 20%, but there may be an arrest of further progression of hair growth. Adrenal androgens are more sensitive than cortisol to the suppressive effects of glucocorticoids. Therefore, glucocorticoids are the mainstay of treatment in patients with CAH. Although glucocorticoids have been reported to restore ovulatory function in some women with PCOS, this effect is highly variable. Because of side effects from excessive glucocorticoids, low doses should be used. Dexamethasone (0.2– 0.5 mg) or prednisone (5–10 mg) should be taken at bedtime to achieve maximal suppression by inhibiting the nocturnal surge of ACTH. Cyproterone acetate is the prototypic antiandrogen. It acts mainly by competitive inhibition of the binding of testosterone and DHT to the androgen receptor. In addition, it may enhance the metabolic clearance of testosterone by inducing hepatic enzymes. Although not available for use in the United States, cyproterone acetate is widely used in Canada, Mexico, and Europe. Cyproterone (50–100 mg) is given on days 1–15 and ethinyl estradiol (50 μg) is given on days 5–26 of the menstrual cycle. Side effects include irregular uterine bleeding, nausea, headache, fatigue, weight gain, and decreased libido.
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Janet E. Hall
Menstrual dysfunction can signal an underlying abnormality that may have long-term health consequences. Although frequent or prolonged bleeding usually prompts a woman to seek medical attention, infrequent or absent bleeding may seem less troubling and the patient may not bring it to the attention of the physician. Thus, a focused menstrual history is a critical part of every encounter with a female patient. Pelvic pain is a common complaint that may relate to an abnormality of the reproductive organs but also may be of gastrointestinal, urinary tract, or musculoskeletal origin. Depending on its cause, pelvic pain may require urgent surgical attention.
MENSTRUAL DISORDERS DEFINITION AND PREVALENCE Amenorrhea refers to the absence of menstrual periods. Amenorrhea is classified as primary if menstrual bleeding has never occurred in the absence of hormonal treatment or secondary if menstrual periods cease for 3–6 months. Primary amenorrhea is a rare disorder that occurs in 35 days or 35 or 7 days. DIAGNOSIS Evaluation of menstrual dysfunction depends on understanding the interrelationships between the four critical components of the reproductive tract: (1) the hypothalamus, (2) the pituitary, (3) the ovaries, and (4) the uterus and outflow tract (Fig. 69-1; Chap. 412). This system is maintained by complex negative and positive feedback loops involving the ovarian steroids (estradiol and progesterone) and peptides (inhibin B and inhibin A) and the hypothalamic (gonadotropin-releasing hormone [GnRH]) and pituitary (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) components of this system (Fig. 69-1). Disorders of menstrual function can be thought of in two main categories: disorders of the uterus and outflow tract and disorders of ovulation. Many of the conditions that cause primary amenorrhea are congenital but go unrecognized until the time of normal puberty (e.g., genetic, chromosomal, and anatomic abnormalities). All causes of secondary amenorrhea also can cause primary amenorrhea.
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Menstrual Disorders and Pelvic Pain
are variably present. Anovulation can also present with intermenstrual intervals 7 days. Frequent or heavy irregular bleeding is termed dysfunctional uterine bleeding if anatomic uterine and outflow tract lesions or a bleeding diathesis has been excluded.
CHAPTER 69
Spironolactone, which usually is used as a mineralocorticoid antagonist, is also a weak antiandrogen. It is almost as effective as cyproterone acetate when used at high enough doses (100–200 mg daily). Patients should be monitored intermittently for hyperkalemia or hypotension, although these side effects are uncommon. Pregnancy should be avoided because of the risk of feminization of a male fetus. Spironolactone can also cause menstrual irregularity. It often is used in combination with an oral contraceptive, which suppresses ovarian androgen production and helps prevent pregnancy. Flutamide is a potent nonsteroidal antiandrogen that is effective in treating hirsutism, but concerns about the induction of hepatocellular dysfunction have limited its use. Finasteride is a competitive inhibitor of 5α-reductase type 2. Beneficial effects on hirsutism have been reported, but the predominance of 5α-reductase type 1 in the PSU appears to account for its limited efficacy. Finasteride would also be expected to impair sexual differentiation in a male fetus, and it should not be used in women who may become pregnant. Eflornithine cream (Vaniqa) has been approved as a novel treatment for unwanted facial hair in women, but long-term efficacy remains to be established. It can cause skin irritation under exaggerated conditions of use. Ultimately, the choice of any specific agent(s) must be tailored to the unique needs of the patient being treated. As noted previously, pharmacologic treatments for hirsutism should be used in conjunction with nonpharmacologic approaches. It is also helpful to review the pattern of female hair distribution in the normal population to dispel unrealistic expectations.
Disorders of the Uterus or Outflow Tract Abnormalities of the uterus and outflow tract typically present as primary amenorrhea. In patients with normal pubertal development and a blind vagina, the differential diagnosis includes obstruction by a transverse vaginal septum or imperforate hymen; müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome), which has been associated with mutations in the WNT4 gene; and androgen insensitivity syndrome (AIS), which is an X-linked recessive disorder that accounts for ~10% of all cases of primary amenorrhea (Chap. 411). Patients with AIS have a 46,XY karyotype, but because of the lack of androgen receptor responsiveness, those with complete AIS have severe underandrogenization and female external genitalia. The absence of pubic and axillary hair distinguishes them clinically from patients with müllerian agenesis, as does an elevated testosterone level. Asherman’s syndrome presents as secondary amenorrhea or hypomenorrhea and results from partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium. Curettage performed for pregnancy complications accounts for >90% of cases; genital tuberculosis is an important cause in regions where it is endemic.
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PART 2 Cardinal Manifestations and Presentation of Diseases
or secondary amenorrhea. They may occur in association with other features suggestive of hypothalamic or pituitary dysfunction, such as short stature, diabetes insipidus, galactorrhea, and headache. Hypogonadotropic hypogonadPrimary Secondary ism also may be seen after cranial irradiation. Hypothalamus 27% 36% In the postpartum period, it may be caused – GnRH by pituitary necrosis (Sheehan’s syndrome) or lymphocytic hypophysitis. Because reproductive dysfunction is commonly associated with hyper– Pituitary 2% 15% prolactinemia from neuroanatomic lesions or medications, prolactin should be measured in all Inhibin B LH patients with hypogonadotropic hypogonadism (Chap. 403). Inhibin A FSH PCOS 7% 30% Isolated hypogonadotropic hypogonadism (IHH) occurs in women, although it is three times more common in men. IHH generally presents with primary amenorrhea, although Ovary 43% 12% 50% have some degree of breast development, + Estradiol and one to two menses have been described in ~10%. IHH is associated with anosmia in about Progesterone 50% of women (termed Kallmann’s syndrome). Uterus/outflow tract 19% 7% Genetic causes of IHH have been identified in ~60% of patients (Chaps. 411 and 412). Functional hypothalamic amenorrhea (HA) is caused by a mismatch between energy expenFigure 69-1 Role of the hypothalamic-pituitary-gonadal axis in the etiology of diture and energy intake. Recent studies suggest amenorrhea. Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus that variants in genes associated with IHH may stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from increase susceptibility to these environmental the pituitary to induce ovarian folliculogenesis and steroidogenesis. Ovarian secretion of inputs, accounting in part for the clinical variestradiol and progesterone controls the shedding of the endometrium, resulting in menses, ability in this disorder. Leptin secretion may and, in combination with the inhibins, provides feedback regulation of the hypothalamus play a key role in transducing the signals from and pituitary to control secretion of FSH and LH. The prevalence of amenorrhea resulting the periphery to the hypothalamus in HA. The from abnormalities at each level of the reproductive system (hypothalamus, pituitary, ovary, hypothalamic-pituitary-adrenal axis also may uterus, and outflow tract) varies depending on whether amenorrhea is primary or secondary. play a role. The diagnosis of HA generally can PCOS, polycystic ovarian syndrome. be made on the basis of a careful history, a physical examination, and the demonstration of low levels of gonadotropins and normal prolactin levels. Eating disorders and chronic disease must be specifically TREATMENT Disorders of the Uterus or Outflow excluded. An atypical history, headache, signs of other hypothalamic dysfunction, or hyperprolactinemia, even if mild, necessitates cranial Tract imaging with computed tomography (CT) or magnetic resonance Obstruction of the outflow tract requires surgical correction. The risk imaging (MRI) to exclude a neuroanatomic cause. of endometriosis is increased with this condition, perhaps because of retrograde menstrual flow. Müllerian agenesis also may require Hypergonadotropic hypogonadism Ovarian failure is considered presurgical intervention to allow sexual intercourse, although vaginal mature when it occurs in women 80% sustained response rates. Ibuprofen, naproxen, ketoprofen, mefanamic acid, and nimesulide are all superior to
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placebo. Treatment should be started a day before expected menses and generally is continued for 2–3 days. Oral contraceptives also reduce symptoms of dysmenorrhea. The use of tocolytics, antiphosphodiesterase inhibitors, and magnesium has been suggested, but
there are insufficient data to recommend them. Failure of response to NSAIDs and/or oral contraceptives is suggestive of a pelvic disorder such as endometriosis, and diagnostic laparoscopy should be considered to guide further treatment.
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Section 9 Alterations in the Skin CHAPTER 70
70
Approach to the Patient with a Skin Disorder Thomas J. Lawley, Kim B. Yancey
Figure 70-2 Nevomelanocytic nevus. Nevi are benign proliferations of nevomelanocytes characterized by regularly shaped hyperpigmented macules or papules of a uniform color. Table 70-1 Description of Primary Skin Lesions Macule: A flat, colored lesion, 2-cm) flat lesion with a color different from the surrounding skin. This differs from a macule only in size. Papule: A small, solid lesion, 5 cm in diameter. Plaque: A large (>1-cm), flat-topped, raised lesion; edges may either be distinct (e.g., in psoriasis) or gradually blend with surrounding skin (e.g., in eczematous dermatitis). Vesicle: A small, fluid-filled lesion, 0.5 cm in diameter. Wheal: A raised, erythematous, edematous papule or plaque, usually representing short-lived vasodilation and vasopermeability. Telangiectasia: A dilated, superficial blood vessel.
Approach to the Patient with a Skin Disorder
The challenge of examining the skin lies in distinguishing normal from abnormal findings, distinguishing significant findings from trivial ones, and integrating pertinent signs and symptoms into an appropriate differential diagnosis. The fact that the largest organ in the body is visible is both an advantage and a disadvantage to those who examine it. It is advantageous because no special instrumentation is necessary and because the skin can be biopsied with little morbidity. However, the casual observer can be misled by a variety of stimuli and overlook important, subtle signs of skin or systemic disease. For instance, the sometimes minor differences in color and shape that distinguish a melanoma (Fig. 70-1) from a benign nevomelanocytic nevus (Fig. 70-2) can be difficult to recognize. A variety of descriptive terms have been developed that characterize cutaneous lesions (Tables 70-1, 70-2, and Tables 70-3; Fig. 70-3), thereby aiding in their interpretation and in the formulation of a differential diagnosis (Table 70-4). For example, the finding of scaling papules, which are present in psoriasis or atopic dermatitis, places the patient in a different diagnostic category than would hemorrhagic papules, which may indicate vasculitis or sepsis (Figs. 70-4 and 70-5, respectively). It is also important to differentiate primary from secondary skin lesions. If the examiner focuses on linear erosions overlying an area of erythema and scaling, he or she may incorrectly assume that the erosion is the primary lesion and that the redness and scale are secondary, whereas the correct interpretation would be that the patient has a pruritic eczematous dermatitis with erosions caused by scratching.
Table 70-2 Description of Secondary Skin Lesions
Figure 70-1 Superficial spreading melanoma. This is the most common type of melanoma. Such lesions usually demonstrate asymmetry, border irregularity, color variegation (black, blue, brown, pink, and white), a diameter >6 mm, and a history of change (e.g., an increase in size or development of associated symptoms such as pruritus or pain).
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Lichenification: A distinctive thickening of the skin that is characterized by accentuated skin-fold markings. Scale: Excessive accumulation of stratum corneum. Crust: Dried exudate of body fluids that may be either yellow (i.e., serous crust) or red (i.e., hemorrhagic crust). Erosion: Loss of epidermis without an associated loss of dermis. Ulcer: Loss of epidermis and at least a portion of the underlying dermis. Excoriation: Linear, angular erosions that may be covered by crust and are caused by scratching. Atrophy: An acquired loss of substance. In the skin, this may appear as a depression with intact epidermis (i.e., loss of dermal or subcutaneous tissue) or as sites of shiny, delicate, wrinkled lesions (i.e., epidermal atrophy). Scar: A change in the skin secondary to trauma or inflammation. Sites may be erythematous, hypopigmented, or hyperpigmented depending on their age or character. Sites on hair-bearing areas may be characterized by destruction of hair follicles.
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Table 70-3 Common Dermatologic Terms
PART 2 Cardinal Manifestations and Presentation of Diseases
Alopecia: Hair loss, partial or complete. Annular: Ring-shaped. Cyst: A soft, raised, encapsulated lesion filled with semisolid or liquid contents. Herpetiform: In a grouped configuration. Lichenoid eruption: Violaceous to purple, polygonal lesions that resemble those seen in lichen planus. Milia: Small, firm, white papules filled with keratin. Morbilliform rash: Generalized, small erythematous macules and/or papules that resemble lesions seen in measles. Nummular: Coin-shaped. Poikiloderma: Skin that displays variegated pigmentation, atrophy, and telangiectases. Polycyclic lesions: A configuration of skin lesions formed from coalescing rings or incomplete rings. Pruritus: A sensation that elicits the desire to scratch. Pruritus is often the predominant symptom of inflammatory skin diseases (e.g., atopic dermatitis, allergic contact dermatitis); it is also commonly associated with xerosis and aged skin. Systemic conditions that can be associated with pruritus include chronic renal disease, cholestasis, pregnancy, malignancy, thyroid disease, polycythemia vera, and delusions of parasitosis.
APPROACH TO THE PATIENT: Skin Disorder In examining the skin it is usually advisable to assess the patient before taking an extensive history. This approach ensures that the entire cutaneous surface will be evaluated, and objective findings can be integrated with relevant historical data. Four basic features of a skin lesion must be noted and considered during a physical examination: the distribution of the eruption, the types of primary and secondary lesions, the shape of individual lesions, and the arrangement of the lesions. An ideal skin examination includes evaluation of the skin, hair, and nails as well as the mucous membranes of the mouth, eyes, nose, nasopharynx, and anogenital region. In the initial examination, it is important that the patient be disrobed as completely as possible to minimize chances of missing important individual skin lesions and permit accurate assessment of the distribution of the eruption. The patient should first be viewed from a distance of about 1.5–2 m (4–6 ft) so that the general character of the skin and the distribution of lesions can be evaluated. Indeed, the distribution of lesions often correlates highly with diagnosis (Fig. 70-6). For example, a hospitalized patient with a generalized erythematous exanthem is more likely to have a drug eruption than is a patient with a similar rash limited to the sun-exposed portions of the face. Once the distribution of the lesions has been established, the nature of the primary lesion
Macule a Brown
Nodule
b Blue
Papule c Red
Plaque
a
Vesicle
b
Bulla
Figure 70-3 A schematic representation of several common primary skin lesions (see Table 70-1).
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must be determined. Thus, when lesions are distributed on elbows, knees, and scalp, the most likely possibility based solely on distribution is psoriasis or dermatitis herpetiformis (Figs. 70-7 and 70-8, respectively). The primary lesion in psoriasis is a scaly papule that soon forms erythematous plaques covered with a white scale, whereas that of dermatitis herpetiformis is an urticarial papule that quickly becomes a small vesicle. In this manner, identification of the primary lesion directs the examiner toward the proper diagnosis. Secondary changes in skin can also be quite helpful. For example, scale represents excessive epidermis, while crust is the result of a discontinuous epithelial cell layer. Palpation of skin lesions can yield insight into the character of an eruption. Thus, red papules on the lower extremities that blanch with pressure can be a manifestation of many different diseases, but hemorrhagic red papules that do not blanch with pressure indicate palpable purpura characteristic of necrotizing vasculitis (Fig. 70-4). The shape of lesions is also an important feature. Flat, round, erythematous papules and plaques are common in many cutaneous diseases. However, target-shaped lesions that consist in part of erythematous plaques are specific for erythema multiforme (Fig. 70-9). Likewise, the arrangement of individual lesions is important. Erythematous papules and vesicles can occur in many conditions, but their arrangement in a specific linear array suggests an external etiology such as allergic contact dermatitis (Fig. 70-10) or primary irritant dermatitis. In contrast, lesions with a generalized arrangement are common and suggest a systemic etiology. As in other branches of medicine, a complete history should be obtained to emphasize the following features: 1. Evolution of lesions a. Site of onset b. Manner in which the eruption progressed or spread c. Duration d. Periods of resolution or improvement in chronic eruptions 2. Symptoms associated with the eruption a. Itching, burning, pain, numbness b. What, if anything, has relieved symptoms c. Time of day when symptoms are most severe 3. Current or recent medications (prescribed as well as over-thecounter) 4. Associated systemic symptoms (e.g., malaise, fever, arthralgias) 5. Ongoing or previous illnesses 6. History of allergies 7. Presence of photosensitivity 8. Review of systems 9. Family history (particularly relevant for patients with melanoma, atopy, psoriasis, or acne) 10. Social, sexual, or travel history
DIAGNOSTIC TECHNIQUES Many skin diseases can be diagnosed on the basis of gross clinical appearance, but sometimes relatively simple diagnostic procedures can yield valuable information. In most instances, they can be performed at the bedside with a minimum of equipment. Skin Biopsy A skin biopsy is a straightforward minor surgical procedure; however, it is important to biopsy a lesion that is most likely to yield diagnostic findings. This decision may require expertise in skin diseases and knowledge of superficial anatomic structures in selected areas of the body. In this procedure, a small area of skin is anesthetized with 1% lidocaine with or without epinephrine. The skin lesion in question can be excised or saucerized with a scalpel or removed by punch biopsy. In the latter technique, a punch is pressed against the surface of the skin and rotated with downward pressure until it penetrates to the subcutaneous tissue. The circular biopsy is then lifted with forceps, and the bottom is cut with iris scissors. Biopsy sites may or may not need suture closure, depending on size and location.
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Table 70-4 Selected Common Dermatologic Conditions Common Distribution Face, upper back, chest
Rosacea
Blush area of cheeks, nose, forehead, chin
Seborrheic dermatitis
Scalp, eyebrows, perinasal areas Antecubital and popliteal fossae; may be widespread Ankles, lower legs over medial malleoli
Atopic dermatitis
Stasis dermatitis
Folliculitis Impetigo
Any hair-bearing area Anywhere
Erythema with greasy yellow-brown scale Patches and plaques of erythema, scaling, and lichenification; pruritus Patches of erythema and scaling on background of hyperpigmentation associated with signs of venous insufficiency Deep vesicles
Herpes simplex
Lips, genitalia
Herpes zoster
Dermatomal, usually trunk but may be anywhere Face, trunk, relative sparing of extremities
Varicella
Palms, soles, sides of fingers and toes
Allergic contact dermatitis
Anywhere
Psoriasis
Elbows, knees, scalp, lower back, fingernails (may be generalized)
Localized erythema, vesiTinea versicolor cles, scale, and pruritus (e.g., fingers, earlobes—nickel; dorsal aspect of foot—shoe; exposed surfaces—poison ivy) Papules and plaques covCandidiasis ered with silvery scale; nails have pits
Lichen planus
Wrists, ankles, mouth (may be widespread) Extensor surfaces of arms and thighs, buttocks
Violaceous flat-topped papules and plaques Keratotic follicular papules with surrounding erythema
Dermatophytosis
Forehead, cheeks, temples, upper lip Periorificial, trunk, extensor surfaces of extremities, flexor wrists, axillae
Tan to brown patches
Insect bites
Chalk-white macules
Cherry angioma Keloid
Actinic keratosis
Sun-exposed areas
Basal cell carcinoma
Face
Squamous cell carcinoma
Face, especially lower lip, ears
Skin-colored or red-brown macule or papule with dry, rough, adherent scale Papule with pearly, telangiectatic border on sun-damaged skin Indurated and possibly hyperkeratotic lesions often showing ulceration and/or crusting
Melasma Vitiligo
Scabies
Dermatofibroma
KOH Preparation A potassium hydroxide (KOH) preparation is performed on scaling skin lesions where a fungal infection is suspected. The edge of such a lesion is scraped gently with a no. 15 scalpel blade. The removed scale is collected on a glass microscope slide and then treated with 1 or 2 drops of a solution of 10–20% KOH. KOH dissolves keratin and allows easier visualization of fungal elements. Brief heating of the slide accelerates dissolution of keratin. When the preparation is viewed under the microscope, the refractile hyphae are seen more easily when the light intensity is reduced and the condenser is lowered. This technique can be used to identify
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Pityriasis rosea
Acrochordons (skin tags)
Usual Morphology Brown plaques with adherent, greasy scale; “stuck on” appearance Follicular pustules Papules, vesicles, pustules, often with honey-colored crusts Grouped vesicles progressing to crusted erosions Vesicles limited to a dermatome (often painful) Lesions arise in crops and quickly progress from erythematous macules, to papules, to vesicles, to pustules, to crusted sites. Symmetric erythematous patches with a collarette of scale
Trunk (Christmas tree pattern); herald patch followed by multiple smaller lesions Chest, back, abdomen, Scaly hyper- or proximal extremities hypopigmented macules
Groin, beneath breasts, Erythematous macerated vagina, oral cavity areas with satellite pustules; white, friable patches on mucous membranes Feet, groin, beard, or Varies with site, (e.g., tinea scalp corporis—scaly annular plaque) Groin, axillae, between Excoriated papules, burrows, fingers and toes, pruritus beneath breasts Anywhere Erythematous papules with central puncta Trunk Red, blood-filled papules Anywhere (site of Firm tumor, pink, purple, or previous injury) brown Anywhere Firm red to brown nodule that shows dimpling of overlying skin with lateral compression Groin, axilla, neck Fleshy papules
Urticaria
Anywhere
Wheals, sometimes with surrounding flare; pruritus
Transient acantholytic dermatosis
Trunk, especially anterior chest
Erythematous papules
Xerosis
Extensor extremities, especially legs
Dry, erythematous, scaling patches; pruritus
Approach to the Patient with a Skin Disorder
Diagnosis Seborrheic keratosis
Dyshidrotic eczema
Keratosis pilaris
Common Distribution Trunk, face
Usual Morphology Open and closed comedones, erythematous papules, pustules, cysts Erythema, telangiectases, papules, pustules
CHAPTER 70
Diagnosis Acne vulgaris
hyphae in dermatophyte infections, pseudohyphae and budding yeasts in Candida infections, and “spaghetti and meatballs” yeast forms in tinea versicolor. The same sampling technique can be used to obtain scale for culture of selected pathogenic organisms. Tzanck Smear A Tzanck smear is a cytologic technique most often used in the diagnosis of herpesvirus infections (herpes simplex virus [HSV] or varicella zoster virus [VZV]) (see Figs. 217-1 and 217-3). An early vesicle, not a pustule or crusted lesion, is unroofed, and the base of the lesion is scraped gently with a scalpel
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PART 2
Figure 70-5 Meningococcemia. An example of fulminant meningococcemia with extensive angular purpuric patches. (Courtesy of Stephen E. Gellis, MD; with permission.)
Cardinal Manifestations and Presentation of Diseases
Figure 70-4 Necrotizing vasculitis. Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small-vessel vasculitis. (Courtesy of Robert Swerlick, MD; with permission.) blade. The material is placed on a glass slide, air-dried, and stained with Giemsa or Wright’s stain. Multinucleated epithelial giant cells suggest the presence of HSV or VZV; culture, immunofluorescence microscopy, or genetic testing must be performed to identify the specific virus. A
Diascopy Diascopy is designed to assess whether a skin lesion will blanch with pressure as, for example, in determining whether a red lesion is hemorrhagic or simply blood-filled. Urticaria (Fig. 70-11) will blanch with pressure, whereas a purpuric lesion caused by necrotizing vasculitis (Fig. 70-4) will not. Diascopy is performed by pressing a microscope slide or magnifying lens against a lesion and noting the amount of blanching that occurs. Granulomas often have an opaque to transparent, brown-pink “apple jelly” appearance on diascopy. Wood’s Light A Wood’s lamp generates 360-nm ultraviolet (“black”) light that can be used to aid the evaluation of certain skin disorders. B
Psoriasis Skin tags Epidermal inclusion cyst
Acne vulgaris
Herpes zoster
Pityriasis rosea
Seborrheic keratoses Keratosis pilaris
Senile angioma Atopic dermatitis
Psoriasis Psoriasis
Lichen planus
Tinea or Candida cruris Actinic keratoses
Folliculitis Dyshidrotic eczema Hand eczema
Perianal lesions Hemorrhoids Condyloma acuminata Herpes simplex Dermatitis Vitiligo
Verruca vulgaris
Atopic dermatitis
Basal cell carcinoma Contact dermatitis Skin tags
Statis ulcer
Verruca plantaris
Seborrheic dermatitis
Seborrheic dermatitis Xanthelasma
Acne rosacea Seborrheic dermatitis
Statis dermatitis
Lichen simplex chronicus
D
Tinea pedis
Herpes labialis
Melasma Actinic keratoses
Dermatofibroma
Asteatotic eczema
Tinea pedis C
Psoriasis
Lichen planus Aphthous stomatitis Geographic tongue
Perleche
Leukoplakia Squamous cell carcinoma Oral hairy leukoplakia
Acne vulgaris
Figure 70-6 Distribution of some common dermatologic diseases and lesions.
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CHAPTER 70
Figure 70-7 Psoriasis. This papulosquamous skin disease is characterized by small and large erythematous papules and plaques with overlying adherent silvery scale.
Figure 70-8 Dermatitis herpetiformis. This disorder typically displays pruritic, grouped papulovesicles on elbows, knees, buttocks, and posterior scalp. Vesicles are often excoriated due to associated pruritus.
Figure 70-9 Erythema multiforme. This eruption is characterized by multiple erythematous plaques with a target or iris morphology. It usually represents a hypersensitivity reaction to drugs (e.g., sulfonamides) or infections (e.g., HSV). (Courtesy of the Yale Resident’s Slide Collection; with permission.)
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Approach to the Patient with a Skin Disorder
Figure 70-10 Allergic contact dermatitis (ACD). A. An example of ACD in its acute phase, with sharply demarcated, weeping, eczematous plaques in a perioral distribution. B. ACD in its chronic phase, with an erythematous, lichenified, weeping plaque on skin chronically exposed to nickel in a metal snap. (B, Courtesy of Robert Swerlick, MD; with permission.) For example, a Wood’s lamp will cause erythrasma (a superficial, intertriginous infection caused by Corynebacterium minutissimum) to show a characteristic coral pink color, and wounds colonized by Pseudomonas will appear pale blue. Tinea capitis caused by certain dermatophytes (e.g., Microsporum canis or M. audouinii) exhibits a yellow fluorescence. Pigmented lesions of the epidermis such as freckles are accentuated, while dermal pigment such as postinflammatory hyperpigmentation fades under a Wood’s light. Vitiligo (Fig. 70-12) appears
Figure 70-11 Urticaria. Discrete and confluent, edematous, erythematous papules and plaques are characteristic of this whealing eruption.
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Table 71-1 Clinical Features of Atopic Dermatitis 1. Pruritus and scratching 2. Course marked by exacerbations and remissions 3. Lesions typical of eczematous dermatitis 4. Personal or family history of atopy (asthma, allergic rhinitis, food allergies, or eczema) 5. Clinical course lasting >6 weeks 6. Lichenification of skin
PART 2 Figure 70-12 Vitiligo. Characteristic lesions display an acral distribution and striking depigmentation as a result of loss of melanocytes.
Cardinal Manifestations and Presentation of Diseases
totally white under a Wood’s lamp, and previously unsuspected areas of involvement often become apparent. A Wood’s lamp may also aid in the demonstration of tinea versicolor and in recognition of ash leaf spots in patients with tuberous sclerosis. Patch Tests Patch testing is designed to document sensitivity to a specific antigen. In this procedure, a battery of suspected allergens is applied to the patient’s back under occlusive dressings and allowed to remain in contact with the skin for 48 h. The dressings are removed, and the area is examined for evidence of delayed hypersensitivity reactions (e.g., erythema, edema, or papulovesicles). This test is best performed by physicians with special expertise in patch testing and is often helpful in the evaluation of patients with chronic dermatitis.
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Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders Leslie P. Lawley, Calvin O. McCall, Thomas J. Lawley
ECZEMA AND DERMATITIS Eczema is a type of dermatitis, and these terms are often used synonymously (e.g., atopic eczema or atopic dermatitis [AD]). Eczema is a reaction pattern that presents with variable clinical findings and the common histologic finding of spongiosis (intercellular edema of the epidermis). Eczema is the final common expression for a number of disorders, including those discussed in the following sections. Primary lesions may include erythematous macules, papules, and vesicles, which can coalesce to form patches and plaques. In severe eczema, secondary lesions from infection or excoriation, marked by weeping and crusting, may predominate. In chronic eczematous conditions, lichenification (cutaneous hypertrophy and accentuation of normal skin markings) may alter the characteristic appearance of eczema. ATOPIC DERMATITIS AD is the cutaneous expression of the atopic state, characterized by a family history of asthma, allergic rhinitis, or eczema. The prevalence of AD is increasing worldwide. Some of its features are shown in Table 71-1. The etiology of AD is only partially defined, but there is a clear genetic predisposition. When both parents are affected by AD, >80% of their children manifest the disease. When only one parent is affected, the prevalence drops to slightly over 50%. A characteristic defect in AD that contributes to the pathophysiology is an
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impaired epidermal barrier. In many patients, a mutation in the gene encoding filaggrin, a structural protein in the stratum corneum, is responsible. Patients with AD may display a variety of immunoregulatory abnormalities, including increased IgE synthesis; increased serum IgE levels; and impaired, delayed-type hypersensitivity reactions. The clinical presentation often varies with age. Half of patients with AD present within the first year of life, and 80% present by 5 years of age. About 80% ultimately coexpress allergic rhinitis or asthma. The infantile pattern is characterized by weeping inflammatory patches and crusted plaques on the face, neck, and extensor surfaces. The childhood and adolescent pattern is typified by dermatitis of flexural skin, particularly in the antecubital and popliteal fossae (Fig. 71-1). AD may resolve spontaneously, but approximately 40% of all individuals affected as children will have dermatitis in adult life. The distribution of lesions in adults may be similar to those seen in childhood; however, adults frequently have localized disease manifesting as lichen simplex chronicus or hand eczema (see below). In patients with localized disease, AD may be suspected because of a typical personal or family history or the presence of cutaneous stigmata of AD such as perioral pallor, an extra fold of skin beneath the lower eyelid (DennieMorgan folds), increased palmar skin markings, and an increased incidence of cutaneous infections, particularly with Staphylococcus aureus. Regardless of other manifestations, pruritus is a prominent characteristic of AD in all age groups and is exacerbated by dry skin. Many of the cutaneous findings in affected patients, such as lichenification, are secondary to rubbing and scratching. TREATMENT
Atopic Dermatitis
Therapy for AD should include avoidance of cutaneous irritants, adequate moisturizing through the application of emollients, judicious use of topical anti-inflammatory agents, and prompt treatment of secondary infection. Patients should be instructed to bathe no more often than daily, using warm or cool water, and to use only mild bath soap. Immediately after bathing, while the skin is still moist, a topical anti-inflammatory agent in a cream or ointment base should be applied to areas of dermatitis, and all other skin
Figure 71-1 Atopic dermatitis. Hyperpigmentation, lichenification, and scaling in the antecubital fossae are seen in this patient with atopic dermatitis. (Courtesy of Robert Swerlick, MD; with permission.)
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CONTACT DERMATITIS Contact dermatitis is an inflammatory skin process caused by an exogenous agent or agents that directly or indirectly injure the skin. In irritant contact dermatitis (ICD), this injury is caused by an inherent characteristic of a compound—for example, a concentrated acid or base. Agents that cause ACD induce an antigen-specific immune response (e.g., poison ivy dermatitis). The clinical lesions of contact dermatitis may be acute (wet and edematous) or chronic (dry, thickened, and scaly), depending on the persistence of the insult (see Fig. 70-10). Irritant Contact Dermatitis ICD is generally well demarcated and often localized to areas of thin skin (eyelids, intertriginous areas) or to areas where the irritant was occluded. Lesions may range from minimal skin erythema to areas of marked edema, vesicles, and ulcers. Prior exposure to the offending agent is not necessary, and the reaction develops in minutes to a few hours. Chronic low-grade irritant dermatitis is the most common type of ICD, and the most common area of involvement is the hands (see below). The most common irritants encountered are chronic wet work, soaps, and detergents. Treatment should be directed toward the avoidance of irritants and the use of protective gloves or clothing. Allergic Contact Dermatitis ACD is a manifestation of delayed-type hypersensitivity mediated by memory T lymphocytes in the skin. Prior exposure to the offending agent is necessary to develop the hypersensitivity reaction, which may take as little as 12 h or as much as 72 h to develop. The most common cause of ACD is exposure to plants, especially to members of the family Anacardiaceae, including the genus Toxicodendron. Poison ivy, poison oak, and poison sumac are members of this genus and cause an allergic reaction marked by erythema, vesiculation, and severe pruritus. The eruption is often linear or angular, corresponding to areas where plants have touched the skin. The sensitizing antigen common to these plants is urushiol, an oleoresin containing the active ingredient pentadecylcatechol. The oleoresin may adhere to skin, clothing, tools, and pets, and contaminated articles may cause dermatitis even after prolonged storage. Blister fluid does not contain urushiol and is not capable of inducing skin eruption in exposed subjects. TREATMENT
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LICHEN SIMPLEX CHRONICUS Lichen simplex chronicus may represent the end stage of a variety of pruritic and eczematous disorders, including AD. It consists of a
circumscribed plaque or plaques of lichenified skin due to chronic scratching or rubbing. Common areas involved include the posterior nuchal region, dorsum of the feet, and ankles. Treatment of lichen simplex chronicus centers on breaking the cycle of chronic itching and scratching. High-potency topical glucocorticoids are helpful in most cases, but, in recalcitrant cases, application of topical glucocorticoids under occlusion, or intralesional injection of glucocorticoids may be required.
CHAPTER 71
areas should be lubricated with a moisturizer. Approximately 30 g of a topical agent is required to cover the entire body surface of an average adult. Low- to mid-potency topical glucocorticoids are employed in most treatment regimens for AD. Skin atrophy and the potential for systemic absorption are constant concerns, especially with more potent agents. Low-potency topical glucocorticoids or nonglucocorticoid anti-inflammatory agents should be selected for use on the face and in intertriginous areas to minimize the risk of skin atrophy. Two nonglucocorticoid anti-inflammatory agents are available: tacrolimus ointment and pimecrolimus cream. These agents are macrolide immunosuppressants that are approved by the U.S. Food and Drug Administration (FDA) for topical use in AD. Reports of broader effectiveness appear in the literature. These agents do not cause skin atrophy, nor do they suppress the hypothalamicpituitary-adrenal axis. However, concerns have emerged regarding the potential for lymphomas in patients treated with these agents. Thus, caution should be exercised when these agents are considered. Currently, they are also more costly than topical glucocorticoids. Barrier-repair products that attempt to restore the impaired epidermal barrier are also nonglucocorticoid agents and are gaining popularity in the treatment of AD. Secondary infection of eczematous skin may lead to exacerbation of AD. Crusted and weeping skin lesions may be infected with S. aureus. When secondary infection is suspected, eczematous lesions should be cultured and patients treated with systemic antibiotics active against S. aureus. The initial use of penicillinase-resistant penicillins or cephalosporins is preferable. Dicloxacillin or cephalexin (250 mg qid for 7–10 days) is generally adequate for adults; however, antibiotic selection must be directed by culture results and clinical response. More than 50% of S. aureus isolates are now methicillin resistant in some communities. Current recommendations for the treatment of infection with these community-acquired methicillinresistant S. aureus (CA-MRSA) strains in adults include trimethoprimsulfamethoxazole (1 double-strength tablet bid), minocycline (100 mg bid), doxycycline (100 mg bid), or clindamycin (300–450 mg qid). Duration of therapy should be 7–10 days. Inducible resistance may limit clindamycin’s usefulness. Such resistance can be detected by the double-disk diffusion test, which should be ordered if the isolate is erythromycin resistant and clindamycin sensitive. As an adjunct, antibacterial washes or dilute sodium hypochlorite baths (0.005% bleach) and intermittent nasal mupirocin may be useful. Control of pruritus is essential for treatment, because AD often represents “an itch that rashes.” Antihistamines are most often used to control pruritus. Diphenhydramine (25 mg every 4–6 h), hydroxyzine (10–25mg every 6 h), or doxepin (10–25 mg at bedtime) are useful primarily due to their sedating action. Higher doses of these agents may be required, but sedation can become bothersome. Patients need to be counseled about driving or operating heavy equipment after taking these medications. When used at bedtime, sedating antihistamines may improve the patient’s sleep. Although they are effective in urticaria, non-sedating antihistamines and selective H2 blockers are of little use in controlling the pruritus of AD. Treatment with systemic glucocorticoids should be limited to severe exacerbations unresponsive to topical therapy. In the patient with chronic AD, therapy with systemic glucocorticoids will generally clear the skin only briefly, and cessation of the systemic therapy will invariably be accompanied by a return, if not a worsening, of the dermatitis. Patients who do not respond to conventional therapies should be considered for patch testing to rule out allergic contact dermatitis (ACD). The role of dietary allergens in AD is controversial, and there is little evidence that they play any role outside of infancy, during which a small percentage of patients with AD may be affected by food allergens.
Contact Dermatitis
If contact dermatitis is suspected and an offending agent is identified and removed, the eruption will resolve. Usually, treatment with high-potency topical glucocorticoids is enough to relieve symptoms while the dermatitis runs its course. For those patients who require systemic therapy, daily oral prednisone—beginning at 1 mg/kg, but usually ≤60 mg/d—is sufficient. The dose should be tapered over 2–3 weeks, and each daily dose should be taken in the morning with food. Identification of a contact allergen can be a difficult and timeconsuming task. Allergic contact dermatitis should be suspected in patients with dermatitis unresponsive to conventional therapy or with an unusual and patterned distribution. Patients should be questioned carefully regarding occupational exposures and topical medications. Common sensitizers include preservatives in topical preparations, nickel sulfate, potassium dichromate, thimerosal, neomycin sulfate, fragrances, formaldehyde, and rubber-curing agents. Patch testing is helpful in identifying these agents but should not be attempted when patients have widespread active dermatitis or are taking systemic glucocorticoids.
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ASTEATOTIC ECZEMA Asteatotic eczema, also known as xerotic eczema or “winter itch,” is a mildly inflammatory dermatitis that develops in areas of extremely dry skin, especially during the dry winter months. Clinically, there may be considerable overlap with nummular eczema. This form of eczema accounts for a large number of physician visits because of the associated pruritus. Fine cracks and scale, with or without erythema, characteristically develop in areas of dry skin, especially on the anterior surfaces of the lower extremities in elderly patients. Asteatotic eczema responds well to topical moisturizers and the avoidance of cutaneous irritants. Overbathing and the use of harsh soaps exacerbate asteatotic eczema.
PART 2 Cardinal Manifestations and Presentation of Diseases
Figure 71-2 Dyshidrotic eczema. This example is characterized by deep-seated vesicles and scaling on palms and lateral fingers, and the disease is often associated with an atopic diathesis.
HAND ECZEMA Hand eczema is a very common, chronic skin disorder in which both exogenous and endogenous factors play important roles. It may be associated with other cutaneous disorders such as AD, and contact with various agents may be involved. Hand eczema represents a large proportion of cases of occupation-associated skin disease. Chronic, excessive exposure to water and detergents, harsh chemicals, or allergens may initiate or aggravate this disorder. It may present with dryness and cracking of the skin of the hands as well as with variable amounts of erythema and edema. Often, the dermatitis will begin under rings, where water and irritants are trapped. Dyshidrotic eczema, a variant of hand eczema, presents with multiple, intensely pruritic, small papules and vesicles on the thenar and hypothenar eminences and the sides of the fingers (Fig. 71-2). Lesions tend to occur in crops that slowly form crusts and then heal. The evaluation of a patient with hand eczema should include an assessment of potential occupation-associated exposures. The history should be directed to identifying possible irritant or allergen exposures. TREATMENT
Hand Eczema
STASIS DERMATITIS AND STASIS ULCERATION Stasis dermatitis develops on the lower extremities secondary to venous incompetence and chronic edema. Patients may give a history of deep venous thrombosis and may have evidence of vein removal or varicose veins. Early findings in stasis dermatitis consist of mild erythema and scaling associated with pruritus. The typical initial site of involvement is the medial aspect of the ankle, often over a distended vein (Fig. 71-3). Stasis dermatitis may become acutely inflamed, with crusting and exudate. In this state, it is easily confused with cellulitis. Chronic stasis dermatitis is often associated with dermal fibrosis that is recognized clinically as brawny edema of the skin. As the disorder progresses, the dermatitis becomes progressively pigmented due to chronic erythrocyte extravasation leading to cutaneous hemosiderin deposition. Stasis dermatitis may be complicated by secondary infection and contact dermatitis. Severe stasis dermatitis may precede the development of stasis ulcers. TREATMENT
S tasis Dermatitis and Stasis Ulceration
Patients with stasis dermatitis and stasis ulceration benefit greatly from leg elevation and the routine use of compression stockings with a gradient of at least 30–40 mmHg. Stockings providing less compression, such as antiembolism hose, are poor substitutes. Use of emollients and/or mid-potency topical glucocorticoids and avoidance of irritants are also helpful in treating stasis dermatitis. Protection of the legs from injury, including scratching, and control of chronic edema are essential to prevent ulcers. Diuretics may be required to adequately control chronic edema. Stasis ulcers are difficult to treat, and resolution is slow. It is extremely important to elevate the affected limb as much as possible. The ulcer should be kept clear of necrotic material by gentle debridement and covered with a semipermeable dressing and a compression dressing or compression stocking. Glucocorticoids
Therapy for hand eczema is directed toward avoidance of irritants, identification of possible contact allergens, treatment of coexistent infection, and application of topical glucocorticoids. Whenever possible, the hands should be protected by gloves, preferably vinyl. The use of rubber gloves (latex) to protect dermatitic skin is sometimes associated with the development of hypersensitivity reactions to components of the gloves. Patients can be treated with cool moist compresses followed by application of a mid- to high-potency topical glucocorticoid in a cream or ointment base. As in AD, treatment of secondary infection is essential for good control. In addition, patients with hand eczema should be examined for dermatophyte infection by KOH preparation and culture (see below). NUMMULAR ECZEMA Nummular eczema is characterized by circular or oval “coinlike” lesions, beginning as small edematous papules that become crusted and scaly. The etiology of nummular eczema is unknown, but dry skin is a contributing factor. Common locations are the trunk or the extensor surfaces of the extremities, particularly on the pretibial areas or dorsum of the hands. Nummular eczema occurs more frequently in men and is most common in middle age. The treatment of nummular eczema is similar to that for AD.
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Figure 71-3 Stasis dermatitis. An example of stasis dermatitis showing erythematous, scaly, and oozing patches over the lower leg. Several stasis ulcers are also seen in this patient.
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TREATMENT
347
Seborrheic Dermatitis
PAPULOSQUAMOUS DISORDERS (Table 71-2)
should not be applied to ulcers, because they may retard healing; however, they may be applied to the surrounding skin to control itching, scratching, and additional trauma. Secondarily infected lesions should be treated with appropriate oral antibiotics, but it should be noted that all ulcers will become colonized with bacteria, and the purpose of antibiotic therapy should not be to clear all bacterial growth. Care must be taken to exclude treatable causes of leg ulcers (hypercoagulation, vasculitis) before beginning the chronic management outlined above. SEBORRHEIC DERMATITIS Seborrheic dermatitis is a common, chronic disorder characterized by greasy scales overlying erythematous patches or plaques. Induration and scale are generally less prominent than in psoriasis, but clinical overlap exists between these diseases (“sebopsoriasis”). The most common location is in the scalp, where it may be recognized as severe dandruff. On the face, seborrheic dermatitis affects the eyebrows, eyelids, glabella, and nasolabial folds (Fig. 71-4). Scaling of the external auditory canal is common in seborrheic dermatitis. In addition, the postauricular areas often become macerated and tender. Seborrheic dermatitis may also develop in the central chest, axilla, groin, submammary folds, and gluteal cleft. Rarely, it may cause widespread generalized dermatitis. Pruritus is variable. Seborrheic dermatitis may be evident within the first few weeks of life, and within this context it typically occurs in the scalp (“cradle cap”), face, or groin. It is rarely seen in children beyond infancy but becomes evident again during adult life. Although it is frequently seen in patients with Parkinson’s disease, in those who have had cerebrovascular accidents, and in those with HIV infection, the overwhelming majority of individuals with seborrheic dermatitis have no underlying disorder.
Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders
Figure 71-4 Seborrheic dermatitis. Central facial erythema with overlying greasy, yellowish scale is seen in this patient. (Courtesy of Jean Bolognia, MD; with permission.)
PSORIASIS Psoriasis is one of the most common dermatologic diseases, affecting up to 2% of the world’s population. It is an immune-mediated disease clinically characterized by erythematous, sharply demarcated papules and rounded plaques covered by silvery micaceous scale. The skin lesions of psoriasis are variably pruritic. Traumatized areas often develop lesions of psoriasis (the Koebner or isomorphic phenomenon). In addition, other external factors may exacerbate psoriasis, including infections, stress, and medications (lithium, beta blockers, and antimalarial drugs). The most common variety of psoriasis is called plaque-type. Patients with plaque-type psoriasis have stable, slowly enlarging plaques, which remain basically unchanged for long periods of time. The most commonly involved areas are the elbows, knees, gluteal cleft, and scalp. Involvement tends to be symmetric. Plaque psoriasis generally develops slowly and runs an indolent course. It rarely remits spontaneously. Inverse psoriasis affects the intertriginous regions, including the axilla, groin, submammary region, and navel; it also tends to affect the scalp, palms, and soles. The individual lesions are sharply demarcated plaques (see Fig. 70-7), but they may be moist and without scale due to their locations. Guttate psoriasis (eruptive psoriasis) is most common in children and young adults. It develops acutely in individuals without psoriasis or in those with chronic plaque psoriasis. Patients present with many small erythematous, scaling papules, frequently after upper respiratory tract infection with β-hemolytic streptococci. The differential diagnosis should include pityriasis rosea and secondary syphilis. In pustular psoriasis, patients may have disease localized to the palms and soles, or the disease may be generalized. Regardless of the extent of disease, the skin is erythematous, with pustules and variable scale. Localized to the palms and soles, it is easily confused with eczema. When it is generalized, episodes are characterized by fever (39°–40°C [102.2°–104.0°F]) lasting several days, an accompanying generalized eruption of sterile pustules, and a background of intense erythema; patients may become erythrodermic. Episodes of fever and pustules are recurrent. Local irritants, pregnancy, medications, infections, and systemic glucocorticoid withdrawal can precipitate this form of psoriasis. Oral retinoids are the treatment of choice in nonpregnant patients.
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Treatment with low-potency topical glucocorticoids in conjunction with a topical antifungal agent, such as ketoconazole cream or ciclopirox cream, is often effective. The scalp and beard areas may benefit from antidandruff shampoos, which should be left in place 3–5 min before rinsing. High-potency topical glucocorticoid solutions (betamethasone or clobetasol) are effective for control of severe scalp involvement. High-potency glucocorticoids should not be used on the face because this treatment is often associated with steroid-induced rosacea or atrophy.
Table 71-2 Papulosquamous Disorders Psoriasis
Lichen planus Pityriasis rosea
Dermatophytosis
Clinical Features Sharply demarcated, erythematous plaques with mica-like scale; predominantly on elbows, knees, and scalp; atypical forms may localize to intertriginous areas; eruptive forms may be associated with infection Purple polygonal papules marked by severe pruritus; lacy white markings, especially associated with mucous membrane lesions Rash often preceded by herald patch; oval to round plaques with trailing scale; most often affects trunk; eruption lines up in skinfolds giving a “fir tree–like” appearance; generally spares palms and soles Polymorphous appearance depending on dermatophyte, body site, and host response; sharply defined to ill-demarcated scaly plaques with or without inflammation; may be associated with hair loss
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Other Notable Features May be aggravated by certain drugs, infection; severe forms seen in association with HIV Certain drugs may induce: thiazides, antimalarial drugs Variable pruritus; self-limited, resolving in 2–8 weeks; may be imitated by secondary syphilis KOH preparation may show branching hyphae; culture helpful
Histologic Features Acanthosis, vascular proliferation Interface dermatitis Pathologic features often nonspecific Hyphae and neutrophils in stratum corneum
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Table 71-3 FDA-Approved Systemic Therapy for Psoriasis Administration Agent Methotrexate
Medication Class Antimetabolite
Route Oral
Frequency Weekly
Acitretin
Retinoid
Oral
Daily
Cyclosporine
Calcineurin inhibitor Oral
Twice daily
Adverse Events (Selected) Hepatotoxicity, pulmonary toxicity, pancytopenia, potential for increased malignancies, ulcerative stomatitis, nausea, diarrhea, teratogenicity Teratogenicity, hepatotoxicity, hyperostosis, hyperlipidemia/pancreatitis, depression, ophthalmologic effects, pseudotumor cerebri Renal dysfunction, hypertension, hyperkalemia, hyperuricemia, hypomagnesemia, hyperlipidemia, increased risk of malignancies
PART 2 Cardinal Manifestations and Presentation of Diseases
Fingernail involvement, appearing as punctate pitting, onycholysis, nail thickening, or subungual hyperkeratosis, may be a clue to the diagnosis of psoriasis when the clinical presentation is not classic. According to the National Psoriasis Foundation, up to 30% of patients with psoriasis have psoriatic arthritis (PsA). There are five subtypes of PsA: symmetric, asymmetric, distal interphalangeal predominant (DIP), spondylitis, and arthritis mutilans. Symmetric arthritis resembles rheumatoid arthritis, but is usually milder. Asymmetric arthritis can involve any joint and may present as “sausage digits.” DIP is the classic form, but occurs in only about 5% of patients with PsA. It may involve fingers and toes. Spondylitis also occurs in about 5% of patients with PsA. Arthritis mutilans is severe and deforming. It affects primarily the small joints of the hands and feet. It accounts for fewer than 5% of PsA cases. An increased risk of metabolic syndrome, including increased morbidity and mortality from cardiovascular events, has been demonstrated in psoriasis patients. Appropriate screening tests should be performed. The etiology of psoriasis is still poorly understood, but there is clearly a genetic component to the disease. In various studies, 30–50% of patients with psoriasis report a positive family history. Psoriatic lesions contain infiltrates of activated T cells that are thought to elaborate cytokines responsible for keratinocyte hyperproliferation, which results in the characteristic clinical findings. Agents inhibiting T cell activation, clonal expansion, or release of proinflammatory cytokines are often effective for the treatment of severe psoriasis (see below). TREATMENT
Psoriasis
Treatment of psoriasis depends on the type, location, and extent of disease. All patients should be instructed to avoid excess drying or irritation of their skin and to maintain adequate cutaneous hydration. Most cases of localized, plaque-type psoriasis can be managed with mid-potency topical glucocorticoids, although their long-term use is often accompanied by loss of effectiveness (tachyphylaxis) and atrophy of the skin. A topical vitamin D analogue (calcipotriene) and a retinoid (tazarotene) are also efficacious in the treatment of limited psoriasis and have largely replaced other topical agents such as coal tar, salicylic acid, and anthralin.
Ultraviolet (UV) light, natural or artificial, is an effective therapy for many patients with widespread psoriasis. Ultraviolet B (UVB), narrowband UVB, and ultraviolet A (UVA) light with either oral or topical psoralens (PUVA) is used clinically. UV light’s immunosuppressive properties are thought to be responsible for its therapeutic activity in psoriasis. It is also mutagenic, potentially leading to an increased incidence of nonmelanoma and melanoma skin cancer. UV-light therapy is contraindicated in patients receiving cyclosporine and should be used with great care in all immunocompromised patients due to the increased risk of skin cancer. Various systemic agents can be used for severe, widespread psoriatic disease (Table 71-3). Oral glucocorticoids should not be used for the treatment of psoriasis due to the potential for development of life-threatening pustular psoriasis when therapy is discontinued. Methotrexate is an effective agent, especially in patients with psoriatic arthritis. The synthetic retinoid acitretin is useful, especially when immunosuppression must be avoided; however, teratogenicity limits its use. The evidence implicating psoriasis as a T cell–mediated disorder has directed therapeutic efforts to immunoregulation. Cyclosporine and other immunosuppressive agents can be very effective in the treatment of psoriasis, and much attention is currently directed toward the development of biologic agents with more selective immunosuppressive properties and better safety profiles (Table 71-4). Experience with these biologic agents is limited, and information regarding combination therapy and adverse events continues to emerge. Use of tumor necrosis factor (TNF-α) inhibitors may worsen congestive heart failure (CHF), and they should be used with caution in patients at risk for or known to have CHF. Further, none of the immunosuppressive agents used in the treatment of psoriasis should be initiated if the patient has a severe infection; patients on such therapy should be routinely screened for tuberculosis. There have been reports of progressive multifocal leukoencephalopathy in association with treatment with the TNF-α inhibitors. Malignancies, including a risk or history of certain malignancies, may limit the use of these systemic agents.
Table 71-4 Biologics Approved for Psoriasis or Psoriatic Arthritis Administration Agent Etanercept
Mechanism of Action Anti-TNF-α
Indication Ps, PsA
Route SC
Frequency Once or twice weekly
Adalimumab
Anti-TNF-α
Ps, PsA
SC
Every other week
Infliximab
Anti-TNF-α
Ps, PsA
IV
Golimumab
Anti-TNF-α
PsA
SC
Initial infusion followed by infusions at weeks 2 and 6, then every 8 weeks Monthly
Ps
SC
Ustekinumab Anti-IL-12 and anti-IL-23
2 doses 4 weeks apart, then every 12 weeks
Warnings Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, hepatotoxicity, CHF, hematologic events, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, hepatotoxicity, CHF, hypersensitivity reactions, neurologic events, potential for increased malignancies Serious infections, neurologic events, potential for increased malignancies
Abbreviations: CHF, congestive heart failure; IL, interleukin; IM, intramuscular; Ps, psoriasis; PsA, psoriatic arthritis; SC, subcutaneous; TNF, tumor necrosis factor.
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CHAPTER 71 Figure 71-6 Pityriasis rosea. In this patient with pityriasis rosea, multiple round to oval erythematous patches with fine central scale are distributed along the skin tension lines on the trunk.
LICHEN PLANUS Lichen planus (LP) is a papulosquamous disorder that may affect the skin, scalp, nails, and mucous membranes. The primary cutaneous lesions are pruritic, polygonal, flat-topped, violaceous papules. Close examination of the surface of these papules often reveals a network of gray lines (Wickham’s striae). The skin lesions may occur anywhere but have a predilection for the wrists, shins, lower back, and genitalia (Fig. 71-5). Involvement of the scalp (lichen planopilaris) may lead to scarring alopecia, and nail involvement may lead to permanent deformity or loss of fingernails and toenails. LP commonly involves mucous membranes, particularly the buccal mucosa, where it can present on a spectrum ranging from a mild, white, reticulate eruption of the mucosa to a severe, erosive stomatitis. Erosive stomatitis may persist for years and may be linked to an increased risk of oral squamous cell carcinoma. Cutaneous eruptions clinically resembling LP have been observed after administration of numerous drugs, including thiazide diuretics, gold, antimalarial agents, penicillamine, and phenothiazines, and in patients with skin lesions of chronic graft-versus-host disease. In addition, LP may be associated with hepatitis C infection. The course of LP is variable, but most patients have spontaneous remissions 6 months to 2 years after the onset of disease. Topical glucocorticoids are the mainstay of therapy.
honey-colored crust (see Fig. 173-3). Lesions may occur on normal skin (primary infection) or in areas already affected by another skin disease (secondary infection). Lesions caused by staphylococci may be tense, clear bullae, and this less common form of the disease is called bullous impetigo. Blisters are caused by the production of exfoliative toxin by S. aureus phage type II. This is the same toxin responsible for staphylococcal scalded-skin syndrome, often resulting in dramatic loss of the superficial epidermis due to blistering. The latter syndrome is much more common in children than in adults; however, it should be considered along with toxic epidermal necrolysis and severe drug eruptions in patients with widespread blistering of the skin. Ecthyma is a deep non-bullous variant of impetigo that causes punched-out ulcerative lesions. It is more often caused by a primary or secondary infection with Streptococcus pyogenes. Ecthyma is a deeper infection than typical impetigo and resolves with scars. Treatment of both ecthyma and impetigo involves gentle debridement of adherent crusts, which is facilitated by the use of soaks and topical antibiotics in conjunction with appropriate oral antibiotics. Furunculosis is also caused by S. aureus, and this disorder has gained prominence in the last decade because of CA-MRSA. A furuncle, or boil, is a painful, erythematous nodule that can occur on any cutaneous surface. The lesions may be solitary but are most often multiple. Patients frequently believe they have been bitten by spiders or insects. Family members or close contacts may also be affected. Furuncles can rupture and drain spontaneously or may need incision and drainage, which may be adequate therapy for small solitary furuncles without cellulitis or systemic symptoms. Whenever possible, lesional material should be sent for culture. Current recommendations for methicillinsensitive infections are β-lactam antibiotics. Therapy for CA-MRSA was discussed previously (see “Atopic Dermatitis”). Warm compresses and nasal mupirocin are helpful therapeutic additions. Severe infections may require IV antibiotics.
PITYRIASIS ROSEA Pityriasis rosea (PR) is a papulosquamous eruption of unknown etiology occurring more commonly in the spring and fall. Its first manifestation is the development of a 2- to 6-cm annular lesion (the herald patch). This is followed in a few days to a few weeks by the appearance of many smaller annular or papular lesions with a predilection to occur on the trunk (Fig. 71-6). The lesions are generally oval, with their long axis parallel to the skinfold lines. Individual lesions may range in color from red to brown and have a trailing scale. PR shares many clinical features with the eruption of secondary syphilis, but palm and sole lesions are extremely rare in PR and common in secondary syphilis. The eruption tends to be moderately pruritic and lasts 3–8 weeks. Treatment is directed at alleviating pruritus and consists of oral antihistamines; mid-potency topical glucocorticoids; and, in some cases, UVB phototherapy.
CUTANEOUS INFECTIONS (Table 71-5) IMPETIGO, ECTHYMA, AND FURUNCULOSIS Impetigo is a common superficial bacterial infection of skin caused most often by S. aureus (Chap. 172) and in some cases by group A β-hemolytic streptococci (Chap. 173). The primary lesion is a superficial pustule that ruptures and forms a characteristic yellow-brown
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Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders
Figure 71-5 Lichen planus. An example of lichen planus showing multiple flat-topped, violaceous papules and plaques. Nail dystrophy, as seen in this patient’s thumbnail, may also be a feature. (Courtesy of Robert Swerlick, MD; with permission.)
ERYSIPELAS AND CELLULITIS See Chap. 156. DERMATOPHYTOSIS Dermatophytes are fungi that infect skin, hair, and nails and include members of the genera Trichophyton, Microsporum, and Epidermophyton (Chap. 243). Tinea corporis, or infection of the relatively hairless skin of the body (glabrous skin), may have a variable appearance depending on the extent of the associated inflammatory reaction. Typical infections consist of erythematous, scaly plaques, with an annular appearance that accounts for the common name “ringworm.” Deep inflammatory nodules or granulomas occur in
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Table 71-5 Common Skin Infections Clinical Features Honey-colored crusted papules, plaques, or bullae
Impetigo Dermatophytosis
Candidiasis
Tinea versicolor
PART 2
Inflammatory or noninflammatory annular scaly plaques; may involve hair loss; groin involvement spares scrotum; hyphae on KOH preparation Inflammatory papules and plaques with satellite pustules, frequently in intertriginous areas; may involve scrotum; pseudohyphae on KOH preparation Hyper- or hypopigmented scaly patches on trunk; characteristic mixture of hyphae and spores (“spaghetti and meatballs”) on KOH preparation
Etiologic Agent Group A Streptococcus and Staphylococcus aureus Trichophyton, Epidermophyton, or Microsporum spp.
Treatment Systemic or topical antistaphylococcal and antistreptoccal antibiotics Topical azoles, systemic griseofulvin, terbinafine, or azoles
Candida albicans and other Candida spp.
Topical nystatin or azoles; systemic azoles for resistant disease
Malassezia furfur
Topical selenium sulfide lotion or azoles
Cardinal Manifestations and Presentation of Diseases
some infections, most often those inappropriately treated with mid- to high-potency topical glucocorticoids. Involvement of the groin (tinea cruris) is more common in males than in females. It presents as a scaling, erythematous eruption sparing the scrotum. Infection of the foot (tinea pedis) is the most common dermatophyte infection and is often chronic; it is characterized by variable erythema, edema, scaling, pruritus, and occasionally vesiculation. The infection may be widespread or localized but generally involves the web space between the fourth and fifth toes. Infection of the nails (tinea unguium or onychomycosis) occurs in many patients with tinea pedis and is characterized by opacified, thickened nails and subungual debris. The distal-lateral variant is most common. Proximal subungual onychomycosis may be a marker for HIV infection or other immunocompromised states. Dermatophyte infection of the scalp (tinea capitis) continues to be common, particularly affecting inner-city children but also affecting adults. The predominant organism is Trichophyton tonsurans, which can produce a relatively noninflammatory infection with mild scale and hair loss that is diffuse or localized. T. tonsurans can also cause a markedly inflammatory dermatosis with edema and nodules. This latter presentation is a kerion. The diagnosis of tinea can be made from skin scrapings, nail scrapings, or hair by culture or direct microscopic examination with potassium hydroxide (KOH). Nail clippings may be sent for histologic examination with periodic acid–Schiff (PAS) stain. TREATMENT
Dermatophytosis
Both topical and systemic therapies may be used in dermatophyte infections. Treatment depends on the site involved and the type of infection. Topical therapy is generally effective for uncomplicated tinea corporis, tinea cruris, and limited tinea pedis. Topical agents are not effective as monotherapy for tinea capitis or onychomycosis (see below). Topical imidazoles, triazoles, and allylamines may be effective therapies for dermatophyte infections, but nystatin is not active against dermatophytes. Topicals are generally applied twice daily, and treatment should continue for 1 week beyond clinical resolution of the infection. Tinea pedis often requires longer treatment courses and frequently relapses. Oral antifungal agents may be required for recalcitrant tinea pedis or tinea corporis. Oral antifungal agents are required for dermatophyte infections involving the hair and nails and for other infections unresponsive to topical therapy. A fungal etiology should be confirmed by direct microscopic examination or by culture before oral antifungal agents are prescribed. All of the oral agents may cause hepatotoxicity. They should not be used in women who are pregnant or breast-feeding. Griseofulvin is approved in the United States for dermatophyte infections involving the skin, hair, or nails. When griseofulvin is used, a daily dose of 500 mg microsized or 375 mg ultramicrosized, administered with a fatty meal, is adequate for most dermatophyte infections. Higher doses are required for some cases of tinea pedis and tinea capitis. Markedly inflammatory tinea capitis may result in scarring and hair loss, and systemic or topical glucocorticoids may be helpful in preventing these sequelae. The duration of griseofulvin
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therapy may be 2 weeks for uncomplicated tinea corporis, 8–12 weeks for tinea capitis, or as long as 6–18 months for nail infections. Due to high relapse rates, griseofulvin is seldom used for nail infections. Common side effects of griseofulvin include gastrointestinal distress, headache, and urticaria. Oral itraconazole is approved for onychomycosis. Itraconazole is given with food as either continuous daily therapy (200 mg/d) or pulses (200 mg bid for 1 week per month). Fingernails require 2 months of continuous therapy or two pulses. Toenails require 3 months of continuous therapy or three pulses. Itraconazole has the potential for serious interactions with other drugs requiring the P450 enzyme system for metabolism. Itraconazole should not be administered to patients with evidence of ventricular dysfunction or patients with known CHF. Terbinafine (250 mg/d) is also effective for onychomycosis, and the granule version is approved for treatment of tinea capitis. Therapy with terbinafine is continued for 6 weeks for fingernail and scalp infections and 12 weeks for toenail infections. Terbinafine has fewer interactions with other drugs than itraconazole, but caution should be used with patients who are on multiple medications. The risk/benefit ratio should be considered when an asymptomatic toenail infection is treated with systemic agents.
TINEA VERSICOLOR Tinea versicolor is caused by a nondermatophytic, dimorphic fungus, Malassezia furfur, a normal inhabitant of the skin. The expression of infection is promoted by heat and humidity. The typical lesions consist of oval scaly macules, papules, and patches concentrated on the chest, shoulders, and back but only rarely on the face or distal extremities. On dark skin the lesions often appear as hypopigmented areas, while on light skin they are slightly erythematous or hyperpigmented. A KOH preparation from scaling lesions will demonstrate a confluence of short hyphae and round spores (“spaghetti and meatballs”). Lotions or shampoos containing sulfur, salicylic acid, or selenium sulfide will clear the infection if used daily for 1–2 weeks and then weekly thereafter. These preparations are irritating if left on the skin for >10 min; thus, they should be washed off completely. Treatment with some oral antifungal agents is also effective, but they do not provide lasting results and are not FDA approved for this indication. A very short course of ketoconazole has been used, as have itraconazole and fluconazole. The patient must sweat after taking the medication if it is to be effective. Griseofulvin is not effective and terbinafine is not reliably effective for tinea versicolor. CANDIDIASIS Candidiasis is a fungal infection caused by a related group of yeasts whose manifestations may be localized to the skin and mucous membranes or, rarely, may be systemic and life-threatening (Chap. 240). The causative organism is usually Candida albicans. These organisms are normal saprophytic inhabitants of the gastrointestinal tract but may overgrow due to broad-spectrum antibiotic therapy, diabetes mellitus, or immunosuppression and cause disease. Candidiasis is a
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TREATMENT
Candidiasis
WARTS Warts are cutaneous neoplasms caused by papillomaviruses. More than 100 different human papillomaviruses (HPVs) have been described. A typical wart, verruca vulgaris, is sessile, dome-shaped, and usually about a centimeter in diameter. Its surface is hyperkeratotic, consisting of many small filamentous projections. The HPV types that cause typical verruca vulgaris also cause typical plantar warts, flat warts (verruca plana), and filiform warts. Plantar warts are endophytic and are covered by thick keratin. Paring of the wart will generally reveal a central core of keratinized debris and punctate bleeding points. Filiform warts are most commonly seen on the face, neck, and skinfolds and present as papillomatous lesions on a narrow base. Flat warts are only slightly elevated and have a velvety, nonverrucous surface. They have a propensity for the face, arms, and legs and are often spread by shaving. Genital warts begin as small papillomas that may grow to form large, fungating lesions. In women, they may involve the labia, perineum, or perianal skin. In addition, the mucosa of the vagina, urethra, and anus can be involved as well as the cervical epithelium. In men, the lesions often occur initially in the coronal sulcus but may be seen on the shaft of the penis, the scrotum, or the perianal skin or in the urethra. Appreciable evidence has accumulated indicating that HPV plays a role in the development of neoplasia of the uterine cervix and anogenital skin (Chap. 117). HPV types 16 and 18 have been most intensely studied and are the major risk factors for intraepithelial neoplasia and squamous cell carcinoma of the cervix, anus, vulva, and penis. The risk is higher among patients immunosuppressed after solid organ transplantation and among those infected with HIV. Recent evidence also implicates other HPV types. Histologic examination of biopsied samples from affected sites may reveal changes associated with typical warts and/or features typical of intraepidermal carcinoma (Bowen’s disease). Squamous cell carcinomas associated with HPV infections have also been observed in extragenital skin (Chap. 105), most commonly in patients immunosuppressed after organ transplantation. Patients on long-term immunosuppression should be monitored for the development of squamous cell carcinoma and other cutaneous malignancies.
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Warts
Treatment of warts, other than anogenital warts, should be tempered by the observation that a majority of warts in normal individuals resolve spontaneously within 1–2 years. There are many modalities available to treat warts, but no single therapy is universally effective. Factors that influence the choice of therapy include the location of the wart, the extent of disease, the age and immunologic status of the patient, and the patient’s desire for therapy. Perhaps the most useful and convenient method for treating warts in almost any location is cryotherapy with liquid nitrogen. Equally effective for nongenital warts, but requiring much more patient compliance, is the use of keratolytic agents such as salicylic acid plasters or solutions. For genital warts, in-office application of a podophyllin solution is moderately effective but may be associated with marked local reactions. Prescription preparations of dilute, purified podophyllin are available for home use. Topical imiquimod, a potent inducer of local cytokine release, has been approved for treatment of genital warts. A new topical compound composed of green tea extracts (sinecatechins) is also available. Conventional and laser surgical procedures may be required for recalcitrant warts. Recurrence of warts appears to be common to all these modalities. A highly effective vaccine for selected types of HPV has been approved by the FDA, and its use appears to reduce the incidence of anogenital and cervical carcinoma. HERPES SIMPLEX See Chap. 216. HERPES ZOSTER See Chap. 217.
ACNE ACNE VULGARIS Acne vulgaris is a self-limited disorder primarily of teenagers and young adults, although perhaps 10–20% of adults may continue to experience some form of the disorder. The permissive factor for the expression of the disease in adolescence is the increase in sebum production by sebaceous glands after puberty. Small cysts, called comedones, form in hair follicles due to blockage of the follicular orifice by retention of keratinous material and sebum. The activity of bacteria (Propionibacterium acnes) within the comedones releases free fatty acids from sebum, causes inflammation within the cyst, and results in rupture of the cyst wall. An inflammatory foreign-body reaction develops as result of extrusion of oily and keratinous debris from the cyst. The clinical hallmark of acne vulgaris is the comedone, which may be closed (whitehead) or open (blackhead). Closed comedones appear as 1- to 2-mm pebbly white papules, which are accentuated when the skin is stretched. They are the precursors of inflammatory lesions of acne vulgaris. The contents of closed comedones are not easily expressed. Open comedones, which rarely result in inflammatory acne lesions, have a large dilated follicular orifice and are filled with easily expressible oxidized, darkened, oily debris. Comedones are usually accompanied by inflammatory lesions: papules, pustules, or nodules. The earliest lesions seen in adolescence are generally mildly inflamed or noninflammatory comedones on the forehead. Subsequently, more typical inflammatory lesions develop on the cheeks, nose, and chin (Fig. 71-7). The most common location for acne is the face, but involvement of the chest and back is common. Most disease remains mild and does not lead to scarring. A small number of patients develop large inflammatory cysts and nodules, which may drain and result in significant scarring. Regardless of the severity, acne may affect a patient’s quality of life. With adequate treatment, this effect may be transient. In the case of severe, scarring acne, the effects can be permanent and profound. Early therapeutic intervention in severe acne is essential. Exogenous and endogenous factors can alter the expression of acne vulgaris. Friction and trauma (from headbands or chin straps of athletic helmets), application of comedogenic topical agents (cosmetics
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Treatment involves removal of any predisposing factors such as antibiotic therapy or chronic wetness and the use of appropriate topical or systemic antifungal agents. Effective topicals include nystatin or azoles (miconazole, clotrimazole, econazole, or ketoconazole). The associated inflammatory response accompanying candidal infection on glabrous skin can be treated with a mild glucocorticoid lotion or cream (2.5% hydrocortisone). Systemic therapy is usually reserved for immunosuppressed patients or individuals with chronic or recurrent disease who fail to respond to appropriate topical therapy. Oral agents approved for the treatment of candidiasis include itraconazole and fluconazole. Oral nystatin is effective only for candidiasis of the gastrointestinal tract. Griseofulvin and terbinafine are not effective.
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very common infection in HIV-infected individuals (Chap. 226). The oral cavity is commonly involved. Lesions may occur on the tongue or buccal mucosa (thrush) and appear as white plaques. Fissured, macerated lesions at the corners of the mouth (perléche) are often seen in individuals with poorly fitting dentures and may also be associated with candidal infection. In addition, candidal infections have an affinity for sites that are chronically wet and macerated, including the skin around nails (onycholysis and paronychia), and in intertriginous areas. Intertriginous lesions are characteristically edematous, erythematous, and scaly, with scattered “satellite pustules.” In males, there is often involvement of the penis and scrotum as well as the inner aspect of the thighs. In contrast to dermatophyte infections, candidal infections are frequently painful and accompanied by a marked inflammatory response. Diagnosis of candidal infection is based upon the clinical pattern and demonstration of yeast on KOH preparation or culture.
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Figure 71-7 Acne vulgaris. An example of acne vulgaris with inflammatory papules, pustules, and comedones. (Courtesy of Kalman Watsky, MD; with permission.)
Figure 71-8 Acne rosacea. Prominent facial erythema, telangiectasia, scattered papules, and small pustules are seen in this patient with acne rosacea. (Courtesy of Robert Swerlick, MD; with permission.)
or hair preparations), or chronic topical exposure to certain industrial compounds may elicit or aggravate acne. Glucocorticoids, topical or systemic, may also elicit acne. Other systemic medications such as oral contraceptive pills, lithium, isoniazid, androgenic steroids, halogens, phenytoin, and phenobarbital may produce acneiform eruptions or aggravate preexisting acne. Genetic factors and polycystic ovary disease may also play a role.
ACNE ROSACEA Acne rosacea, commonly referred to simply as rosacea, is an inflammatory disorder predominantly affecting the central face. Persons most often affected are Caucasians of northern European background, but rosacea also occurs in patients with dark skin. Rosacea is seen almost exclusively in adults, only rarely affecting patients 1.5 cm (see “Hyperpigmentation,” above), axillary freckling, and multiple Lisch
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nodules, are seen in von Recklinghausen’s disease (NF type I) (Chap. 118). In some patients, the neurofibromas are localized and unilateral due to somatic mosaicism. Angiofibromas are firm pink to skin-colored papules that measure from 3 mm to a few centimeters in diameter. When multiple lesions are located on the central cheeks (adenoma sebaceum), the patient has tuberous sclerosis or multiple endocrine neoplasia (MEN) syndrome, type 1. The former is an autosomal disorder due to mutations in two different genes, and the associated findings are discussed in the section on ash leaf spots as well as in Chap. 118. Neuromas (benign proliferations of nerve fibers) are also firm, skincolored papules. They are more commonly found at sites of amputation and as rudimentary supernumerary digits. However, when there are multiple neuromas on the eyelids, lips, distal tongue, and/or oral mucosa, the patient should be investigated for other signs of the MEN syndrome, type 2b. Associated findings include marfanoid habitus, protuberant lips, intestinal ganglioneuromas, and medullary thyroid carcinoma (>75% of patients; Chap. 408). Adnexal tumors are derived from pluripotent cells of the epidermis that can differentiate toward hair, sebaceous, apocrine, or eccrine glands or remain undifferentiated. Basal cell carcinomas (BCCs) are examples of adnexal tumors that have little or no evidence of differentiation. Clinically, they are translucent papules with rolled borders, telangiectasias, and central erosion. BCCs commonly arise in sundamaged skin of the head and neck as well as the upper trunk. When a
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YELLOW LESIONS Several systemic disorders are characterized by yellow-colored cutaneous papules or plaques—hyperlipidemia (xanthomas), gout (tophi), diabetes (necrobiosis lipoidica), pseudoxanthoma elasticum, and MuirTorre syndrome (sebaceous tumors). Eruptive xanthomas are the most common form of xanthomas and are associated with hypertriglyceridemia (primarily hyperlipoproteinemia types I, IV, and V). Crops of yellow papules with erythematous halos occur primarily on the extensor surfaces of the extremities and the buttocks, and they spontaneously involute with a fall in serum triglycerides. Types II and III result in one or more of the following types of xanthoma: xanthelasma, tendon xanthomas, and plane xanthomas. Xanthelasma are found on the eyelids, whereas tendon xanthomas are frequently associated with the Achilles and extensor finger tendons; plane xanthomas are flat and favor the palmar creases, neck, upper trunk, and flexural folds. Tuberous xanthomas are frequently associated with hypertriglyceridemia, but they
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PINK LESIONS The cutaneous lesions associated with primary systemic amyloidosis are often pink in color and translucent. Common locations are the face, especially the periorbital and perioral regions, and flexural areas. On biopsy, homogeneous deposits of amyloid are seen in the dermis and in the walls of blood vessels; the latter lead to an increase in vessel wall fragility. As a result, petechiae and purpura develop in clinically normal skin as well as in lesional skin following minor trauma, hence the term pinch purpura. Amyloid deposits are also seen in the striated muscle of the tongue and result in macroglossia. Even though specific mucocutaneous lesions are present in only ~30% of the patients with primary systemic (AL) amyloidosis, the diagnosis can be made via histologic examination of abdominal subcutaneous fat, in conjunction with a serum free light chain assay. By special staining, amyloid deposits are seen around blood vessels or individual fat cells in 40–50% of patients. There are also three forms of amyloidosis that are limited to the skin and that should not be construed as cutaneous lesions of systemic amyloidosis. They are macular amyloidosis (upper back), lichen amyloidosis (usually lower extremities), and nodular amyloidosis. In macular and lichen amyloidosis, the deposits are composed of altered epidermal keratin. Early-onset macular and lichen amyloidosis have been associated with MEN syndrome, type 2a. Patients with multicentric reticulohistiocytosis also have pinkcolored papules and nodules on the face and mucous membranes as well as on the extensor surface of the hands and forearms. They have a polyarthritis that can mimic rheumatoid arthritis clinically. On histologic examination, the papules have characteristic giant cells that are not seen in biopsies of rheumatoid nodules. Pink to skin-colored papules that are firm, 2–5 mm in diameter, and often in a linear arrangement are seen in patients with papular mucinosis. This disease is also referred to as generalized lichen myxedematosus or scleromyxedema. The latter name comes from the induration of the face and extremities that may accompany the papular eruption. Biopsy specimens of the papules show localized mucin deposition, and serum protein electrophoresis plus immunofixation electrophoresis demonstrates a monoclonal spike of IgG, usually with a λ light chain.
are also seen in patients with hypercholesterolemia and are found most frequently over the large joints or hand. Biopsy specimens of xanthomas show collections of lipid-containing macrophages (foam cells). Patients with several disorders, including biliary cirrhosis, can have a secondary form of hyperlipidemia with associated tuberous and plane xanthomas. However, patients with plasma cell dyscrasias have normolipemic plane xanthomas. This latter form of xanthoma may be ≥12 cm in diameter and is most frequently seen on the upper trunk or side of the neck. It is important to note that the most common setting for eruptive xanthomas is uncontrolled diabetes mellitus. The least specific sign for hyperlipidemia is xanthelasma, because at least 50% of the patients with this finding have normal lipid profiles. In tophaceous gout, there are deposits of monosodium urate in the skin around the joints, particularly those of the hands and feet. Additional sites of tophi formation include the helix of the ear and the olecranon and prepatellar bursae. The lesions are firm, yellow in color, and occasionally discharge a chalky material. Their size varies from 1 mm to 7 cm, and the diagnosis can be established by polarized light microscopy of the aspirated contents of a lesion. Lesions of necrobiosis lipoidica are found primarily on the shins (90%), and patients can have diabetes mellitus or develop it subsequently. Characteristic findings include a central yellow color, atrophy (transparency), telangiectasias, and a red to red-brown border. Ulcerations can also develop within the plaques. Biopsy specimens show necrobiosis of collagen and granulomatous inflammation. In pseudoxanthoma elasticum (PXE), due to mutations in the gene ABCC6, there is an abnormal deposition of calcium on the elastic fibers of the skin, eye, and blood vessels. In the skin, the flexural areas such as the neck, axillae, antecubital fossae, and inguinal area are the primary sites of involvement. Yellow papules coalesce to form reticulated plaques that have an appearance similar to that of plucked chicken skin. In severely affected skin, hanging, redundant folds develop. Biopsy specimens of involved skin show swollen and irregularly clumped elastic fibers with deposits of calcium. In the eye, the calcium deposits in Bruch’s membrane lead to angioid streaks and choroiditis; in the arteries of the heart, kidney, gastrointestinal tract, and extremities, the deposits lead to angina, hypertension, gastrointestinal bleeding, and claudication, respectively. Adnexal tumors that have differentiated toward sebaceous glands include sebaceous adenoma, sebaceous carcinoma, and sebaceous hyperplasia. Except for sebaceous hyperplasia, which is commonly seen on the face, these tumors are fairly rare. Patients with Muir-Torre syndrome have one or more sebaceous adenoma(s), and they can also have sebaceous carcinomas and sebaceous hyperplasia as well as keratoacanthomas. The internal manifestations of Muir-Torre syndrome include multiple carcinomas of the gastrointestinal tract (primarily colon) as well as cancers of the larynx, genitourinary tract, and breast.
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patient has multiple BCCs, especially prior to age 30, the possibility of the nevoid basal cell carcinoma syndrome should be raised. It is inherited as an autosomal dominant trait and is associated with jaw cysts, palmar and plantar pits, frontal bossing, medulloblastomas, and calcification of the falx cerebri and diaphragma sellae. Tricholemmomas are also skin-colored adnexal tumors but differentiate toward hair follicles and can have a wartlike appearance. The presence of multiple tricholemmomas on the face and cobblestoning of the oral mucosa points to the diagnosis of Cowden disease (multiple hamartoma syndrome) due to mutations in the phosphatase and tensin homolog (PTEN) gene. Internal organ involvement (in decreasing order of frequency) includes fibrocystic disease and carcinoma of the breast, adenomas and carcinomas of the thyroid, and gastrointestinal polyposis. Keratoses of the palms, soles, and dorsal aspect of the hands are also seen.
RED LESIONS Cutaneous lesions that are red in color have a wide variety of etiologies; in an attempt to simplify their identification, they will be subdivided into papules, papules/plaques, and subcutaneous nodules. Common red papules include arthropod bites and cherry hemangiomas; the latter are small, bright-red, dome-shaped papules that represent a benign proliferation of capillaries. In patients with AIDS (Chap. 226), the development of multiple red hemangioma-like lesions points to bacillary angiomatosis, and biopsy specimens show clusters of bacilli that stain positive with the Warthin-Starry stain; the pathogens have been identified as Bartonella henselae and Bartonella quintana. Disseminated visceral disease is seen primarily in immunocompromised hosts but can occur in immunocompetent individuals. Multiple angiokeratomas are seen in Fabry disease, an X-linked recessive lysosomal storage disease that is due to a deficiency of α-galactosidase A. The lesions are red to red-blue in color and can be quite small in size (1–3 mm), with the most common location being the lower trunk. Associated findings include chronic renal disease, peripheral neuropathy, and corneal opacities (cornea verticillata). Electron photomicrographs of angiokeratomas and clinically normal skin demonstrate lamellar lipid deposits in fibroblasts, pericytes, and endothelial
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cells that are diagnostic of this disease. Widespread acute eruptions of erythematous papules are discussed in the section on exanthems. There are several infectious diseases that present as erythematous papules or nodules in a lymphocutaneous or sporotrichoid pattern, i.e., in a linear arrangement along the lymphatic channels. The two most common etiologies are Sporothrix schenckii (sporotrichosis) and the atypical mycobacterium Mycobacterium marinum. The organisms are introduced as a result of trauma, and a primary inoculation site is often seen in addition to the lymphatic nodules. Additional causes include Nocardia, Leishmania, and other atypical mycobacteria and dimorphic fungi; culture of lesional tissue will aid in the diagnosis. The diseases that are characterized by erythematous plaques with scale are reviewed in the papulosquamous section, and the various forms of dermatitis are discussed in the section on erythroderma. Additional disorders in the differential diagnosis of red papules/ plaques include cellulitis, polymorphous light eruption (PMLE), cutaneous lymphoid hyperplasia (lymphocytoma cutis), cutaneous lupus, lymphoma cutis, and leukemia cutis. The first three diseases represent primary cutaneous disorders, although cellulitis may be accompanied by a bacteremia. PMLE is characterized by erythematous papules and plaques in a primarily sun-exposed distribution—dorsum of the hand, extensor forearm, and upper trunk. Lesions follow exposure to UV-B and/or UV-A, and in higher latitudes, PMLE is most severe in the late spring and early summer. A process referred to as “hardening” occurs with continued UV exposure, and the eruption fades, but in temperate climates, it will recur in the spring. PMLE must be differentiated from cutaneous lupus, and this is accomplished by observation of the natural history, histologic examination, and direct immunofluorescence of the lesions. Cutaneous lymphoid hyperplasia (pseudolymphoma) is a benign polyclonal proliferation of lymphocytes in the skin that pre sents as infiltrated pink-red to red-purple papules and plaques; it must be distinguished from lymphoma cutis. Several types of red plaques are seen in patients with systemic lupus, including (1) erythematous urticarial plaques across the cheeks and nose in the classic butterfly rash; (2) erythematous discoid lesions with fine or “carpet-tack” scale, telangiectasias, central hypopigmentation, peripheral hyperpigmentation, follicular plugging, and atrophy located on the face, scalp, external ears, arms, and upper trunk; and (3) psoriasiform or annular lesions of subacute cutaneous lupus with hypopigmented centers located primarily on the extensor arms and upper trunk. Additional mucocutaneous findings include (1) a violaceous flush on the face and V of the neck; (2) photosensitivity; (3) urticarial vasculitis (see “Urticaria,” above); (4) lupus panniculitis (see below); (5) diffuse alopecia; (6) alopecia secondary to discoid lesions; (7) periungual telangiectasias and erythema; (8) EM-like lesions that may become bullous; (9) oral ulcers; and (10) distal ulcerations secondary to Raynaud’s phenomenon, vasculitis, or livedoid vasculopathy. Patients with only discoid lesions usually have the form of lupus that is limited to the skin. However, up to 10% of these patients eventually develop systemic lupus. Direct immunofluorescence of involved skin, in particular discoid lesions, shows deposits of IgG or IgM and C3 in a granular distribution along the dermal-epidermal junction. In lymphoma cutis, there is a proliferation of malignant lymphocytes in the skin, and the clinical appearance resembles that of cutaneous lymphoid hyperplasia—infiltrated pink-red to red-purple papules and plaques. Lymphoma cutis can occur anywhere on the surface of the skin, whereas the sites of predilection for lymphocytomas include the malar ridge, tip of the nose, and earlobes. Patients with nonHodgkin’s lymphomas have specific cutaneous lesions more often than those with Hodgkin’s disease, and, occasionally, the skin nodules precede the development of extracutaneous non-Hodgkin’s lymphoma or represent the only site of involvement (e.g., primary cutaneous B cell lymphoma). Arcuate lesions are sometimes seen in lymphoma and lymphocytoma cutis as well as in CTCL. Adult T cell leukemia/ lymphoma that develops in association with HTLV-1 infection is characterized by cutaneous plaques, hypercalcemia, and circulating CD25+ lymphocytes. Leukemia cutis has the same appearance as lymphoma cutis, and specific lesions are seen more commonly in monocytic leukemias than in lymphocytic or granulocytic leukemias. Cutaneous
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chloromas (granulocytic sarcomas) may precede the appearance of circulating blasts in acute myelogenous leukemia and, as such, represent a form of aleukemic leukemia cutis. Sweet syndrome is characterized by pink-red to red-brown edematous plaques that are frequently painful and occur primarily on the head, neck, and upper (and, less often, lower) extremities. The patients also have fever, neutrophilia, and a dense dermal infiltrate of neutrophils in the lesions. In ~10% of the patients, there is an associated malignancy, most commonly acute myelogenous leukemia. Sweet syndrome has also been reported with inflammatory bowel disease, systemic lupus erythematosus, and solid tumors (primarily of the genitourinary tract) as well as drugs (e.g., all-trans-retinoic acid, granulocyte colony-stimulating factor [G-CSF]). The differential diagnosis includes neutrophilic eccrine hidradenitis; bullous forms of pyoderma gangrenosum; and, occasionally, cellulitis. Extracutaneous sites of involvement include joints, muscles, eye, kidney (proteinuria, occasionally glomerulonephritis), and lung (neutrophilic infiltrates). The idiopathic form of Sweet syndrome is seen more often in women, following a respiratory tract infection. Common causes of erythematous subcutaneous nodules include inflamed epidermoid inclusion cysts, acne cysts, and furuncles. Panniculitis, an inflammation of the fat, also presents as subcutaneous nodules and is frequently a sign of systemic disease. There are several forms of panniculitis, including erythema nodosum, erythema induratum/nodular vasculitis, lupus panniculitis, lipodermatosclerosis, α1-antitrypsin deficiency, factitial, and fat necrosis secondary to pancreatic disease. Except for erythema nodosum, these lesions may break down and ulcerate or heal with a scar. The shin is the most common location for the nodules of erythema nodosum, whereas the calf is the most common location for lesions of erythema induratum. In erythema nodosum, the nodules are initially red but then develop a blue color as they resolve. Patients with erythema nodosum but no underlying systemic illness can still have fever, malaise, leukocytosis, arthralgias, and/or arthritis. However, the possibility of an underlying illness should be excluded, and the most common associations are streptococcal infections, upper respiratory viral infections, sarcoidosis, and inflammatory bowel disease, in addition to drugs (oral contraceptives, sulfonamides, penicillins, bromides, iodides). Less common associations include bacterial gastroenteritis (Yersinia, Salmonella) and coccidioidomycosis followed by tuberculosis, histoplasmosis, brucellosis, and infections with Chlamydophila pneumoniae or Chlamydia trachomatis, Mycoplasma pneumoniae, or hepatitis B virus. Erythema induratum and nodular vasculitis have overlapping features clinically and histologically, and whether they represent two separate entities or the ends of a single disease spectrum is a point of debate; in general, the latter is usually idiopathic and the former is associated with the presence of Mycobacterium tuberculosis DNA by PCR within skin lesions. The lesions of lupus panniculitis are found primarily on the cheeks, upper arms, and buttocks (sites of abundant fat) and are seen in both the cutaneous and systemic forms of lupus. The overlying skin may be normal, erythematous, or have the changes of discoid lupus. The subcutaneous fat necrosis that is associated with pancreatic disease is presumably secondary to circulating lipases and is seen in patients with pancreatic carcinoma as well as in patients with acute and chronic pancreatitis. In this disorder, there may be an associated arthritis, fever, and inflammation of visceral fat. Histologic examination of deep incisional biopsy specimens will aid in the diagnosis of the particular type of panniculitis. Subcutaneous erythematous nodules are also seen in cutaneous polyarteritis nodosa and as a manifestation of systemic vasculitis when there is involvement of medium-sized vessels, e.g., systemic polyarteritis nodosa, allergic granulomatosis, or granulomatosis with polyangiitis (Wegener’s) (Chap. 385). Cutaneous polyarteritis nodosa presents with painful subcutaneous nodules and ulcers within a red-purple, netlike pattern of livedo reticularis. The latter is due to slowed blood flow through the superficial horizontal venous plexus. The majority of lesions are found on the lower extremities, and while arthralgias and myalgias may accompany cutaneous polyarteritis nodosa, there is no evidence of systemic involvement. In both the cutaneous and systemic
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forms of vasculitis, skin biopsy specimens of the associated nodules will show the changes characteristic of a necrotizing vasculitis and/or granulomatous inflammation.
VIOLACEOUS LESIONS Violaceous papules and plaques are seen in lupus pernio, lymphoma cutis, and cutaneous lupus. Lupus pernio is a particular type of sarcoidosis that involves the tip and alar rim of the nose as well as the earlobes,
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BROWN AND BLACK LESIONS Brown- and black-colored papules are reviewed in “Hyperpigmentation,” above. CUTANEOUS METASTASES These are discussed last because they can have a wide range of colors. Most commonly, they present as either firm, skin-colored subcutaneous nodules or firm, red to red-brown papulonodules. The lesions of lymphoma cutis range from pink-red to plum in color, whereas metastatic melanoma can be pink, blue, or black in color. Cutaneous metastases develop from hematogenous or lymphatic spread and are most often due to the following primary carcinomas: in men, melanoma, oropharynx, lung, and colon; and in women, breast, melanoma, and ovary. These metastatic lesions may be the initial presentation of the carcinoma, especially when the primary site is the lung.
Skin Manifestations of Internal Disease
BLUE LESIONS Lesions that are blue in color are the result of vascular ectasias, hyperplasias and tumors or melanin pigment within the dermis. Venous lakes (ectasias) are compressible dark-blue lesions that are found commonly in the head and neck region. Venous malformations are also compressible blue papulonodules and plaques that can occur anywhere on the body, including the oral mucosa. When there are multiple rather than single congenital lesions, the patient may have the blue rubber bleb syndrome or Maffucci’s syndrome. Patients with the blue rubber bleb syndrome also have vascular anomalies of the gastrointestinal tract that may bleed, whereas patients with Maffucci’s syndrome have associated osteochondromas. Blue nevi (moles) are seen when there are collections of pigment-producing nevus cells in the dermis. These benign papular lesions are dome-shaped and occur most commonly on the dorsum of the hand or foot or in the head and neck region.
PURPLE LESIONS Purple-colored papules and plaques are seen in vascular tumors, such as Kaposi’s sarcoma (Chap. 226) and angiosarcoma, and when there is extravasation of red blood cells into the skin in association with inflammation, as in palpable purpura (see “Purpura,” below). Patients with congenital or acquired AV fistulas and venous hypertension can develop purple papules on the lower extremities that can resemble Kaposi’s sarcoma clinically and histologically; this condition is referred to as pseudo-Kaposi’s sarcoma (acral angiodermatitis). Angiosarcoma is found most commonly on the scalp and face of elderly patients or within areas of chronic lymphedema and presents as purple papules and plaques. In the head and neck region, the tumor often extends beyond the clinically defined borders and may be accompanied by facial edema.
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RED-BROWN LESIONS The cutaneous lesions in sarcoidosis (Chap. 390) are classically red to red-brown in color, and with diascopy (pressure with a glass slide), a yellow-brown residual color is observed that is secondary to the granulomatous infiltrate. The waxy papules and plaques may be found anywhere on the skin, but the face is the most common location. Usually there are no surface changes, but occasionally the lesions will have scale. Biopsy specimens of the papules show “naked” granulomas in the dermis, i.e., granulomas surrounded by a minimal number of lymphocytes. Other cutaneous findings in sarcoidosis include annular lesions with an atrophic or scaly center, papules within scars, hypopigmented papules and patches, alopecia, acquired ichthyosis, erythema nodosum, and lupus pernio (see below). The differential diagnosis of sarcoidosis includes foreign-body granulomas produced by chemicals such as beryllium and zirconium, late secondary syphilis, and lupus vulgaris. Lupus vulgaris is a form of cutaneous tuberculosis that is seen in previously infected and sensitized individuals. There is often underlying active tuberculosis elsewhere, usually in the lungs or lymph nodes. Lesions occur primarily in the head and neck region and are red-brown plaques with a yellowbrown color on diascopy. Secondary scarring and squamous cell carcinomas can develop within the plaques. Cultures or PCR analysis of the lesions should be performed, along with an interferon γ release assay of peripheral blood, because it is rare for the acid-fast stain to show bacilli within the dermal granulomas. A generalized distribution of red-brown macules and papules is seen in the form of mastocytosis known as urticaria pigmentosa (Chap. 376). Each lesion represents a collection of mast cells in the dermis, with hyperpigmentation of the overlying epidermis. Stimuli such as rubbing cause these mast cells to degranulate, and this leads to the formation of localized urticaria (Darier’s sign). Additional symptoms can result from mast cell degranulation and include headache, flushing, diarrhea, and pruritus. Mast cells also infiltrate various organs such as the liver, spleen, and gastrointestinal tract, and accumulations of mast cells in the bones may produce either osteosclerotic or osteolytic lesions on radiographs. In the majority of these patients, however, the internal involvement remains indolent. A subtype of chronic cutaneous small-vessel vasculitis, erythema elevatum diutinum (EED), also presents with papules that are red-brown in color. The papules coalesce into plaques on the extensor surfaces of knees, elbows, and the small joints of the hand. Flares of EED have been associated with streptococcal infections.
with lesions that are violaceous in color rather than red-brown. This form of sarcoidosis is associated with involvement of the upper respiratory tract. The plaques of lymphoma cutis and cutaneous lupus may be red or violaceous in color and were discussed above.
PURPURA (Table 72-16) Purpura are seen when there is an extravasation of red blood cells into the dermis and, as a result, the lesions do not blanch with pressure. This is in contrast to those erythematous or violetcolored lesions that are due to localized vasodilatation—they do blanch with pressure. Purpura (≥3 mm) and petechiae (≤2 mm) are divided into two major groups: palpable and nonpalpable. The most frequent causes of nonpalpable petechiae and purpura are primary cutaneous disorders such as trauma, solar (actinic) purpura, and capillaritis. Less common causes are steroid purpura and livedoid vasculopathy (see “Ulcers,” below). Solar purpura are seen primarily on the extensor forearms, whereas steroid purpura secondary to potent topical glucocorticoids or endogenous or exogenous Cushing’s syndrome can be more widespread. In both cases, there is alteration of the supporting connective tissue that surrounds the dermal blood vessels. In contrast, the petechiae that result from capillaritis are found primarily on the lower extremities. In capillaritis, there is an extravasation of erythrocytes as a result of perivascular lymphocytic inflammation. The petechiae are bright red, 1–2 mm in size, and scattered within yellowbrown patches. The yellow-brown color is caused by hemosiderin deposits within the dermis. Systemic causes of nonpalpable purpura fall into several categories, and those secondary to clotting disturbances and vascular fragility will be discussed first. The former group includes thrombocytopenia (Chap. 140), abnormal platelet function as is seen in uremia, and clotting factor defects. The initial site of presentation for thrombocytopenia-induced petechiae is the distal lower extremity. Capillary fragility leads to nonpalpable purpura in patients with systemic amyloidosis (see “Papulonodular Skin Lesions,” above), disorders of collagen production such as Ehlers-Danlos syndrome, and scurvy. In scurvy, there are flattened corkscrew hairs with surrounding hemorrhage on the lower extremities, in addition to gingivitis. Vitamin C is a cofactor for lysyl hydroxylase, an enzyme involved in the posttranslational modification of procollagen that is necessary for cross-link formation.
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Table 72-16 Causes of Purpura
PART 2
I. Primary cutaneous disorders A. Nonpalpable 1. Trauma 2. Solar (actinic, senile) purpura 3. Steroid purpura 4. Capillaritis 5. Livedoid vasculopathy in the setting of venous hypertensiona II. Systemic diseases A. Nonpalpable 1. Clotting disturbances a. Thrombocytopenia (including ITP) b. Abnormal platelet function c. Clotting factor defects 2. Vascular fragility a. Amyloidosis (within normal-appearing skin) b. Ehlers-Danlos syndrome c. Scurvy 3. Thrombi a. Disseminated intravascular coagulation b. Warfarin (Coumadin)-induced necrosis c. Heparin-induced thrombocytopenia and thrombosis d. Antiphospholipid antibody syndrome e. Monoclonal cryoglobulinemia f. Vasculopathy induced by levamisole-adulterated cocaine g. Thrombotic thrombocytopenic purpura h. Thrombocytosis i Homozygous protein C or protein S deficiency 4. Emboli a. Cholesterol b. Fat 5. Possible immune complex a. Gardner-Diamond syndrome (autoerythrocyte sensitivity) b. Waldenström's hypergammaglobulinemic purpura B. Palpable 1. Vasculitis a. Cutaneous small-vessel vasculitis, including in the setting of systemic vasculitides b. Polyarteritis nodosa 2. Embolib a. Acute meningococcemia b. Disseminated gonococcal infection c. Rocky Mountain spotted fever d. Ecthyma gangrenosum
Cardinal Manifestations and Presentation of Diseases
Also associated with underlying disorders that lead to hypercoagulability, e.g., factor V Leiden, protein C dysfunction/deficiency. bBacterial (including rickettsial), fungal, or parasitic. a
Abbreviation: ITP, idiopathic thrombocytopenic purpura.
In contrast to the previous group of disorders, the purpura (noninflammatory with a retiform outline) seen in the following group of diseases are associated with thrombi formation within vessels. It is important to note that these thrombi are demonstrable in skin biopsy specimens. This group of disorders includes disseminated intravascular coagulation (DIC), monoclonal cryoglobulinemia, thrombocytosis, thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, and reactions to warfarin and heparin (heparin-induced thrombocytopenia and thrombosis). DIC is triggered by several types of infection (gramnegative, gram-positive, viral, and rickettsial) as well as by tissue injury and neoplasms. Widespread purpura and hemorrhagic infarcts of the distal extremities are seen. Similar lesions are found in purpura fulminans, which is a form of DIC associated with fever and hypotension that
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occurs more commonly in children following an infectious illness such as varicella, scarlet fever, or an upper respiratory tract infection. In both disorders, hemorrhagic bullae can develop in involved skin. Monoclonal cryoglobulinemia is associated with plasma cell dyscrasias, chronic lymphocytic leukemia, and lymphoma. Purpura, primarily of the lower extremities, and hemorrhagic infarcts of the fingers, toes, and ears are seen in these patients. Exacerbations of disease activity can follow cold exposure or an increase in serum viscosity. Biopsy specimens show precipitates of the cryoglobulin within dermal vessels. Similar deposits have been found in the lung, brain, and renal glomeruli. Patients with thrombotic thrombocytopenic purpura can also have hemorrhagic infarcts as a result of intravascular thromboses. Additional signs include microangiopathic hemolytic anemia and fluctuating neurologic abnormalities, especially headaches and confusion. Administration of warfarin can result in painful areas of erythema that become purpuric and then necrotic with an adherent black eschar; the condition is referred to as warfarin-induced necrosis. This reaction is seen more often in women and in areas with abundant subcutaneous fat—breasts, abdomen, buttocks, thighs, and calves. The erythema and purpura develop between the third and tenth day of therapy, most likely as a result of a transient imbalance in the levels of anticoagulant and procoagulant vitamin K–dependent factors. Continued therapy does not exacerbate preexisting lesions, and patients with an inherited or acquired deficiency of protein C are at increased risk for this particular reaction as well as for purpura fulminans and calciphylaxis. Purpura secondary to cholesterol emboli are usually seen on the lower extremities of patients with atherosclerotic vascular disease. They often follow anticoagulant therapy or an invasive vascular procedure such as an arteriogram but also occur spontaneously from disintegration of atheromatous plaques. Associated findings include livedo reticularis, gangrene, cyanosis, and ischemic ulcerations. Multiple step sections of the biopsy specimen may be necessary to demonstrate the cholesterol clefts within the vessels. Petechiae are also an important sign of fat embolism and occur primarily on the upper body 2–3 days after a major injury. By using special fixatives, the emboli can be demonstrated in biopsy specimens of the petechiae. Emboli of tumor or thrombus are seen in patients with atrial myxomas and marantic endocarditis. In the Gardner-Diamond syndrome (autoerythrocyte sensitivity), female patients develop large ecchymoses within areas of painful, warm erythema. Intradermal injections of autologous erythrocytes or phosphatidyl serine derived from the red cell membrane can reproduce the lesions in some patients; however, there are instances where a reaction is seen at an injection site of the forearm but not in the midback region. The latter has led some observers to view GardnerDiamond syndrome as a cutaneous manifestation of severe emotional stress. More recently, the possibility of platelet dysfunction (as assessed via aggregation studies) has been raised. Waldenström’s hypergammaglobulinemic purpura is a chronic disorder characterized by petechiae on the lower extremities. There are circulating complexes of IgG–antiIgG molecules, and exacerbations are associated with prolonged standing or walking. Palpable purpura are further subdivided into vasculitic and embolic. In the group of vasculitic disorders, cutaneous small-vessel vasculitis, also known as leukocytoclastic vasculitis (LCV), is the one most commonly associated with palpable purpura (Chap. 385). Underlying etiologies include drugs (e.g., antibiotics), infections (e.g., hepatitis C virus), and autoimmune connective tissue diseases (e.g., rheumatoid arthritis, Sjögren’s syndrome, lupus). Henoch-Schönlein purpura (HSP) is a subtype of acute LCV that is seen more commonly in children and adolescents following an upper respiratory infection. The majority of lesions are found on the lower extremities and buttocks. Systemic manifestations include fever, arthralgias (primarily of the knees and ankles), abdominal pain, gastrointestinal bleeding, and nephritis. Direct immunofluorescence examination shows deposits of IgA within dermal blood vessel walls. Renal disease is of particular concern in adults with HSP. In polyarteritis nodosa, specific cutaneous lesions result from a vasculitis of arterial vessels (arteritis), or there
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Table 72-17 Causes of Mucocutaneous Ulcers
ULCERS The approach to the patient with a cutaneous ulcer is outlined in Table 72-17. Peripheral vascular diseases of the extremities are reviewed in Chap. 302, as is Raynaud’s phenomenon. Livedoid vasculopathy (livedoid vasculitis; atrophie blanche) represents a combination of a vasculopathy plus intravascular thrombosis. Purpuric lesions and livedo reticularis are found in association with painful ulcerations of the lower extremities. These ulcers are often slow to heal, but when they do, irregularly shaped white scars form. The majority of cases are secondary to venous hypertension, but possible underlying illnesses include cryofibrinogenemia and disorders of hypercoagulability, e.g., the antiphospholipid syndrome (Chaps. 142 and 379). In pyoderma gangrenosum, the border of untreated active ulcers has a characteristic appearance consisting of an undermined necrotic violaceous edge and a peripheral erythematous halo. The ulcers often begin as pustules that then expand rather rapidly to a size as large as 20 cm. Although these lesions are most commonly found on the lower extremities, they can arise anywhere on the surface of the body, including sites of trauma (pathergy). An estimated 30–50% of cases are idiopathic, and the most common associated disorders are ulcerative colitis and Crohn’s disease. Less commonly, pyoderma gangrenosum is associated with seropositive rheumatoid arthritis, acute and chronic myelogenous leukemia, hairy cell leukemia, myelofibrosis, or a monoclonal gammopathy, usually IgA. Because the histology of pyoderma gangrenosum may be nonspecific
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Skin Manifestations of Internal Disease
I. Primary cutaneous disorders A. Peripheral vascular disease (Chap. 302) 1. Venous 2. Arteriala B. Livedoid vasculopathy in the setting of venous hypertensionb C. Squamous cell carcinoma, e.g., within scars, basal cell carcinomas D. Infections, e.g., ecthyma caused by Streptococcus (Chap. 173) E. Physical, e.g., trauma, pressure F. Drugs, e.g., hydroxyurea II. Systemic diseases A. Lower legs 1. Small-vessel and medium-vessel vasculitisc 2. Hemoglobinopathies (Chap. 127) 3. Cryoglobulinemia,c cryofibrinogenemia 4. Cholesterol embolic 5. Necrobiosis lipoidicad 6. Antiphospholipid syndrome (Chap. 141) 7. Neuropathice (Chap. 417) 8. Panniculitis 9. Kaposi's sarcoma, acral angiodermatitis 10. Diffuse dermal angiomatosis B. Hands and feet 1. Raynaud's phenomenon (Chap. 302) 2. Buerger disease C. Generalized 1. Pyoderma gangrenosum, but most commonly legs 2. Calciphylaxis (Chap. 424) 3. Infections, e.g., dimorphic fungi, leishmaniasis 4. Lymphoma D. Face, especially perioral, and anogenital 1. Chronic herpes simplexf III. Mucosal A. Behçet's syndrome (Chap. 387) B. Erythema multiforme major, Stevens-Johnson syndrome, TEN C. Primary blistering disorders (Chap. 73) D. Lupus erythematosus, lichen planus E. Inflammatory bowel disease F. Acute HIV infection G. Reactive arthritis (formerly known as Reiter's syndrome)
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may be an associated LCV. Arteritis leads to an infarct of the skin, and this explains the irregular outline of the purpura (see below). Several types of infectious emboli can give rise to palpable purpura. These embolic lesions are usually irregular in outline as opposed to the lesions of LCV, which are circular in outline. The irregular outline is indicative of a cutaneous infarct, and the size corresponds to the area of skin that received its blood supply from that particular arteriole or artery. The palpable purpura in LCV are circular because the erythrocytes simply diffuse out evenly from the postcapillary venules as a result of inflammation. Infectious emboli are most commonly due to gram-negative cocci (meningococcus, gonococcus), gram-negative rods (Enterobacteriaceae), and gram-positive cocci (Staphylococcus). Additional causes include Rickettsia and, in immunocompromised patients, Aspergillus and other opportunistic fungi. The embolic lesions in acute meningococcemia are found primarily on the trunk, lower extremities, and sites of pressure, and a gunmetal-gray color often develops within them. Their size varies from a few millimeters to several centimeters, and the organisms can be cultured from the lesions. Associated findings include a preceding upper respiratory tract infection; fever; meningitis; DIC; and, in some patients, a deficiency of the terminal components of complement. In disseminated gonococcal infection (arthritis-dermatitis syndrome), a small number of inflammatory papules and vesicopustules, often with central purpura or hemorrhagic necrosis, are found on the distal extremities. Additional symptoms include arthralgias, tenosynovitis, and fever. To establish the diagnosis, a Gram stain of these lesions should be performed. Rocky Mountain spotted fever is a tick-borne disease that is caused by Rickettsia rickettsii. A several-day history of fever, chills, severe headache, and photophobia precedes the onset of the cutaneous eruption. The initial lesions are erythematous macules and papules on the wrists, ankles, palms, and soles. With time, the lesions spread centripetally and become purpuric. Lesions of ecthyma gangrenosum begin as edematous, erythematous papules or plaques and then develop central purpura and necrosis. Bullae formation also occurs in these lesions, and they are frequently found in the girdle region. The organism that is classically associated with ecthyma gangrenosum is Pseudomonas aeruginosa, but other gram-negative rods such as Klebsiella, Escherichia coli, and Serratia can produce similar lesions. In immunocompromised hosts, the list of potential pathogens is expanded to include Candida and other opportunistic fungi (e.g., Aspergillus, Fusarium).
Underlying atherosclerosis. bAlso associated with underlying disorders that lead to hypercoagulability, e.g., factor V Leiden, protein C dysfunction/deficiency, antiphospholipid antibodies. cReviewed in section on Purpura. dReviewed in section on Papulonodular Skin Lesions. eFavors plantar surface of the foot. fSign of immunosuppression. a
Abbreviation: TEN, toxic epidermal necrolysis.
(dermal infiltrate of neutrophils when in untreated state), the diagnosis requires clinicopathologic correlation, in particular, the exclusion of similar-appearing ulcers such as necrotizing vasculitis, Meleney’s ulcer (synergistic infection at a site of trauma or surgery), dimorphic fungi, cutaneous amebiasis, spider bites, and factitial. In the myeloproliferative disorders, the ulcers may be more superficial with a pustulobullous border, and these lesions provide a connection between classic pyoderma gangrenosum and acute febrile neutrophilic dermatosis (Sweet syndrome).
FEVER AND RASH The major considerations in a patient with a fever and a rash are inflammatory diseases versus infectious diseases. In the hospital setting, the most common scenario is a patient who has a drug rash plus a fever secondary to an underlying infection. However, it should be
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emphasized that a drug reaction can lead to both a cutaneous eruption and a fever (“drug fever”), especially in the setting of DRESS, AGEP, or serum sickness–like reaction. Additional inflammatory diseases that are often associated with a fever include pustular psoriasis, erythroderma, and Sweet syndrome. Lyme disease, secondary syphilis, and viral and bacterial exanthems (see “Exanthems,” above) are examples of infectious diseases that produce a rash and a fever. Lastly, it is important to determine whether or not the cutaneous lesions represent septic emboli (see “Purpura,” above). Such lesions usually have evidence of ischemia in the form of purpura, necrosis, or impending necrosis (gunmetal-gray color). In the patient with thrombocytopenia, however, purpura can be seen in inflammatory reactions such as morbilliform drug eruptions and infectious lesions.
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73
Immunologically Mediated Skin Diseases Kim B. Yancey, Thomas J. Lawley
A number of immunologically mediated skin diseases and immunologically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, histologic, and immunopathologic findings. Clinically, these disorders are characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, result in death (largely due to loss of epidermal barrier function and/or secondary infection). The major features of the more common immunologically mediated skin diseases are summarized in this chapter (Table 73-1), as are the autoimmune systemic disorders with cutaneous manifestations.
AUTOIMMUNE CUTANEOUS DISEASES PEMPHIGUS VULGARIS Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky’s sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominantly occurs in patients >40 years of age. PV typically begins on mucosal surfaces and often progresses to involve the skin. This disease is characterized by fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin (Fig. 73-1). The mouth, scalp, face, neck, axilla, groin, and trunk are typically involved. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present for some time at sites of healed lesions. Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epidermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane; hence, blister formation takes place within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosinophil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not in uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies to cell-surface autoantigens. Such circulating autoantibodies
Table 73-1 Immunologically Mediated Blistering Diseases Disease Pemphigus vulgaris
Clinical Manifestations Flaccid blisters, denuded skin, oromucosal lesions Pemphigus foliaceus Crusts and shallow erosions on scalp, central face, upper chest, and back Paraneoplastic Painful stomatitis with papulosquapemphigus mous or lichenoid eruptions that may progress to blisters Bullous pemphigoid Pemphigoid gestationis Dermatitis herpetiformis Linear IgA disease
Epidermolysis bullosa acquisita
Mucous membrane pemphigoid
Histology Acantholytic blister formed in suprabasal layer of epidermis Acantholytic blister formed in superficial layer of epidermis Acantholysis, keratinocyte necrosis, and vacuolar interface dermatitis
Immunopathology Cell surface deposits of IgG on keratinocytes Cell surface deposits of IgG on keratinocytes
Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ Large tense blisters on flexor Subepidermal blister with Linear band of IgG and/or C3 in surfaces and trunk eosinophil-rich infiltrate epidermal BMZ Pruritic, urticarial plaques rimmed Teardrop-shaped, subepider- Linear band of C3 in epidermal by vesicles and bullae on the trunk mal blisters in dermal papillae; BMZ and extremities eosinophil-rich infiltrate Extremely pruritic small papules and Subepidermal blister with Granular deposits of IgA in dermal vesicles on elbows, knees, buttocks, neutrophils in dermal papillae papillae and posterior neck Pruritic small papules on extensor Subepidermal blister with Linear band of IgA in epidermal surfaces; occasionally larger, neutrophil-rich infiltrate BMZ arciform blisters Blisters, erosions, scars, and milia Subepidermal blister that may Linear band of IgG and/or C3 in on sites exposed to trauma; wideor may not include a leukoepidermal BMZ spread, inflammatory, tense blisters cytic infiltrate may be seen initially Erosive and/or blistering lesions of Subepidermal blister that may Linear band of IgG, IgA, and/or C3 mucous membranes and possibly or may not include a leukoin epidermal BMZ the skin; scarring of some sites cytic infiltrate
Autoantigensa Dsg3 (plus Dsg1 in patients with skin involvement) Dsg1
Plakin protein family members and desmosomal cadherins (see text for details) BPAG1, BPAG2 BPAG2 (plus BPAG1 in some patients) Epidermal transglutaminase
BPAG2 (see text for specific details) Type VII collagen
BPAG2, laminin-332, or others
Autoantigens bound by these patients’ autoantibodies are defined as follows: Dsg1, desmoglein 1; Dsg3, desmoglein 3; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2.
a
Abbreviation: BMZ, basement membrane zone.
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can be demonstrated in 80–90% of PV patients by indirect immunofluorescence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies to desmogleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have IgG autoantibodies to Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies to both Dsg3 and Dsg1. Experimental studies have shown that autoantibodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity. Recent studies have shown that the anti-Dsg autoantibody profile in these patients’ sera as well as the tissue distribution of Dsg3 and Dsg1 determine the site of blister formation in patients with PV. Coexpression of Dsg3 and Dsg1 by epidermal cells protects against pathogenic IgG antibodies to either of these cadherins but not against pathogenic autoantibodies to both. PV can be life-threatening. Prior to the availability of glucocorticoids, mortality rates ranged from 60% to 90%; the current figure is ~5%. Common causes of morbidity and death are infection and
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Immunologically Mediated Skin Diseases
B
Figure 73-1 Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in multiple erosions and crusted plaques. B. Involvement of the oral mucosa, which is almost invariable, may present with erosions on the gingiva, buccal mucosa, palate, posterior pharynx, or tongue. (B, Courtesy of Robert Swerlick, MD; with permission.)
PEMPHIGUS FOLIACEUS Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usually just beneath the stratum corneum. Hence, PF is a more superficial blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely have intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. PF has immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demonstrates IgG on the surface of keratinocytes. Similarly, patients with PF have circulating IgG autoantibodies directed against the surface of keratinocytes. In PF, autoantibodies are directed against Dsg1, a 160kDa desmosomal cadherin. These autoantibodies can be quantitated by ELISA. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., expression in oral mucosa that is compensated by coexpression of Dsg3) are thought to account for the distribution of lesions in this disease. Endemic forms of PF are found in south-central rural Brazil, where the disease is known as fogo salvagem (FS), as well as in selected sites in Latin America and Tunisia. Endemic PF, like other forms of this disease, is mediated by IgG autoantibodies to Dsg1. Clusters of FS overlap with those of leishmaniasis, a disease transmitted by bites of the sand fly Lutzomyia longipalis. Recent studies have shown that sand-fly salivary antigens (specifically, the LJM11 salivary protein) are recognized by IgG autoantibodies from FS patients (as well as by monoclonal antibodies to Dsg1 derived from these patients). Moreover, mice immunized with LJM11 produce antibodies to Dsg1. Thus, these findings suggest that insect bites may deliver salivary antigens that initiate a cross-reactive humoral immune response, which may lead to FS in genetically susceptible individuals. Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, >30 cases of thymoma and/or myasthenia gravis have been reported in association with pemphigus, usually with PF. Patients may also develop pemphigus as a consequence of drug exposure; drug-induced pemphigus usually resembles PF rather than PV. Drugs containing a thiol group in their chemical structure (e.g., penicillamine, captopril, enalapril) are most commonly associated with drug-induced pemphigus. Nonthiol drugs linked to pemphigus include penicillins, cephalosporins, and piroxicam. It has
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complications of treatment with glucocorticoids. Bad prognostic factors include advanced age, widespread involvement, and the requirement for high doses of glucocorticoids (with or without other immunosuppressive agents) for control of disease. The course of PV in individual patients is variable and difficult to predict. Some patients experience remission, while others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids. Patients with moderate to severe PV are usually started on prednisone at 1 mg/kg per day. If new lesions continue to appear after 1–2 weeks of treatment, the dose may need to be increased and/or prednisone may need to be combined with other immunosuppressive agents such as azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), or cyclophosphamide (1–2 mg/kg per day). Patients with severe, treatment-resistant disease may derive benefit from plasmapheresis (six high-volume exchanges [i.e., 2–3 L per exchange] over ~2 weeks), IV immunoglobulin (IVIg) (2 g/kg over 3–5 days every 6–8 weeks), or rituximab (375 mg/m2 per week × 4, or 1000 mg on days 1 and 15). It is important to bring severe or progressive disease under control quickly in order to lessen the severity and/or duration of this disorder. Accordingly, some have suggested that rituximab and daily glucocorticoids should be used early in PV patients to avert the development of treatmentresistant disease.
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been suggested that thiol-containing and non-thiol-containing drugs induce pemphigus via biochemical and immunologic mechanisms, respectively—hence, the better prognosis upon drug withdrawal in cases of pemphigus induced by thiol-containing medications. Some cases of drug-induced pemphigus are durable and require treatment with systemic glucocorticoids and/or immunosuppressive agents. PF is generally a less severe disease than PV and carries a better prognosis. Localized disease can sometimes be treated with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids. Patients with severe, treatment-resistant disease may require more aggressive interventions, as described above for patients with PV.
PART 2 Cardinal Manifestations and Presentation of Diseases
PARANEOPLASTIC PEMPHIGUS Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically have painful mucosal erosive lesions in association with papulosquamous and/or lichenoid eruptions that often progress to blisters. Palm and sole involvement are common in these patients and raise the possibility that prior reports of neoplasiaassociated erythema multiforme actually may have represented unrecognized cases of PNP. Biopsies of lesional skin from these patients show varying combinations of acantholysis, keratinocyte necrosis, and vacuolar-interface dermatitis. Direct immunofluorescence microscopy of a patient’s skin shows deposits of IgG and complement on the surface of keratinocytes and (variably) similar immunoreactants in the epidermal basement membrane zone. Patients with PNP have IgG autoantibodies to cytoplasmic proteins that are members of the plakin family (e.g., desmoplakins I and II, bullous pemphigoid antigen [BPAG]1, envoplakin, periplakin, and plectin) and to cell-surface proteins that are members of the cadherin family (e.g., Dsg1 and Dsg3). Passive transfer studies have shown that autoantibodies from patients with PNP are pathogenic in animal models. The predominant neoplasms associated with PNP are non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tumors, Waldenström’s macroglobulinemia, and Castleman’s disease; the last-mentioned neoplasm is particularly common among children with PNP. Rare cases of seronegative PNP have been reported in patients with B cell malignancies previously treated with rituximab. In addition to severe skin lesions, many patients with PNP develop life-threatening bronchiolitis obliterans. PNP is generally resistant to conventional therapies (i.e., those used to treat PV); rarely, a patient’s disease may ameliorate or even remit following ablation or removal of underlying neoplasms. BULLOUS PEMPHIGOID Bullous pemphigoid (BP) is a polymorphic autoimmune subepidermal blistering disease usually seen in the elderly. Initial lesions may consist of urticarial plaques; most patients eventually display tense blisters on either normal-appearing or erythematous skin (Fig. 73-2). The lesions are usually distributed over the lower abdomen, groin, and flexor surface of the extremities; oral mucosal lesions are found in some patients. Pruritus may be nonexistent or severe. As lesions evolve, tense blisters tend to rupture and be replaced by erosions with or without surmounting crust. Nontraumatized blisters heal without scarring. The major histocompatibility complex class II allele HLA-DQβ1*0301 is prevalent in patients with BP. Despite isolated reports, several studies have shown that patients with BP do not have a higher incidence of malignancy than appropriately age- and gender-matched controls. Biopsies of early lesional skin demonstrate subepidermal blisters and histologic features that roughly correlate with the clinical character of the particular lesion under study. Lesions on normal-appearing skin generally contain a sparse perivascular leukocytic infiltrate with some eosinophils; conversely, biopsies of inflammatory lesions typically show an eosinophil-rich infiltrate at sites of vesicle formation and in perivascular areas. In addition to eosinophils, cell-rich lesions also contain mononuclear cells and neutrophils. It is not possible to distinguish BP from other subepidermal blistering diseases by routine histologic studies alone.
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Figure 73-2 Bullous pemphigoid with tense vesicles and bullae on erythematous, urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.) Direct immunofluorescence microscopy of normal-appearing perilesional skin from patients with BP shows linear deposits of IgG and/ or C3 in the epidermal basement membrane. The sera of ~70% of these patients contain circulating IgG autoantibodies that bind the epidermal basement membrane of normal human skin in indirect immunofluorescence microscopy. IgG from an even higher percentage of patients reacts with the epidermal side of 1 M NaCl split skin (an alternative immunofluorescence microscopy test substrate used to distinguish circulating IgG autoantibodies to the basement membrane in patients with BP from those in patients with similar, yet different, subepidermal blistering diseases; see below). In BP, circulating autoantibodies recognize 230- and 180-kDa hemidesmosome-associated proteins in basal keratinocytes (i.e., BPAG1 and BPAG2, respectively). Autoantibodies to BPAG2 are thought to deposit in situ, activate complement, produce dermal mast-cell degranulation, and generate granulocyte-rich infiltrates that cause tissue damage and blister formation. BP may persist for months to years, with exacerbations or remissions. Extensive involvement may result in widespread erosions and compromise cutaneous integrity; elderly and/or debilitated patients may die. The mainstay of treatment is systemic glucocorticoids. Local or minimal disease can sometimes be controlled with topical glucocorticoids alone; more extensive lesions generally respond to systemic glucocorticoids either alone or in combination with immunosuppressive agents. Patients usually respond to prednisone (0.75–1 mg/kg per day). In some instances, azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), or cyclophosphamide (1–2 mg/kg per day) are necessary adjuncts. PEMPHIGOID GESTATIONIS Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare, nonviral, subepidermal blistering disease of pregnancy and the puerperium. PG may begin during any trimester of pregnancy or present shortly after delivery. Lesions are usually distributed over the abdomen, trunk, and extremities; mucous membrane lesions are rare. Skin lesions in these patients may be quite polymorphic and consist of erythematous urticarial papules and plaques, vesiculopapules, and/or frank bullae. Lesions are almost always extremely pruritic. Severe exacerbations of PG frequently follow delivery, typically within 24–48 h. PG tends to recur in subsequent pregnancies, often beginning earlier during such gestations. Brief flare-ups of disease may occur with resumption of menses and may develop in patients later exposed to oral contraceptives. Occasionally, infants of affected mothers have transient skin lesions.
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LINEAR IgA DISEASE Linear IgA disease, once considered a variant form of DH, is actually a separate and distinct entity. Clinically, patients with linear IgA disease may resemble individuals with DH, BP, or other subepidermal blistering diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques that develop predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pruritus resembles that seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 haplotype or an associated enteropathy and therefore are not candidates for treatment with a gluten-free diet. Histologic alterations in early lesions may be virtually indistinguishable from those in DH. However, direct immunofluorescence microscopy of normal-appearing perilesional skin reveals a linear band of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease have circulating IgA basement membrane autoantibodies directed against neoepitopes in the proteolytically processed extracellular domain of BPAG2. These patients generally respond to treatment with dapsone (50–200 mg/d).
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DERMATITIS HERPETIFORMIS Dermatitis herpetiformis (DH) is an intensely pruritic, papulovesicular skin disease characterized by lesions symmetrically distributed over extensor surfaces (i.e., elbows, knees, buttocks, back, scalp, and posterior neck) (see Fig. 70-8). Primary lesions in this disorder consist of papules, papulovesicles, or urticarial plaques. Because pruritus is prominent, patients may present with excoriations and crusted papules but no observable primary lesions. Patients sometimes report that their pruritus has a distinctive burning or stinging component; the onset of such local symptoms reliably heralds the development of distinct clinical lesions 12–24 h later. Almost all DH patients have associated, usually subclinical, gluten-sensitive enteropathy (Chap. 349), and >90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH may present at any age, including in childhood; onset in the second to fourth decades is most common. The disease is typically chronic. Biopsy of early lesional skin reveals neutrophil-rich infiltrates within dermal papillae. Neutrophils, fibrin, edema, and microvesicle formation at these sites are characteristic of early disease. Older lesions may demonstrate nonspecific features of a subepidermal bulla or an excoriated papule. Because the clinical and histologic features of this disease can be variable and resemble those of other subepidermal blistering disorders, the diagnosis is confirmed by direct immunofluorescence microscopy of normal-appearing perilesional skin. Such studies demonstrate granular deposits of IgA (with or without complement components) in the papillary dermis and along the epidermal basement membrane zone. IgA deposits in the skin are unaffected by control of disease with medication; however, these immunoreactants diminish in intensity or disappear in patients maintained for long periods on a strict gluten-free diet (see below). Patients with DH have granular deposits of IgA in their epidermal basement membrane zone and should be distinguished from individuals with linear IgA deposits at this site (see below). Although most DH patients do not report overt gastrointestinal symptoms or have laboratory evidence of malabsorption, biopsies of the small bowel usually reveal blunting of intestinal villi and a lymphocytic infiltrate in the lamina propria. As is true for patients with celiac disease, this gastrointestinal abnormality can be reversed by a glutenfree diet. Moreover, if maintained, this diet alone may control the skin disease and eventuate in clearance of IgA deposits from these patients’ epidermal basement membrane zones. Subsequent gluten exposure in such patients alters the morphology of their small bowel, elicits a flareup of their skin disease, and is associated with the reappearance of IgA in their epidermal basement membrane zones. As in patients with
celiac disease, dietary gluten sensitivity in patients with DH is associated with IgA endomysial autoantibodies that target tissue transglutaminase. Studies indicate that patients with DH also have high-avidity IgA autoantibodies to epidermal transglutaminase 3 and that the latter is co-localized with granular deposits of IgA in the papillary dermis of DH patients. Patients with DH also have an increased incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, and autoantibodies to gastric parietal cells. These associations likely relate to the high frequency of the HLA-B8/DRw3 haplotype in these patients, because this marker is commonly linked to autoimmune disorders. The mainstay of treatment of DH is dapsone, a sulfone. Patients respond rapidly (24–48 h) to dapsone (50–200 mg/d), but require careful pretreatment evaluation and close follow-up to ensure that complications are avoided or controlled. All patients taking dapsone at >100 mg/d will have some hemolysis and methemoglobinemia, which are expected pharmacologic side effects of this agent. Gluten restriction can control DH and lessen dapsone requirements; this diet must rigidly exclude gluten to be of maximal benefit. Many months of dietary restriction may be necessary before a beneficial result is achieved. Good dietary counseling by a trained dietitian is essential.
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Biopsies of early lesional skin show teardrop-shaped subepidermal vesicles forming in dermal papillae in association with an eosinophilrich leukocytic infiltrate. Differentiation of PG from other subepidermal bullous diseases by light microscopy is difficult. However, direct immunofluorescence microscopy of perilesional skin from PG patients reveals the immunopathologic hallmark of this disorder: linear deposits of C3 in the epidermal basement membrane. These deposits develop as a consequence of complement activation produced by low-titer IgG anti–basement membrane autoantibodies directed against BPAG2, the same hemidesmosome-associated protein that is targeted by autoantibodies in patients with BP—a subepidermal bullous disease that resembles PG clinically, histologically, and immunopathologically. The goals of therapy in patients with PG are to prevent the development of new lesions, relieve intense pruritus, and care for erosions at sites of blister formation. Many patients require treatment with moderate doses of daily glucocorticoids (i.e., 20–40 mg of prednisone) at some point in their course. Mild cases (or brief flare-ups) may be controlled by vigorous use of potent topical glucocorticoids. Infants born of mothers with PG appear to be at increased risk of being born slightly premature or “small for dates.” Current evidence suggests that there is no difference in the incidence of uncomplicated live births between PG patients treated with systemic glucocorticoids and those managed more conservatively. If systemic glucocorticoids are administered, newborns are at risk for development of reversible adrenal insufficiency.
EPIDERMOLYSIS BULLOSA ACQUISITA Epidermolysis bullosa acquisita (EBA) is a rare, noninherited, polymorphic, chronic, subepidermal blistering disease. (The inherited form is discussed in Chap. 427.) Patients with classic or noninflammatory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered a mechanobullous disease. Other patients with EBA have widespread inflammatory scarring and bullous lesions that resemble severe BP. Inflammatory EBA may evolve into the classic, noninflammatory form of this disease. Rarely, patients present with lesions that predominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Studies suggest that EBA is sometimes associated with inflammatory bowel disease (especially Crohn’s disease). The histology of lesional skin varies with the character of the lesion being studied. Noninflammatory bullae are subepidermal, feature a sparse leukocytic infiltrate, and resemble the lesions in patients with porphyria cutanea tarda. Inflammatory lesions consist of neutrophilrich subepidermal blisters. EBA patients have continuous deposits of IgG (and frequently C3) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in association with anchoring fibrils. Approximately 50% of EBA patients have demonstrable circulating IgG basement membrane autoantibodies directed against type VII collagen—the collagen species that makes up anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP). Studies have shown that passive transfer of experimental or clinical IgG against type
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VII collagen can produce lesions in mice that clinically, histologically, and immunopathologically resemble those in patients with inflammatory EBA. Treatment of EBA is generally unsatisfactory. Some patients with inflammatory EBA may respond to systemic glucocorticoids, either alone or in combination with immunosuppressive agents. Other patients (especially those with neutrophil-rich inflammatory lesions) may respond to dapsone. The chronic, noninflammatory form of EBA is largely resistant to treatment, although some patients may respond to cyclosporine, azathioprine, or IVIg.
PART 2 Cardinal Manifestations and Presentation of Diseases
MUCOUS MEMBRANE PEMPHIGOID Mucous membrane pemphigoid (MMP) is a rare, acquired, subepithelial immunobullous disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Common sites include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin lesions (present in about one-third of patients) tend to predominate on the scalp, face, and upper trunk and generally consist of a few scattered erosions or tense blisters on an erythematous or urticarial base. MMP is typically a chronic and progressive disorder. Serious complications may arise as a consequence of ocular, laryngeal, esophageal, or anogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblepharon, ankyloblepharon, entropion, corneal opacities, and (in severe cases) blindness. Similarly, erosive lesions of the larynx may cause hoarseness, pain, and tissue loss that, if unrecognized and untreated, may eventuate in complete destruction of the airway. Esophageal lesions may result in stenosis and/or strictures that could place patients at risk for aspiration. Strictures may also complicate anogenital involvement. Biopsies of lesional tissue generally show subepithelial vesiculo bullae and a mononuclear leukocytic infiltrate. Neutrophils and eosinophils may be seen in biopsies of early lesions; older lesions may demonstrate a scant leukocytic infiltrate and fibrosis. Direct immunofluorescence microscopy of perilesional tissue typically reveals deposits of IgG, IgA, and/or C3 in the epidermal basement membrane. Because many patients with MMP exhibit no evidence of circulating basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although MMP was once thought to be a single nosologic entity, it is now largely regarded as a disease phenotype that may develop as a consequence of an autoimmune reaction to a variety of molecules in the epidermal basement membrane (e.g., BPAG2, laminin-332, type VII collagen, and other antigens yet to be completely defined). Studies suggest that MMP patients with autoantibodies to laminin-332 have an increased relative risk for cancer. Treatment of MMP is largely dependent upon the sites of involvement. Due to potentially severe complications, patients with ocular, laryngeal, esophageal, and/or anogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter in combination with another immunosuppressive agent (e.g., azathioprine, mycophenolate mofetil, cyclophosphamide, or rituximab) or IVIg. Less threatening forms of the disease may be managed with topical or intralesional glucocorticoids.
Figure 73-3 Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.) involvement (i.e., dermatomyositis sine myositis) have also been reported. The most common manifestation is a purple-red discoloration of the upper eyelids, sometimes associated with scaling (“heliotrope” erythema; Fig. 73-3) and periorbital edema. Erythema on the cheeks and nose in a “butterfly” distribution may resemble the malar eruption of SLE. Erythematous or violaceous scaling patches are common on the upper anterior chest, posterior neck, scalp, and the extensor surfaces of the arms, legs, and hands. Erythema and scaling may be particularly prominent over the elbows, knees, and dorsal interphalangeal joints. Approximately one-third of patients have violaceous, flat-topped papules over the dorsal interphalangeal joints that are pathognomonic of dermatomyositis (Gottron’s papules). Thin violaceous papules and plaques on the elbows and knees of patients with dermatomyositis are referred to as Gottron’s sign (Fig. 73-4). These lesions can be contrasted with the erythema and scaling on the dorsum of the fingers that spares the skin over the interphalangeal joints of some SLE patients. Periungual telangiectasia may be prominent in patients with dermatomyositis. Lacy or reticulated erythema may be associated with fine scaling on the extensor and lateral surfaces of the thighs and upper arms. Other patients, particularly those with long-standing disease, develop areas of hypopigmentation, hyperpigmentation, mild atrophy, and telangiectasia known as poikiloderma. Poikiloderma is rare in both SLE and scleroderma and thus can serve as a clinical sign that distinguishes dermatomyositis from these two diseases. Cutaneous changes may
AUTOIMMUNE SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS FEATURES DERMATOMYOSITIS The cutaneous manifestations of dermatomyositis (Chap. 388) are often distinctive but at times may resemble those of systemic lupus erythematosus (SLE) (Chap. 378), scleroderma (Chap. 382), or other overlapping connective tissue diseases (Chap. 382). The extent and severity of cutaneous disease may or may not correlate with the extent and severity of the myositis. The cutaneous manifestations of dermatomyositis are similar, whether the disease appears in children or in the elderly, except that calcification of subcutaneous tissue is a common late sequela in childhood dermatomyositis. The cutaneous signs of dermatomyositis may precede or follow the development of myositis by weeks to years. Cases lacking muscle
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Figure 73-4 Gottron’s papules. Dermatomyositis often involves the hands as erythematous flat-topped papules over the knuckles. Periungual telangiectases are also evident.
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Figure 73-5 Acute cutaneous lupus erythematosus (LE). A. Acute cutaneous LE on the face, showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. B. Acute cutaneous LE on the upper chest, demonstrating brightly erythematous and slightly edematous papules and plaques. (B, Courtesy of Robert Swerlick, MD; with permission.)
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LUPUS ERYTHEMATOSUS The cutaneous manifestations of lupus erythematosus (LE) (Chap. 378) can be divided into acute, subacute, and chronic or discoid types. Acute cutaneous LE is characterized by erythema of the nose and malar eminences in a “butterfly” distribution (Fig. 73-5A). The erythema is often sudden in onset, accompanied by edema and fine scale, and
correlated with systemic involvement. Patients may have widespread involvement of the face as well as erythema and scaling of the extensor surfaces of the extremities and upper chest (Fig. 73-5B). These acute lesions, while sometimes evanescent, usually last for days and are often associated with exacerbations of systemic disease. Skin biopsy of acute lesions may show only a sparse dermal infiltrate of mononuclear cells and dermal edema. In some instances, cellular infiltrates around blood vessels and hair follicles are notable, as is hydropic degeneration of basal cells of the epidermis. Direct immunofluorescence microscopy of lesional skin frequently reveals deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone. Treatment is aimed at control of systemic disease. Photoprotection is very important in this as well as in other forms of LE. Subacute cutaneous lupus erythematosus (SCLE) is characterized by a widespread photosensitive, nonscarring eruption. In most patients, renal and central nervous system involvement is mild or absent. SCLE may present as a papulosquamous eruption that resembles psoriasis or as annular polycyclic lesions that resemble those seen in erythema multiforme. In the papulosquamous form, discrete erythematous papules arise on the back, chest, shoulders, extensor surfaces of the arms, and dorsum of the hands; lesions are uncommon on the central face and the flexor surfaces of the arms as well as below the waist. These slightly scaling papules tend to merge into large plaques, some with a reticulate appearance. The annular form involves the same areas and presents with erythematous papules that evolve into oval, circular, or polycyclic lesions. The lesions of SCLE are more widespread but have less tendency for scarring than lesions of discoid LE. Skin biopsy reveals a dense mononuclear cell infiltrate around hair follicles and blood vessels in the superficial dermis, combined with hydropic degeneration of basal cells in the epidermis. Direct immunofluorescence microscopy of lesional skin reveals deposits of immunoglobulin(s) in the epidermal basement membrane zone in about one-half of these cases. A particulate pattern of IgG deposition throughout the epidermis has been associated with SCLE. Most SCLE patients have anti-Ro autoantibodies. Local therapy alone is usually unsuccessful. Most patients require treatment with aminoquinoline antimalarial drugs. Low-dose therapy with oral glucocorticoids is sometimes necessary. Photoprotective measures against both ultraviolet B and ultraviolet A wavelengths are very important. Discoid lupus erythematosus (DLE, also called chronic cutaneous LE) is characterized by discrete lesions, most often found on the face, scalp, and/or external ears. The lesions are erythematous papules or plaques with a thick, adherent scale that occludes hair follicles (follicular plugging). When the scale is removed, its underside shows small excrescences that correlate with the openings of hair follicles (so-called “carpet tacking”), a finding relatively specific for DLE. Longstanding lesions develop central atrophy, scarring, and hypopigmentation but frequently have erythematous, sometimes raised borders (Fig. 73-6). These lesions persist for years and tend to expand slowly. Up to 15% of patients with DLE eventually meet the American College of Rheumatology criteria for SLE. However, typical discoid lesions are frequently seen in patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, atrophy of the epidermis, hydropic degeneration of basal keratinocytes, and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Direct immunofluorescence microscopy demonstrates immunoglobulin(s) and complement deposits at the basement membrane zone in ~90% of cases. Treatment is focused on control of local cutaneous disease and consists mainly of photoprotection and topical or intralesional glucocorticoids. If local therapy is ineffective, use of aminoquinoline antimalarial agents may be indicated.
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be similar in dermatomyositis and various overlap syndromes where thickening and binding down of the skin of the hands (sclerodactyly) as well as Raynaud’s phenomenon can be seen. However, the presence of severe muscle disease, Gottron’s papules, heliotrope erythema, and poikiloderma serves to distinguish patients with dermatomyositis. Skin biopsy of the erythematous, scaling lesions of dermatomyositis may reveal only mild nonspecific inflammation but sometimes may show changes indistinguishable from those found in SLE, including epidermal atrophy, hydropic degeneration of basal keratinocytes, edema of the upper dermis, and a mild mononuclear cell infiltrate. Direct immunofluorescence microscopy of lesional skin is usually negative, although granular deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone have been described in some patients. Treatment should be directed at the systemic disease. Topical glucocorticoids are sometimes useful; patients should avoid exposure to ultraviolet irradiation and aggressively use photoprotective measures, including broad-spectrum sunscreens.
SCLERODERMA AND MORPHEA The skin changes of scleroderma (Chap. 382) usually begin on the hands, feet, and face, with episodes of recurrent nonpitting edema. Sclerosis of the skin commences distally on the fingers (sclerodactyly) and spreads proximally, usually accompanied by resorption of bone of the fingertips, which may have punched out ulcers, stellate scars, or areas of hemorrhage (Fig. 73-7). The fingers may actually shrink and
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Figure 73-6 Discoid (chronic cutaneous) lupus erythematosus. Violaceous, hyperpigmented, atrophic plaques, often with evidence of follicular plugging that may result in scarring, are typical. become sausage-shaped, and, because the fingernails are usually unaffected, they may curve over the end of the fingertips. Periungual telangiectases are usually present, but periungual erythema is rare. In advanced cases, the extremities show contractures and calcinosis cutis. Facial involvement includes a smooth, unwrinkled brow, taut skin over the nose, shrinkage of tissue around the mouth, and perioral radial furrowing (Fig. 73-8). Matlike telangiectases are often present, particularly on the face and hands. Involved skin feels indurated, smooth, and bound to underlying structures; hyper- and hypopigmentation are common as well. Raynaud’s phenomenon (i.e., cold-induced blanching, cyanosis, and reactive hyperemia) is documented in almost all patients and can precede development of scleroderma by many years. Linear scleroderma is a limited form of disease that presents in a linear, bandlike distribution and tends to involve deep as well as superficial layers of skin. The combination of calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia has been termed the CREST syndrome. Centromere antibodies have been reported in a very high percentage of patients with the CREST syndrome but in only a small minority of patients with scleroderma. Skin biopsy reveals thickening of the dermis and homogenization of collagen bundles. Direct immunofluorescence microscopy of lesional skin is usually negative. Morphea is characterized by localized thickening and sclerosis of skin; it dominates on the trunk. This disorder may affect children or adults. Morphea begins as erythematous or flesh-colored plaques that become sclerotic, develop central hypopigmentation, and have an
Figure 73-7 Scleroderma showing acral sclerosis and focal digital ulcers.
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Figure 73-8 Scleroderma often eventuates in development of an expressionless, masklike facies.
erythematous border. In most cases, patients have one or a few lesions, and the disease is termed localized morphea. In some patients, widespread cutaneous lesions may occur without systemic involvement (generalized morphea). Many adults with generalized morphea have concomitant rheumatic or other autoimmune disorders. Skin biopsy of morphea is indistinguishable from that of scleroderma. Scleroderma and morphea are usually quite resistant to therapy. For this reason, physical therapy to prevent joint contractures and to maintain function is employed and is often helpful. Treatment options for early, rapidly progressive disease include phototherapy (UVA1 or PUVA) or methotrexate (15–20 mg/week) alone or in combination with daily glucocorticoids. Diffuse fasciitis with eosinophilia is a clinical entity that can sometimes be confused with scleroderma. There is usually a sudden onset of swelling, induration, and erythema of the extremities, frequently following significant physical exertion. The proximal portions of the extremities (upper arms, forearms, thighs, calves) are more often involved than are the hands and feet. While the skin is indurated, it usually displays a woody, dimpled, or “pseudocellulite” appearance rather than being bound down as in scleroderma; contractures may occur early secondary to fascial involvement. The latter may also cause muscle groups to be separated and veins to appear depressed (i.e., the “groove sign”). These skin findings are accompanied by peripheralblood eosinophilia, increased erythrocyte sedimentation rate, and sometimes hypergammaglobulinemia. Deep biopsy of affected areas of skin reveals inflammation and thickening of the deep fascia overlying muscle. An inflammatory infiltrate composed of eosinophils and mononuclear cells is usually found. Patients with eosinophilic fasciitis appear to be at increased risk for developing bone marrow failure or other hematologic abnormalities. While the ultimate course of eosinophilic fasciitis is uncertain, many patients respond favorably to treatment with prednisone in doses of 40–60 mg/d. The eosinophilia-myalgia syndrome, a disorder with epidemic numbers of cases reported in 1989 and linked to ingestion of l-tryptophan manufactured by a single company in Japan, is a multisystem disorder characterized by debilitating myalgias and absolute eosinophilia in association with varying combinations of arthralgias, pulmonary symptoms, and peripheral edema. In a later phase (3–6 months after initial symptoms), these patients often develop localized sclerodermatous skin changes, weight loss, and/or neuropathy (Chap. 382). The precise cause of this syndrome, which may resemble other sclerotic skin conditions, is unknown. However, the implicated lots of l-tryptophan contained the contaminant 1,1-ethylidene bis[tryptophan]. This contaminant may be pathogenic or may be a marker for another substance that provokes the disorder.
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Cutaneous Drug Reactions Kanade Shinkai, Robert S. Stern, Bruce U. Wintroub
USE OF PRESCRIPTION DRUGS IN THE UNITED STATES
INCIDENCE OF CUTANEOUS REACTIONS Several large cohort studies established that acute cutaneous reaction to drugs affected about 3% of hospital inpatients. Reactions usually occur a few days to 4 weeks after initiation of therapy. Many drugs of common use are associated with a 1–2% rate of rashes during premarketing clinical trials. The risk is often higher when medications are used in general, unselected populations. The rate may reach 3–7% for amoxicillin, sulfamethoxazole, many anticonvulsants, and anti-HIV agents. In addition to acute eruptions, a variety of skin diseases can be induced or exacerbated by prolonged use of drugs (e.g., pruritus, pigmentation, nail or hair disorders, psoriasis, bullous pemphigoid, photosensitivity, and even cutaneous neoplasms). These drug reactions are not frequent, but neither their incidence nor their impact on public health has been evaluated. In a series of 48,005 inpatients over a 20-year period, morbilliform rash (91%) and urticaria (6%) were the most frequent skin reactions. Severe reactions are actually too rare to be detected in such cohorts. Although rare, severe cutaneous reactions to drugs have an important impact on health because of significant sequelae, including mortality. Adverse drug rashes are responsible for hospitalization, increase the duration of hospital stay, and are life threatening. Some populations are at increased risk of drug reactions, including patients with collagen vascular diseases, bone marrow graft recipients, and those with acute Epstein-Barr virus infection. The pathophysiology underlying this association is unknown, but may be related to immunocompromise or immune dysregulation. Risk of drug allergy, including severe hypersensitivity reactions, is increased with HIV infection; individuals with advanced HIV disease (e.g., CD4 T lymphocyte count 39°C (102.2°F), sore throat, and conjunctivitis resulting from mucosal lesions. Intestinal and pulmonary involvement is associated with a poor prognosis, as are a greater extent of epidermal detachment and older age. About 10% and 30% of SJS- and TEN-affected persons die from their disease, respectively. Drugs that most commonly cause SJS or TEN are sulfonamides, nevirapine (1 in 1000 risk of SJS or TEN), allopurinol, lamotrigine, aromatic anticonvulsants, and NSAIDs, specifically oxicam. Frozen-section skin biopsy may aid in rapid diagnosis. At this time, SJS and TEN have no proven effective treatment. The best results come from early diagnosis, immediate discontinuation of any suspected drug, supportive therapy, and paying close attention to ocular complications and infection. Systemic glucocorticoid therapy (prednisone 1–2 mg/kg) may be useful early in the evolution of the disease, but long-term systemic glucocorticoid use has been associated with higher mortality. Cyclosporine may be a possible therapy for SJS/TEN. After initial enthusiasm for the use of intravenous immunoglobulin (IVIG) in the treatment of SJS/TEN, some recent data questions whether IVIG benefits these patients. Randomized studies to more definitively assess the potential benefit of systemic glucocorticoids and IVIG are lacking and difficult to perform but are necessary.
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Figure 74-9 Toxic epidermal necrolysis. (Photo credit: Lindy Peta Fox, MD, and Jubin Ryu, MD, PhD.)
Cutaneous Generalized erythema Facial edema Skin pain Palpable purpura Target lesions Skin necrosis Blisters or epidermal detachment Positive Nikolsky's sign Mucous membrane erosions Urticaria Swelling of tongue General High fever (temperature >40°C [>104°F]) Enlarged lymph nodes Arthralgias or arthritis Shortness of breath, wheezing, hypotension Laboratory Results Eosinophil count >1000/μL Lymphocytosis with atypical lymphocytes Abnormal liver or kidney function tests
383
EARLY DIAGNOSIS OF SEVERE ERUPTIONS Rapid recognition of adverse drug reactions that may become serious or life threatening is paramount. Table 74-2 lists clinical and laboratory features that, if present, suggest that the reaction may be serious. Table 74-3 provides key features of the most serious adverse cutaneous reactions. Intensity of symptoms and rapid progression of signs should raise the suspicion of a severe eruption. Any doubt should lead to prompt consultation with a dermatologist and/or referral of the patient to a specialized center. CONFIRMATION OF DRUG REACTION The probability of drug etiology varies with the pattern of the reaction. Only fixed drug eruptions are always drug-induced. Morbilliform eruptions are usually viral in children and drug-induced in adults. Among severe reactions, drugs account for 10–20% of anaphylaxis and vasculitis and between 70–90% of AGEP, DIHS, SJS, or TEN. Skin biopsy helps in characterizing the reaction but does not indicate drug causality. Blood counts and liver and renal function tests are important for evaluating organ involvement. The association of mild elevation of liver enzymes and high eosinophil count is frequent but not specific for a drug reaction. Blood tests that could identify an alternative cause, antihistone antibody tests (to rule out drug-induced lupus), and serology or polymerase chain reaction for infections may be of great importance to determine a cause. WHAT DRUG(S) TO SUSPECT AND WITHDRAW Most cases of drug eruptions occur during the first course of treatment with a new medication. A notable exception is IgE-mediated urticaria and anaphylaxis that need presensitization and develop a few minutes to a few hours after rechallenge. Characteristic times of onset to drug reaction are as follows: 4–14 days for morbilliform eruptions, 2–4 days for AGEP, 5–28 days for SJS/TEN, and 14–48 days for DIHS. A drug chart, compiling information of all current and past medications/ supplements and the timing of administration relative to the rash, is a key diagnostic tool to identifying the inciting drug. Medications introduced for the first time in the relevant time frame are prime suspects. Two other important elements to suspect causality at this stage are (1) previous experience with the drug in the population and (2) alternative etiologic candidates.
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Table 74-3 Clinical Features of Severe Cutaneous Drug Reactions Mucosal Lesions Erosions usually at two or more sites
Toxic epidermal necrolysisa
Erosions usually at two or more sites
Hypersensitivity syndrome
Infrequent
Acute generalized exanthematous pustulosis
About 20% erosions (mouth, tongue)
Serum sickness or reactions resembling serum sickness
Absent
Anticoagulant-induced necrosis
Infrequent
Angioedema
Often involved
PART 2
Diagnosis Stevens-Johnson syndrome
Cardinal Manifestations and Presentation of Diseases
Typical Skin Lesions Small blisters on dusky purpuric macules or atypical targets; rare areas of confluence; detachment ≤10% of body surface area Individual lesions like those seen in Stevens-Johnson syndrome; confluent erythema; outer layer of epidermis separates readily from basal layer with lateral pressure; large sheet of necrotic epidermis; total detachment of >30% of body surface area Severe exanthematous rash (may become purpuric), exfoliative dermatitis, facial edema
Frequent Signs and Symptoms Most cases involve fever
Alternative Causes Not Related to Drugs 10–20% cause not determined
Nearly all cases involve fever, 10–20% cause not deter"acute skin failure," leukopenia mined
30–50% of cases involve fever, Cutaneous lymphoma lymphadenopathy, hepatitis, nephritis, myocarditis, eosinophilia, atypical lymphocytes Initially nonfollicular, small Fever, burning, pruritus, facial Infection pustules overlying edematous swelling, leukocytosis, hypoerythema, sometimes leading calcemia to superficial erosions Morbilliform lesions, someFever, arthralgias Infection times with urticarial plaques (typically polycyclic) Erythema then purpura and Pain in affected areas Disseminated intravascular necrosis, especially of fatty coagulopathy, septicemia areas Urticaria or swelling of central Respiratory distress, cardiovas- Insect stings, foods part of face cular collapse
Overlap of Stevens-Johnson syndrome and toxic epidermal necrolysis have features of both and attachment of 10–30% of body surface area may occur.
a
Source: Adapted from JC Roujeau, RS Stern: N Engl J Med 331:1272, 1994.
The decision to continue or discontinue any medication will depend on the severity of the reaction, the severity of the primary disease, the degree of suspicion of causality, and the feasibility of an alternative safer treatment. In any potentially fatal drug reaction, elimination of all possible suspect drugs or unnecessary medications should be attempted. Some rashes may resolve when “treating through” a benign drug-related eruption. The decision to treat through an eruption should, however, remain the exception and withdrawal of every suspect drug the general rule. On the other hand, drugs that are not suspected and are important for the patient (e.g., antihypertensive agents) generally should not be quickly withdrawn. This approach prevents reluctance to future use of these agents. RECOMMENDATION FOR FUTURE USE OF DRUGS The aims are (1) to prevent the recurrence of the drug eruption and (2) not to compromise future treatments by contraindicating otherwise useful medications. Begin with thorough assessment of drug causality. Drug causality is evaluated based on timing of the reaction, evaluation of other possible causes, effect of drug withdrawal or continuation, and knowledge of medications that have been associated with the observed reaction. Combination of these criteria leads to considering the causality as definite, probable, possible, or unlikely. The RegiSCAR group has proposed a useful algorithm called Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) to determine drug causality in SJS/ TEN. A drug with a “definite” or “probable” causality should be contraindicated, a warning card or medical alert tag (e.g., wristband) should be given to the patient, and the drugs should be listed in the patient’s medical chart as an allergy. A drug with a “possible” causality may be submitted to further investigations depending on the expected need for future treatment. A drug with “unlikely” causality or that has been continued when the reaction improved or was reintroduced without a reaction can be administered safely.
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The usefulness of laboratory tests to determine causality is still debated. Many in vitro immunologic assays have been developed, but the predictive value of these tests has not been validated in any large series of affected patients; these tests exist primarily for research and not clinical purposes. In some cases, diagnostic rechallenge may be appropriate, even for drugs with high rates of adverse reactions. Desensitization is often successful in HIV-infected patients with morbilliform eruptions to sulfonamides but is not recommended in HIV-infected patients who manifested erythroderma or a bullous reaction in response to their earlier sulfonamide exposure. In patients with history suggesting immediate IgE-mediated reactions to penicillin, skin-prick testing with penicillins or cephalosporins has proved useful for identifying patients at risk of anaphylactic reactions to these agents. However, skin tests themselves carry a small risk of anaphylaxis. Negative skin tests do not totally rule out IgE-mediated reactivity, but the risk of anaphylaxis in response to penicillin administration in patients with negative skin tests is about 1%. In contrast, two-thirds of patients with a positive skin test experience an allergic response upon rechallenge. For patients with delayed-type hypersensitivity, the clinical utility of skin tests is more questionable. At least one of a combination of several tests (prick, patch, and intradermal) is positive in 50–70% of patients with a reaction “definitely” attributed to a single medication. This low sensitivity corresponds to the observation that readministration of drugs with negative skin testing resulted in eruptions in 17% of cases. CROSS-SENSITIVITY Because of the possibility of cross-sensitivity among chemically related drugs, many physicians recommend avoidance of not only the medication that induced the reaction but also all drugs of the same pharmacologic class.
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Acknowledgment We acknowledge the contribution of Dr. Jean-Claude Roujeau to this chapter in the 17th edition.
Photosensitivity and Other Reactions to Light Alexander G. Marneros, David R. Bickers
SOLAR RADIATION Sunlight is the most visible and obvious source of comfort in the environment. The sun provides the beneficial effects of warmth and vitamin D synthesis. However, acute and chronic sun exposure also has pathologic consequences. Few effects of sun exposure beyond those affecting the skin have been identified, but cutaneous exposure to sunlight is the major cause of human skin cancer and can have immunosuppressive effects as well. The sun’s energy reaching the earth’s surface is limited to components of the ultraviolet (UV) spectrum, the visible spectrum, and portions of the infrared spectrum. The cutoff at the short end of the UV spectrum at ~290 nm is due primarily to stratospheric ozone—formed by highly energetic ionizing radiation—that prevents penetration to the earth’s surface of the shorter, more energetic, potentially more harmful wavelengths of solar radiation. Indeed, concern about destruction of the ozone layer by chlorofluorocarbons released into the atmosphere has led to international agreements to reduce production of those chemicals. Measurements of solar flux showed a twentyfold regional variation in the amount of energy at 300 nm that reaches the earth’s surface. This variability relates to seasonal effects, the path that sunlight traverses through ozone and air, the altitude (a 4% increase for each 300 m of elevation), the latitude (increasing intensity with decreasing latitude), and the amount of cloud cover, fog, and pollution. The major components of the photobiologic action spectrum that are capable of affecting human skin include the UV and visible wavelengths between 290 and 700 nm. In addition, the wavelengths beyond 700 nm in the infrared spectrum primarily emit heat and in certain circumstances may exacerbate the pathologic effects of energy in the UV and visible spectra. The UV spectrum reaching the earth represents 30) sunscreens, and, in severe cases, systemic immunosuppression, such as with azathioprine. The management of drug photosensitivity involves first and foremost the elimination of exposure to the chemical agents responsible for the reaction and the minimization of sun exposure. The acute symptoms of phototoxicity may be ameliorated by cool moist compresses, topical glucocorticoids, and systemically administered NSAIDs. In severely affected individuals, a rapidly tapered course of systemic glucocorticoids may be useful. Judicious use of analgesics may be necessary. Photoallergic reactions require a similar management approach. Furthermore, patients with persistent light reaction and chronic actinic dermatitis must be meticulously protected against light exposure. In selected patients to whom chronic systemic high-dose glucocorticoids pose unacceptable risks, it may be necessary to employ an immunosuppressive drug such as azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil. Porphyria The porphyrias (Chap. 430) are a group of diseases that have in common inherited or acquired derangements in the synthesis of heme. Heme is an iron-chelated tetrapyrrole or porphyrin, and the nonmetal chelated porphyrins are potent photosensitizers that absorb light intensely in both the short (400–410 nm) and the long (580–650 nm) portions of the visible spectrum. Heme cannot be reutilized and must be synthesized continuously. The two body compartments with the largest capacity for its production are the bone marrow and the liver. Accordingly, the porphyrias originate in one or the other of these organs, with an end result of excessive endogenous production of potent photosensitizing porphyrins. The porphyrins circulate in the bloodstream and diffuse into the skin, where they absorb solar energy, become photoexcited, generate ROS, and evoke cutaneous photosensitivity. The mechanism of porphyrin photosensitization is known to be photodynamic, or oxygen-dependent, and is mediated by ROS such as singlet oxygen and superoxide anions. Porphyria cutanea tarda is the most common type of porphyria and is associated with decreased activity of the enzyme uroporphyrinogen decarboxylase. There are two basic types of PCT: (1) the sporadic or acquired type, generally seen in individuals ingesting ethanol or receiving estrogens; and (2) the inherited type, in which there is autosomal dominant transmission of deficient enzyme activity. Both forms are associated with increased hepatic iron stores. In both types of PCT, the predominant feature is chronic photosensitivity characterized by increased fragility of sun-exposed skin, particularly areas subject to repeated trauma such as the dorsa of the hands, the forearms, the face, and the ears. The predominant skin lesions are vesicles and bullae that rupture, producing moist erosions (often with a hemorrhagic base) that heal slowly, with crusting and purplish discoloration of the affected skin. Hypertrichosis, mottled pigmentary change, and scleroderma-like induration are associated features. The diagnosis can be confirmed biochemically by measurement of urinary porphyrin excretion, plasma porphyrin assay, and assay of erythrocyte and/or hepatic uroporphyrinogen decarboxylase. Multiple mutations of the uroporphyrinogen decarboxylase gene have been identified in human populations. Some patients with PCT have associated mutations in the HFE gene, which is linked to hemochromatosis; these mutations could contribute to the iron overload seen in PCT, although iron status as measured by serum ferritin, iron levels, and transferrin saturation is no different from that in PCT patients without HFE mutations. Prior hepatitis C virus infection appears to be an independent risk factor for PCT. Treatment of PCT consists of repeated phlebotomies to diminish the excessive hepatic iron stores and/or intermittent low doses of chloroquine and hydroxychloroquine. Long-term remission of the disease can be achieved if the patient eliminates exposure to porphyrinogenic agents and prolonged exposure to sunlight.
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Erythropoietic protoporphyria originates in the bone marrow and is due to a decrease in the mitochondrial enzyme ferrochelatase secondary to numerous gene mutations. The major clinical features include acute photosensitivity characterized by subjective burning and stinging of exposed skin that often develops during or just after sun exposure. There may be associated skin swelling and, after repeated episodes, a waxlike scarring. The diagnosis is confirmed by demonstration of elevated levels of free erythrocyte protoporphyrin. Detection of increased plasma protoporphyrin helps distinguish erythropoietic protoporphyria from lead poisoning and iron-deficiency anemia, in both of which erythrocyte protoporphyrin levels are elevated in the absence of cutaneous photosensitivity and elevated plasma protoporphyrin levels. Treatment includes reduction of sun exposure and oral administration of the carotenoid β-carotene, which is an effective scavenger of free radicals. This drug increases tolerance to sun exposure in some affected individuals, although it has no effect on deficient ferrochelatase. An algorithm for managing patients with photosensitivity is presented in Fig. 75-1.
ALGORITHM FOR PATIENT DIAGNOSIS OF PHOTOSENSITIVITY Photosensitivity Laboratory screen Plasma porphyrin
ANA Ro/La
+
Porphyria
+ –
–
Lupus erythematosus dermatomyositis
History of exposure to photosensitizing drug + –
Discontinue drug
Rash disappears
Rash persists
Drug photosensitivity
Phototesting History of association of rash to exposure Delayed
Immediate Phototest with UV-B, UV-A, and visible; read MED at 30 min
Unrelated
Phototest with UV-B, UV-A, and visible; read MED at 24 h
–
+
–
Solar urticaria Drug photosensitivity + Photoallergic contact dermatitis
UV-A +
UV-B (± UV-A) +
Photo Patch Test
Chronic actinic dermatitis –
Polymorphous light eruption Lupus erythematosus Atopic dermatitis with photoaggravation
Figure 75-1 Algorithm for the diagnosis of a patient with photosensitivity. ANA, antinuclear antibody; MED, minimal erythemal dose; UV-A and UV-B, ultraviolet spectrum segments including wavelengths of 320–400 nm and 290–320 nm, respectively.
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Since photosensitivity of the skin results from exposure to sunlight, it follows that absolute avoidance of sunlight will eliminate these disorders. However, contemporary lifestyles make this approach impractical for most individuals. Thus better approaches to photoprotection have been sought. Natural photoprotection is provided by structural proteins in the epidermis, particularly keratins and melanin. The amount of melanin and its distribution in cells are genetically regulated, and individuals of darker complexion (skin types IV–VI) are at decreased risk for the development of acute sunburn and cutaneous malignancy. Other forms of photoprotection include clothing and sunscreens. Clothing constructed of tightly woven sun-protective fabrics, irrespective of color, affords substantial protection. Wide-brimmed hats, long sleeves, and trousers all reduce direct exposure. Sunscreens are now considered over-the-counter drugs, and a monograph from the U.S. Food and Drug Administration (FDA) has recognized category I ingredients as safe and effective. Those ingredients are listed in Table 75-5. Sunscreens are rated for their photoprotective effect by their sun protection factor (SPF). The SPF is simply a ratio of the time required to produce sunburn erythema with and without sunscreen application. The SPF of most sunscreens reflects protection from UV-B but not from UV-A. The FDA monograph stipulates that sunscreens must be rated on a scale ranging from minimal (SPF ffi2 and 2 L in the average-sized adult), signs of hypovolemic shock including confusion, dyspnea, diaphoresis, hypotension, and tachycardia appear (Chap. 129). Such patients have significant deficits in vital organ perfusion and require immediate volume replacement. With acute hemolysis, the signs and symptoms depend on the mechanism that leads to red cell destruction. Intravascular hemolysis with release of free hemoglobin may be associated with acute back pain, free hemoglobin in the plasma and urine, and renal failure. Symptoms associated with more chronic or progressive anemia depend on the age of the patient and the adequacy of blood supply to critical organs. Symptoms associated with moderate anemia include fatigue, loss of stamina, breathlessness, and tachycardia (particularly with physical exertion). However, because of the intrinsic compensatory mechanisms that govern the O2–hemoglobin dissociation curve, the gradual onset of anemia—particularly in young patients—may not be associated with signs or symptoms until the anemia is severe (hemoglobin 55%. Manifestations range from digital ischemia to Budd-Chiari syndrome with hepatic vein thrombosis. Abdominal vessel thromboses are particularly common. Neurologic symptoms such as vertigo, tinnitus, headache, and visual disturbances may occur. Hypertension is often present. Patients with polycythemia vera may have aquagenic pruritus and symptoms related to hepatosplenomegaly. Patients may have easy bruising, epistaxis, or bleeding from the gastrointestinal tract. Peptic ulcer disease is common. Patients with hypoxemia may develop cyanosis on minimal exertion or have headache, impaired mental acuity, and fatigue. The physical examination usually reveals a ruddy complexion. Splenomegaly favors polycythemia vera as the diagnosis (Chap. 131).
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PART 2
The presence of cyanosis or evidence of a right-to-left shunt suggests congenital heart disease presenting in the adult, particularly tetralogy of Fallot or Eisenmenger’s syndrome (Chap. 236). Increased blood viscosity raises pulmonary artery pressure; hypoxemia can lead to increased pulmonary vascular resistance. Together, these factors can produce cor pulmonale. Polycythemia can be spurious (related to a decrease in plasma volume; Gaisbock’s syndrome), primary, or secondary in origin. The secondary causes are all associated with increases in EPO levels: either a physiologically adapted appropriate elevation based on tissue hypoxia (lung disease, high altitude, CO poisoning, high-affinity hemoglobinopathy) or an abnormal overproduction (renal cysts, renal artery stenosis, tumors with ectopic EPO production). A rare familial form of polycythemia is associated with normal EPO levels but hyperresponsive EPO receptors due to mutations.
Cardinal Manifestations and Presentation of Diseases
APPROACH TO THE PATIENT: Polycythemia As shown in Fig. 77-18, the first step is to document the presence of an increased red cell mass using the principle of isotope dilution by administering 51Cr-labeled autologous red blood cells to the patient and sampling blood radioactivity over a 2-h period. If the red cell mass is normal (32 mL/kg in women), serum EPO levels should be measured. If EPO levels are low or unmeasurable, the patient most likely has polycythemia vera. A mutation in JAK2 (Val617Phe), a key member of the cytokine intracellular signaling pathway, can be found in 90–95% of patients with polycythemia vera. Many of those without this particular JAK2 mutation have mutations in exon 12. As a practical matter, few centers assess red
AN APPROACH TO DIAGNOSING PATIENTS WITH POLYCYTHEMIA Increased hct or hgb normal Measure RBC mass
Dx: Relative erythrocytosis
elevated Measure serum EPO levels
low
Confirm JAK2 mutation
Dx: Polycythemia vera
elevated Measure arterial O2 saturation
low
Diagnostic evaluation for heart or lung disease, e.g., COPD, high altitude, AV or intracardiac shunt
normal no smoker? yes
Measure hemoglobin O2 affinity normal increased
Measure carboxyhemoglobin levels elevated Dx: Smoker’s polycythemia
Dx: O2 affinity hemoglobinopathy
normal
Search for tumor as source of EPO IVP/renal ultrasound (renal Ca or cyst) CT of head (cerebellar hemangioma) CT of pelvis (uterine leiomyoma) CT of abdomen (hepatoma)
Figure 77-18 An approach to the differential diagnosis of patients with an elevated hemoglobin (possible polycythemia). AV, atrioventricular; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EPO, erythropoietin; hct, hematocrit; hgb, hemoglobin; IVP, intravenous pyelogram; RBC, red blood cell.
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cell mass in the setting of an increased hematocrit. The short workup is to measure EPO levels, check for JAK2 mutation, and perform an abdominal ultrasound to assess spleen size. Tests that support the diagnosis of polycythemia vera include elevated white blood cell count, increased absolute basophil count, and thrombocytosis. If serum EPO levels are elevated, one needs to distinguish whether the elevation is a physiologic response to hypoxia or related to autonomous EPO production. Patients with low arterial O2 saturation (80 mL of blood per cycle, based on the quantity of blood loss required to produce iron-deficiency anemia. A complaint of heavy menses is subjective and has a poor correlation with excessive blood loss. Predictors of menorrhagia include bleeding resulting in irondeficiency anemia or a need for blood transfusion, passage of clots >1 inch in diameter, and changing a pad or tampon more than hourly. Menorrhagia is a common symptom in women with underlying bleeding disorders and is reported in the majority of women with VWD, women with factor XI deficiency, and symptomatic carriers of hemophilia. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, including bleeding after dental extractions, postoperative bleeding, and postpartum bleeding, and are much more likely to have menorrhagia beginning at menarche than women with menorrhagia due to other causes. Postpartum hemorrhage (PPH) is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD and symptomatic carriers of hemophilia A in whom levels of VWF and factor VIII usually normalize during pregnancy, PPH
403
Bleeding and Thrombosis
APPROACH TO THE PATIENT: Bleeding and Thrombosis
TABLE 78-1 Primary Hemostatic (Platelet Plug) Disorders
CHAPTER 78
residues of fibrin fragments to enhance these reactions further. This creates a highly efficient mechanism to generate plasmin focally on the fibrin clot, which then becomes plasmin’s substrate for digestion to fibrin degradation products. Plasmin cleaves fibrin at distinct sites of the fibrin molecule, leading to the generation of characteristic fibrin fragments during the process of fibrinolysis (Fig. 78-2). The sites of plasmin cleavage of fibrin are the same as those in fibrinogen. However, when plasmin acts on covalently cross-linked fibrin, d-dimers are released; hence, d-dimers can be measured in plasma as a relatively specific test of fibrin (rather than fibrinogen) degradation. d-Dimer assays can be used as sensitive markers of blood clot formation and have been validated for clinical use to exclude the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism in selected populations. In addition, d-dimer measurement can be used to stratify patients, particularly women, for risk of recurrent venous thromboembolism (VTE) when measured 1 month after discontinuation of anticoagulation given for treatment of an initial idiopathic event. d-Dimer levels may be elevated in the absence of VTE in elderly people. Physiologic regulation of fibrinolysis occurs primarily at three levels: (1) plasminogen activator inhibitors (PAIs), specifically PAI-1 and PAI-2, inhibit the physiologic plasminogen activators; (2) the thrombin-activatable fibrinolysis inhibitor (TAFI) limits fibrinolysis; and (3) α2-antiplasmin inhibits plasmin. PAI-1 is the primary inhibitor of tPA and uPA in plasma. TAFI cleaves the N-terminal lysine residues of fibrin, which aid in localization of plasmin activity. α2-Antiplasmin is the main inhibitor of plasmin in human plasma, inactivating any nonfibrin clot-associated plasmin.
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PART 2 Cardinal Manifestations and Presentation of Diseases
may be delayed. Women with a history of PPH have a high risk of recurrence with subsequent pregnancies. Rupture of ovarian cysts with intraabdominal hemorrhage has also been reported in women with underlying bleeding disorders. Tonsillectomy is a major hemostatic challenge, because intact hemostatic mechanisms are essential to prevent excessive bleeding from the tonsillar bed. Bleeding may occur early after surgery or after approximately 7 days postoperatively, with loss of the eschar at the operative site. Similar delayed bleeding is seen after colonic polyp resection. Gastrointestinal (GI) bleeding and hematuria are usually due to underlying pathology, and procedures to identify and treat the bleeding site should be undertaken, even in patients with known bleeding disorders. VWD, particularly types 2 and 3, has been associated with angiodysplasia of the bowel and GI bleeding. Hemarthroses and spontaneous muscle hematomas are characteristic of moderate or severe congenital factor VIII or IX deficiency. They can also be seen in moderate and severe deficiencies of fibrinogen, prothrombin, and factors V, VII, and X. Spontaneous hemarthroses occur rarely in other bleeding disorders except for severe VWD, with associated factor VIII levels 50%, thus making prolongation of clot formation due to a factor deficiency dependent on the factor missing from the added plasma. Testing for Antiphospholipid Antibodies Antibodies to phospholipids (cardiolipin) or phospholipid-binding proteins (β2-microglobulin and others) are detected by enzyme-linked immunosorbent assay (ELISA). When these antibodies interfere with phospholipid-dependent coagulation tests, they are termed lupus anticoagulants. The aPTT has variability sensitivity to lupus anticoagulants, depending in part on the aPTT reagents used. An assay using a sensitive reagent has been termed an LA-PTT. The dilute Russell viper venom test (dRVVT) and the tissue thromboplastin inhibition (TTI) test are modifications of standard tests with the phospholipid reagent decreased, thus increasing the sensitivity to antibodies that interfere with the phospholipid component. The tests, however, are not specific for lupus anticoagulants, because factor deficiencies or other inhibitors will also result in prolongation. Documentation of a lupus anticoagulant requires not only prolongation of a phospholipid-dependent coagulation test but also lack of correction when mixed with normal plasma and correction with the addition of activated platelet membranes or certain phospholipids (e.g., hexagonal phase).
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Measures of Platelet Function The bleeding time has been used to assess bleeding risk; however, it has not been found to predict bleeding risk with surgery, and it is not recommended for use for this indication. The PFA-100 and similar instruments that measure platelet-dependent coagulation under flow conditions are generally more sensitive and specific for platelet disorders and VWD than the bleeding time; however, data are insufficient to support their use to predict bleeding risk or monitor response to therapy, and they will be normal in some patients with platelet disorders or mild VWD. When they are used in the evaluation of a patient with bleeding symptoms, abnormal results, as with the bleeding time, require specific testing, such as VWF assays and/or platelet aggregation studies. Because all of these “screening” assays may miss patients with mild bleeding disorders, further studies are needed to define their role in hemostasis testing. For classic platelet aggregometry, various agonists are added to the patient’s platelet-rich plasma and platelet aggregation is measured. Tests of platelet secretion in response to agonists can also be measured. These tests are affected by many factors, including numerous medications, and the association between minor defects in aggregation or secretion in these assays and bleeding risk is not clearly established. Acknowledgment Robert I. Handin, MD, contributed this chapter in the 16th edition, and some material from that chapter has been retained here.
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407
Patrick H. Henry, Dan L. Longo
This chapter is intended to serve as a guide to the evaluation of patients who present with enlargement of the lymph nodes (lymphadenopathy) or the spleen (splenomegaly). Lymphadenopathy is a rather common clinical finding in primary care settings, whereas palpable splenomegaly is less so.
LYMPHADENOPATHY Lymphadenopathy may be an incidental finding in patients being examined for various reasons, or it may be a presenting sign or symptom of the patient’s illness. The physician must eventually decide whether the lymphadenopathy is a normal finding or one that requires further study, up to and including biopsy. Soft, flat, submandibular nodes (8 million) possible combinations of chromosomes. Together with the genetic exchanges that occur during recombination, chromosomal segregation generates tremendous diversity, and each gamete is genetically unique. The process of recombination and the independent segregation of chromosomes provide the foundation for performing linkage analyses, whereby one attempts to correlate the inheritance of certain chromosomal regions (or linked genes) with the presence of a disease or genetic trait (see below). After the first meiotic division, which results in two daughter cells (2n), the two chromatids of each chromosome separate during a second meiotic division to yield four gametes with a haploid state (1n). When the egg is fertilized by sperm, the two haploid sets are combined, thereby restoring the diploid state (2n) in the zygote. REGULATION OF GENE EXPRESSION Regulation by Transcription Factors The expression of genes is regulated by DNA-binding proteins that activate or repress transcription. The number of DNA sequences and transcription factors that regulate transcription is much greater than originally anticipated. Most genes contain at least 15–20 discrete regulatory elements within 300 bp of the transcription start site. This densely packed promoter region often contains binding sites for ubiquitous transcription factors such as CAAT box/enhancer binding protein (C/EBP), cyclic AMP response element–binding (CREB) protein, selective promoter factor 1 (Sp-1),
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or activator protein 1 (AP-1). However, factors involved in cell-specific expression may also bind to these sequences. Key regulatory elements may also reside at a large distance from the proximal promoter. The globin and the immunoglobulin genes, for example, contain locus control regions that are several kilobases away from the structural sequences of the gene. Specific groups of transcription factors that bind to these promoter and enhancer sequences provide a combinatorial code for regulating transcription. In this manner, relatively ubiquitous factors interact with more restricted factors to allow each gene to be expressed and regulated in a unique manner that is dependent on developmental state, cell type, and numerous extracellular stimuli. Regulatory factors also bind within the gene itself, particularly in the intronic regions. The transcription factors that bind to DNA actually represent only the first level of regulatory control. Other proteins—co-activators and co-repressors—interact with the DNA-binding transcription factors to generate large regulatory complexes. These complexes are subject to control by numerous cell-signaling pathways and enzymes, leading to phosphorylation, acetylation, sumoylation, and ubiquitination. Ultimately, the recruited transcription factors interact with, and stabilize, components of the basal transcription complex that assembles at the site of the TATA box and initiator region. This basal transcription factor complex consists of >30 different proteins. Gene transcription occurs when RNA polymerase begins to synthesize RNA from the DNA template. A large number of identified genetic diseases involve transcription factors (Table 82-2). The field of functional genomics is based on the concept that understanding alterations of gene expression under various physiologic and pathologic conditions provides insight into the underlying functional role of the gene. By revealing specific gene expression profiles, this knowledge may be of diagnostic and therapeutic relevance. The largescale study of expression profiles, which takes advantage of microarray and bead array technologies, is also referred to as transcriptomics
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429 SNPs (612,977)
q36.3
q35 q36.1
q34
q33
q31.33 q32.1
q31.2 q31.31
q31.1
q22.3
q22.1
q21.3
p21.13
q21.11
q11.23
q11.22
q11.21
p13 p12.3 p12.1 p11.2
p14.1
p15.1 p14.3
p15.3
p21.1
p22.3 p22.1 p21.3
Known Genes (1260)
Chromosome 7
116.94 Mb
116.98 Mb
117.02 Mb
117.06 Mb
200 Kb
CFTR Gene
SNPs Intronic
Splice site
Coding region, synonymous
Coding region, nonsynonymous
Coding region, frameshift
Principles of Human Genetics
20 Kb
Chapter 82
116.90 Mb
Figure 82-3 Chromosome 7 is shown with the density of single-nucleotide polymorphisms (SNPs) and genes above. A 200-kb region in 7q31.2 containing the CFTR gene is shown below. The CFTR gene contains 27 exons. More than 1900 mutations in this gene have been found in patients with cystic fibrosis. A 20-kb region encompassing exons 4–9 is shown further amplified to illustrate the SNPs in this region. because the complement of mRNAs transcribed by the cellular genome is called the transcriptome. Most studies of gene expression have focused on the regulatory DNA elements of genes that control transcription. However, it should be emphasized that gene expression requires a series of steps, including mRNA processing, protein translation, and posttranslational modifications, all of which are actively regulated (Fig. 82-2).
Figure 82-4 The origin of haplotypes is due to repeated recombination events occurring in multiple generations. Over time, this leads to distinct haplotypes. These haplotype blocks can often be characterized by genotyping selected Tag single-nucleotide polymorphisms (SNPs), an approach that facilitates performing genome-wide association studies (GWAS).
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Epigenetic Regulation of Gene Expression Epigenetics describes mechanisms and phenotypic changes that are not a result of variation in the primary DNA nucleotide sequence, but are caused by secondary modifications of DNA or histones. These modifications include heritable changes such as X-inactivation and imprinting, but they can also result from dynamic posttranslational protein modifications in response to environmental influences such as diet, age, or drugs. The epigenetic modifications result in altered expression of individual genes or chromosomal loci encompassing multiple genes. The term epigenome describes the constellation of covalent modifications of DNA and histones that impact chromatin structure, as well as noncoding transcripts that modulate the transcriptional activity of DNA. Although the primary DNA sequence is usually identical in all cells of an organism, tissue-specific changes in the epigenome contribute to determining the transcriptional signature of a cell (transcriptome) and hence the protein expression profile (proteome). Mechanistically, DNA and histone modifications can result in the activation or silencing of gene expression (Fig. 82-7). DNA methylation involves the addition of a methyl group to cytosine residues. This is
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usually restricted to cytosines of CpG dinucleotides, which are abundant throughout the genome. Methylation of these dinucleotides is thought to represent a defense mechanism that minimizes the expression of sequences that have been incorporated into the Duplicated genome such as retroviral sequences. CpG dinucleotides Area also exist in so-called CpG islands, stretches of DNA Deleted characterized by a high CG content, which are found in Area the majority of human gene promoters. CpG islands in 2 promoter regions are typically unmethylated, and the lack of methylation facilitates transcription. Histone methylation involves the addition of a methyl 1 group to lysine residues in histone proteins (Fig. 82-7). Depending on the specific lysine residue being methylated, this alters chromatin configuration, either making it more open or tightly packed. Acetylation of histone 0 proteins is another well-characterized mechanism that results in an open chromatin configuration, which favors active transcription. Acetylation is generally more dynamic than methylation, and many transcriptional –1 activation complexes have histone acetylase activity, whereas repressor complexes often contain deacetylases and remove acetyl groups from histones. Other histone modifications, whose effects are incompletely character–2 ized, include phosphorylation and sumoylation. Lastly, noncoding RNAs that bind to DNA can have a signifiChromosome 8 cant impact on transcriptional activity. Physiologically, epigenetic mechanisms play an Figure 82-5 Copy number variations (CNV) encompass relatively large regions important role in several instances. For example, of the genome that have been duplicated or deleted. Chromosome 8 is shown with X-inactivation refers to the relative silencing of one CNV detected by genomic hybridization. An increase in the signal strength indicates a of the two X chromosome copies present in females. duplication, a decrease reflects a deletion of the covered chromosomal regions. The inactivation process is a form of dosage compensation such that females (XX) do not generally express twice as many X-chromosomal gene products as males (XY). In a given cell, the choice of which chromosome is inactivated occurs randomly in humans. But A A a a A a once the maternal or paternal X chromosome is inactivated, it will B B b b B b remain inactive, and this information is transmitted with each cell C C c c C c division. The X-inactive specific transcript (Xist) gene encodes a large noncoding RNA that mediates the silencing of the X chromosome from D D d d D d which it is transcribed by coating it with Xist RNA. The inactive X chromosome is highly methylated and has low levels of histone acetylation. Chromatids Homologous chromosomes Epigenetic gene inactivation also occurs on selected chromosomal regions of autosomes, a phenomenon referred to as genomic imprinting. Through this mechanism, a small subset of genes is only expressed in a monoallelic fashion. Imprinting is heritable and leads to the preferA a A a A a A a A a A a ential expression of one of the parental alleles, which deviates from the B b B b B b B b B b B b usual biallelic expression seen for the majority of genes. Remarkably, c c C C c c C C C c C c imprinting can be limited to a subset of tissues. Imprinting is mediated through DNA methylation of one of the alleles. The epigenetic d d D D D d D d D d D d marks on imprinted genes are maintained throughout life, but during Cross-over Double cross-over No cross-over zygote formation, they are activated or inactivated in a sex-specific manner (imprint reset) (Fig. 82-8), which allows a differential expression pattern in the fertilized egg and the subsequent mitotic divisions. Appropriate expression of imprinted genes is important for normal A a A a A a A a A a A a development and cellular functions. Imprinting defects and uniparental B b B b B b B b B b B b disomy, which is the inheritance of two chromosomes or chromosomal c c C C c c C C C c C c regions from the same parent, are the cause of several developmental disorders such as Beckwith-Wiedemann syndrome, Silver-Russell D d D d d d D D D d D d syndrome, Angelman’s syndrome, and Prader-Willi syndrome (see Recombination Recombination No recombination below). Monoallelic loss-of-function mutations in the GNAS1 gene lead in gametes in gametes in gametes to Albright’s hereditary osteodystrophy (AHO). Paternal transmission of GNAS1 mutations leads to an isolated AHO phenotype (pseudopFigure 82-6 Crossing-over and genetic recombination. During seudohypoparathyroidism), whereas maternal transmission leads to chiasma formation, either of the two sister chromatids on one chroAHO in combination with hormone resistance to parathyroid hormosome pairs with one of the chromatids of the homologous chromone, thyrotropin, and gonadotropins (pseudohypoparathyroidism mosome. Genetic recombination occurs through crossing-over and type IA). These phenotypic differences are explained by tissue-specific results in recombinant and nonrecombinant chromosome segments imprinting of the GNAS1 gene, which is expressed primarily from the in the gametes. Together with the random segregation of the matermaternal allele in the thyroid, gonadotropes, and the proximal renal nal and paternal chromosomes, recombination contributes to genetic tubule. In most other tissues, the GNAS1 gene is expressed biallelically. diversity and forms the basis of the concept of linkage.
log2 (ratio)
Normal
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TABLE 82-2 Selected Examples of Diseases Caused by Mutations and Rearrangements in Transcription Factor Classes Transcription Factor Class Example Nuclear receptors Androgen receptor Zinc finger proteins Basic helix-loop-helix Homeobox
WT1 MITF IPF1
Leucine zipper
Retina leucine zipper (NRL) SRY
High mobility group (HMG) proteins Forkhead Paired box T-box Cell cycle control proteins Co-activators
CBFA2 PML-RAR
Sex reversal Maturity onset of diabetes mellitus types 1, 3, 5 Waardenburg’s syndrome types 1 and 3 Holt-Oram syndrome (thumb anomalies, atrial or ventricular septum defects, phocomelia) Li-Fraumeni syndrome, other cancers Rubinstein-Taybi syndrome Spinocerebellar ataxia 17 (CAG expansion) von Hippel–Lindau syndrome (renal cell carcinoma, pheochromocytoma, pancreatic tumors, hemangioblastomas) Autosomal dominant inheritance, somatic inactivation of second allele (Knudson two-hit model) Familial thrombocytopenia with propensity to acute myelogenous leukemia Acute promyelocytic leukemia t(15;17)(q22;q11.2-q12) translocation
Abbreviations: CREB, cAMP responsive element–binding protein; HNF, hepatocyte nuclear factor; PML, promyelocytic leukemia; RAR, retinoic acid receptor; SRY, sex-determining region Y; VHL, von Hippel–Lindau.
It is caused by mutations in the MECP2 gene, which encodes a methylbinding protein. The ensuing aberrant methylation results in abnormal gene expression in neurons, which are otherwise normally developed. Remarkably, epigenetic differences also occur among monozygotic twins. Although twins are epigenetically indistinguishable during the early years of life, older monozygotic twins exhibit differences in the overall content Methylated DNA Cytosine Methylation and genomic distribution of DNA methylaMethylation tion and histone acetylation, which would NH2 NH2 be expected to alter gene expression in variCH3 ous tissues. N N In cancer, the epigenome is characterized by simultaneous losses and gains of DNA O O N N methylation in different genomic regions, as well as repressive histone modifications. Hyper- and hypomethylation are associated with mutations in genes that control DNA methylation. Hypomethylation is thought to Histone Modifications Unmethylated DNA Histone Acetylation remove normal control mechanisms that prevent expression of repressed DNA regions. It is also associated with genomic instability. Hypermethylation, in contrast, results in the silencing of CpG islands in promoter Acetylation regions of genes, including tumor-suppressor Methylation genes. Epigenetic alterations are considered Phosphorylation to be more easily reversible compared to Sumoylation Transcription NH2 genetic changes, and modification of the epigenome with demethylating agents and histone Figure 82-7 Epigenetic modifications of DNA and histones. Methylation of cytosine resideacetylases is being explored in clinical trials. dues is associated with gene silencing. Methylation of certain genomic regions is inherited (imprinting), and it is involved in the silencing of one of the two X chromosomes in females MODELS OF GENETIC DISEASE (X-inactivation). Alterations in methylation can also be acquired, e.g., in cancer cells. Covalent Several organisms have been studied extenposttranslational modifications of histones play an important role in altering DNA accessibilsively as genetic models, including M. musity and chromatin structure and hence in regulating transcription. Histones can be reversibly culus (mouse), D. melanogaster (fruit fly), modified in their amino-terminal tails, which protrude from the nucleosome core particle, by C. elegans (nematode), S. cerevisiae (baker’s acetylation of lysine, phosphorylation of serine, methylation of lysine and arginine residues, and yeast), and E. coli (colonic bacterium). The sumoylation. Acetylation of histones by histone acetylases (HATs), e.g., leads to unwinding of chromatin and accessibility to transcription factors. Conversely, deacetylation by histone deacet- ability to use these evolutionarily distant organisms as genetic models that are r elevant ylases (HDACs) results in a compact chromatin structure and silencing of transcription. In patients with isolated renal resistance to parathyroid hormone (pseudohypoparathyroidism type IB), defective imprinting of the GNAS1 gene results in decreased Gsα expression in the proximal renal tubules. Rett’s syndrome is an X-linked dominant disorder resulting in developmental regression and stereotypic hand movements in affected girls.
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Runt Chimeric proteins due to translocations
Associated Disorder Complete or partial androgen insensitivity (recessive missense mutations) Spinobulbar muscular atrophy (CAG repeat expansion) WAGR syndrome: Wilms’ tumor, aniridia, genitourinary malformations, mental retardation Waardenburg’s syndrome type 2A Maturity onset of diabetes mellitus type 4 (heterozygous mutation/haploinsufficiency) Pancreatic agenesis (homozygous mutation) Autosomal dominant retinitis pigmentosa
Chapter 82
General transcription factors Transcription elongation factor
HNF4α, HNF1α, HNF1β PAX3 TBX5 P53 CREB binding protein (CBP) TATA-binding protein (TBP) VHL
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its functional consequences. Some mutations may be lethal, others are less deleterious, and some may confer an evolutionary advantage. mat pat pat mat Mutations can occur in the germline (sperm or oocytes); these can be transmitted to progeny. Alternatively, mutations can occur during embryogenesis or in somatic tissues. Mutations that occur during development Active Inactive Inactive Active lead to mosaicism, a situation in which tissues Unmethylated Methylated Methylated Unmethylated are composed of cells with different genetic constitutions. If the germline is mosaic, a mutation can be transmitted to some progeny but not others, which sometimes leads to conGermline development: fusion in assessing the pattern of inheritance. Somatic mutations that do not affect cell Imprint reset survival can sometimes be detected because of variable phenotypic effects in tissues (e.g., Maternal germline Paternal germline pigmented lesions in McCune-Albright syndrome). Other somatic mutations are assomat pat pat mat ciated with neoplasia because they confer a growth advantage to cells. Epigenetic events may also influence gene expression or facilitate genetic damage. With the exception of triplet nucleotide repeats, which can expand Active Active Inactive Inactive (see below), mutations are usually stable. Unmethylated Unmethylated Methylated Methylated Mutations are structurally diverse—they can involve the entire genome, as in triploidy (one extra set of chromosomes), or gross numerical or structural alterations in chromosomes or individual genes (Chap. 83e). Large deletions may affect a portion of a gene or an entire gene, or, if several genes are involved, they may lead to a contiguous gene syndrome. Unequal crossing-over between Zygote homologous genes can result in fusion gene mutations, as illustrated by color blindness. pat mat Mutations involving single nucleotides are referred to as point mutations. Substitutions are called transitions if a purine is replaced by another purine base (A ↔ G) or if a pyrimidine is replaced by another pyrimidine (C ↔ T). Inactive Active Changes from a purine to a pyrimidine, or Methylated Unmethylated vice versa, are referred to as transversions. If the DNA sequence change occurs in a coding region and alters an amino acid, it is Figure 82-8 A few genomic regions are imprinted in a parent-specific fashion. The called a missense mutation. Depending on the unmethylated chromosomal regions are actively expressed, whereas the methylated regions functional consequences of such a missense are silenced. In the germline, the imprint is reset in a parent-specific fashion: both chromomutation, amino acid substitutions in differsomes are unmethylated in the maternal (mat) germline and methylated in the paternal (pat) ent regions of the protein can lead to distinct germline. In the zygote, the resulting imprinting pattern is identical with the pattern in the phenotypes. somatic cells of the parents. Mutations can occur in all domains of a gene (Fig. 82-9). A point mutation occurring to human physiology reflects a surprising conservation of genetic pathways and gene function. Transgenic mouse models have been within the coding region leads to an amino acid substitution if the particularly valuable, because many human and mouse genes exhibit codon is altered (Fig. 82-10). Point mutations that introduce a presimilar structure and function and because manipulation of the mouse mature stop codon result in a truncated protein. Large deletions may genome is relatively straightforward compared to that of other mam- affect a portion of a gene or an entire gene, whereas small deletions malian species. Transgenic strategies in mice can be divided into two and insertions alter the reading frame if they do not represent a mulmain approaches: (1) expression of a gene by random insertion into the tiple of three bases. These “frameshift” mutations lead to an entirely genome, and (2) deletion or targeted mutagenesis of a gene by homolo- altered carboxy terminus. Mutations in intronic sequences or in exon gous recombination with the native endogenous gene (knock-out, junctions may destroy or create splice donor or splice acceptor sites. knock-in). Previous versions of this chapter provide more detail about Mutations may also be found in the regulatory sequences of genes, the technical principles underlying the development of genetically modi- resulting in reduced or enhanced gene transcription. Certain DNA sequences are particularly susceptible to mutagenfied animals. Several databases provide comprehensive information about natural and transgenic animal models, the associated phenotypes, esis. Successive pyrimidine residues (e.g., T-T or C-C) are subject to the formation of ultraviolet light–induced photoadducts. If these and integrated genetic, genomic, and biologic data (Table 82-1). pyrimidine dimers are not repaired by the nucleotide excision repair pathway, mutations will be introduced after DNA synthesis. The TRANSMISSION OF GENETIC DISEASE Origins and Types of Mutations A mutation can be defined as any dinucleotide C-G, or CpG, is also a hot spot for a specific type of change in the primary nucleotide sequence of DNA regardless of mutation. In this case, methylation of the cytosine is associated with
Maternal somatic cell
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it is often unclear whether it creates a mutation with functional consequences or a benign polymorphism. In this situation, the sequence alteration is described as variant of unknown significance (VUS).
1
*
A
1 Promoter 5'UTR
2 intron 1
3 intron 2
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Poly A
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Wild-type
Chapter 82
Mutation rates Mutations represent an important cause of genetic diversity as well as disease. Mutation rates are difficult to determine in humans because many mutations are silent and because testing is often not adequate ε Gγ Aγ ψβ β δ to detect the phenotypic consequences. Mutation rates vary in different genes –10 kb 0 kb 10 kb 20 kb 30 kb 40 kb 50 kb 60 kb but are estimated to occur at a rate of ~10−10/bp per cell division. Germline β-Globin Gene Cluster mutation rates (as opposed to somatic Figure 82-9 Point mutations causing β thalassemia as example of allelic heterogeneity. The mutations) are relevant in the transβ-globin gene is located in the globin gene cluster. Point mutations can be located in the promoter, mission of genetic disease. Because the CAP site, the 5’-untranslated region, the initiation codon, each of the three exons, the introns, the population of oocytes is estabor the polyadenylation signal. Many mutations introduce missense or nonsense mutations, whereas lished very early in development, only others cause defective RNA splicing. Not shown here are deletion mutations of the β-globin gene or ~20 cell divisions are required for comlarger deletions of the globin locus that can also result in thalassemia. ▼, promoter mutations; *, CAP pleted oogenesis, whereas spermatosite; •, 5’UTR; 1 , initiation codon; ♦, defective RNA processing; ✦, missense and nonsense genesis involves ~30 divisions by the mutations; A , Poly A signal. time of puberty and 20 cell divisions each year thereafter. Consequently, the probability of acquiring new point an enhanced rate of deamination to uracil, which is then replaced with mutations is much greater in the male germline than the female thymine. This C → T transition (or G → A on the opposite strand) germline, in which rates of aneuploidy are increased (Chap. 83e). accounts for at least one-third of point mutations associated with Thus, the incidence of new point mutations in spermatogonia polymorphisms and mutations. In addition to the fact that certain increases with paternal age (e.g., achondrodysplasia, Marfan’s syntypes of mutations (C → T or G → A) are relatively common, the drome, neurofibromatosis). It is estimated that about 1 in 10 sperm nature of the genetic code also results in overrepresentation of certain carries a new deleterious mutation. The rates for new mutations are calculated most readily for autosomal dominant and X-linked amino acid substitutions. Polymorphisms are sequence variations that have a frequency of disorders and are ~10−5−10−6/locus per generation. Because most at least 1%. Usually, they do not result in a perceptible phenotype. monogenic diseases are relatively rare, new mutations account for Often they consist of single base-pair substitutions that do not alter a significant fraction of cases. This is important in the context of the protein coding sequence because of the degenerate nature of the genetic counseling, because a new mutation can be transmitted genetic code (synonymous polymorphism), although it is possible to the affected individual but does not necessarily imply that the that some might alter mRNA stability, translation, or the amino parents are at risk to transmit the disease to other children. An acid sequence (nonsynonymous polymorphism) (Fig. 82-10). The exception to this is when the new mutation occurs early in germline detection of sequence variants poses a practical problem because development, leading to gonadal mosaicism. Wild-type
DNA GCA CTC CTA TCG CAC GCT CGG GAG GGC GAA AAT GAG AGC T T C A C C G A C T T C A T A T G C L L S H A R E G E N E S A AA F T D F I C Silent mutation DNA GCA CTC CTA TCG CAC GCT CGT GAG GGC GAA AAT GAG AGC L L S H A R E G E N E S Heterozygous point mutation A AA Missense mutation DNA GCA CTC CTA TCG CAC GCT CCG GAG GGC GAA AAT GAG AGC L L S H A P E G E N E S A AA
TTC ACC GAC TTC ATA TGC F I C F T D TAC Y
Nonsense mutation DNA GCA CTC CTA TCG CAC GCT CGG GAG GGC TAA AAT GAG AGC Homozygous point mutation L L S H A R E G X A AA 1 bp Deletion with frameshift
TTC ACC TAC TTC ATA TGC F T Y F I C
DNA GCA CTC CTA CGC ACG CTC GGG AGG GCG AAA ATG AGA GC L L R T L G R A K M R A AA A
B
Figure 82-10 A. Examples of mutations. The coding strand is shown with the encoded amino acid sequence. B. Chromatograms of sequence analyses after amplification of genomic DNA by polymerase chain reaction.
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Unequal crossing-over Normally, DNA recombination in germ cells occurs with remarkable fidelity to maintain the precise junction sites for the exchanged DNA sequences (Fig. 82-6). However, mispairing of homologous sequences leads to unequal crossover, with gene duplication on one of the chromosomes and gene deletion on the other chromosome. A significant fraction of growth hormone (GH) gene deletions, for example, involve unequal crossing-over (Chap. 402). The GH gene is a member of a large gene cluster that includes a GH variant gene as well as several structurally related chorionic somatomammotropin genes and pseudogenes (highly homologous but functionally inactive relatives of a normal gene). Because such gene clusters contain multiple homologous DNA sequences arranged in tandem, they are particularly prone to undergo recombination and, consequently, gene duplication or deletion. On the other hand, duplication of the PMP22 gene because of unequal crossing-over results in increased gene dosage and type IA Charcot-Marie-Tooth disease. Unequal crossing-over resulting in deletion of PMP22 causes a distinct neuropathy called hereditary liability to pressure palsy (Chap. 459). Glucocorticoid-remediable aldosteronism (GRA) is caused by a gene fusion or rearrangement involving the genes that encode aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1), normally arranged in tandem on chromosome 8q. These two genes are 95% identical, predisposing to gene duplication and deletion by unequal crossing-over. The rearranged gene product contains the regulatory regions of 11β-hydroxylase fused to the coding sequence of aldosterone synthetase. Consequently, the latter enzyme is expressed in the adrenocorticotropic hormone (ACTH)–dependent zona fasciculata of the adrenal gland, resulting in overproduction of mineralocorticoids and hypertension (Chap. 406). Gene conversion refers to a nonreciprocal exchange of homologous genetic information. It has been used to explain how an internal portion of a gene is replaced by a homologous segment copied from another allele or locus; these genetic alterations may range from a few nucleotides to a few thousand nucleotides. As a result of gene conversion, it is possible for short DNA segments of two chromosomes to be identical, even though these sequences are distinct in the parents. A practical consequence of this phenomenon is that nucleotide substitutions can occur during gene conversion between related genes, often altering the function of the gene. In disease states, gene conversion often involves intergenic exchange of DNA between a gene and a related pseudogene. For example, the 21-hydroxylase gene (CYP21A2) is adjacent to a nonfunctional pseudogene (CYP21A1P). Many of the nucleotide substitutions that are found in the CYP21A2 gene in patients with congenital adrenal hyperplasia correspond to sequences that are present in the CYP21A1P pseudogene, suggesting gene conversion as one cause of mutagenesis. In addition, mitotic gene conversion has been suggested as a mechanism to explain revertant mosaicism in which an inherited mutation is “corrected” in certain cells. For example, patients with autosomal recessive generalized atrophic benign epidermolysis bullosa have acquired reverse mutations in one of the two mutated COL17A1 alleles, leading to clinically unaffected patches of skin. Insertions and deletions Although many instances of insertions and deletions occur as a consequence of unequal crossing-over, there is also evidence for internal duplication, inversion, or deletion of DNA sequences. The fact that certain deletions or insertions appear to occur repeatedly as independent events indicates that specific regions within the DNA sequence predispose to these errors. For example, certain regions of the DMD gene, which encodes dystrophin, appear to be hot spots for deletions and result in muscular dystrophy (Chap. 462e). Some regions within the human genome are rearrangement hot spots and lead to CNVs. Errors in DNA repair Because mutations caused by defects in DNA repair accumulate as somatic cells divide, these types of mutations are particularly important in the context of neoplastic disorders (Chap. 102e). Several genetic disorders involving DNA repair enzymes underscore their importance. Patients with xeroderma pigmentosum have defects in DNA damage recognition or in the nucleotide excision and repair pathway (Chap. 105). Exposed skin is dry and pigmented
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and is extraordinarily sensitive to the mutagenic effects of ultraviolet irradiation. More than 10 different genes have been shown to cause the different forms of xeroderma pigmentosum. This finding is consistent with the earlier classification of this disease into different complementation groups in which normal function is rescued by the fusion of cells derived from two different forms of xeroderma pigmentosum. Ataxia telangiectasia causes large telangiectatic lesions of the face, cerebellar ataxia, immunologic defects, and hypersensitivity to ionizing radiation (Chap. 450). The discovery of the ataxia telangiectasia mutated (ATM) gene reveals that it is homologous to genes involved in DNA repair and control of cell cycle checkpoints. Mutations in the ATM gene give rise to defects in meiosis as well as increasing susceptibility to damage from ionizing radiation. Fanconi’s anemia is also associated with an increased risk of multiple acquired genetic abnormalities. It is characterized by diverse congenital anomalies and a strong predisposition to develop aplastic anemia and acute myelogenous leukemia (Chap. 132). Cells from these patients are susceptible to chromosomal breaks caused by a defect in genetic recombination. At least 13 different complementation groups have been identified, and the loci and genes associated with Fanconi’s anemia have been cloned. HNPCC (Lynch’s syndrome) is characterized by autosomal dominant transmission of colon cancer, young age (200 5–30/200–1000 6–34/37–180 6–39/40–88 15–31/34–400 13–36/55–86
XR XR AD, variable penetrance AD AD AD AD
FMR-1 protein FMR-2 protein Myotonin protein kinase Huntingtin Ataxin 1 Ataxin 2 Ataxin 3
19p13.1-13.2
CAG
4–16/20–33
AD
3p21.1-p12 5q31
CAG CAG
4–19/37 to >300 6–26/66–78
AD AD
Alpha 1A voltage-dependent L-type calcium channel Ataxin 7 Protein phosphatase 2A
12p
CAG
7–23/49–75
AD
Atrophin 1
9q13-21
GAA
7–22/200–900
AR
Frataxin
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XR, X-linked recessive.
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TABLE 82-5 Genes and Loci Involved in Mono- and Polygenic Forms of Diabetes Disorder Monogenic permanent neonatal diabetes mellitus
Chromosomal Location 11p15.1
Other Factors AD
7p15-p13 11p15.5 11p15.1
AR AR, hyperproinsulinemia AD or AR
9p24.2
AR, diabetes, congenital hypothyroidism
HNF4α (hepatocyte nuclear factor 4α) GCK (glucokinase) HNF1α (hepatocyte nuclear factor 1α) IPF1 (insulin receptor substrate) HNF1β (hepatocyte nuclear factor 1β) NeuroD1 (neurogenic differentiation factor 1) KLF1 (Kruppel-like factor 1) CEL (carboxyl ester lipase) PAX4 (paired box transcription factor 4) INS (insulin) BLK (B-lymphocyte-specific tyrosine kinase) Genes and loci identified by linkage/association studies
20q12-q13.1 7p15-p13 12q24.2 13q12.1 17cen-q21.3 2q32 19p13.13-p13.12 9q34.3 7q32 11p15.5 8p23-p22
AD inheritance
Chapter 82 Heavily influenced by diet, energy expenditure, obesity
PPARG, KCNJ11/ABCC8, TCF7L2, IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX, FTO, HNF1B, NOTCH2, THADA, ADAMSTS9, JAZF1, CDC122/CAMK1D, KCNQ1, TSPAN8/LGR5, IRS1, DUSP9, PROX1, BCK11A, G6PC2, GCKR, ADCY5, SLC2A2, WFS1, ZBED3, DGKB/TMEM195, GCK, KLF14, TP53INP1, GLIS3, TLE4, ADRA2A, CENTD2, CRY2, FADS1, MADD, MTNR1B, HMGA1, HNF1A, IGF1A, IGF1, C2CD4B, PRC1, VPS13C, ZFAND6, GIPR Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MODY, maturity onset diabetes of the young.
The identification of genetic variations and environmental factors that either predispose to or protect against disease is essential for predicting disease risk, designing preventive strategies, and developing novel therapeutic approaches. The study of rare monogenic diseases may provide insight into some of the genetic and molecular mechanisms important in the pathogenesis of complex diseases. For example, the identification of the genes causing monogenic forms of permanent neonatal diabetes mellitus or maturity-onset diabetes defined them as candidate genes in the pathogenesis of diabetes mellitus type 2 (Tables 82-2 and 82-5). Genome scans have identified numerous genes and loci that may be associated with susceptibility to development of diabetes mellitus in certain populations. Efforts to identify susceptibility genes require very large sample sizes, and positive results may depend on ethnicity, ascertainment criteria, and statistical analysis. Association studies analyzing the potential influence of (biologically functional) SNPs and SNP haplotypes on a particular phenotype are providing new insights into the genes involved in the pathogenesis of these common disorders. Large variants ([micro]deletions, duplications, and inversions) present in the human population also contribute to the pathogenesis of complex disorders, but their contributions remain poorly understood. Linkage and Association Studies There are two primary strategies for mapping genes that cause or increase susceptibility to human disease: (1) classic linkage can be performed based on a known genetic model or, when the model is unknown, by studying pairs of affected relatives; or (2) disease genes can be mapped using allelic association studies (Table 82-6). Genetic linkage Genetic linkage refers to the fact that genes are physically connected, or linked, to one another along the chromosomes.
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Maturity-onset diabetes of the young (MODY): Monogenic forms of diabetes mellitus MODY 1 MODY 2 MODY 3 MODY 4 MODY 5 (renal cysts, diabetes) MODY 6 MODY 7 MODY 8 MODY 9 MODY 10 MODY 11 Diabetes mellitus type 2; loci and genes linked and/or associated with susceptibility for diabetes mellitus type 2
Genes or Susceptibility Locus KCNJ11 (inwardly rectifying potassium channel Kir6.2) GCK (glucokinase) INS (insulin) ABCC8 (ATP-binding cassette, subfamily c, member 8; sulfonylurea receptor) GLIS3 (GLIS family zinc finger protein 3)
Two fundamental principles are essential for understanding the concept of linkage: (1) when two genes are close together on a chromosome, they are usually transmitted together, unless a recombination event separates them (Figs. 82-6); and (2) the odds of a crossover, or recombination event, between two linked genes is proportional to the distance that separates them. Thus, genes that are farther apart are more likely to undergo a recombination event than genes that are very close together. The detection of chromosomal loci that segregate with a disease by linkage can be used to identify the gene responsible for the disease (positional cloning) and to predict the odds of disease gene transmission in genetic counseling. Polymorphisms are essential for linkage studies because they provide a means to distinguish the maternal and paternal chromosomes in an individual. On average, 1 out of every 1000 bp varies from one person to the next. Although this degree of variation seems low (99.9% identical), it means that >3 million sequence differences exist between any two unrelated individuals and the probability that the sequence at such loci will differ on the two homologous chromosomes is high (often >70–90%). These sequence variations include variable number of tandem repeats (VNTRs), short tandem repeats (STRs), and SNPs. Most STRs, also called polymorphic microsatellite markers, consist of di-, tri-, or tetranucleotide repeats that can be characterized readily using the polymerase chain reaction (PCR). Characterization of SNPs, using DNA chips or beads, permits comprehensive analyses of genetic variation, linkage, and association studies. Although these sequence variations often have no apparent functional consequences, they provide much of the basis for variation in genetic traits. In order to identify a chromosomal locus that segregates with a disease, it is necessary to characterize polymorphic DNA markers from affected and unaffected individuals of one or several pedigrees. One can
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TABLE 82-6 Genetic Approaches for Identifying Disease Genes Method Linkage Studies Classical linkage analysis (parametric methods)
Allele-sharing methods (nonparametric methods) Affected sib and relative pair analyses Sib pair analysis
Association Studies Case-control studies
Indications and Advantages
Limitations
Analysis of monogenic traits
Difficult to collect large informative pedigrees
Suitable for genome scan
Difficult to obtain sufficient statistical power for complex traits
Control population not required Useful for multifactorial disorders in isolated populations Suitable for identification of susceptibility genes in polygenic and multifactorial disorders Suitable for genome scan Control population not required if allele frequencies are known Statistical power can be increased by including parents and relatives
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Transmission disequilibrium test (TDT)
Suitable for identification of susceptibility genes in polygenic and multifactorial disorders Suitable for testing specific allelic variants of known candidate loci Facilitated by HapMap data, making GWAS more feasible
Whole-genome association studies
Does not necessarily need relatives
Linkage disequilibrium
Difficult to collect sufficient number of subjects Difficult to obtain sufficient statistical power for complex traits Reduced power compared to classical linkage, but not sensitive to specification of genetic mode
Requires large sample size and matched control population False-positive results in the absence of suitable control population Candidate gene approach does not permit detection of novel genes and pathways Susceptibility genes can vary among different populations
Genes, the Environment, and Disease
Abbreviation: GWAS, genome-wide association study.
then assess whether certain marker alleles cosegregate with the disease. Markers that are closest to the disease gene are less likely to undergo recombination events and therefore receive a higher linkage score. Linkage is expressed as a lod (logarithm of odds) score—the ratio of the probability that the disease and marker loci are linked rather than unlinked. Lod scores of +3 (1000:1) are generally accepted as supporting linkage, whereas a score of –2 is consistent with the absence of linkage. Allelic association, linkage disequilibrium, and haplotypes Allelic association refers to a situation in which the frequency of an allele is significantly increased or decreased in individuals affected by a particular disease in comparison to controls. Linkage and association differ in several aspects. Genetic linkage is demonstrable in families or sibships. Association studies, on the other hand, compare a population of affected individuals with a control population. Association studies can be performed as case-control studies that include unrelated affected individuals and matched controls or as family-based studies that compare the frequencies of alleles transmitted or not transmitted to affected children. Allelic association studies are particularly useful for identifying susceptibility genes in complex diseases. When alleles at two loci occur more frequently in combination than would be predicted (based on known allele frequencies and recombination fractions), they are said to be in linkage disequilibrium. Evidence for linkage disequilibrium can be helpful in mapping disease genes because it suggests that the two loci are tightly linked. Detecting the genetic factors contributing to the pathogenesis of common complex disorders remains a great challenge. In many instances, these are low-penetrance alleles (e.g., variations that individually have a subtle effect on disease development, and they can only be identified by unbiased GWAS) (Catalog of Published GenomeWide Association Studies; Table 82-1) (Fig. 82-14). Most variants occur in noncoding or regulatory sequences but do not alter protein structure. The analysis of complex disorders is further complicated by ethnic differences in disease prevalence, differences in allele frequencies in known susceptibility genes among different populations, locus and allelic heterogeneity, gene-gene and gene-environment interactions, and the possibility of phenocopies. The data generated by the HapMap Project are greatly facilitating GWAS for the characterization of complex disorders. Adjacent SNPs are inherited together
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as blocks, and these blocks can be identified by genotyping selected marker SNPs, so-called Tag SNPs, thereby reducing cost and workload (Fig. 82-4). The availability of this information permits the characterization of a limited number of SNPs to identify the set of haplotypes present in an individual (e.g., in cases and controls). This, in turn, permits performing GWAS by searching for associations of certain haplotypes with a disease phenotype of interest, an essential step for unraveling the genetic factors contributing to complex disorders. Population genetics In population genetics, the focus changes from alterations in an individual’s genome to the distribution pattern of different genotypes in the population. In a case where there are only two alleles, A and a, the frequency of the genotypes will be p2 + 2pq + q2 = 1, with p2 corresponding to the frequency of AA, 2pq to the frequency of Aa, and q2 to aa. When the frequency of an allele is known, the frequency of the genotype can be calculated. Alternatively, one can determine an allele frequency if the genotype frequency has been determined. Allele frequencies vary among ethnic groups and geographic regions. For example, heterozygous mutations in the CFTR gene are relatively common in populations of European origin but are rare in the African population. Allele frequencies may vary because certain allelic variants confer a selective advantage. For example, heterozygotes for the sickle cell mutation, which is particularly common in West Africa, are more resistant to malarial infection because the erythrocytes of heterozygotes provide a less favorable environment for Plasmodium parasites. Although homozygosity for the sickle cell mutation is associated with severe anemia and sickle crises (Chap. 127), heterozygotes have a higher probability of survival because of the reduced morbidity and mortality from malaria; this phenomenon has led to an increased frequency of the mutant allele. Recessive conditions are more prevalent in geographically isolated populations because of the more restricted gene pool.
APPROACH TO THE PATIENT: Inherited Disorders For the practicing clinician, the family history remains an essential step in recognizing the possibility of a hereditary predisposition to disease. When taking the history, it is useful to draw a detailed
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443 50
Effect size
Rare: Common variants with high effect on complex disease
Rare alleles Mendelian disease
High
3.0 Low frequency variants with intermediate effect
Intermediate 1.5 Modest 1.1
Typical: Common variants with low effect on complex disease
Rare variants with small effect: difficult to identify
Low 0.001
0.005 Rare
0.05 Low frequency
Common
Allele frequency Figure 82-14 Relationship between allele frequency and effect size in monogenic and polygenic disorders. In classic Mendelian disorders, the allele frequency is typically low but has a high impact (single gene disorder). This contrasts with polygenic disorders that require the combination of multiple low impact alleles that are frequently quite common in the general population.
IDENTIFYING THE DISEASE-CAUSING GENE Genomic medicine aims to enhance the quality of medical care through the use of genotypic analysis (DNA testing) to identify genetic predisposition to disease, to select more specific pharmacotherapy, and to design individualized medical care based on genotype.
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Genotype can be deduced by analysis of protein (e.g., hemoglobin, apoprotein E), mRNA, or DNA. However, technologic advances have made DNA analysis particularly useful because it can be readily applied. DNA testing is performed by mutational analysis or linkage studies in individuals at risk for a genetic disorder known to be present in a family. Mass screening programs require tests of high sensitivity and specificity to be cost-effective. Prerequisites for the success of genetic screening programs include the following: that the disorder is potentially serious; that it can be influenced at a presymptomatic stage by changes in behavior, diet, and/or pharmaceutical manipulations; and that the screening does not result in any harm or discrimination. Screening in Jewish populations for the autosomal recessive neurodegenerative storage disease TaySachs has reduced the number of affected individuals. In contrast, screening for sickle cell trait/disease in African Americans has led to unanticipated problems of discrimination by health insurers and employers. Mass screening programs harbor additional potential problems. For example, screening for the most common genetic alteration in cystic fibrosis, the ΔF508 mutation with a frequency of ~70% in northern Europe, is feasible and seems to be effective. One has to keep in mind, however, that there is pronounced allelic heterogeneity and that the disease can be caused by about 2000 other mutations. The search for these less common mutations would substantially increase costs but not the effectiveness of the screening program as a whole. Next-generation genome sequencing permits comprehensive and cost-effective mutational analyses after selective enrichment of candidate genes. For example, tests that sequence all the common genes causing hereditary deafness are already commercially available. Occupational screening programs aim to detect individuals with increased risk for certain professional activities (e.g., α1 antitrypsin deficiency and smoke or dust exposure). Integrating genomic data into electronic medical records is evolving and may provide significant decision support at the point of care, for example, by providing the clinician with genomic data and decision algorithms for the prescription of drugs that are subject to pharmacogenetic influences.
Principles of Human Genetics
pedigree of the first-degree relatives (e.g., parents, siblings, and children), because they share 50% of genes with the patient. Standard symbols for pedigrees are depicted in Fig. 82-11. The family history should include information about ethnic background, age, health status, and deaths, including infants. Next, the physician should explore whether there is a family history of the same or related illnesses to the current problem. An inquiry focused on commonly occurring disorders such as cancers, heart disease, and diabetes mellitus should follow. Because of the possibility of age-dependent expressivity and penetrance, the family history will need intermittent updating. If the findings suggest a genetic disorder, the clinician should assess whether some of the patient’s relatives may be at risk of carrying or transmitting the disease. In this circumstance, it is useful to confirm and extend the pedigree based on input from several family members. This information may form the basis for genetic counseling, carrier detection, early intervention, and disease prevention in relatives of the index patient (Chap. 84). In instances where a diagnosis at the molecular level may be relevant, it is important to identify an appropriate laboratory that can perform the appropriate test. Genetic testing is available for a rapidly growing number of monogenic disorders through commercial laboratories. For uncommon disorders, the test may only be performed in a specialized research laboratory. Approved laboratories offering testing for inherited disorders can be identified in continuously updated online resources (e.g., GeneTests; Table 82-1). If genetic testing is considered, the patient and the family should be counseled about the potential implications of positive results, including psychological distress and the possibility of discrimination. The patient or caretakers should be informed about the meaning of a negative result, technical limitations, and the possibility of false-negative and inconclusive results. For these reasons, genetic testing should only be performed after obtaining informed consent. Published ethical guidelines address the specific aspects that should be considered when testing children and adolescents. Genetic testing should usually be limited to situations in which the results may have an impact on medical management.
Chapter 82
Very rare
Mutational Analyses DNA sequence analysis is now widely used as a diagnostic tool and has significantly enhanced diagnostic accuracy. It is used for determining carrier status and for prenatal testing in monogenic disorders (Chap. 84). Numerous techniques,
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discussed in previous versions of this chapter, are available for the detection of mutations. In a very broad sense, one can distinguish between techniques that allow for screening of known mutations (screening mode) or techniques that definitively characterize mutations. Analyses of large alterations in the genome are possible using classic methods such as cytogenetics, fluorescent in situ hybridization (FISH), and Southern blotting (Chap. 83e), as well as more sensitive novel techniques that search for multiple single exon deletions or duplications. More discrete sequence alterations rely heavily on the use of PCR, which allows rapid gene amplification and analysis. Moreover, PCR makes it possible to perform genetic testing and mutational analysis with small amounts of DNA extracted from leukocytes or even from single cells, buccal cells, or hair roots. DNA sequencing can be performed directly on PCR products or on fragments cloned into plasmid vectors amplified in bacterial host cells. Sequencing of all exons of the genome or selected chromosomes, or sequencing of numerous candidate genes in a single run, is now possible with next-generation sequencing platforms. The majority of traditional diagnostic methods were gel-based. Novel technologies for the analysis of mutations, genotyping, largescale sequencing, and mRNA expression profiles are undergoing rapid evolution. DNA chip technologies allow hybridization of DNA or RNA to hundreds of thousands of probes simultaneously. Microarrays are being used clinically for mutational analysis of several human disease genes, as well as for the identification of viral or bacterial sequence variations. With advances in high-throughput DNA sequencing technology, complete sequencing of the genome or an exome has entered the clinical realm. Although comprehensive sequencing of large genomic regions or multiple genes is already a reality, the subsequent bioinformatics analysis, assembly of sequence fragments, and comparative alignments remains a significant and commonly underestimated challenge. The discovery of incidental (or secondary) findings that are unrelated to the indication for the sequencing analysis but indicators of other disorders of potential relevance for patient care can pose a difficult ethical dilemma. It can lead to the detection of undiagnosed medically actionable genetic conditions, but can also reveal deleterious mutations that cannot be influenced, as numerous sequence variants are of unknown significance. A general algorithm for the approach to mutational analysis is outlined in Fig. 82-15. The importance of a detailed clinical phenotype cannot be overemphasized. This is the step where one should also consider the possibility of genetic heterogeneity and phenocopies. If obvious candidate genes are suggested by the phenotype, they
can be analyzed directly. After identification of a mutation, it is essential to demonstrate that it segregates with the phenotype. The functional characterization of novel mutations is labor intensive and may require analyses in vitro or in transgenic models in order to document the relevance of the genetic alteration. Prenatal diagnosis of numerous genetic diseases in instances with a high risk for certain disorders is now possible by direct DNA analysis. Amniocentesis involves the removal of a small amount of amniotic fluid, usually at 16 weeks of gestation. Cells can be collected and submitted for karyotype analyses, FISH, and mutational analysis of selected genes. The main indications for amniocentesis include advanced maternal age (>35 years), an abnormal serum triple marker test (α-fetoprotein, β human chorionic gonadotropin, pregnancy-associated plasma protein A, or unconjugated estriol), a family history of chromosomal abnormalities, or a Mendelian disorder amenable to genetic testing. Prenatal diagnosis can also be performed by chorionic villus sampling (CVS), in which a small amount of the chorion is removed by a transcervical or transabdominal biopsy. Chromosomes and DNA obtained from these cells can be submitted for cytogenetic and mutational analyses. CVS can be performed earlier in gestation (weeks 9–12) than amniocentesis, an aspect that may be of relevance when termination of pregnancy is a consideration. Later in pregnancy, beginning at about 18 weeks of gestation, percutaneous umbilical blood sampling (PUBS) permits collection of fetal blood for lymphocyte culture and analysis. Recently, the entire fetal genome has been determined prenatally from cells taken from the mother’s plasma through deep sequencing and the counting of parental haplotypes, or by inferring it from DNA sequences obtained from blood samples from the mother, father, and umbilical cord. These approaches enable screening for clinically relevant and deleterious alleles inherited from the parents, as well as for de novo germline mutations, and they may have the potential to change the diagnosis of genetic disorders in the prenatal setting. In combination with in vitro fertilization (IVF) techniques, it is even possible to perform genetic diagnoses in a single cell removed from the four- to eight-cell embryo or to analyze the first polar body from an oocyte. Preconceptual diagnosis thereby avoids therapeutic abortions but is costly and labor intensive. It should be emphasized that excluding a specific disorder by any of these approaches is never equivalent to the assurance of having a normal child. Mutations in certain cancer susceptibility genes such as BRCA1 and BRCA2 may identify individuals with an increased risk for the development of malignancies and result in risk-reducing interventions. The detection of mutations is an important diagnostic and
Characterization of phenotype Familial or sporadic genetic disorder
Population-based genetic screening
Pedigree analysis
Gene unknown
Gene known or candidate genes
Linkage analysis
Mutational analysis
Susceptibility genes or loci
Enrichment of linked region Deep-sequencing Determine functional properties of identified mutations in vitro and in vivo
Genetic counseling Testing of other family members
Treatment based on pathophysiology
Figure 82-15 Approach to genetic disease.
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prognostic tool in leukemias and lymphomas. The demonstration of the presence or absence of mutations and polymorphisms is also relevant for the rapidly evolving field of pharmacogenomics, including the identification of differences in drug treatment response or metabolism as a function of genetic background. For example, the thiopurine drugs 6-mercaptopurine and azathioprine are commonly used cytotoxic and immunosuppressive agents. They are metabolized by thiopurine methyltransferase (TPMT), an enzyme with variable activity associated with genetic polymorphisms in 10% of whites and complete deficiency in about 1 in 300 individuals. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity, including fatal myelosuppression. Characterization of these polymorphisms allows mercaptopurine doses to be modified based on TPMT genotype. Pharmacogenomics may increasingly permit individualized drug therapy, improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care (chap. 5).
Principles of Human Genetics
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ETHICAL ISSUES Determination of the association of genetic defects with disease, comprehensive data of an individual’s genome, and studies of genetic variation raise many ethical and legal issues. Genetic information is generally regarded as sensitive information that should not be readily accessible without explicit consent (genetic privacy). The disclosure of genetic information may risk possible discrimination by insurers or employers. The scientific components of the Human Genome Project have been paralleled by efforts to examine ethical, social, and legal implications. An important milestone emerging from these endeavors consists in the Genetic Information Nondiscrimination Act (GINA), signed into law in 2008, which aims to protect asymptomatic individuals against the misuse of genetic information for health insurance and employment. It does not, however, protect the symptomatic individual. Provisions of the U.S. Patient Protection and Affordable Care Act, effective in 2014, will fill this gap and prohibit exclusion from, or termination of, health insurance based on personal health status. Potential threats to the maintenance of genetic privacy consist in the emerging integration of genomic data into electronic medical records, compelled disclosures of health records, and direct-to-consumer genetic testing. It is widely accepted that identifying disease-causing genes can lead to improvements in diagnosis, treatment, and prevention. However, the information gleaned from genotypic results can have quite different impacts, depending on the availability of strategies to modify the course of disease (chap. 84). For example, the identification of mutations that cause MEN 2 or hemochromatosis allows specific interventions for affected family members. On the other hand, at present, the identification of an Alzheimer’s or Huntington’s disease gene does not currently alter therapy and outcomes. Most genetic disorders are likely to fall into an intermediate category where the opportunity for prevention or treatment is significant but limited (chap. 84). However, the progress in this area is unpredictable, as underscored by the finding that angiotensin II receptor blockers may slow disease progression in Marfan’s syndrome. Genetic test results can generate anxiety in affected individuals and family members. Comprehensive sequence analyses are particularly challenging because most individuals can be expected to harbor several serious recessive gene mutations. The impact of genetic testing on health care costs is currently unclear. It is likely to vary among disorders and depend on the availability of effective therapeutic modalities. A significant problem arises from the marketing of genetic testing directly to consumers by commercial companies. The validity of these tests has not been defined, and there are numerous concerns about the lack of appropriate regulatory oversight, the accuracy and confidentiality of genetic information, the availability of counseling, and the handling of these results. Many issues raised by the genome project are familiar, in principle, to medical practitioners. For example, an asymptomatic
patient with increased low-density lipoprotein (LDL) cholesterol, high blood pressure, or a strong family history of early myocardial infarction is known to be at increased risk of coronary heart disease. In such cases, it is clear that the identification of risk factors and an appropriate intervention are beneficial. Likewise, patients with phenylketonuria, cystic fibrosis, or sickle cell anemia are often identified as having a genetic disease early in life. These precedents can be helpful for adapting policies that relate to genetic information. We can anticipate similar efforts, whether based on genotypes or other markers of genetic predisposition, to be applied to many disorders. One confounding aspect of the rapid expansion of information is that our ability to make clinical decisions often lags behind initial insights into genetic mechanisms of disease. For example, when genes that predispose to breast cancer such as BRCA1 are described, they generate tremendous public interest in the potential to predict disease, but many years of clinical research are still required to rigorously establish genotype and phenotype correlations. Genomics may contribute to improvements in global health by providing a better understanding of pathogens and diagnostics, and through contributions to drug development. There is, however, concern about the development of a “genomics divide” because of the costs associated with these developments and uncertainty as to whether these advances will be accessible to the populations of developing countries. The World Health Organization has summarized the current issues and inequities surrounding genomic medicine in a detailed report titled “Genomics and World Health.” Whether related to informed consent, participation in research, or the management of a genetic disorder that affects an individual or his or her family, there is a great need for more information about fundamental principles of genetics. The pervasive nature of the role of genetics in medicine makes it important for physicians and other health care professionals to become more informed about genetics and to provide advice and counseling in conjunction with trained genetic counselors (chap. 84). The application of screening and prevention strategies will therefore require intensive patient and physician education, changes in health care financing, and legislation to protect patient’s rights.
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83e
Chromosome Disorders Nancy B. Spinner, Laura K. Conlin
CHROMOSOME DISORDERS
METHODS FOR CHROMOSOME ANALYSIS STANDARD CYTOGENETIC ANALYSIS Standard cytogenetic analysis refers to the examination of banded human chromosomes. Banded chromosome analysis allows for both the determination of the number and identity of chromosomes in the cell and recognition of abnormal banding patterns associated with a structural rearrangement. A stained band is defined as the part of a chromosome that is clearly distinguishable from its adjacent segments by appearing darker or lighter with one or more banding techniques. Cytogenetic analysis is most commonly carried out on cells in mitosis, requiring dividing cells. Actively growing cells are most often obtained from peripheral blood; however, it is only a small subset of the blood cells that are actually used for cytogenetic analysis. Often, chemicals, like phytohemagglutinin (PHA), are used to specially stimulate growth of T cells in a blood sample. Other sources of dividing cells include skin-derived fibroblasts, amniotic fluid or placental tissue (for prenatal diagnosis), or tumor tissue (for cancer diagnosis). After culturing, cells are treated with a mitotic spindle inhibitor, which prevents
telomere p arm
p22.3 p2
p21.3
p1
p11.2
centromere q1 q21.1 q arm q2
telomere
q23
q28
Figure 83e-1 Ideogram of the X chromosome and a G-banded X chromosome. The labeling of the X ideogram shows the positioning of the p and q arms, the centromere, and the telomeres. The numbering of the bands is also demonstrated, indicating the broadest subbands (p1, p2, q1, q2) and the further subdivisions to the right. Numbering begins at the centromere and moves out along each arm toward the telomeres.
83e-1
Chapter 83e Chromosome Disorders
Alterations of the chromosomes (numerical and structural) occur in about 1% of the general population, in 8% of stillbirths, and in close to 50% of spontaneously aborted fetuses. The 3 × 109 base pairs that encode the human genome are packaged into 23 pairs of chromosomes, which consist of discrete portions of DNA, bound to several classes of regulatory proteins. Technical advances that led to the ability to analyze human chromosomes immediately translated into the revelation that human disorders can be caused by an abnormality of chromosome number. In 1959, the clinically recognizable disorder, Down syndrome, was demonstrated to result from having three copies of chromosome 21 (trisomy 21). Very soon thereafter, in 1960, a small, structurally abnormal chromosome was recognized in the cells of some patients with chronic myelogenous leukemia (CML), and this abnormal chromosome is now known as the Philadelphia chromosome. Since these early discoveries, the techniques for analysis of human chromosomes, and DNA in general, have gone through several revolutions, and with each technical advancement, our understanding of the role of chromosomal abnormalities in human disease has expanded. While early studies in the 1950s and 1960s easily identified abnormalities of chromosome number (aneuploidy) and large structural alterations such as deletions (chromosomes with missing regions), duplications (extra copies of chromosome regions), or translocations (where portions of the chromosomes are rearranged), many other types of structural alterations could only be identified as techniques improved. The first important technical advance was the introduction of chromosome banding in the late 1960s, a technique that allowed for the staining of the chromosomes, so that each chromosome could be recognized by its pattern of alternating dark and light (or fluorescent and nonfluorescent) bands. Other technical innovations ranged from the introduction of fluorescence in situ hybridization in the 1980s to use of array-based and sequencing technologies in the early 2000s. Currently, we can appreciate that many types of chromosome abnormalities contribute to human disease including aneuploidy; structural alterations such as deletions and duplications, translocations, or inversions; uniparental disomy, where two copies of one chromosome (or a portion of a chromosome) are inherited from one parent; complex alterations such as isochromosomes, markers, and rings; and mosaicism for all of the aforementioned abnormalities. The first chromosome disorders identified had very striking and generally severe phenotypes, because the abnormalities involved large regions of the genome, but as methods have become more sensitive, it is now possible to recognize many more subtle phenotypes, often involving smaller genomic regions.
the separation of the chromatids during metaphase. Halting mitosis in metaphase is essential, because chromosomes are at their most condensed state during this stage of mitosis. The banding pattern of a metaphase chromosome is easily recognizable and is ideal for karyotyping. There are several different types of chromosome staining techniques, including R-banding, C-banding, and quinacrine staining, but the most commonly used is G-banding. G-banding is accomplished by treatment of the chromosomes with a proteolytic enzyme, such as trypsin, which digests some of the proteins holding DNA in a threedimensional structure, followed by staining with a dye (Giemsa) that binds DNA. The resulting patterns have both dark and light bands; in general, the light bands occur in regions on the chromosome in which genes are actively being transcribed, and dark bands are in regions of less active transcription. The banded human karyotype has now been standardized based on an internationally agreed upon system for designating not only individual chromosomes but also chromosome regions, providing a way in which structural rearrangements and variants can be described in terms of their composition. The normal human female karyotype is referred to as 46,XX (46 chromosomes, with 22 pairs of autosomes and two of the same type of sex chromosomes [two Xs], indicating this is a female); and the normal human male karyotype is referred to as 46,XY (46 chromosomes, with 22 pairs of autosomes and one of each type of sex chromosome [one X and one Y], indicating this is a male). The anatomy of a chromosome includes the central constriction, known as the centromere, which is critical for movement of the chromosomes during mitosis and meiosis; the two chromosome arms (p for the smaller or petite arm, and q for the longer arm); and the chromosome ends, which contain the telomeres. The telomeres are made up of a hexanucleotide repeat (TTAGGG)n, and unlike the centromere, they are not visible at the light microscope level. Telomeres are functionally important because they confer stability to the end of the chromosome. Broken chromosomes tend to fuse end to end, whereas a normal chromosome with an intact telomere structure is stable. To create the standard chromosome-banding map, each chromosome is divided into segments that are numbered, and then further subdivided. The precise band names are recorded in an international document so that each band has a distinct number. Figure 83e-1 shows an ideogram (chromosome map with bands) of the X chromosome and a G-banded X chromosome. This system provides a way for a chromosome abnormality to be written, with an indication of which band is deleted, duplicated, or rearranged.
PART 3 Genes, the Environment, and Disease
MOLECULAR CYTOGENETICS Molecular cytogenetics provides a link between chromosome and molecular analysis and overcomes some of the limitations of standard cytogenetics. Deletions smaller than several million base pairs are not routinely detectable by standard G-banding techniques, and chromosomal abnormalities with indistinct or novel banding patterns can be difficult or impossible to interpret. To carry out cytogenetic analysis, cells must be dividing, which is not always possible to obtain (e.g., in autopsy or tumor material that has already been fixed). Finally, growth selection or bias may occasionally cause the results of cytogenetic studies to be misleading because cells that proliferate in vitro may not be representative of the original population, as is often the case with tumor specimens. Fluorescence in situ hybridization (FISH) is a combined cytogenetic-molecular technique that solves many of the aforementioned problems. FISH permits determination of the number and location of specific DNA sequences in human cells. FISH can be performed on metaphase chromosomes, as with G-banding, but can also be performed on cells not actively progressing through mitosis. FISH performed on nondividing cells is referred to as interphase or nuclear FISH (Fig. 83e-2). The FISH procedure relies on the complementarity between the two strands of the DNA double helix and uses a molecular probe, which can be a pool of sequences across an entire chromosome, a DNA sequence for a repetitive part of the genome (e.g., centromeres or telomeres), or a specific DNA sequence found only once in the genome (e.g., a disease-associated gene). The choice of probes for FISH studies is important and will vary with the information needed for the diagnosis of a particular disorder. The most common type of probes are locus-specific probes, which are used to determine if a critical gene or region is absent (indicating a deletion), or present in the normal
15
number of copies, or if an additional copy of the region is present. FISH on metaphase chromosomes will give the additional information of the location of the additional copy, which is necessary information to determine whether a structural rearrangement, such as a translocation, is present. FISH can also be performed with probes that bind to repeated sequences, such as DNA found in centromeres or telomeres, or with probes that bind to an entire chromosome (“painting” probes), to determine the chromosome composition of an abnormal chromosome. Interphase FISH studies can also help to identify structural alterations when probes are used that map to both sides of a translocation breakpoint. Each side of the breakpoint is labeled in a different color, and when no translocation is present the two probes appear to be overlapping. When a translocation is present, the two probes appear separate from one another. These set of probes, called “breakapart” probes, are commonly used to detect recurrent translocations in cancer cells. ARRAY-BASED METHODOLOGIES (CYTOGENOMICS) Array-based methods were introduced into the clinical lab beginning in 2003 and quickly revolutionized the field of cytogenetics. These techniques used arrays (collections of DNA segments from the entire genome) which could be interrogated with respect to copy number. With standard cytogenetics, the missing or extra pieces of DNA have to be big enough to see in the microscope on banded chromosomes (usually larger than 5 Mb). FISH requires a preselection of an informative molecular probe prior to analysis. In contrast, array-based techniques permit analysis of many regions of the genome in a single analysis, with greatly increased resolution over standard cytogenetics. Array-based techniques allow for scanning of the genome for small deletions or duplications quickly and accurately. The resolution of the
B
A
C (1pxl = 127KB)
Log R ratio
83e-2
duplication
1.00 0.75 0.50 0.25 0.00 –0.25 –0.50 –0.75 –1.00
15
p13
p12
p11.2
q11.2
q14
q21.1
q21.3
q22.2
q23
q26.1 q26.2 q26.3
D
Figure 83e-2 G-banding, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) array demonstrate an abnormal chromosome 15. A. G-banding shows an abnormal chromosome 15, with unrecognizable material in place of the p arm in the chromosome on the right (top arrow). B. Metaphase FISH (only chromosome 15s are shown) using a probe from the 15q telomere region (red) and a control probe that maps outside of the duplicated region (green). C. Interphase FISH demonstrates three copies of the 15q tel probe in red, and two copies of the 15q control probe (green). D. Genome-wide SNP array demonstrates the increased copy number for a portion of 15q. Note that the G-banding alone indicates the abnormal chromosome 15, but the origin of the extra material can only be demonstrated by FISH or array. The FISH analysis requires additional information about possible genetic causes to select the correct probe. The array can exactly identify the origin of the extra material, but by itself would not provide positional information.
83e-3
Table 83e-1 Comparison of Cytogenetic and Cytogenomic Techniques Method G-banding Metaphase FISH Interphase FISH CGH Array SNP Array
Requires Growing Cells Yes Yes No No No
Detects Deletions and Duplications Yes Yes Yes Yes Yes
Detects Balanced Structural Rearrangements Yes Yes Some No No
Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphism (SNP) Analysis CGH and SNP-based genotyping arrays can both be used for the analysis of genomic deletions and duplications. For both techniques, oligonucleotide probes are placed onto a slide or chip in a grid format. Each of these probes is specific for a particular genomic region. In array CGH, the amount of DNA from a patient is compared to that in a clinically normal control, or pool of controls, for each of the probes present on the array. DNA from a patient is fluorescently labeled with a dye of one color, and DNA from a control individual is labeled with another color. These DNA samples are then hybridized at the same time to the array. The resulting fluorescent signal will vary depending on whether both the control and patient DNA are present in equal amounts or if one has a different copy number than the other. SNP platforms use arrays targeting SNPs that are distributed across the genome. SNP arrays vary in density of markers and in the technology used for genotyping, depending on the manufacturer of the array. SNP arrays were initially designed to determine genotypes at a biallelic, polymorphic base (e.g., CC, CT, or TT) and have been increasingly used in genome-wide association studies to identify disease susceptibility genes. SNP arrays were subsequently adapted to identify genomic deletions and duplications (Fig. 83e-2). SNP arrays, in addition to identifying copy number changes, can also detect regions of the genome that have an excess of homozygous genotypes and absence of heterozygous genotypes (e.g., CC and TT genotypes only, with no CT genotypes). Absence of heterozygosity is sometimes associated with uniparental disomy (discussed later in this chapter) but is also observed when an individual’s parents are related to one another (identity by descent). Regions of homozygosity have been used to help identify genes in which homozygous mutations result in disease phenotypes in families with known consanguinity. Array-based techniques (which we will now refer to as cytogenomic analysis) have proven superior to chromosome analysis in the identification of clinically significant deletions or duplications. It is estimated that for a deletion or duplication to be visualized by standard cytogenetics it must be minimally between 5 and 10 million base pairs in size. In almost all cases, deletions and duplications of this size contain multiple genes, and these deletions and duplications are disease causing. However, utilization of array-based cytogenomic testing, which can routinely identify deletions and duplications smaller than 50,000 base pairs, reveals that clinically normal individuals all have some deletions and duplications. This presents a dilemma for the analyst to discern which smaller copy number variations (CNVs) are disease causing (pathogenic) and which are likely benign polymorphisms. Although initially burdensome, the cytogenomics community has been curating these CNVs for almost a decade, and databases have been created reporting CNVs routinely seen in clinically normal individuals and those routinely seen in individuals with clinical abnormalities. Nevertheless, each copy number variant that is identified in an
Detection Limits (Lower Limit) 5–10 million bases 40–250 thousand bases 40–250 thousand bases Single exon or single gene Single exon or single gene
individual undergoing genomic testing must be evaluated for gene content and overlap with CNVs in other patients and in controls. Array technologies are DNA based, unlike cytogenetic technologies, which are cell based. Although resolution of gains and losses are greatly increased with array technology, this technique cannot identify structural changes. When DNA is extracted for array studies, chromosomal structure is lost because the DNA is fragmented for better hybridization to the slides. As an example, the array may be able to detect a duplication of a small region of a chromosome, but no information on the location of this extra material can be determined from this test. The location of this extra copy in the genome may be critical, as the chromosomal material may be involved in a translocation, insertion, marker, or other complex rearrangement. Depending on the chromosomal position of this extra material, the patient may have different clinical outcomes, and recurrence risks for the family can be significantly different. Often, combinations of array-based and cytogenetic-based techniques are required to fully characterize chromosomal abnormalities (see Table 83e-1 for comparison of these technologies). NEXT-GENERATION SEQUENCING—BASED METHODOLOGIES Recent advances in genomic sequencing, known as next-generation sequencing (NGS), have vastly increased the speed and throughput of DNA sequence analysis. NGS is rapidly finding its way into the diagnostic lab for detection of clinically relevant intragenic mutations, and new bioinformatic tools for analysis of genomic deletions and duplications are being developed. It is anticipated that NGS will soon allow the complete analysis of a patient’s genome, with identification of intragenic mutations as well as chromosome abnormalities resulting in gain or loss of genetic material. Identification of completely balanced translocations is the most challenging for NGS, but recent reports of successes in this area suggest that in a matter of time, sequencing will be used for all types of genomic analysis.
INDICATIONS FOR CHROMOSOME/CYTOGENOMIC ANALYSIS Cytogenetic analysis is most commonly used for (1) examination of the fetal chromosomes or genome during pregnancy (prenatal diagnosis) or in the event of a spontaneous miscarriage; (2) examination of chromosomes in the neonatal or pediatric population to look for an underlying diagnosis in the case of congenital or developmental anomalies, including short stature and abnormalities of sexual differentiation or progression; (3) chromosome analysis in adults who are facing fertility problems; or (4) examination of cancer cells to look for alterations that aid in establishing a diagnosis or contributing to the prognosis of a tumor (Table 83e-2). PRENATAL DIAGNOSIS Prenatal diagnosis is carried out by analysis of samples obtained by four techniques: amniocentesis, chorionic villous sampling, fetal blood sampling, and analysis of cell free DNA from maternal serum. Amniocentesis, which has been the most commonly used test to date, is usually performed between 15 and 17 weeks of gestational age and carries a small but significant risk for miscarriage. Amniocentesis can be performed as early as 12 weeks, but because there is a lower volume of fluid, the risks for fetal injury or miscarriage are greater. Chorionic villous sampling (CVS) or placental biopsy is routinely carried out earlier than amniocentesis, between 10 and 12 weeks, but a reported increase in limb defects when the procedure is carried out earlier than
Chapter 83e Chromosome Disorders
test is a function of the number of probes or DNA sequences present on the array. Arrays may use probes of different sizes (ranging from 50 to 200,000 base pairs of DNA) and different probe densities depending on the requirements of the application. Low-resolution platforms can have hundreds of probes, targeted to known disease regions, whereas high-resolution platforms can have millions of probes spread across the entire genome. Depending on the size of the probes and the probe placement across the genome, array-based testing may be able to detect single exon deletions or duplications.
Detects Uniparental Disomy No No No No Some
83e-4
Table 83e-2 Indications for Cytogenetic and Cytogenomic Analysis across the Lifespan Timing of Testing Prenatal
Neonatal and Childhood
Adult
PART 3
Indications for Testing Advanced maternal age Abnormalities on ultrasound Increased risk for genetic disorder on maternal serum screen Multiple congenital anomalies Intellectual disability Autism Developmental delay Failure to thrive Short stature Disorders of sexual development History of familial chromosomal alteration Cancer Infertility Recurrent miscarriage Cancer
Genes, the Environment, and Disease
10 weeks has resulted in reduced use of this test in some centers. Fetal blood sampling (percutaneous umbilical blood sampling [PUBS]) is a riskier procedure that is carried out in the second or third trimester of pregnancy, usually to follow up on an unclear finding from an amniocentesis (such as mosaicism) or an ultrasound abnormality that was detected later in pregnancy. One of the far-reaching recent advances in prenatal diagnosis of chromosome and other genetic disorders is the utilization of cell free fetal DNA that can be identified in maternal serum. The obvious advantages of using fetal DNA obtained from maternal serum is that the DNA can be obtained at minimal risk to the pregnancy, because it requires a maternal blood sample, rather than amniotic fluid which is obtained by puncturing the uterine membranes and carries a risk of miscarriage or infection. Although cell free fetal DNA screening, also called noninvasive prenatal screening, has started to be offered clinically, it requires further confirmation of fetal tissues when an abnormal result is identified. Furthermore, ethical concerns have been raised, because it is feared that the ease of doing this test may encourage testing for individuals who are not truly prepared to deal with the choices that accompany diagnosis of a genetic disease and this testing may change the ethical implications of prenatal testing. Nevertheless, this is an active of area of research, both in terms of the technology and the utilization and implications. Common Indications Common indications for prenatal diagnosis by cytogenetic or cytogenomic analysis are (1) advanced maternal age, (2) presence of an abnormality of the fetus on ultrasound examination, and (3) abnormalities in maternal serum screening that reveal an increased risk for chromosome abnormality. Maternal age is well known to be an important risk factor for having a fetus with trisomy. At a maternal age less than 25 years, 2% of all clinically recognized pregnancies are trisomic, but by a maternal age of 36 years, this figure increases to 10%, and by the maternal age of 42 years, the figure increases to >33%. Based on the risk of having a chromosomally abnormal fetus in comparison to the risk for an adverse event from amniocentesis or CVS, the recommendation is that women over the age of 35 consider prenatal testing if they want to know the chromosomal status of their fetus. The precise mechanism for the maternal age effect is not known, but it is believed that it involves a breakdown in the process of chromosome segregation. A similar effect is not seen for trisomy and paternal age. This difference may reflect the fact that oocytes are generated early in ovary development in the female, whereas spermatogonia are generated continuously after puberty in the male. Abnormalities on prenatal ultrasound are the second most frequent indication for prenatal genetic screening. Ultrasound screening can
reveal structural or functional anomalies in the fetus, which might be associated with chromosome or genomic disorders. Follow-up chromosome studies may therefore be recommended. Maternal serum screening results are the third most frequent indication for prenatal chromosome analysis. There have been several versions of maternal serum screening offered over the past few decades. Currently, the “quad” screen analyzes levels of α fetoprotein (AFP), human chorionic gonadotropin (hCG), estriol, and inhibin-A. The values of these analytes are used to adjust the maternal age–predicted risk of a trisomy 21 or trisomy 18 fetus. POSTNATAL INDICATIONS Postnatal indications for cytogenetic or cytogenomic analysis in neonates or children are varied, and the list has been growing with the increasing ability to diagnose smaller genomic alterations via array-based techniques. Common indications include multiple congenital anomalies, suspicion of a known cytogenetic or cytogenomic syndrome, intellectual disability or developmental delay both with and without accompanying dysmorphic features, autism, failure to thrive in infancy or short stature during childhood, and disorders of sexual development. The ability to detect smaller genomic alterations with involvement of fewer genes, sometimes as few as a single gene, suggests that a wider range of phenotypes could be investigated by cytogenomic analysis. Reasons for chromosome testing in adults include recurrent miscarriages or infertility, where balanced chromosome rearrangements such as reciprocal translocations may occur. Additionally, some adults with anomalies who were not diagnosed when they were children are referred for cytogenetic analysis, often when other members of their family want to understand any potential genetic implications, as they plan their own families.
TYPES OF CHROMOSOME ABNORMALITIES NUMERICAL CHROMOSOME ABNORMALITIES Aneuploidy (extra or missing chromosomes) is the most common type of abnormality, occurring in 3/1000 newborns and at much higher frequency (about 35%) in spontaneously aborted fetuses. The only autosomal trisomies that are compatible with being live born in humans are trisomies 13, 18, and 21, although there are several chromosomes that can be trisomic in mosaic form. Trisomy 21 is associated with the relatively common disorder Down syndrome. Down syndrome has characteristic features including recognizable facial features, along with intellectual disability and abnormalities of multiple other organ systems including the heart. Both trisomy 13 and trisomy 18 are much more severe disorders than Down syndrome, with low frequency of patients surviving past 1 year of age. Trisomy 13 is characterized by low birth weight, postaxial polydactyly, microcephaly, ocular malformations such as anophthalmia or microphthalmia, cleft lip and palate, cardiac defects, and renal malformations. Trisomy 18 neonates have distinct facial characteristics at birth accompanied by an abnormal neurologic exam, underdeveloped genitalia, general lack of responsiveness, and structural birth defects such as congenital heart disease, esophageal atresia, and omphalocele. Mosaicism refers to the presence of two or more populations of cells with distinct chromosome constitutions: for example, an individual with a normal female karyotype in some cells (46,XX) and trisomy 21 in other cells (47,XX,+21). In general, individuals who are mosaic for a chromosomal abnormality have less severe phenotypes than individuals with that same finding in every cell. The severity and presentation of phenotypes are related to the mosaic levels and the tissue distribution of the abnormal cells. There are a number of trisomies that have been reported in mosaic form including mosaic trisomies for chromosomes 8, 9, 14, 17, and 22. A number of trisomies have also been reported in spontaneous abortions (SABs) that have not been seen in live-born individuals, including trisomy 16, which is the most common trisomy in SABs. Monosomy for human chromosomes is very rare, with the single exception being monosomy for the X chromosome, associated with Turner syndrome (45,X). Monosomy for the X chromosome occurs in 1% of all conceptions, yet 98% of these conceptions do not go to term and result in SABs. Trisomies for
the sex chromosomes also occur, with 47,XXX (trisomy X or triple X syndrome), 47,XXY (Klinefelter syndrome), and 47,XYY all reported in individuals with relatively mild phenotypes (Chap. 410). Klinefelter syndrome is the most common clinically recognized sex chromosome abnormality, and clinical features include gynecomastia, azoospermia, small testes, and hypogonadism. The 47,XYY karyotype is most often found in boys with developmental delay and or behavioral difficulties, but population-based studies have shown that intelligence for individuals with this karyotype is generally within the normal range, although slightly lower than that found in siblings.
Figure 83e-3 Segregation of a balanced translocation in a mother, with inheritance of an unbalanced form in her child. Note that the mother has two rearranged chromosomes, but her child only received one of these, resulting in extra copies of a region of the blue chromosome, with loss of some material from the red chromosome.
83e-5
Chapter 83e Chromosome Disorders
STRUCTURAL CHROMOSOME ABNORMALITIES Structural chromosome abnormalities include deletions, duplications, translocations, inversions, as well as other types of abnormalities, each relatively rare, but nonetheless contributing to clinical disease resulting from chromosome anomalies. These rare alterations include isochromosomes, ring chromosomes, dicentric chromosomes, and marker chromosomes (structurally abnormal chromosomes that cannot be identified based on cytogenetics alone). Both translocations and inversions can be completely balanced in some cases, such that there is no disruption of coding regions of the genome, with a completely normal clinical phenotype; however, carriers are at risk for unbalanced forms of these rearrangements in their offspring. Reciprocal translocations are found in approximately 1/500–1/600 individuals in the general population and result from the exchange of chromosomal segments between at least two chromosomes. These usually occur between nonhomologous chromosomes and can be identified based on an altered banding pattern on G-banding. Balanced translocation carriers are at risk for abnormal chromosome segregation during meiosis and therefore have a higher risk for infertility, SAB, and live-born offspring with multiple congenital malformations. These phenotypes are observed when only one of the pairs of chromosomes involved in a translocation is inherited from a parent, resulting in an unbalanced genotype (Fig. 83e-3). Sometimes the exchanged segments are so small that they cannot be appreciated by
banding (cryptic translocation), and these are sometimes recognized when a phenotypically affected child with an unbalanced form is born. Parental chromosomes can then be studied by FISH to determine if the rearrangement is inherited from a parent with a balanced form of the translocation. The majority of reciprocal, apparently balanced translocations occur in phenotypically normal individuals. The risk for a clinical abnormality when a new reciprocal translocation is identified (usually during prenatal diagnostic studies) is about 7%. Analysis of cytogenetically reciprocal translocations using arrays has demonstrated that translocations in clinically normal individuals are more likely to show no deletions or duplications at the breakpoint, whereas translocations in clinically affected individuals are more likely to have breakpoint-associated deletions or duplications. Most reciprocal translocations occur uniquely, at apparently random positions throughout the genome; however, there are a few exceptions with multiple cases of recurrent translocations occurring. These recurrent translocations include t(11;22), which results in Emanuel syndrome in the unbalanced form, and several translocations involving a region on 4p, 8p, and 12p. These recurrent translocations occur in regions of the genome that contain specific types of AT-rich repeats, or other repeat sequences, that are prone to rearrangement. A special category of translocations is the Robertsonian translocations, which involve the acrocentric chromosomes. An acrocentric chromosome has unique genetic material only on the long arm of the chromosomes, whereas the short arm contains repetitive DNA. The acrocentric chromosomes are 13, 14, 15, 21, and 22. Robertsonian translocations occur when an entire long arm of an acrocentric chromosome is translocated onto the short arm of another acrocentric chromosome. Balanced carriers of a Robertsonian translocation contain only 45 chromosomes, with one chromosome consisting of two long arms of an acrocentric chromosome. Technically, this is an unbalanced translocation, as two short arms of the acrocentric chromosomes are missing; however, because the short arms are repetitive, there is no phenotypic consequence. Unbalanced Robertsonian carriers have 46 chromosomes, but have three copies of the long arm of an acrocentric chromosome. The most
83e-6
PART 3 Genes, the Environment, and Disease
common Robertsonian translocation involves chromosomes 13 and 14. Unbalanced Robertsonian translocations involving chromosomes 13 and 21 result in trisomy 13 and Down syndrome, respectively. Approximately 4% of patients with Down syndrome have a translocation, and because recurrence risks are different for families of these individuals, all patients with clinically identified Down syndrome should have a karyotype to look for translocations. Inversions are another type of chromosome abnormality involving rearranged segments, where there are two breaks within a chromosome, with the intervening chromosomal material inserted in an inverted orientation. As with reciprocal translocations, if a break occurs within a gene or control region for a gene, a clinical phenotype may result, but often there are no consequences for the inversion carrier; however, there is risk for abnormalities in the offspring of carriers, as recombinant chromosomes may result after crossing over between a normal chromosome and an inverted chromosome during meiosis. Deletion refers to the loss of a chromosomal segment, which results in the presence of only a single copy of that region in an individual’s genome. A deletion can be at the end of a chromosome (terminal), or it can be within the chromosome (interstitial). Deletions that are visible at the microscopic level in standard cytogenetic analysis are generally greater than 5 Mb in size. Smaller deletions have been identified by FISH and by chromosomal microarray. The clinical consequences of a deletion depend on the number and function of genes in the deleted region. Genes that cause a phenotype when a single copy is deleted are known as haploinsufficient genes (one copy is not sufficient), and it is estimated that less than 10% of genes are haploinsufficient. Genes associated with disease that are not haploinsufficient include genes for known recessive disorders, such as cystic fibrosis or Tay-Sachs disease. The first chromosome deletion syndromes were diagnosed clinically and were subsequently demonstrated to be caused by a chromosome deletion on cytogenetic analysis. Examples of these disorders include the Wolf-Hirschhorn syndrome, which is associated with deletions of a small region of the short arm of chromosome 4 (4p); the cri-du-chat syndrome, associated with deletion of a small region of the short arm of chromosome 5 (5p); Williams syndrome, which is associated with interstitial deletions of the long arm of chromosome 7 (7q11.23); and the DiGeorge/velocardiofacial syndromes, associated with interstitial deletions of the long arm of chromosome 22 (22q11.2). Initial cytogenetic studies were able to provide a rough localization of the deletions in different patients, but with the increased usage of arrays, precise mapping of the extent and gene content of these deletions has become much easier. In many cases, one or two genes that are critical for the phenotype associated with these deletions have been identified. In other cases, the phenotype stems from the deletion of multiple genes. The increased utilization of genomic testing by array, which can identify deletions that are much smaller than those detectable by standard cytogenetic analysis, has resulted in the discovery of several new cytogenomic disorders. These include the 1q21.1, 15q13.3, 16p11.2, and 17q21.31 microdeletion syndromes. Duplication of genomic regions is better tolerated than deletion, as evidenced by the viability of several autosomal trisomies (whole chromosome duplications) but no autosomal monosomies (whole chromosome deletions). There are several duplication syndromes where the duplicated region of the genome is present as a supernumerary chromosome. Utilization of chromosome microarray analysis has made analysis of the origins of duplicated chromosome material straightforward (Fig. 83e-2). Recurrent syndromes associated with supernumerary chromosomes include the inverted duplication 15 (inv dup 15) syndrome, caused by the presence of a marker chromosome derived from chromosome 15, with two copies of proximal 15q resulting in tetrasomy (four copies) of this region. The inv dup 15 syndrome has a distinct phenotype and is associated with hypotonia, developmental delay, intellectual disability, epilepsy, and autistic behavior. Another syndrome is the cat eye syndrome, named for the “cat-eyelike” appearance of the pupil, resulting from a coloboma of the iris. This syndrome results from a supernumerary chromosome derived from a portion of chromosome 22, and the marker chromosomes can vary in size and are often mosaic. Consistent with expectations of a
mosaic disorder, the phenotype of this syndrome is highly variable and includes renal malformations, urinary tract anomalies, congenital heart defects, anal atresia with fistula, imperforate anus, and mild to moderate intellectual disability. Another rare duplication syndrome is the Pallister-Killian syndrome (PKS), which illustrates the principle of tissue-specific mosaicism. Individuals with PKS have coarse facial features with pigmentary skin anomalies, localized alopecia, profound intellectual disability, and seizures. The disorder is caused by a supernumerary isochromosome for the short arm of chromosome 12 (isochromosome 12p). Isochromosomes consist of two copies of one chromosome arm (p or q), rather than one copy of each arm. This isochromosome is not generally seen in peripheral blood lymphocytes when they are analyzed by G-banding, but it is detected in fibroblasts. Array technology has been reported to detect the isochromosome in uncultured peripheral blood in some patients, and it has been hypothesized that a growth bias against cells with the isochromosome prevents their identification in cytogenetic studies. Numerical abnormalities, translocations, and deletions are the most common chromosome alterations observed in the diagnostic laboratory, but in addition to inversions and duplications, several other types of abnormal chromosomes have been reported, including ring chromosomes, where the two ends of the chromosome fuse to form a circle, and insertions, where a piece of one chromosome is inserted into another chromosome or elsewhere into the same chromosome. Uniparental disomy (UPD) is the inheritance of a pair of chromosomes (or part of a chromosome) from only one parent. This usually occurs as a result of nondisjunction during meiosis, with a gamete missing or having an extra copy of a chromosome. A resulting fertilized egg would then have only one parental contribution for a given chromosome pair, or a trisomy for a given chromosome. If the monosomy or trisomy is not compatible with life, the embryo may undergo a “rescue” to normal copy number. If a monosomy is rescued, the single chromosome may be duplicated, resulting in a cell with two identical chromosomes (monosomy rescue) (Fig. 83e-4). In the case of trisomies, a subsequent nondisjunction can result in cells where one of the extra chromosomes is lost (trisomy rescue) (Fig. 83e-4). For trisomy rescue, there is a one in three chance that the lost
A
B
Figure 83e-4 Mechanisms of formation of uniparental disomy. Panel A demonstrates nondisjunction in one parent (mother, represented in red), with trisomy in the zygote. A subsequent nondisjunction, with loss of the paternal chromosome (represented in blue), restores the diploid karyotype but leaves two copies of the maternal chromosome (maternal uniparental disomy [UPD]). Panel B demonstrates nondisjunction in one parent (mother, indicated by red oval), resulting in only one copy of this chromosome in the zygote. Subsequent nondisjunction duplicates the single chromosome, rescuing the monosomy, but resulting in two copies of the paternal chromosome (represented in blue; paternal UPD).
ACQUIRED CHROMOSOME ABNORMALITIES IN CANCER Chromosome changes can occur during meiosis or mitosis and can occur at any point across the lifespan. Mosaicism for a developmental disorder is one consequence of mitotic chromosome abnormalities,
and another consequence is cancer, when the chromosome change confers a growth or proliferation advantage on the cell. The types of chromosome abnormalities seen in cancer are similar to those seen in the developmental disorders (e.g., aneuploidy, deletion, duplication, translocation, isochromosomes, rings, inversion). Tumor cells often have multiple chromosome changes, some of which happen early in the development of a tumor, and may contribute to its selective advantage, whereas others are secondary effects of the deregulation that characterizes many tumors. Chromosome changes in cancer have been studied extensively and have been shown to provide important diagnostic, classification, and prognostic information. The identification of cancer type–specific translocation breakpoints has led to the identification of a number of cancer-associated genes.�For example, the small abnormal chromosome found to be associated with chronic myelogenous leukemia (CML) in 1960 was shown to be the result of translocation between chromosomes 9 and 22 once techniques for analysis of banded chromosomes were introduced, and subsequently, the translocation breakpoint was cloned to reveal the c-abl oncogene on chromosome 9. This translocation produces a fusion protein, which has been targeted for treatment of CML. For detailed discussion of cancer genetics, see Chap. 101e.
83e-7
Chapter 83e Chromosome Disorders
chromosome will be the sole chromosome from one parent, resulting in a cell with two chromosomes from the same parent. UPD is sometimes associated with clinical abnormalities, and this can occur by two mechanisms. UPD can cause disease when there is an imprinted gene on the involved chromosome, resulting in altered gene expression. Imprinting is the chemical marking of the parental origin of a chromosome, and genes that are imprinted are only expressed from either the maternal or paternal chromosome (Chap. 82). Imprinting therefore results in the differential expression of affected genes, based on parent of origin. Imprinting usually occurs through differential modification of the chromosome from one of the parents, and methylation is one of several epigenetic mechanisms (others include histone acetylation, ubiquitylation, and phosphorylation). Imprinted chromosomes that are associated with phenotypes include paternal UPD6 (associated with neonatal diabetes), maternal UPD7 and UPD11 (associated with Russell-Silver syndrome), paternal UPD11 (associated with Beckwith-Wiedemann syndrome), paternal UPD14, maternal UPD15 (Angelman syndrome), and paternal UPD15 (Prader-Willi syndrome). UPD can also result in disease if the two copies from the same parent are the same chromosome (uniparental isodisomy), and the chromosome contains an allele involving a pathogenic mutation associated with a recessive disorder. Two copies of the deleterious allele would result in the associated disease, even though only one parent is a disease carrier.
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The Practice of Genetics in Clinical Medicine Susan M. Domchek, J. Larry Jameson, Susan Miesfeldt
APPLICATIONS OF MOLECULAR GENETICS IN CLINICAL MEDICINE
PART 3 Genes, the Environment, and Disease
Genetic testing for inherited abnormalities associated with disease risk is increasingly used in the practice of clinical medicine. Germline alterations include chromosomal abnormalities (Chap. 83e), specific gene mutations with autosomal dominant or recessive patterns of transmission (Chap. 82), and single nucleotide polymorphisms with small relative risks associated with disease. Germline alterations are responsible for disorders beyond classic Mendelian conditions with genetic susceptibility to common adult-onset diseases such as asthma, hypertension, diabetes mellitus, macular degeneration, and many forms of cancer. For many of these diseases, there is a complex interplay of genes (often multiple) and environmental factors that affect lifetime risk, age of onset, disease severity, and treatment options. The expansion of knowledge related to genetics is changing our understanding of pathophysiology and influencing our classification of diseases. Awareness of genetic etiology can have an impact on clinical management, including prevention and screening for or treatment of a range of diseases. Primary care physicians are relied upon to help patients navigate testing and treatment options. Consequently, they must understand the genetic basis for a large number of genetically influenced diseases, incorporate personal and family history to determine the risk for a specific mutation, and be positioned to provide counseling. Even if patients are seen by genetic specialists who assess genetic risk and coordinate testing, primary care providers should provide information to their patients regarding the indications, limitations, risks, and benefits of genetic counseling and testing. They must also be prepared to offer risk-based management following genetic risk assessment. Given the pace of genetics, this is an increasingly difficult task. The field of clinical genetics is rapidly moving from single gene testing to multigene panel testing, with techniques such as wholeexome and -genome sequencing on the horizon, increasing the complexity of test selection and interpretation, as well as patient education and medical decision making.
COMMON ADULT-ONSET GENETIC DISORDERS INHERITANCE PATTERNS Adult-onset hereditary diseases follow multiple patterns of inheritance. Some are autosomal dominant conditions. These include many common cancer susceptibility syndromes such as hereditary breast and ovarian cancer (due to germline BRCA1 and BRCA2 mutations) and Lynch syndrome (caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2). In both of these examples, inherited mutations are associated with a high penetrance (lifetime risk) of cancer, although risk is not 100%. In other conditions, although there is autosomal dominant transmission, there is lower penetrance, thereby making the disorders more difficult to recognize. For example, germline mutations in CHEK2 increase the risk of breast cancer, but with a moderate lifetime risk in the range of 20–40%, as opposed to 50–70% for mutations in BRCA1 or BRCA2. Other adult-onset hereditary diseases are transmitted in an autosomal recessive fashion where two mutant alleles are necessary to cause disease. Examples include hemochromatosis and MYH-associated colon cancer. There are more pediatric-onset autosomal recessive disorders, such as lysosomal storage diseases and cystic fibrosis. The genetic risk for many adult-onset disorders is multifactorial. Risk can be conferred by genetic factors at a number of loci, which individually have very small effects (usually with relative risks of 35 years) Consanguinity Previous history of a child with birth defects or a genetic disorder Personal or family history suggestive of a genetic disorder High-risk ethnic groups Documented genetic alteration in a family member Ultrasound or prenatal testing suggesting a genetic disorder
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disorders, asymptomatic patients should be advised that a positive test result does not always translate into future disease development. In addition, the role of nongenetic factors, such as environmental exposures and lifestyle, must be discussed in the context of multifactorial disease risk and disease prevention. Finally, patients should understand the natural history of the disease as well as the potential options for intervention, including screening, prevention, and in certain circumstances, pharmacologic treatment or prophylactic surgery.
THERAPEUTIC INTERVENTIONS BASED ON GENETIC RISK FOR DISEASE Specific treatments are available for a number of genetic disorders. Strategies for the development of therapeutic interventions have a long history in childhood metabolic diseases; however, these principles have been applied in the diagnosis and management of adult-onset diseases as well (Table 84-2). Hereditary hemochromatosis is usually caused
by mutations in HFE (although other genes have been less commonly associated) and manifests as a syndrome of iron overload, which can lead to liver disease, skin pigmentation, diabetes mellitus, arthropathy, impotence in males, and cardiac issues (Chap. 428). When identified early, the disorder can be managed effectively with therapeutic phlebotomy. Therefore, when the diagnosis of hemochromatosis has been made in a proband, it is important to counsel and offer testing to other family members in order to minimize the impact of the disorder. Preventative measures and therapeutic interventions are not restricted to metabolic disorders. Identification of familial forms of long QT syndrome, associated with ventricular arrhythmias, allows early electrocardiographic testing and the use of prophylactic antiarrhythmic therapy, overdrive pacemakers, or defibrillators. Individuals with familial hypertrophic cardiomyopathy can be screened by ultrasound, treated with beta blockers or other drugs, and counseled about the importance of avoiding strenuous exercise and dehydration. Those with Marfan’s syndrome can be treated with beta blockers or
TABLE 84-2 Example of Genetic Testing and Possible Interventions
PART 3
Genetic Disorder Oncologic Lynch syndrome (HNPCC) Familial adenomatous polyposis Hereditary breast and ovarian cancer
Inheritance
Genes
Interventions
AD AD AD
MLH1, MSH2, MSH6, PMS2 APC BRCA1, BRCA2
Genes, the Environment, and Disease
Hereditary diffuse gastric cancer Hematologic Factor V Leiden Hemophilia A Hemophilia B Glucose 6-phosphate dehydrogenase deficiency Cardiovascular Hypertrophic cardiomyopathy
AD
CDH1
Early endoscopic screening; risk-reducing surgery Early and frequent endoscopy; prophylactic colectomy Risk reducing salpingo-oophorectomy; intensified breast surveillance including breast MRI; risk-reducing mastectomy Prophylactic gastrectomy; enhanced breast cancer surveillance
AD XL XL XL
F5 F8 F9 G6PD
Avoidance of thrombogenic risk factors Factor VIII replacement Factor IX replacement Avoidance of oxidant drugs and certain foods
AD
Long QT syndrome
AD, AR
Marfan’s syndrome
AD
>10 genes including MYBPC3, MYH7, TNNT2, TPM1 >10 genes including KCNQ1, SCN5A, KCNE1, KCNE2 FBN1
Echocardiographic screening; pharmacologic intervention; myomectomy Electrocardiographic screening; pharmacologic intervention; implantable cardiac defibrillator devices Echocardiographic screening; prophylactic beta blockers; aortic valve replacement as indicated
Gastrointestinal Familial Mediterranean fever Hemochromatosis Pulmonary α1 Antitrypsin deficiency
AR AR
MEFV HFE
Colchicine Phlebotomy
AR
SERPINA1
Cystic fibrosis
AR
CFTR
Avoidance of smoking and occupational and environmental toxins Chest physiotherapy; agents to promote airway secretion clearance; CFTR modulators (G551D mutations); lung transplantation
Endocrine Neurohypophyseal diabetes insipidus Familial hypocalciuric hypercalcemia Multiple endocrine neoplasia type 2
AD AD AD
AVP CASR RET
Replace vasopressin Avoidance of parathyroidectomy Prophylactic thyroidectomy; screening for pheochromocytoma and hyperparathyroidism
Renal Polycystic kidney disease
AD, AR
PKD1, PKD2, PKHD1
XL, AR
AVPR2, AQP2
Prevention of hypertension; prevention of urinary tract infections; kidney transplantation Fluid replacement; thiazides with or without amiloride
AD AD
RYR1, CACNA1S SCN4A
XL
DMD
Avoidance of precipitating anesthetics Diet rich in calcium and low in potassium; thiazides or acetazolamide Corticosteroids; physical therapy
AR
ATP7B
Zinc, trientene
Nephrogenic diabetes insipidus Neurologic Malignant hyperthermia Hyperkalemic periodic paralysis Duchenne’s and Becker’s muscular dystrophy Wilson’s disease
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; HNPCC, hereditary nonpolyposis colorectal cancer; MRI, magnetic resonance imaging; XL, X-linked.
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The Practice of Genetics in Clinical Medicine
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angiotensin II receptor blockers and monitored for the development of aortic aneurysms. The field of pharmacogenetics identifies genes that alter drug metabolism or confer susceptibility to toxic drug reactions. Pharmacogenetics seeks to individualize drug therapy in an attempt to improve treatment outcomes and reduce toxicity. Examples include thiopurine methyltransferase (TPMT) deficiency, dihydropyrimidine dehydrogenase deficiency, malignant hyperthermia, and glucose6-phosphate deficiency. Despite successes in this area, it is not always clear how to incorporate pharmacogenetics into clinical care. For example, although there is an association with CYP2C6 and VKORC1 genotypes and warfarin dosing, there is no evidence that incorporating genotyping into clinical practice improves patient outcomes. The identification of germline abnormalities that increase the risk of specific types of cancer is rapidly changing clinical management. Identifying family members with mutations that predispose to FAP or Lynch syndrome leads to recommendations of early cancer screening and prophylactic surgery, as well as consideration of chemoprevention and attention to healthy lifestyle habits. Similar principles apply to familial forms of melanoma as well as cancers of the breast, ovary, and thyroid. In addition to increased screening and prophylactic surgery, the identification of germline mutations associated with cancer may also lead to the development of targeted therapeutics, for example, the ongoing development of PARP inhibitors in those with BRCA-associated cancers. Although the role of genetic testing in the clinical setting continues to evolve, such testing holds the promise of allowing early and more targeted interventions that can reduce morbidity and mortality. Rapid technologic advances are changing the ways in which genetic testing is performed. As genetic testing becomes less expensive and technically easier to perform, it is anticipated that there will be an expansion of its use. This will present challenges, but also opportunities. It is critical that physicians and other health care professionals keep current with advances in genetic medicine in order to facilitate appropriate referral for genetic counseling and judicious use of genetic testing, as well as to provide state-of-the-art, evidence-based care for affected or at-risk patients and their relatives.
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85e
Mitochondrial DNA and Heritable Traits and Diseases Karl Skorecki, Doron Behar
TABLE 85e-1 Functions of Mitochondria All Cells and Tissues Oxidative phosphorylation Apoptosis (programmed cell death) Tissue- or Cell-Specific Cholesterol metabolism Amino and organic acid metabolism Fatty acid beta oxidation Sex steroid synthesis Heme synthesis Hepatic ammonia detoxification Neurotransmitter metabolism
85e-1
MITOCHONDRIAL DNA STRUCTURE AND FUNCTION As a result of its circular structure and extranuclear location, the replication and transcription mechanisms of mtDNA differ from the corresponding mechanisms in the nuclear genome, whose nucleosomal packaging and structure are more complex. Because each cell contains many copies of mtDNA, and because the number of mitochondria can vary during the lifetime of each cell, mtDNA copy number is not directly coordinated with the cell cycle. Thus, vast differences in mtDNA copy number are observed between different cell types and tissues and during the lifetime of a cell. Another important feature of the mtDNA replication process is a reduced stringency of proofreading and replication error correction, leading to a greater degree of sequence variation compared to the nuclear genome. Some of these sequence variants are silent polymorphisms that do not have the potential for a phenotypic or pathogenic effect, whereas others may be considered pathogenic mutations. With respect to transcription, initiation can occur on both strands and proceeds through the production of an intronless polycistronic precursor RNA, which is then processed to produce the 13 individual mRNA and 24 individual tRNA and rRNA products. The 37 mtDNA genes comprise fully 93% of the 16,569 nucleotides of the mtDNA in what is known as the coding region. The control region consists of ~1.1 kilobases (kb) of noncoding DNA, which is thought to have an important role in replication and transcription initiation. MATERNAL INHERITANCE AND LACK OF RECOMBINATION In contrast to homologous pair recombination that takes place in the nucleus, mtDNA molecules do not undergo recombination, such that mutational events represent the only source of mtDNA genetic diversification. Moreover, with very rare exceptions, it is only the maternal DNA that is transmitted to the offspring. The fertilized oocyte degrades mtDNA carried from the sperm in a complex process involving the ubiquitin proteasome system. Thus, although mothers transmit their mtDNA to both their sons and daughters, only the daughters are able to transmit the inherited mtDNA to future generations. Accordingly, mtDNA sequence variation and associated phenotypic traits and diseases are inherited exclusively along maternal lines. As noted below, because of the complex relationship between mtDNA mutations and disease expression, sometimes this maternal inheritance is difficult to recognize at the clinical or pedigree level. However, evidence of paternal transmission can almost certainly rule out an mtDNA genetic origin of phenotypic variation or disease; conversely, a disease affecting both sexes without evidence of paternal transmission strongly suggests a heritable mtDNA disorder (Fig. 85e-2). MULTIPLE COPY NUMBER (POLYPLOIDY), HIGH MUTATION RATE, HETEROPLASMY, AND MITOTIC SEGREGATION Each aerobic cell in the body has multiple mitochondria, often numbering many hundreds or more in cells with extensive energy production requirements. Furthermore, the number of copies of mtDNA within each mitochondrion varies from several to hundreds; this is true of both somatic as well as germ cells, including oocytes in females. In the case of somatic cells, this means that the impact of most newly acquired somatic mutations is likely to be very small in terms of total cellular or organ system function; however, because of the manyfold higher mutation rate during mtDNA replication, numerous different mutations may accumulate with aging of the organism. It has been proposed that the total cumulative burden of acquired somatic mtDNA mutations with age may result in an overall perturbation of mitochondrial function, contributing to age-related reduction in the efficiency of oxidative phosphorylation and increased production of damaging ROS. The accumulation of such acquired somatic mtDNA mutations with aging may contribute to age-related diseases, such as metabolic syndrome and diabetes, cancer, and neurodegenerative and cardiovascular disease in any given individual. However, somatic mutations are not carried forward to the next generation, and the
Chapter 85e Mitochondrial DNA and Heritable Traits and Diseases
Mitochondria are cytoplasmic organelles whose major function is to generate ATP by the process of oxidative phosphorylation under aerobic conditions. This process is mediated by the respiratory electron transport chain (ETC) multiprotein enzyme complexes I–V and the two electron carriers, coenzyme Q (CoQ) and cytochrome c. Other cellular processes to which mitochondria make a major contribution include apoptosis (programmed cell death) and additional cell type–specific functions (Table 85e-1). The efficiency of the mitochondrial ETC in ATP production is a major determinant of overall body energy balance and thermogenesis. In addition, mitochondria are the predominant source of reactive oxygen species (ROS), whose rate of production also relates to the coupling of ATP production to oxygen consumption. Given the centrality of oxidative phosphorylation to the normal activities of almost all cells, it is not surprising that mitochondrial dysfunction can affect almost any organ system (Fig. 85e-1). Thus, physicians in many disciplines might encounter patients with mitochondrial diseases and should be aware of their existence and characteristics. The integrated activity of an estimated 1500 gene products is required for normal mitochondrial biogenesis, function, and integrity. Almost all of these are encoded by nuclear genes and thus follow the rules and patterns of nuclear genomic inheritance (Chap. 84). These nuclear-encoded proteins are synthesized in the cell cytoplasm and imported to their location of activity within the mitochondria through a complex biochemical process. In addition, the mitochondria contain their own small genome consisting of numerous copies (polyploidy) per mitochondrion of a circular, double-strand mitochondrial DNA (mtDNA) molecule comprising 16,569 nucleotides. This mtDNA sequence (also known as the “mitogenome”) might represent the remnants of endosymbiotic prokaryotes from which mitochondria are thought to have originated. The mtDNA sequence contains a total of 37 genes, of which 13 encode mitochondrial protein components of the ETC (Fig. 85e-2). The remaining 22 tRNA- and 2 rRNA-encoding genes are dedicated to the process of translating the 13 mtDNAencoded proteins. This dual nuclear and mitochondrial genetic control of mitochondrial function results in unique and diagnostically challenging patterns of inheritance. The current chapter focuses on heritable traits and diseases related to the mtDNA component of the dual genetic control of mitochondrial function. The reader is referred to Chaps. 84 and 462e for consideration of mitochondrial disease originating from mutations in the nuclear genome. The latter include (1) disorders due to mutations in nuclear genes directly encoding structural components or assembly factors of the oxidative phosphorylation complexes, (2) disorders due to mutations in nuclear genes encoding proteins indirectly related to oxidative phosphorylation, and (3) mtDNA depletion syndromes (MDS) characterized by a reduction
of mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA.
85e-2
PART 3 Genes, the Environment, and Disease
individual, play a pivotal role in the manifestation and severity of disease and are crucial to understanding the complexity of inheritance of mtDNA disorders. At the level of the oocyte, the percentage of mtDNA molecules bearing each version of the polymorphic sequence variant or mutation depends on stochastic events related to partitionLiver Hepatopathy ing of mtDNA molecules during the process of oogenesis itself. Thus, oocytes Skeletal muscle differ from each other in the degree of Weakness ATP Fatigue heteroplasmy for that sequence variant Myopathy or mutation. In turn, the heteroplasmic Neuropathy state is carried forward to the zygote and to the organism as a whole, to varying degrees, depending on mitotic segregaNuclear Subunits Oxidative DNA phosphorylation tion of mtDNA molecules during organ Kidney system development and maintenance. Fanconi's syndrome For this reason, in vitro fertilization, Glomerulopathy Brain followed by preimplantation genetic Seizures diagnosis (PGD), is not as predictive Myoclonus of the genetic health of the offspring in Ataxia the case of mtDNA mutations as in the Mitochondrial Stroke case of the nuclear genome. Similarly, DNA Dementia Pancreas the impact of somatic mtDNA mutaMigraine Diabetes mellitus tions acquired during development and subsequently also shows an enormous spectrum of variability. Nuclear DNA Blood Mitotic segregation refers to the Pearson's syndrome unequal distribution of wild-type and mutant versions of mtDNA molecules Inner ear during all cell divisions that occur durSensorineural ing prenatal development and subsehearing loss Colon quently throughout the lifetime of an Pseudo-obstruction individual. The phenotypic effect or disease impact will, thus, be a funcFigure 85e-1 Dual genetic control and multiple organ system manifestations of m itochondrial tion not only of the inherent disruptive disease. (Reproduced with permission from DR Johns: Mitochondrial DNA and disease. N Engl J Med effect (pathogenicity) on the mtDNA333:638, 1995.) encoded gene (coding region mutations) or integrity of the mtDNA molhereditary impact of mtDNA mutagenesis requires separate consider- ecule (control region mutations), but also of its distribution among the multiple copies of mtDNA in the various mitochondria, cells, ation of events in the female germline. The multiple mtDNA copy number within each cell, including the and tissues of the affected individual. Thus, one consequence can maternal germ cells, results in the phenomenon of heteroplasmy, in be the generation of a bottleneck due to the marked decline in given contrast to much greater uniformity (homoplasy) of somatic nuclear sets of mtDNA variants, consequent to such mitotic segregation. DNA sequence. Heteroplasmy for a given mtDNA sequence variant Heterogeneity arises from differences in the degree of heteroplasmy or mutation arises as a result of the coexistence within a cell, tissue, among oocytes of the affected female, together with subsequent or individual of mtDNA molecules bearing more than one version of mitotic segregation of the pathogenic mutation during tissue and the sequence variant (Fig. 85e-3). The importance of the heteroplasmy organ development, and throughout the lifetime of the individual phenomena to the understanding of mtDNA-related mitochondrial offspring. The actual expression of disease might then depend on a diseases is critical. The coexistence of mutant and nonmutant mtDNA threshold percentage of mitochondria whose function is disrupted by and the variation of the mutant load among individuals from the mtDNA mutations. This in turn confounds hereditary transmission same maternal sibship, and across organs and tissues within the same patterns and hence genetic diagnosis of pathogenic heteroplasmic mutations. Generally, if the proportion of mutant mtDNA is less than 60%, the individual is unlikely to be affected, whereas proportions exceeding 90% cause clinical disease. I Heart Conduction disorder Wolff-Parkinson-White syndrome Cardiomyopathy
II
III Figure 85e-2 Maternal inheritance of mitochondrial DNA (mtDNA) disorders and heritable traits. Affected women (filled circles) transmit the trait to their children. Affected men (filled squares) do not transmit the trait to any of their offspring.
Eye Optic neuropathy Ophthalmoplegia Retinopathy
HOMOPLASMIC VARIANTS AND HUMAN MTDNA PHYLOGENY In contrast to classic mtDNA diseases, most of which begin in childhood and are the result of heteroplasmic mutations as noted above, during the course of human evolution, certain mtDNA sequence variants have drifted to a state of homoplasmy, wherein all of the mtDNA molecules in the organism contain the new sequence variant. This arises due to a “bottleneck” effect followed by genetic drift during the very process of oogenesis itself (Fig. 85e-3). In other words, during certain stages of oogenesis, the mtDNA copy number becomes so substantially reduced that the particular mtDNA species bearing the novel or derived sequence variant may become the increasingly predominant,
Oocyte maturation and mtDNA amplification Mutant mitochondrion Normal mitochondrion Nucleus
Fertilization
High level of mutation (affected offspring)
Intermediate level of mutation (mildly affected offspring)
Primordial germ cell containing mutant mtDNA
Low level of mutation (unaffected offspring)
D-loop, in turn comprising two adjacent hypervariable regions (HVR-I and HVR-II). Together with the absence of recombination, this amplifies drift to high frequencies of novel haplotypes. As a result, mtDNA haplotypes are more highly partitioned across geographically defined populations than sequence variants in other parts of the genome. Despite extensive research, it has not been well established that such haplotype-based partitioning has a significant influence on human health conditions. However, mtDNA-based phylogenetic analysis can be used both as a quality assurance tool and as a filter in distinguishing neutral mtDNA variants comprising human mtDNA phylogeny from potentially deleterious mutations.
85e-3
MITOCHONDRIAL DNA DISEASE
The true prevalence of mtDNA disease is difficult to estimate because of the phenotypic heterogeneity that occurs as a function of heteroplasmy, the challenge of detecting Mature oocytes and assessing heteroplasmy in different affected tissues, and the other unique features of mtDNA function and Figure 85e-3 Heteroplasmy and the mitochondrial genetic bottleneck. inheritance described above. It is estimated that at least During the production of primary oocytes, a selected number of mitochondrial 1 in 200 healthy humans harbors a pathogenic mtDNA DNA (mtDNA) molecules are transferred into each oocyte. Oocyte maturation is mutation with the potential to causes disease, but that associated with the rapid replication of this mtDNA population. This restriction- heteroplasmic germline pathogenic mtDNA mutations amplification event can lead to a random shift of mtDNA mutational load actually affect up to approximately 1 in 8500 individuals. between generations and is responsible for the variable levels of mutated mtDNA The true disease burden relating to mtDNA sequence observed in affected offspring from mothers with pathogenic mtDNA mutations. variation will only be known when the following capaMitochondria that contain mutated mtDNA are shown in red, and those with bilities become available: (1) ability to distinguish a normal mtDNA are shown in green. (Reproduced with permission from R Taylor, D Turnbull: Mitochondrial DNA mutations in human disease. Nat Rev Genetics 6:389, 2005.) completely neutral sequence variant from a true phenotype-modifying or pathogenic mutation, (2) accurate assessment of heteroplasmy that can be determined with fidelity, and (3) a systems biology approach (Chap. 87e) and eventually exclusive, version of the mtDNA for that particular to determine the network of epistatic interactions of mtDNA sequence nucleotide site. All of the offspring of a woman bearing an mtDNA variations with mutations in the nuclear genome. sequence variant or mutation that has become homoplasmic will also be homoplasmic for that variant and will transmit the sequence variant OVERVIEW OF CLINICAL AND PATHOLOGIC FEATURES OF forward in subsequent generations. Considerations of reproductive fitness limit the evolutionary or HUMAN MTDNA DISEASE population emergence of homoplasmic mutations that are lethal or Given the vital roles of mitochondria in all nucleated cells, it is not cause severe disease in infancy or childhood. Thus, with a number of surprising that mtDNA mutations can affect numerous tissues with notable exceptions (e.g., mtDNA mutations causing Leber’s hereditary pleiotropic effects. More than 200 different disease-causing, mostly optic neuropathy; see below), most homoplasmic mutations are con- heteroplasmic mtDNA mutations have been described affecting ETC sidered to be neutral markers of human evolution, which are useful function. Figure 85e-4 provides a partial mtDNA map of some of the and interesting in the population genetics analysis of shared maternal better characterized of these disorders. A number of clinical clues can ancestry but which have little significance in human phenotypic varia- increase the index of suspicion for a heteroplasmic mtDNA mutation as an etiology of a heritable trait or disease, including (1) familial tion or disease predisposition. More importantly is the understanding that this accumulation clustering with absence of paternal transmission; (2) adherence to one of homoplastic mutations occurs at a genetic locus that is transmit- of the classic syndromes (see below) or paradigmatic combinations of ted only through the female germline and that lacks recombination. disease phenotypes involving several organ systems that normally do In turn, this enables reconstruction of the sequential topology and not fit together within a single nuclear genomic mutation category; radiating phylogeny of mutations accumulated through the course of (3) a complex of laboratory and pathologic abnormalities that reflect human evolution since the time of the most recent common mtDNA disruption in cellular energetics (e.g., lactic acidosis and neurodegenancestor of all contemporary mtDNA sequences, some 200,000 years erative and myodegenerative symptoms with the finding of ragged red ago. The term haplogroup is usually used to define major branching fibers, reflecting the accumulation of abnormal mitochondria under points in the human mtDNA phylogeny, nested one within the other, the muscle sarcolemmal membrane); or (4) a mosaic pattern reflecting which often demonstrate striking continental geographic ancestral a heteroplasmic state. Heteroplasmy can sometimes be elegantly demonstrated at the partitioning. At the level of the complete mtDNA sequence, the term haplotype is usually used to describe the sum of mutations observed tissue level using histochemical staining for enzymes in the oxidative for a given mtDNA sequence and as compared to a reference sequence, phosphorylation pathway, with a mosaic pattern indicating heterogesuch that all haplotypes falling within a given haplogroup share the neity of the genotype for the coding region for the mtDNA-encoded total sum of mutations that have accumulated since the most recent enzyme. Complex II, CoQ, and cytochrome c are exclusively encoded common ancestor and the bifurcation point they mark. The remain- by nuclear DNA. In contrast, complexes I, III, IV, and V contain at ing observed variants are private to each haplotype. Consequentially, least some subunits encoded by mtDNA. Just 3 of the 13 subunits human mtDNA sequence is an almost perfect molecular prototype of the ETC complex IV enzyme, cytochrome c oxidase, are encoded for a nonrecombining locus, and its variation has been extensively by mtDNA, and, therefore, this enzyme has the lowest threshold for used in phylogenetic studies. Moreover, the mtDNA mutation rate is dysfunction when a threshold level of mutated mtDNA is reached. considerably higher than the rate observed for the nuclear genome, Histochemical staining for cytochrome c oxidase activity in tissues especially in the control region, which contains the displacement, or of patients affected with heteroplasmic inherited mtDNA mutations Primary oocytes
Chapter 85e Mitochondrial DNA and Heritable Traits and Diseases
85e-4
PART 3 Genes, the Environment, and Disease
is an excellent tool for rapidly and accurately obtaining a patient’s predominant MELAS LS, MELAS, mtDNA sequence and also lower freMyopathy, myoglobinuria multisystem disease PEO quency heteroplasmic variants. This is Cardiomyopathy Cardiomyopathy enabled by deep coverage of the genome ECM PEO, LHON, MELAS, ECM, LHON, myopathy, through multiple independent sequence F myopathy, cardiomyopathy, 12s cardiomyopathy, MELAS PT V reads. Accordingly, recent studies makdiabetes and deafness and parkinsonism 16S ing use of NGS techniques have demonCyt b Myopathy, LHON Cardiomyopathy L1 strated sequence accuracy equivalent to cardiomyopathy, PEO ECM E Sanger-type sequencing, but also have ND1 LHON, MELAS, Myopathy, MELAS ND6 uncovered heretofore unappreciated I diabetes, Myopathy, lymphoma Q heteroplasmy rates ranging between 10 LHON and dystonia M Cardiomyopathy and 50% and detection of single-nucleLHON ND5 LS, MELAS otide heteroplasmy down to levels of ND2 LS, ataxia, Cardiomyopathy, ECM 95% of cases, LHON shows areas of increased T2 signal, typically involving the posterior is due to one of three homoplasmic point mutations of mtDNA that cerebrum and not conforming to the distribution of major arteries. affect genes encoding different subunits of complex I of the mitochon- Electrocardiogram (ECG) may show evidence of cardiomyopathy, drial ETC; however, not all individuals who inherit a primary LHON preexcitation, or incomplete heart block. Electromyography and mtDNA mutation develop optic neuropathy, and males are four to five nerve conduction studies are consistent with a myopathic process, but times more likely than females to be affected, indicating that additional axonal and sensory neuropathy may coexist. Muscle biopsy typically environmental (e.g., tobacco exposure) or genetic factors are important shows ragged red fibers with the modified Gomori trichrome stain in the etiology of the disorder. Both the nuclear and mitochondrial or “ragged blue fibers” resulting from the hyperintense reaction with genomic backgrounds modify disease penetrance. Indeed, a region of the histochemical staining for succinate dehydrogenase. The diagthe X chromosome containing a high-risk haplotype for LHON was nosis of MELAS is based on a combination of clinical findings and recently identified, supporting the formulation that nuclear genes act molecular genetic testing. Mutations in the mtDNA gene MT-TL1 as modifiers and affording an explanation for the male prevalence encoding tRNAleu are causative. The most common mutation, present of LHON. This haplotype can be used in predictive genomic testing in approximately 80% of individuals with typical clinical findings, is and prenatal screening for this disease. In contrast to the other clas- an A-to-G transition at nucleotide 3243 (m.3243A>G). Mutations can sic mtDNA disorders, it is of interest that patients with this syndrome usually be detected in mtDNA from leukocytes in individuals with typical MELAS; however, the occurrence of heteroplasmy can result in varying tissue distribution of mutated mtDNA. In the absence TABLE 85e-2 Common Features of mtDNA-Associated Diseases in Adults of specific treatment, various manifestations of MELAS are treated Neurologic: stroke, epilepsy, migraine headache, peripheral neuropathy, craaccording to standard modalities for prevention, surveillance, and nial neuropathy (optic atrophy, sensorineural deafness, dysphagia, dysphasia) treatment. Skeletal myopathy: ophthalmoplegia, exercise intolerance, myalgia Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem Cardiac: conduction block, cardiomyopathy disorder characterized by myoclonus, seizures, ataxia, and myopathy Respiratory: hypoventilation, aspiration pneumonitis with ragged red fibers. Hearing loss, exercise intolerance, neuropathy, Endocrine: diabetes mellitus, premature ovarian failure, hypothyroidism, and short stature are often present. Almost all MERRF patients have hypoparathyroidism mutation in the mtDNA tRNAlys gene, and the m.8344A>G mutation Ophthalmologic: cataracts, pigment retinopathy, neurologic and myopathic in the mtDNA gene encoding the lysine amino acid tRNA is respon(optic atrophy, ophthalmoplegia) sible for 80–90% of MERRF cases.
85e-6
TABLE 85e-3 Mitochondrial Diseases due to mtDNA Point Mutations and Large-Scale Rearrangements Disease NARP, Leigh disease MELAS
MERRF
Deafness
Chronic progressive external ophthalmoplegia (PEO) Pearson syndrome Kearns-Sayre syndrome (KSS)
Phenotype Loss of central vision leading to blindness in young adult life Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; may m anifest only as diabetes mellitus Myoclonic epilepsy, ragged red fibers in muscle, ataxia, increased CSF protein, sensorineural deafness, dementia Progressive sensorineural deafness, often induced by aminoglycoside antibiotics Nonsyndromic sensorineural deafness
PART 3
Late-onset bilateral ptosis and ophthalmoplegia, proximal muscle weakness, and exercise intolerance Pancreatic insufficiency, pancytopenia, lactic acidosis External ophthalmoplegia, heart block, retinal pigmentation, ataxia
Most Frequent mtDNA Mutations m.1778G>A, m.14484T>C, m.3460G>A Point mutation in tRNAleu
Homoplasmic (usually) Heteroplasmic
Maternal Maternal
Heteroplasmic
Maternal
Point mutation in tRNAlys
Heteroplasmic
Maternal
m.1555A>G mutation in 12S rRNA m.7445A>G mutation in 12S rRNA Single deletions or duplications
Homoplasmic
Maternal
Homoplasmic
Maternal
Heteroplasmic
Mostly sporadic, somatic mutations
Large deletion
Heteroplasmic
The 5-kb “common deletion”
Heteroplasmic
Sporadic, somatic mutations Sporadic, somatic mutations
Abbreviations: CSF, cerebrospinal fluid; NARP, neuropathy, ataxia, and retinitis pigmentosa.
Genes, the Environment, and Disease
Neuropathy, ataxia, and retinitis pigmentosa (NARP) is characterized by moderate diffuse cerebral and cerebellar atrophy and symmetric lesions of the basal ganglia on magnetic resonance imaging (MRI). A heteroplasmic m.8993T>G mutation in the ATPase 6 subunit gene has been identified as causative. Ragged red fibers are not observed in muscle biopsy. When >95% of mtDNA molecules are mutant, a more severe clinical, neuroradiologic. and neuropathologic picture (Leigh syndrome) emerges. Point mutations in the mtDNA gene encoding the 12S rRNA result in heritable nonsyndromic hearing loss. One such mutation causes heritable ototoxic susceptibility to aminoglycoside antibiotics, which opens a pathway for a simple pharmacogenetic test in the appropriate clinical settings. Kearns-Sayre syndrome (KSS), sporadic progressive external ophthalmoplegia (PEO), and Pearson syndrome are three disease phenotypes caused by large-scale mtDNA rearrangements including partial deletions or partial duplication. The majority of single large-scale rearrangements of mtDNA are thought to result from clonal amplification of a single sporadic mutational event, occurring in the maternal oocyte or during early embryonic development. Because germline involvement is rare, most cases are sporadic rather than inherited. KSS is characterized by the triad of onset before age 20, chronic progressive external ophthalmoplegia, and pigmentary retinopathy. Cerebellar syndrome, heart block, increased cerebrospinal fluid protein content, diabetes mellitus, and short stature are also part of the syndrome. Single deletions/duplication can also result in milder phenotypes such as PEO, characterized by late-onset progressive external ophthalmoplegia, proximal myopathy, and exercise intolerance. In both KSS and PEO, diabetes mellitus and hearing loss are frequent accompaniments. Pearson syndrome is also characterized by diabetes mellitus from pancreatic insufficiency, together with pancytopenia and lactic acidosis, caused by the large-scale sporadic deletion of several mtDNA genes. Two important dilemmas in classic mtDNA disease have benefited from recent important research insights. The first relates to the greater involvement of neuronal, muscular, renal, hepatic, and pancreatic manifestations in mtDNA disease in these syndromes. This observation has appropriately been mostly attributed to the high energy utilization of the involved tissues and organ systems and, hence, greater dependency on mitochondrial ETC integrity and health. However, because mutations are stochastic events, mitochondrial mutations should occur in any organ during embryogenesis and development. Recently, additional explanations have been suggested based on studies of the common m.3243A>G transition. The proportion of this m utation in peripheral blood cells was shown to decrease exponentially with age.
A selective process acting at the stem cell level with a strong bias against the mutated form would have its greatest effect to reduce the mutant mtDNA only in highly proliferating cells, such as those derived from the hematopoietic system. Tissues and organs with lower cell turnover, such as those involved with mtDNA mutations, would not benefit from this effect and, thus, would be the most affected. The other dilemma arises from the observation that only a subset of mtDNA mutations accounts for the majority of the familial mtDNA diseases. The random occurrence of mutations in the mtDNA sequence should yield a more uniform distribution of disease-causing mutations. However, recent studies using the introduction of one severe and one mild point mutation into the female germline of experimental animals demonstrated selective elimination during oogenesis of the severe mutation and selective retention of the milder mutation, with the emergence of mitochondrial disease in offspring after multiple generations. Thus, oogenesis itself can act as an “evolutionary” filter for mtDNA disease. THE INVESTIGATION OF SUSPECTED mtDNA DISEASE The clinical presentations of classic syndromes, groupings of disease manifestations in multiple organ systems, or unexplained isolated presentations of one of the disease features of a classic mtDNA syndrome should prompt a systematic clinical investigation as outlined in Fig. 85e-6. Indeed, mitochondrial disease should be considered in the differential diagnosis of any progressive multisystem disorder. Despite the centrality of disruptive oxidative phosphorylation, an elevated blood lactate level is neither specific nor sensitive because there are many causes of blood lactic acidosis, and many patients with mtDNA defects presenting in adulthood have normal blood lactate. An elevated cerebrospinal fluid lactate is a more specific test for mitochondrial disease if there is central nervous system involvement. The serum creatine kinase may be elevated but is often normal, even in the presence of a proximal myopathy. Urinary organic and amino acids may also be abnormal, reflecting metabolic and kidney proximal tubule dysfunction. Every patient with seizures or cognitive decline should have an electroencephalogram. A brain computed tomography (CT) scan may show calcified basal ganglia or bilateral hypodense regions with cortical atrophy. MRI is indicated in patients with brainstem signs or stroke-like episodes. For some mitochondrial diseases, it is possible to obtain an accurate diagnosis with a simple molecular genetic screen. For examples, 95% of patients with LHON harbor one of three mtDNA point mutations (m.11778A>G, m.A3460A>G, or m.14484T>C). These patients have very high levels of mutated mtDNA in peripheral blood cells, and
IMPACT OF HOMOPLASMIC SEQUENCE VARIATION ON HERITABLE TRAITS AND DISEASE
CLINICAL AND LABORATORY INVESTIGATION OF SUSPECTED MTDNA DISORDER Clinical investigations Blood: creatine kinase, liver functions, glucose, lactate Urine: organic and amino acids CSF: glucose, protein, lactate Cardiac x-ray, ECG, ECHO EEG, EMG, nerve conduction Brain CT/MRI
Specific point mutation syndrome: e.g., MELAS, MERRF, and LHON
Yes
PCR/RFLP analysis of blood for known mutations No
Histochemistry
Muscle biopsy
Molecular genetic analysis rearrangements PCR/RFLP for common point mutation mtDNA automated sequencing
Figure 85e-6 Clinical and laboratory investigation of a suspected mitochondrial DNA (mtDNA) disorder. CSF, cerebrospinal fluid; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; EEG, electroencephalogram; EMG, electromyogram; LHON, Leber’s hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stoke-like episodes; MERFF, myoclonic epilepsy with ragged red fibers; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism. therefore, it is appropriate to send a blood sample for molecular genetic analysis by polymerase chain reaction (PCR) or restriction fragment length polymorphism. The same is true for most MERRF patients who harbor a point mutation in the lysine tRNA gene at position 8344. In contrast, patients with the m.3243A>G MELAS mutation often have low levels of mutated mtDNA in blood. If clinical suspicion is strong enough to warrant peripheral blood testing, then patients with a negative result should be investigated further by performing a skeletal muscle biopsy. Muscle biopsy histochemical analysis is the cornerstone for investigation of patients with suspected mitochondrial disease. Histochemical analysis may show subsarcolemmal accumulation of mitochondria with the appearance of ragged red fibers. Electron microscopy might show abnormal mitochondria with paracrystalline inclusions. Muscle histochemistry may show cytochrome c oxidase (COX)–deficient fibers, which indicate mitochondrial dysfunction (Fig. 85e-5). Respiratory chain complex assays may also show reduced enzyme function. Either of these two abnormalities confirms the presence of a mitochondrial disease, to be followed by an in-depth molecular genetic analysis. Recent evidence has provided important insights into the importance of nuclear-mtDNA genomic cross-talk and has provided a descriptive framework for classifying and understanding disorders that emanate from perturbations in this cross-talk. Although not strictly considered as mtDNA genetic disorders, manifestations do overlap those highlighted above (Fig. 85e-7).
The relationship among the degree of heteroplasmy, tissue distribution of the mutant mtDNA, and disease phenotype simplifies inference of a clear causative relationship between heteroplasmic mutation and disease. With the exception of certain mutations (e.g., those causing most cases of LHON), drift to homoplasmy of such mutations would be precluded normally by the severity of impaired oxidative phosphorylation and the consequent reduction in reproductive fitness. Therefore, sequence variants that have reached homoplasmy should be neutral in terms of human evolution and, hence, useful only for tracing human evolution, demography, and migration, as described above. One important exception is in the case of one or more of the homoplasmic population-level variants, which designate the mtDNA haplogroup J, and the interaction with the mtDNA mutations causing LHON. Reduced disease predilection suggests that one or more of the ancient sequence variants designating mtDNA haplogroup J appears to attenuate predisposition to degenerative disease, in the face of other risk factors. Whether or not additional epistatic interactions between population-level mtDNA haplotypes and common health conditions will be found remains to be determined. If such influences do exist, then they are more likely to be relevant to health conditions in the postreproductive age groups, wherein evolutionary filters would not have had the opportunity to censor deleterious effects and interactions and wherein the effects of oxidative stress may play a role. Although much has been written about the possible associations of populationlevel common mtDNA variants and human health and disease phenotypes or adaptation to different environmental influences (e.g., climate), a word of caution is in order. Many studies that purport to show such associations with phenotypes such as longevity, athletic performance, and metabolic and neurodegenerative disease are limited by small sample sizes, possible genotyping inaccuracies, and the possibility of population stratification or ethnic ancestry bias. Because mtDNA haplogroups are so prominently partitioned along phylogeographic lines, it is difficult to rule out the possibility that a haplogroup for which an association has been found is simply a marker for differences in Multiple ΔmtDNA
ANT1
adPEO
adPEO
Twinkle mtDNA depletion
Deoxyguanosine kinase MPV17 Thymidine kinase (TK2) RRMB2 (p53-R2) Succinyl-CoA synthase (SUCLA2, SUCLG1)
TP Thymidine phosphorylase
Patient Control
adPEO arPEO Pol γ A
Twinkle
B
Pol γA
Alpers’ like Alpers’s. IOSCA SCAE
dNTP pool Pyrimidine salvage
Figure 85e-7 Disorders associated with perturbations in nuclear- mitochondrial genomic cross-talk. Clinical features and genes associated with multiple mitochondrial DNA (mtDNA) deletions, mtDNA depletion, and mitochondrial neurogastrointestinal encephalomyopathy syndromes. ANT, adenine nucleotide translocators; adPEO, autosomal dominant progressive external ophthalmoplegia; arPEO, autosomal recessive progressive external ophthalmoplegia; IOSCA, infantile-onset spinocerebellar ataxia; SCAE, spinocerebellar ataxia and epilepsy. (Reproduced with permission from A Spinazzola, M Zeviani: Disorders from perturbations of nuclear-mitochondrial intergenomic cross-talk. J Intern Med 265:174, 2009.)
Chapter 85e Mitochondrial DNA and Heritable Traits and Diseases
Study of respiratorychain complexes activities
85e-7
85e-8
IMPACT OF ACQUIRED SOMATIC mtDNA MUTATION ON HUMAN HEALTH AND DISEASE
PART 3 Genes, the Environment, and Disease
Studies on aging humans and animals have shown a potentially important correlation of age with the accumulation of heterogeneous mtDNA mutations, especially in those organ systems that undergo the most prominent age-related degenerative tissue phenotype. Sequencing of PCR-amplified single mtDNA molecules has demonstrated an average of two to three point mutations per molecule in elderly subjects when compared with younger ones. Point mutations observed include those responsible for known heritable heteroplasmic mtDNA disorders, such as the m.3344A>G and m.3243A>G mutations responsible for the MERRF and MELAS syndromes, respectively. However, the cumulative burden of these acquired somatic point mutations with age was observed to remain well below the threshold expected for phenotypic expression (G mutation of the 12SrRNA encoding gene.
is a function of the stochastic differential segregation and copy number of mutant mtDNA during the oogenesis bottleneck and, subsequently, following tissue and organ development in the offspring, it is rarely predictable with any degree of accuracy. For this reason, prenatal diagnosis (PND) and PGD techniques that have evolved into integral and well-accepted standards of practice are severely hampered in the case of mtDNA-related diseases. The value of PND and PGD is limited, partly due to the absence of data on the rules that govern the segregation of wild-type and mutant mtDNA species (heteroplasmy) among tissue in the developing embryo. Three factors are required to ensure the reliability of PND and PGD: (1) a close correlation between the mutant load and the disease severity, (2) a uniform distribution of mutant load among tissues, and (3) no major change in mutant load with time. These criteria are suggested to be fulfilled for the NARP m.8993T>G mutation but do not seem to apply to other mtDNA disorders. In fact, the level of mutant mtDNA in a chorionic villous or amniotic fluid sample may be very different from the level in the fetus, and it would be difficult to deduce whether the mutational load in the prenatal samples provides clinically useful information regarding the postnatal and adult state.
85e-10 Normal conception Mother carrying mutant mitichondrial DNA
A
Oocyte donation B
Nuclear transfer into donated oocytes: a future possibility?
Preimplantation genetic diagnosis C
D Unrelated donor unfertilized oocytes are enucleated
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Implanted embryo is derived from donor oocytes fertilized with the partner’s sperm in vitro
Preimplantation embryo sampling and selection of low risk embryos for implantation into uterus
Carrier mother’s oocytes are fertilized in vitro and injected into an enucleated donor oocyte
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The likelihood that adherent mitochondria will also be transferred means that prenatal testing is also recommended
Genes, the Environment, and Disease
Offspring
Figure 85e-9 Possible approaches for prevention of mitochondrial DNA (mtDNA) disease. A. No intervention: offspring’s mutant mtDNA load will vary greatly. B. Oocyte donation: currently permitted in some constituencies but limited by the availability of oocyte donors. C. Preimplantation genetic diagnosis: available for some mtDNA diseases (reliable in determining background nuclear genomic haplotype risk). D. Nuclear transfer: research stage, including initial studies in nonhuman primates. Red represents mutant mtDNA, pink and white represent successively higher proportions of normal mtDNA. Blue represents genetic material from an unrelated donor. (Adapted with permission from J Poulton et al: Preventing transmission of maternally inherited mitochondrial DNA diseases. Br Med J 338:b94, 2009.)
86e
The Human Microbiome Jeffrey I. Gordon, Rob Knight
The technologies that allowed us to decipher the human genome have revolutionized our ability to delineate the composition and functions of the microbial communities that colonize our bodies and make up our microbiota. Each body habitat, including the skin, nose, mouth, airways, gastrointestinal tract, and vagina, harbors a distinctive community of microbes. Efforts to understand our microbiota and its collection of microbial genes (our microbiome) are changing our views of “self” and deepening our understanding of many normal physiologic, metabolic, and immunologic features and their interpersonal and intrapersonal variations. In addition, this area of research is beginning to provide new insights into diseases not previously known to have microbial “contributors” and is suggesting new strategies for treatment
and prevention. Key terms used in the discussion of the human microbiome are defined in Table 86e-1. We are holobionts—collections of human and microbial cells that function together in an elaborate symbiosis. The aggregate number of microbial cells in our microbiota exceeds the number of human cells in our adult bodies by up to 10-fold, and each healthy adult is estimated to harbor 105–106 microbial genes, in contrast to ~20,000 Homo sapiens genes. Members of our microbiota can function as mutualists (i.e., both host and microbe benefit from each other’s presence), as commensals (one partner benefits; the other is seemingly unaffected), and as potential or overt pathogens (one partner benefits; the other is harmed). Many clinicians view pathogens as individual microbial species or strains that can elicit disease in susceptible hosts. An emerging, more ecologic view is that pathogens do not function in isolation; rather, their invasion, emergence, and effects on the host reflect interactions with other members of a microbiota. An even more expansive view is that multiple organisms in a community conspire to
Term Culture-independent analysis Diversity (alpha and beta) Domains of life Dysbiosis
Definition A type of analysis in which the culture of microbes is not required but rather information is extracted directly from environmental samples Alpha diversity measures the effective number of species (kinds of organisms) at the level of individual habitats, sites, or samples. Beta diversity measures differences in the number of kinds of organisms across habitats, sites, or samples. The three major branches of life on Earth: the Eukarya (including humans), the Bacteria, and the Archaea Any deleterious condition arising from a structural and/or functional aberration in one or more of the host organism’s microbial communities Gnotobiotics The rearing of animals under sterile (germ-free) conditions. These animals can subsequently be colonized at various stages of the life cycle with defined collections of microbes. Holobiont The biologic entity consisting of a host and all its internal and external symbionts, their gene repertoires, and their functions Human microbiome In ecology, biome refers to a habitat and the organisms in it. In this sense, the human microbiome would be defined as the collection of microorganisms associated with the human body. However, the term microbiome is also used to refer to the collective genomes and genes present in members of a given microbiota (see “Microbiota,” below), and the human metagenome is the sum of the human genome and microbial genes (microbiome). A core human microbiome is defined as everything shared in a given body habitat among all or the vast majority of human microbiomes. A core microbiome may include a common set of genomes and genes encoding various protein families and/or metabolic capabilities. Microbial genes that are variably represented in different humans may contribute to distinctive physiologic/metabolic phenotypes. Metagenomics An emerging field encompassing culture-independent studies of the structures and functions of microbial communities as well as the interactions of these communities with the habitats they occupy. Metagenomics includes (1) shotgun sequencing of microbial DNA isolated directly from a given environment and (2) high-throughput screening of expression libraries constructed from cloned community DNA to identify specific functions such as antibiotic resistance (functional metagenomics). DNA-level analyses provide the foundation for profiling of mRNAs and proteins produced by a microbiome (metatranscriptomics and metaproteomics) and for identification of a community’s metabolic network (metametabolomics). Microbial source tracking A collection of methods for assessing the environments of origin for microbes. One method, SourceTracker, uses a Bayesian approach to identify each bacterial taxon’s origins and estimates the proportions of each community made up by bacteria originating from different environments. Microbiota A microbial community—including Bacteria, Archaea, Eukarya, and viruses—that occupies a given habitat Pan-genome The group of genes found in genomes that make up a given microbial phylotype, including both core genes found in all genomes and variably represented genes found in a subset of genomes within the phylotype Phylogenetic analysis Characterization of the evolutionary relationships between organisms and their gene products Phylogenetic tree A “tree” in which organisms are shown according to their relationships to hypothetical common ancestors. When built from molecular sequences, the branch lengths are proportional to the amount of evolutionary change separating each ancestor–descendant pair. Phylotype A phylogenetic group of microbes, currently defined by a threshold percentage identity shared among their small-subunit rRNA genes (e.g., ≥97% for a species-level phylotype) Principal coordinates An ordination method for visualizing multivariate data based on the similarity/dissimilarity of the measured entities (e.g., visualization analysis of bacterial communities based on their UniFrac distances; see “UniFrac,” below) Random Forests analysis/ Machine learning is a collection of approaches that allow a computer to learn without being explicitly programmed. Random Forests machine learning is a machine-learning method for classification and regression that uses multiple decision trees during a training step. Rarefaction A procedure in which subsampling is used to assess whether all the diversity present in a given sample or set of samples has been observed at a given sampling depth and to extrapolate how much additional sampling would be needed to observe all the diversity Resilience A community’s ability to return to its initial state after a perturbation Shotgun sequencing A method for sequencing large DNA regions or collections of regions by fragmenting DNA and sequencing the resulting smaller sections Succession (primary and Succession (in an ecologic context) refers to changes in the structure of a community through time. Primary succession describes the secondary) sequence of colonizations and extinctions that occur in a new habitat. Secondary succession refers to changes in community structure after a disturbance. UniFrac A measure of the phylogenetic dissimilarity between two communities, calculated as the unshared proportion of the phylogenetic tree containing all the organisms present in either community
Chapter 86e The Human Microbiome
Table 86e-1 Glossary of Terms Used in Discussion of the Human Microbiome
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produce pathogenic effects in certain host and environmental contexts (a pathologic community). The ability to characterize microbial communities without culturing their component members has spawned the field of metagenomics (Table 86e-1). Metagenomics reflects a confluence of experimental and computational advances in the genome sciences as well as a more ecologic understanding of medical microbiology, according to which the functions of a given microbe and its impact on human biology depend on the context of other microbes in the same community. Traditional microbiology relies on culturing individual microbes, but metagenomics skips this step, instead sequencing DNA isolated directly from a given microbial community. The resulting datasets facilitate follow-up functional studies, such as the profiling of RNA and protein products expressed from the microbiome or the characterization of a microbial community’s metabolic activities. Metagenomics provides insight into how microbial communities vary in several situations critical to human health. One such situation is how microbial communities are assembled following birth and how they operate over time, including responses of established communities to various perturbations. Another is how microbial communities normally vary between different anatomic sites within an individual and between different groups of people representing different ages, physiologic states, lifestyles, geographies, and gender. Yet another is how microbial communities vary in disease; whether such variations are consistent among individuals grouped according to current criteria for a disease or its subtypes; whether the microbiota or microbiome provides new ways of classifying disease states; and, importantly, whether the structural and functional configurations of microbial communities are a cause or a consequence of disease. Analysis of our microbiomes also addresses one of the most fundamental questions in genetics: How does environment select our genes and directly influence their function? Each human encounters a unique environment during the course of his or her lifetime. Part of this personally experienced environment is incorporated into the genes and capabilities of our microbial communities. The microbiome therefore expands our conceptualization of “human” genetic potential from a single set of genes “fixed” at birth to a microbiome with additional genes and capabilities acquired via a process influenced by our family and life experiences, including modifiable lifestyle choices such as diet. This view recognizes a previously underappreciated dimension of human evolution that occurs at the level of our microbiomes and inspires us to determine how—and how fast—this microbial evolution effects changes in our human biology. For example, Westernization is associated with loss of bacterial species diversity (richness) in the microbiota, and this loss may be associated with the suite of Western diseases. The study of our microbiomes also raises important questions about personal identity, how we define the origins of health disparities, and privacy. Further, it offers the possibility of entirely new approaches to disease prevention and treatment, including regenerative medicine, which involves administration of microbial species (probiotics) to individuals harboring communities that have not developed into a mature, fully functional state or that have been perturbed in ways that can be restored by the addition of species that fill unoccupied “jobs” (niches). This chapter provides a general overview of how human microbial communities are analyzed; reviews ecologic principles that guide our understanding of microbial communities in health and disease; summarizes recent studies that establish correlations and, in some cases, causal relationships between our microbiota/microbiomes and various diseases; and discusses challenges faced in the translation of these findings to new therapeutic interventions. A TOOLBOX FOR METAGENOMIC ANALYSES OF HUMAN MICROBIAL COMMUNITIES Life on Earth has been classified into three domains: Bacteria, Archaea, and Eukarya. The habitats of the surface-exposed human body harbor members of each domain plus their viruses. In large part, microbial diversity has not been characterized by culture-based approaches, partly because we do not know how to re-create the metabolic milieu fashioned by these communities in their native habitats and
partly because a few organisms tend to outgrow the others. Cultureindependent methods readily identify which organisms are present in a microbiota and their relative abundance. The gene widely used to identify microbes and their evolutionary relationships encodes the major RNA component of the small subunit (SSU) of ribosomes. Within each domain of life, the SSU gene is highly conserved, allowing the SSU gene sequences present in different organisms in that domain to be accurately aligned and regions of nucleotide sequence variation to be identified. Pairwise comparisons of SSU ribosomal RNA (rRNA) genes from different microbes allow construction of a phylogenetic tree that represents an evolutionary map on which previously unknown organisms can be assigned a position. This approach, known as molecular phylogenetics, permits characterization of each organism on the basis of its evolutionary distance from other organisms. Different phylogenetic types (phylotypes) can be viewed as comprising branches on an evolutionary tree. Characterization of Bacteria Because members of the Bacteria dominate our microbiota, most studies defining our various body habitat– associated microbial communities have sequenced the bacterial SSU gene that encodes 16S rRNA. This gene has a mosaic structure, with highly conserved domains flanking more variable regions. The most straightforward way to identify bacterial taxonomic groups (taxa) in a given community is to sequence polymerase chain reaction (PCR) products (amplicons) generated from the 16S rRNA genes present in that community. PCR primers directed at the conserved regions of the gene yield PCR amplicons encompassing one or more of that gene’s nine variable regions. PCR primer design is critical: differential annealing with primer pairs designed to amplify different variable regions can lead to over- or underrepresentation of specific taxa, and different regions within the 16S rRNA gene can have different patterns of evolution. Therefore, caution must be exercised in comparisons of the relative abundance of taxa in samples characterized in different studies, as methodologic differences can lead to larger perceived differences in the inferred taxonomy than actually exist. A key innovation is multiplex sequencing. Amplicons from each microbial-community DNA sample are tagged by incorporation of a unique oligonucleotide barcode into the PCR primer. Amplicons harboring these sample-specific barcodes can then be pooled together so that multiple samples representing multiple communities can be sequenced simultaneously (Fig. 86e-1). One important choice is the tradeoff between the number of samples that can be processed simultaneously and the number of sequences generated per sample. Interpersonal differences in the bacterial components of the microbiota are typically large, as are differences between communities occupying different body habitats in the same individual (see below); thus fewer than 1000 16S rRNA reads are characteristically required to discriminate community type. However, the identification of systematic differences in microbiota composition that correlate with physiologic status or disease state is confounded by the substantial interpersonal variation that occurs normally. Sequencing of bacterial 16S rRNA genes creates a challenge for medical microbiology: how to define the taxonomic groups present in a community in a systematic and informative manner, so that one community can be compared with and contrasted to another. Within each domain of life, microbes are classified in a hierarchy beginning with phylum (the broadest group) followed by class, order, family, genus, and species. To determine taxonomy, 16S rRNA sequences are aligned on the basis of their sequence similarity—a process known as picking operational taxonomic units (OTUs). Grouping of 16S rRNA sequences from a given variable region into “bins” that share ≥97% nucleotide sequence identity (97%ID OTUs) is a commonly accepted, albeit arbitrary, way to define a species. Looking beyond the 16S rRNA gene, we find that different isolates (strains) of a given bacterial species have overlapping but not identical sets of genes in their genomes. The aggregate set of genes identified in all isolates (strains) of a given species-level phylotype represents its pan-genome. Most species are represented by multiple strains, sometimes with markedly different functions (for example,
Extract DNA; PCR amplify SSU rRNA genes with barcoded primers
Multiplex sequencing of SSU rRNA gene amplicons
Screen, assign sequences to samples using barcode
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Figure 86e-1 Pipeline for culture-independent studies of a microbiota. (A) DNA is extracted directly from a sampled human body habitat– associated microbial community. The precise location of the community and relevant patient clinical data are collected. Polymerase chain reaction (PCR) is used to amplify portions of small-subunit (SSU) rRNA genes (e.g., the genes encoding bacterial 16S rRNA) containing one or more variable regions. Primers with sample-specific, error-correcting barcodes are designed to recognize the more conserved regions of the 16S rRNA gene that flank the targeted variable region(s). (B) Barcoded amplicons from multiple samples (communities 1–3) are pooled and sequenced in batch in a highly parallel next-generation DNA sequencer. (C) The resulting reads are then processed, with barcodes denoting which sample the sequence came from. After barcode sequences are removed in silico, reads are aligned and grouped according to a specified level of shared identity; e.g., sequences that share ≥97% nucleotide sequence identity are regarded as representing a species. Once reads are binned into operational taxonomic units (OTUs) in this fashion, they are placed on a phylogenetic tree of all known bacteria and their phylogeny is inferred. (D) Communities can be compared to one another by either taxon-based methods, in which phylogeny is not considered and the number of shared taxa are simply scored, or phylogenetic methods, in which community similarity is considered in light of the evolutionary relationships of community members. The UniFrac metric is commonly used for phylogeny-based comparisons. In stylized examples (i), (ii), and (iii), communities with varying degrees of similarity are shown. Each circle represents an OTU colored on the basis of its community of origin and placed on a master phylogenetic tree that includes all lineages from all communities. Branches (horizontal lines) are colored with each community that contains members from that branch. The three examples vary in the amount of branch length shared between the OTUs from each community. In (i), there is no shared branch length, and thus the three communities have a similarity score of 0. In (ii), the communities are identical, and a similarity score of 1 is assigned. In (iii), there is an intermediate level of similarity: communities represented in red and green share more branch length and thus have a higher similarity score than red vs. blue or green vs. blue. The amount of shared branch length in each pairwise community comparison provides a distance matrix. (E) The results of taxon- or phylogeny-based distance matrices can be displayed by principal coordinates analysis (PCoA), which plots each community spatially such that the largest component of variance is captured on the x-axis (PC1) and the second largest component of variance is displayed on the y-axis (PC2). In the example shown, the three communities in example (iii) from panel D are compared. Note that for shotgun sequencing of whole-community DNA (microbiome analysis), reads are compared with genes that are present in the genomes of sequenced cultured microbes and/or with genes that have been annotated by hierarchical functional classification schemes in various databases, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG). Communities can then be compared on the basis of the distribution of functional groups in their microbiomes—an approach analogous to taxon-based methods for 16S rRNA–based comparisons—and the results plotted with PCoA. enteropathogenic versus commensal Escherichia coli). Differences in genome content among strains of a given species reflect differences in community membership as well as differences in the selective pressures these strains experience within and between habitats. Horizontal gene transfer among members of a microbiota—mediated by phage, plasmids, and other mechanisms—is a major contributor to this strain-level variation. Strain-level diversity can be important in any consideration of how microbial communities differ between individuals and how these communities accommodate perturbations. For example, the great bacterial strain-level diversity that exists in the gut is thought to be one of the features that allows this microbiota, which occupies a constantly
perfused ecosystem exposed to the complex and varying set of substances we ingest, to adapt to changing circumstances rather than depending on one strain to occupy a given niche important for proper community functioning. In ecologic studies of different environments, such as grasslands, forests, and reefs, increased diversity within a community increases its capacity to respond to disturbances and to restore itself (i.e., its resilience); the same is likely true of microbial ecosystems. When characterizing the mechanisms by which a given species produces an effect or effects on humans, it is important to consider the strain being tested; strain-level diversity has an impact on discovery and development efforts aimed at identifying next-generation probiotics that can be used therapeutically to promote health or treat disease.
Chapter 86e The Human Microbiome
(i)
Cluster samples based on UniFrac distances calculated from (iii), machine learning, feature identification, etc.
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Identification of Archaeal and Eukaryotic Members Surveys based on SSU rRNA gene sequencing have largely focused on Bacteria, yet the census of “who’s there” in human body habitat–associated communities must also include the other two domains of life: Archaea and Eukarya. Differences in the sequences of archaeal and bacterial 16S rRNA genes, first recognized by Carl Woese in 1977, allowed these two domains of life to be distinguished. The representation of Archaea in human microbial communities is less well defined than that of Bacteria, in part due to the difficulty in optimizing the design of PCR primers that specifically target conserved regions of archaeal (versus bacterial) 16S rRNA genes. Identifying archaeal members is important to our understanding of the functional properties of the microbiota. For example, a major challenge faced by microbial communities when breaking down polysaccharides (the most abundant biologic polymers on Earth) is the maintenance of redox balance in the setting of maximal energy production. Many microbial species have branched fermentation pathways that allow them to dispose of reducing equivalents (e.g., by the production of H2, which is energetically efficient). However, there is a caveat: the hydrogen must be removed or it will inhibit reoxidation of pyridine nucleotides. Therefore, hydrogen-consuming (hydrogenotrophic) species are key to maximizing the energy-extracting capacity of primary fermenters. In the human gut, hydrogenotrophs include a phylogenetically diverse group of bacterial acetogens, a more limited group of sulfatereducing bacteria that generate hydrogen sulfide, and methaneproducing archaeal organisms (methanogens) that can represent up to 10% of the anaerobes present in the feces of some humans. However, the degree of archaeal diversity in the gut microbiota of healthy individuals appears to be low. Culture-independent surveys of eukaryotic diversity are also confounded by challenges related to the design of PCR primers that target the eukaryotic SSU gene (18S rRNA) as well as the internal transcribed spacer regions of rRNA operons. Metagenomic studies of healthy human adults living in countries with distinct cultural traditions and disparate geographic features and locations have revealed that the degree of eukaryotic diversity is lower than that of bacterial diversity. In the gut, which contains far more microbes than any other body habitat, the representation of fungi is significantly lower in individuals living in Westernized societies than in those living in non-Western societies. The most abundant fungal sequences belong to the phylumlevel taxa Ascomycota and Microsporidia. The phyla Ascomycota and Basidiomycota appear to be mutually exclusive, and the presence of Candida in particular correlates with recent consumption of carbohydrates. Elucidation of Viral Dynamics Viruses are the most abundant biologic entity on Earth. Viral particles outnumber microbial cells by 10:1 in most environments. Humans are no exception in terms of viral colonization; our feces alone contain 108–109 viral particles per gram. Despite this abundance, many eukaryotic viral communities remain incompletely characterized, in part because the identification of viruses within metagenomic sequencing datasets is itself very challenging. Characterizing viral diversity requires different approaches: because no single gene is found in all viruses, no universal phylogenetic “barcode of life” equivalent to the SSU rRNA gene exists. One approach has been to selectively purify virus-like particles from community biospecimens, amplify the small amounts of DNA that are recovered, and randomly fragment the DNA and sequence the fragments (shotgun sequencing). The resulting sequences can be assembled into larger contigs whose function can be computationally predicted from homology to known genes, and the information obtained can be used to populate/expand nonredundant viral databases. These annotated nonredundant databases can then be used for more targeted mining of the rapidly expanding number of shotgun sequencing datasets generated from total-community DNA for known or putative DNA viruses. Given the dominance of bacteria in the gut microbiota, it is not surprising that phages (viruses that infect bacteria) dominate the identifiable components of the gut’s DNA virome. Prophages are a manifestation of a so-called temperate viral–bacterial host dynamic, in which
a phage is integrated into its host bacterium’s genome. This temperate dynamic provides a way to constantly refashion the genomes of bacterial species through horizontal gene transfer. Genes encoded by a prophage genome may expand the niche and fitness of their bacterial host, for example, by enabling the metabolism of previously inaccessible nutrient sources. Prophage integration can also protect the host strain from superinfection, “immunizing” the strain against infection by closely related phages. A temperate prophage life cycle allows the virus to expand in a 1:1 ratio with its bacterial host. If the integrated virus conveys increased fitness, the prevalence of the bacterial host and its phage will increase in the microbiota. Induction of a lytic cycle, where the prophage replicates and kills the host, may follow. Lytic cycles can cause high bacterial turnover. Lysis debris (e.g., components of capsules) can be used as nutrient sources by surviving bacteria; this change in the energy dynamic in a community is referred to as a phage shunt. A subpopulation of bacteria that undergoes lytic induction may sweep away other sensitive species present in the community, thus increasing the niche space available for survivors (i.e., those bacteria that already have an integrated prophage). Periodic induction of prophages leads to a “constant diversity dynamic” that helps maintain community structure and function. Interest in viral communities has expanded in recent years, especially given a potentially therapeutic role for phages as an alternative or adjunct to antibiotics. Virome members have evolved elegant survival mechanisms that allow them to evade host defenses, diversify, and establish elaborate and mutually beneficial symbioses with their hosts. A number of recent studies have tried to adapt these mechanisms for therapeutic purposes (e.g., the use of synthetic phages to treat Pseudomonas aeruginosa infections in burn patients or in other settings). Phage therapy is not a new idea: Félix d’Herelle, co-discoverer of phages, recognized their potential medical applications nearly a century ago. However, only recently have our technologic capabilities and our knowledge of the human microbiota made phage therapy realistically attainable within our lifetimes. ECOLOGIC PRINCIPLES AND PARAMETERS FOR COMPARING MICROBIAL COMMUNITIES At many levels, different people are very much alike: our genomes are >99% identical, and we have similar collections of human cells. However, our microbial communities differ drastically, both between people and between habitats within a single human body. The greatest variation (beta diversity, described below) is between body sites. For example, the difference between the microbial communities residing in a person’s mouth versus the same person’s gut is comparable to the difference in communities residing in soil versus seawater. Even within a body site, the differences among people are not subtle: gut, skin, and oral communities can all differ by 80–90%, even from the broad, bacterial species–level view. The English poet John Donne said that “no man is an island”; however, from a microbial perspective, each of us consists of not just one isolated island but rather a whole archipelago of distinct habitats that exchange microbes with one another and with the outside environment at some as yet undetermined level. Before we can discuss these differences and understand their relevance to human disease, it is important to understand some basic terms and ecologic principles. Alpha Diversity Alpha diversity is defined as the effective number of species present in a given sample. Communities that are compositionally more diverse (i.e., have more OTUs) or that are phylogenetically more diverse are defined as having greater alpha diversity. Alpha diversity can be measured by plotting the number of different types of SSU rRNA sequences identified at a given phylogenetic level (species, genera, etc.) in a sample as a function of the number of SSU rRNA gene reads collected. The most commonly used metrics of alpha diversity are Sobs (the number of species observed in a given number of sequences), Chao1 (a measure based on the number of species observed only once), the Shannon index (a measure of the number of bits of information gained by revealing the identity of a randomly chosen member of the community), and phylogenetic diversity
(a measure of the total branch length of a phylogenetic tree encompassing a sample). Diversity estimators are particularly sensitive to errors introduced during PCR and sequencing.
Co-Occurrence Analysis Co-occurrence analysis seeks to identify which phylotypes are co-distributed across individuals in a given body habitat and/or between habitats and to determine the factors that explain the observed patterns of co-distribution. Positive correlations tend to reflect shared preferences for certain environmental features, while negative correlations typically reflect divergent preferences or a competitive relationship. Syntrophic (cross-feeding) relationships reflect interdependent interactions based on nutrient-sharing strategies. For example, in food webs, the products of one organism’s metabolism can be used by the other for its own unique metabolic capabilities (e.g., the interactions between fermentative organisms and methanogens). Enterotype Analysis Enterotype analysis seeks to classify individuals into discrete groups based on the configuration of their microbiotas, essentially drawing boundaries on a map defined by principal coordinates analysis or other ordination techniques. The first enterotype analysis used supervised clustering to define three major types of human-gut microbial configurations across three distinct human studies and provided a view that presupposed the existence of three
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Chapter 86e The Human Microbiome
Beta Diversity Beta diversity refers to the differences between communities and can be defined with phylogenetic or nonphylogenetic distance measurements. UniFrac is a commonly used phylogenetic metric that compares the evolutionary history of different microbial communities, noting the degree to which any two communities share branch length on a tree of microbial life: the more similar communities are to each other, the more branch length they share (Fig. 86e-1). UniFrac-based measurements of distances between communities can be visually represented with principal coordinates analysis or other geometric techniques that project a high-dimensional dataset down onto a small number of dimensions for a more approachable analysis (Fig. 86e-1). Principal coordinates analysis can also be applied to nonphylogenetic methods for comparing communities, such as Euclidean distance, Jensen-Shannon divergence, or Bray-Curtis dissimilarity, which operate independent of evolutionary tree data but can make biologic patterns more difficult to identify. The taxonomic data or distance matrices can also be used as input into a range of machinelearning algorithms (such as Random Forests) that employ supervised classification to identify differences between labeled groups of samples. Supervised classification is useful for identifying differences between cases and controls but can obscure important patterns intrinsic to the data, including confounding variables such as different sequencing runs or patient populations. As noted above, the greatest beta diversity is that among body sites. This fact underscores the need to specify body habitat in microbiota analyses of any type, including microbial surveillance studies examining the flow of normal and pathogenic organisms into and out of different body sites in patients and their health care providers. Several other key points have emerged from beta diversity studies of humanassociated microbial communities—notably, that (1) there is a high level of interpersonal variability in every body habitat studied to date, (2) intrapersonal variation in a given body habitat is less pronounced, and (3) family members have more similar communities than unrelated individuals living in separate households. Thus, a person is his/ her own best control, and examination of an individual over time as a function of disease state or treatment intervention is desirable. Similarly, family members serve as logical reference controls, although age is a major covariate that affects microbiota structure. Studies of fecal samples obtained from twins over time have shown that the overall degree of phylogenetic similarity of bacterial communities does not differ significantly between monozygotic and dizygotic twin pairs, although monozygotic twin pairs may be more similar in some populations at earlier ages. These results, together with intervention studies in mice and epidemiologic observations in humans, emphasize that early environmental exposures are a very important determinant of adult-gut microbial ecology. In humans, the initial exposures depend on delivery mode: babies sampled within 20 min of birth have relatively undifferentiated microbial communities in the mouth, the skin, and the gut. For vaginally delivered babies, these communities resemble the specific microbial communities found in the mother’s vagina. For babies delivered by cesarean section, the communities resemble skin communities. Although studies of older children and of adults stratified by delivery mode are still rare in the literature, these differences have been shown to persist until at least 4 months of age and perhaps until age 7 years. The infant gut microbiota changes to resemble the adult gut community over the first 3 years of life; comparable studies have not been done in other body habitats to date. Exposures to environmental microbial reservoirs can continue to influence community structure. For example, unrelated cohabiting adults have more similar microbiotas in all of their body habitats than do non-cohabiting adults, and humans resemble the dogs they live with, at least in terms of skin microbiota. Gender and sexual maturation may also affect the microbiota structure, although efforts to isolate these variables are complicated by many confounding factors; any gender effect must be small compared with the effects of other variables such as
diet (except in the case of the female urinary tract, which is influenced by the vaginal microbiota). The vaginal microbiota illustrates another intriguing aspect of the contributions made by various factors to interpersonal differences in microbial community structure within a given body habitat. Bacterial 16S rRNA–based studies of the midvaginal microbiota in sexually active women have documented significant differences in community configurations between four self-reported ethnic groups: Caucasian, black, Hispanic, and Asian. Unlike most other body habitats that have been surveyed, this ecosystem is dominated by a single genus, Lactobacillus. Four species of this genus together account for more than half of the bacteria in most vaginal communities. Five community categories have been defined: four are dominated by L. iners, L. crispatus, L. gasseri, and L. jensenii, respectively, and the fifth has proportionally fewer lactobacilli and more anaerobes. The representation of these community categories is distinct within each of the four ethnic groups and correlates with vaginal pH and Nugent score (the latter being a biomarker for bacterial vaginosis). Longitudinal studies of individuals are being conducted to identify factors that determine the assembly of these distinct communities—both within and among ethnic groups—as well as their resistance to or resilience after various physiologic and pathologic disturbances. For example, the menstrual cycle and pregnancy turn out to be surprisingly significant factors (cause larger changes) compared with sexual activity. Yet another factor affecting beta diversity is spatial location within a habitat. Several surveys show that the skin harbors bacterial communities with predictable, albeit complex, biogeographic features. To determine whether these differences are due to differences in local environmental factors, to the history of a given site’s exposure to microbes, or to a combination of the two, reciprocal microbiota transplantation has been performed. Microbial communities from one region of the skin were depleted by treatment with germicidal agents, and the region (plot) was inoculated with a “foreign” microbiota harvested from different regions of the skin or from different body habitats from the same or another individual. Community assembly at the site of transplantation was then tracked over time. Remarkably, assembly proceeded differently at different sites: forearm plots receiving a tongue microbiota remained more similar to tongue communities than to native forearm communities in terms of their composition and diversity, while forehead plots inoculated with tongue bacteria changed to become more similar to native forehead communities. Thus, in addition to the history of exposure to tongue bacteria, environmental factors operating at the forehead plot likely shape community assembly. Intriguingly, the factors that shape fungal skin communities appear to be entirely different from those that shape bacterial skin communities. The palm and forearm have high bacterial and low fungal diversity, whereas the feet have the opposite diversity pattern. Moreover, fungal communities are generally shaped by location (foot, torso, head), whereas bacterial communities are generally shaped by moisture phenotype (dry, moist, or sebaceous).
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clusters. Subsequent work has shown that the range of variability in the gut microbiota of children and of non-Western populations greatly exceeds the variability captured in the populations used to define the original enterotypes; in addition, even in Western populations, the variability follows more of a continuum dominated by a gradient in the abundance of the genera Bacteroides and Prevotella. Another consideration in enterotype analysis is whether location on a map defined by healthy human variation is relevant to predisposition to disease or whether instead rare species with particular functions are more important discriminants.
PART 3 Genes, the Environment, and Disease
Functional Redundancy Functional redundancy arises when functions are performed by many bacterial taxa. Thus interpersonal differences in microbial bacterial diversity (i.e., which bacteria are present) are not necessarily accompanied by comparable degrees of difference in functional diversity (i.e., what these bacteria can do). Characterization of a microbiome by shotgun sequencing is important because, unlike SSU rRNA analyses, shotgun sequencing provides a direct readout of the genes (and, via comparative genomics, their functions) in a given community. One fundamental question is the degree to which variations in the species occupying a given body habitat correlate with variations in a community’s functional capabilities. For example, the neutral theory of community assembly developed by macroecologists suggests that species are added to the community without respect to function, automatically endowing the community with functional redundancy. If applicable to the microbial world, neutral community assembly would predict a high level of variation in the types of microbial lineages that occupy a given body habitat in different individuals, although the broad functions encoded in the microbiomes of these communities could be quite similar. Shotgun sequencing of the fecal microbiome has revealed that different microbial communities converge on the same functional state: in other words, there is a group of microbial genes represented in the guts of unrelated as well as related individuals. The same principle holds true at other body sites (Fig. 86e-2). The “core” gut microbiome is enriched in functions related to microbial survival (e.g., translation; metabolism of nucleotides, carbohydrates, and amino acids) and in functions that benefit the host (nutrient and energy partitioning from the diet to microbes and host). The latter functions encompass the food webs mentioned above, in which products of one type of microbe become the substrates for other microbes. These webs, which can be incredibly elaborate, change as microbes adjust their patterns of gene expression and metabolism in response to alterations in nutrient availability. Thus the sum of all the activities of the members of a microbial community can be viewed as an emergent rather than a fixed property. It is important to note that pairwise comparisons have shown that family members have functionally more similar gut microbiomes than do unrelated individuals. Thus, intrafamilial transmission of a gut microbiome within a given generation and across multiple generations could shape the biologic features of humans belonging to a kinship and modulate/mediate risks for a variety of diseases.
Dorsal surface tongue—Phyla
Dorsal surface tongue— Metabolic pathways
Fecal—Phyla
Fecal—Metabolic pathways
Firmicutes Actinobacteria Bacteroidetes Proteobacteria Fusobacteria Tenericutes Spirochaetes Cyanobacteria Verrucomicrobia TM7
Central carbohydrate metabolism Cofactor and vitamin biosynthesis Oligosaccharide and ployol transport system Purine metabolism ATP synthesis Phosphate and amino acid transport system Aminoacyl tRNA Pyrimidine metabolism Ribosome Aromatic amino acid metabolism
Figure 86e-2 Interpersonal variation in organismal representation in body habitat–associated communities is more extensive than interpersonal variation in gene functional features. Bacterial taxonomy and metabolic function are compared in 107 oral microbiota and microbiome samples (top) and in 139 fecal microbiota and microbiome samples (bottom). Samples represent an arbitrarily chosen subset from 242 healthy young adults living in the United States, with equal numbers of men and women. The same DNA extracts from the same samples were used for both taxonomic and functional classifications; each sample was analyzed by bacterial 16S rRNA amplicon sequencing (mean, 5400 sequences per sample) and by shotgun sequencing of community DNA (mean, 2.9 billion bases per sample). Taxonomic groups vary dramatically in their representation among different samples, with different characteristic bacterial phyla in the oral versus the fecal microbiota; e.g., members of the Actinobacteria and Fusobacteria are far more common in the mouth than in the gut, while members of Bacteroidetes are far more common in fecal samples. In contrast, metabolic pathways are far more consistently represented in different samples, even when the species that contribute to these pathways are completely different. These results suggest a high degree of functional redundancy in microbial ecosystems—similar to that observed in macroecosystems, in which many fundamentally different lineages of organisms can play the same ecologic roles (e.g., pollinator or top predator). (Adapted from Human Microbiome Project Consortium: Nature 486:207, 2012; and CA Lozupone et al: Nature 489:220, 2012.)
Stability Like other ecosystems, human body habitat– associated microbial communities vary over time, and an understanding of this variation is essential for a functional understanding of our microbiota. Few high-resolution time series of individual healthy adults have been published to date, but one available daily time series suggests that individuals tend to resemble themselves microbially day to day over a span of 6–15 months, retaining their separate identities during cohabitation. The development of low-error amplicon sequencing methods has provided a much more reliable
way for defining stability at the strain level than was available in the past. Application of these methods to the guts of healthy individuals sampled over time has disclosed that a healthy adult gut harbors a persistent collection of ~100 bacterial species and several hundred strains. The stability of the bacterial components follows a power law: bacterial strains acquired early in life can persist in the gut for decades, although
their proportional representation changes as a function of numerous factors, including diet. Whole-genome sequencing of culturable components of the microbiota of study participants has confirmed that strains are retained in individuals for prolonged periods and are shared among family members.
ESTABLISHING CAUSAL RELATIONSHIPS BETWEEN THE GUT MICROBIOTA AND NORMAL PHYSIOLOGIC, METABOLIC, AND IMMUNOLOGIC PHENOTYPES AS WELL AS DISEASE STATES Gnotobiotic animals are raised in germ-free environments—with no exposure to microbes—and then colonized at specific stages of life with specified microbial communities. Gnotobiotic mice provide an excellent system for controlling host genotype, microbial community composition, diet, and housing conditions. Microbial communities
The Cardiovascular System The gut microbiota affects the elaborate microvasculature underlying the small-intestinal epithelium: capillary network density is markedly reduced in adult germ-free animals but can be restored to normal levels within 2 weeks after gut microbiota transplantation. Mechanistic studies have shown that the microbiota promotes vascular remodeling in the gut through effects on a novel extravascular tissue factor–protease-activated receptor (PAR1) signaling pathway. Heart weight measured echocardiographically or as wet mass and normalized to tibial length or lean body weight is significantly reduced in germ-free mice; this difference is eliminated within 2 weeks after colonization with a gut microbiota. During fasting, a gut microbiota–dependent increase in hepatic ketogenesis (regulated by peroxisome proliferator–activated receptor α) occurs, and myocardial metabolism is directed to ketone body utilization. Analyses of isolated, perfused working hearts from germ-free and colonized animals, together with in vivo assessments, have shown that myocardial performance in germ-free mice is maintained by increasing glucose utilization. However, heart weight is significantly reduced in both fasted and fed mice; this heart-mass phenotype is completely reversed in germ-free mice fed a ketogenic diet. These findings illustrate how the gut microbiota benefits the host during periods of nutrient deprivation and represent one link between gut microbes and cardiovascular metabolism and health. Conventionally raised apoE-deficient mice develop a less severe form of atherosclerosis than their germ-free counterparts when fed a high-fiber diet. This protective effect of the microbiota is obviated when animals are fed a diet low in fiber and high in simple sugars and fat. A number of the beneficial effects attributed to diets with high proportional representation of whole grains, fruits, and vegetables are thought to be mediated by end products of microbial metabolism of dietary compounds, including short-chain fatty acids and metabolites derived from flavonoids. Conversely, microbes can convert otherwise harmless dietary compounds into metabolites that increase risk for cardiovascular disease. Studies of mice and human volunteers have revealed that gut microbiota metabolism of dietary L-carnitine, which is present in large amounts in red meat, yields trimethylamineN-oxide, which can accelerate atherosclerosis in mice by suppressing reverse cholesterol transport. Yet another facet of microbial influence on cardiovascular physiology was revealed in a study of mice deficient in Olfr78 (a G protein– coupled receptor expressed in the juxtaglomerular apparatus, where it regulates renin secretion in response to short-chain fatty acids) or Gpr41 (another short-chain fatty acid receptor that, together with Olfr78, is expressed in the smooth muscle cells present in small resistance vessels). This study demonstrated that the microbiota can modulate host blood pressure via short-chain fatty acids produced by microbial fermentation. Bone Adult germ-free mice have greater bone mass than their conventionally raised counterparts. This increase in bone mass is associated with reduced numbers of osteoclasts per unit bone surface area, reduced numbers of CD11b+/GR1 osteoclast precursors in bone marrow, decreased numbers of CD4+ T cells, and reduced levels of expression of the osteolytic cytokine tumor necrosis factor α. Colonization with a normal gut microbiota resolves these observed differences between germ-free and conventionally raised animals. Brain Adult germ-free and conventionally raised mice differ significantly in levels of 38 out of 196 identified cerebral metabolites, 10 of which have known roles in brain function; included in the latter group are N-acetylaspartic acid (a marker of neuronal health and attenuation),
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Chapter 86e The Human Microbiome
Resilience The ability of a microbiota or microbiome to rebound from a short-term perturbation, such as antibiotic administration or an infection, is defined as its resilience. This capacity can be visualized as a ball rolling over a landscape of local minima; essentially, the community moves into a new state and, to recover, must move through another, unstable state. In some cases, recovery will lead to the original stable state; in others, it will lead to a new stable state, which may be either healthy or unhealthy. Changes in, for example, diet or host physiologic status may introduce alterations into the landscape itself, making it easier to move from the initial state to any one of a number of other states, potentially with different health consequences. Microbial communities in our body habitats differ widely in resilience. For example, hand washing leads to profound changes in the microbial community, greatly increasing diversity (presumably because of the preferential removal of high-abundance, dominant phylotypes such as Propionibacterium). Within 6 h, the hand microbiota rebounds to resemble the original hand communities. The effects of repeated hand washing still need to be defined; for example, the surface microbiota on the skin (as measured by scrape biopsies) consists of ~50,000 microbial cells/cm2, whereas the subsurface microbiota (as measured by punch biopsies) consists of ~1,000,000 microbial cells/cm2. In a study of three healthy adult volunteers given a short course of ciprofloxacin (500 mg by mouth twice a day for 5 days—a regimen commonly used against uncomplicated urinary tract infections), overall gut-community configuration came to resemble baseline within 6 months after treatment cessation, although some taxa failed to recover. However, the effects of the antibiotic perturbation were highly individualized. Administration of a second course of treatment months later led to altered-community states, relative to baseline, in all three volunteers; again, the extent of the alteration differed with the individual. Crucially, as shown in this and other studies, a given bacterial taxon can respond differently to the same antibiotic in different individuals; this observation suggests that the rest of the microbial community plays an important role in determining the effects of antibiotics on a per-individual basis. In any body habitat, the microbial-community state after disturbance may be degraded. However, this degraded state may itself be resilient, and it may therefore be difficult to restore a more functional state. For example, Clostridium difficile infection can persist for years. The development and resilience of a degraded state may be driven by positive feedback loops, such as reactive oxygen species cascades involving host macrophages that promote the further growth of proinflammatory Proteobacteria, as well as negative-feedback loops such as depletion of the butyrate needed for promotion of a healthy gut epithelial barrier and further establishment of beneficial members of the microbiota. Consequently, microbiota-based therapies may require either (1) the elimination of a feedback loop that prevents establishment of a new community or (2) identification of a direction for change and a stimulus of sufficient magnitude (e.g., invasion and establishment of microbes from a fecal transplant or from a defined consortium of cultured, sequenced members of the human gut microbiota; see below) to overcome the resilience mechanisms inherent in the degraded state. A critical unresolved question that especially affects infants, whose microbiota is changing rapidly, is whether intervention during periods of rapid change or during periods of relative stability is generally more effective.
harvested from donor mice with defined genotypes and phenotypes can be used to determine how the donors’ microbial communities affect the properties of formerly germ-free recipients. The recipients may also affect the transplanted microbiota and its microbiome. Thus gnotobiotic mice afford investigators an opportunity to marry comparative studies of donor communities to functional assays of community properties and to determine how (and for how long) these functions influence host biology.
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pipecolic acid (a presynaptic modulator of γ-aminobutyric acid levels), and serine (an obligatory co-agonist at the glycine site of the N-methyl-d-aspartate receptor). Propionate, a short-chain fatty acid product of gut microbial-community metabolism of dietary fiber, affects expression of genes involved in intestinal gluconeogenesis via a gut–brain neural circuit involving free fatty-acid receptor 3; this effect provides a mechanistic explanation for the documented beneficial impact of dietary fiber in enhancing insulin sensitivity and reducing body mass and adiposity. Studies of a mouse model (maternal immune activation) with stereotyped/repetitive and anxiety-like behaviors indicate that treatment with a member of the human gut microbiota, Bacteroides fragilis, corrects gut barrier (permeability) defects; reduces elevated levels of 4-ethylphenylsulfate, a metabolite seen in the maternal immune activation model that has been causally associated with the animals’ behavioral phenotypes; and ameliorates some behavioral effects. These observations highlight the importance of further exploration of potentially co-evolved relationships between the microbiota and host behavior.
PART 3 Genes, the Environment, and Disease
Immune Function Many foundational studies have shown that the gut microbiota plays a key role in the maturation of the innate as well as the adaptive components of the immune system. The intestinal epithelium, which is composed of four principal cell lineages (enterocytes plus goblet, Paneth, and enteroendocrine cells), acts as a physical and functional barrier to microbial penetration. Goblet cells produce mucus that overlies the epithelium, where it forms two layers: an outer (luminal-facing) looser layer that harbors microbes and a denser lower layer that normally excludes microbes. Members of the Paneth cell lineage reside at the base of crypts of Lieberkühn and secrete antimicrobial peptides. Studies in mice have demonstrated that Paneth cells directly sense the presence of a microbiota through expression of the signaling adaptor protein MyD88, which helps transduce signals to host cells upon recognition of microbial products through Toll-like receptors (TLRs). This recognition drives expression of antibacterial products (e.g., the lectin RegIIIγ) that act to prevent microbial translocation across the gut mucosal barrier. The intestine is enriched for B cells that produce IgA, which is secreted into the lumen; there it functions to exclude microbes from crossing the mucosal barrier and to restrict dissemination of food antigens. The microbiota plays a key role in development of an IgA response: germ-free mice display a marked reduction in IgA+ B cells. The absence of a normal IgA response can lead to a massive increase in bacterial load. B cell–derived IgA that targets specific members of the gut microbiota plays an important role in preventing activation of microbiota-specific T cells. Gut bacterial species elicit development of protective TH17 and TH1 responses that help ward off pathogen attack. Members of the microbiota also promote the development of a specialized population of CD4+ T cells that prevent unwarranted inflammatory responses. These regulatory T cells (Tregs) are characterized by expression of the transcription factor forkhead box P3 (FOXP3) and by expression of other cellsurface markers. There is a paucity of Tregs in the colonic lamina propria of germ-free mice. Specific members of the microbiota—including a consortium of Clostridium strains isolated from the mouse and human gut as well as several human-gut Bacteroides species —expand the Treg compartment and enhance immunosuppressive functions. The microbiota is a key trigger in the development of inflammatory bowel disease (IBD) in mice that harbor mutations in genes associated with IBD risk in humans. Moreover, components of the gut microbiota can modify the activity of the immune system to ameliorate or prevent IBD. Mice containing a mutant ATG16L1 allele linked to Crohn’s disease are particularly susceptible to IBD. Upon infection with mouse norovirus and treatment with dextran sodium sulfate, expression of a hypomorphic ATG16L1 allele leads to defects in small-intestinal Paneth cells and renders mice significantly more susceptible to ileitis than are wild-type control animals. This process is dependent on the gut microbiota and highlights how the intersection of host genetics, infectious agents, and the microbiota can lead to severe immune
pathology; i.e., the pathogenic potential of a microbiota may be context-dependent, requiring a confluence of factors. An important observation is that members of the gut microbiota, including B. fragilis or members of Clostridium, prevent the severe inflammation that develops in mouse models mimicking various aspects of human IBD. The gut microbiota has been implicated in promoting immunopathology outside of the intestine. Multiple sclerosis develops in conventionally raised mice whose CD4+ T cell compartment is reactive to myelin oligodendrocyte protein; their germ-free counterparts are completely protected from development of multiple sclerosis–like symptoms. This protection is reversed by colonization with a gut microbiota from conventionally raised animals. Inflammasomes are cytoplasmic multiprotein complexes that sense stress and damage-associated patterns. Mice deficient in NLRP6, a component of the inflammasome, are more susceptible to colitis induced by administration of dextran sodium sulfate. This enhanced susceptibility is associated with alterations in the gut microbiota of these animals relative to that of wild-type controls. Mice are coprophagic, and co-housing of NLRP6-deficient mice with wild-type mice is sufficient to transfer the enhanced susceptibility to colitis induced by dextran sodium sulfate. Similar findings have been reported for mice deficient in the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain). ASCdeficient mice are more susceptible to the development of a model of nonalcoholic steatohepatitis. This susceptibility is associated with alterations in gut microbiota structure and can be transferred to wildtype animals by co-housing. Obesity and Diabetes Germ-free mice are resistant to diet-induced obesity. Genetically obese ob/ob mice have gut microbial-community structures that are profoundly altered from those in their lean wildtype (+/+) and heterozygous +/ob littermates. Transplantation of the ob/ob mouse microbiota into wild-type germ-free animals transmits an increased-adiposity phenotype not seen in mice receiving microbiota transplants from +/+ and +/ob littermates. These differences are not attributable to differences in food consumption but rather are associated with differences in microbial community metabolism. Roux-en-Y gastric bypass produces pronounced decreases in weight and adiposity as well as improved glucose metabolism—changes that are not ascribable simply to decreased caloric intake or reduced nutrient absorption. 16S rRNA analyses have documented that changes in the gut microbiota after this surgery are conserved among mice, rats, and humans; animal studies have demonstrated these changes along the length of the gut but most prominently downstream of the site of surgical manipulation of the bowel. Notably, transplantation of the gut microbiota from mice that have undergone Roux-en-Y gastric bypass to germ-free mice that have not had this surgery produces reductions in weight and adiposity not seen in recipients of microbiotas from mice that underwent sham surgery. The gut microbiota confers protection against the development of type 1 diabetes mellitus in the non-obese diabetic (NOD) mouse model. Disease incidence is significantly lower in conventionally raised male NOD mice than in their female counterparts, while germ-free males are as susceptible as their female counterparts. Castration of males increases disease incidence, while androgen treatment of females provides protection. Transfer of the gut microbiota from adult male NOD mice to female NOD weanlings is sufficient to reduce the severity of disease relative to that among females receiving a microbiota from an adult female or an unmanipulated female. The blocking of protection by treatment with flutamide highlights a functional role for testosterone signaling in this microbiota-mediated protection against type 1 diabetes. NOD mice deficient in MyD88, a key component of the TLR signaling pathway, do not develop diabetes and exhibit increased relative abundance of members of the family-level taxon Lactobacillaceae. Consistent with these findings, investigators have documented lower levels of representation of members of the genus Lactobacillus in children with type 1 diabetes than in healthy controls. Components of lactobacilli have been shown to promote gut barrier integrity. Studies
in various animal models indicate that translocation of bacterial components, including bacterial lipopolysaccharides, across a leaky gut barrier triggers low-grade inflammation, which contributes to insulin resistance. Mice deficient in TLR5 exhibit alterations in the gut microbiota and hyperphagia, and they develop features of metabolic syndrome, including hypertension, hyperlipidemia, insulin resistance, and increased adiposity. The gut microbiota regulates biosynthesis as well as metabolism of host-derived products; these products can signal through host receptors to shape host physiology. An example of this symbiosis is provided by bile acids, which direct metabolic effects that are largely mediated through the farnesoid X receptor (FXR, also known as NR1H4). In leptin-deficient mice, FXR deficiency protects against obesity and improves insulin sensitivity. In mice with diet-induced obesity that are subjected to vertical sleeve gastrectomy, the surgical procedure results in elevated levels of circulating bile acids, changes in the gut microbiota, weight loss, and improved glucose homeostasis. However, weight reduction and improved insulin sensitivity are mitigated in animals with engineered FXR-deficiency.
Characterizing the Effects of the Human Microbiota on Host Biology in Mice and Humans Questions about the relationship between human microbial communities and health status can be posed in the following general format: Is there a consistent configuration of the microbiota definable in the study population that is associated with a given disease state? How is the configuration affected by remission/relapse or by treatment? If a reconfiguration does occur with treatment, is it durable? How is host biology related to the configuration or reconfiguration? What is the effect size? Are correlations robust to individuals from different families and communities representing different ages, geographic locales, and lifestyles? As in all studies involving human microbial ecology, the issue of what constitutes a suitable reference control is extremely important. Should we choose the person himself or herself, family members, or age- or gender-matched individuals living in the same locale and representing similar cultural traditions? Critically, are the relationships observed between microbial community structure and expressed functions a response to disease state (i.e., side effects of other processes), or are they a contributing cause? In this sense, we are challenged to evolve a set of Koch’s postulates that can be applied to whole microbial communities or components of communities rather than just to a single purified organism. As in other circumstances in which experiments to determine causality of human disease are difficult or unethical, Hill’s criteria, which examine the strength, consistency, and biologic plausibility of epidemiologic data, can be useful. Sets of mono- and dizygotic twins and their family members represent a valuable resource for initially teasing out relationships between environmental exposures, genotypes, and our own microbial ecology. Similarly, monozygotic twins discordant for various disease states enhance the ability to determine whether various diseases can be linked to a person’s microbiota and microbiome. A twin-pair sampling design rather than a conventional unrelated case–control design has advantages owing to the pronounced between-family variability in microbiota/microbiome composition and the potential for multiple states of a community associated with disease. Transplantation of a microbiota from suitable human donor controls representing different disease states and communities (e.g., twins discordant for a disease)
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Chapter 86e The Human Microbiome
Xenobiotic Metabolism Evidence is accumulating that pharmacogenomic studies need to consider the gene repertoire present in our H. sapiens genome as well as that in our microbiomes. For example, digoxin is inactivated by the human gut bacterium Eggerthella lenta, but only by strains with a cytochrome-containing operon. Expression of this operon is induced by digoxin and inhibited by arginine. Studies in gnotobiotic mice established that dietary protein affects (reduces) microbial metabolism of digoxin, with corresponding alterations in levels of the drug in both serum and urine. These findings reinforce the need to consider strain-level diversity in the gut microbiota when examining interpersonal variations in the metabolism of orally administered drugs.
to germ-free mice is helpful in establishing a causal role for the community in pathogenesis and for providing insights relevant to underlying mechanisms. In addition, transplantation provides a preclinical platform for identifying next-generation probiotics, prebiotics, or combinations of the two (synbiotics). Obesity and obesity-associated metabolic dysfunction illustrate these points. The gut microbiotas (and microbiomes) of obese individuals are significantly less diverse than those of lean individuals; the implication is that there may be unfilled niches (unexpressed functions) that contribute to obesity and its associated metabolic abnormalities. Le Chatelier and colleagues observed a bimodal distribution of gene abundance in their analysis of 292 fecal microbiomes: low-gene-count (LGC) individuals averaged 380,000 microbial genes per gut microbiome, while high-gene-count (HGC) individuals averaged 640,000 genes. LGC individuals had an increased risk for type 2 diabetes and other metabolic abnormalities, whereas the HGC group was metabolically healthy. When gene content was used to identify taxa that discriminated HGC and LGC individuals, the results revealed associations between anti-inflammatory bacterial species such as Faecalibacterium prausnitzii and the HGC group and between proinflammatory species such as Ruminococcus gnavus and the LGC group. LGC microbiomes had significantly greater representation of genes assigned to tricarboxylic acid cycle modules, peroxidases, and catalases—an observation suggesting a greater capacity to handle oxygen exposure and oxidative stress; HGC microbiomes were enriched in genes involved in the production of organic acids, including lactate, propionate, and butyrate— a result suggesting increased fermentative capacity. Transplantation of an uncultured fecal microbiota from twins stably discordant for obesity or of bacterial culture collections generated from their microbiota transmits their discordant adiposity phenotypes as well as obesity-associated metabolic abnormalities to recipient germfree mice. Co-housing of the recipient coprophagic gnotobiotic mice results in invasion of specific bacterial species from the transplanted lean twin’s culture collection into the guts of cage mates harboring the obese twin’s culture collection (but not vice versa), thereby preventing the latter animals from developing obesity and its associated metabolic abnormalities. It is noteworthy that invasion and prevention of obesity and metabolic phenotypes are dependent on the type of human diets fed to animals: prevention is associated with a diet low in saturated fats and high in fruit and vegetable content, but not with a diet high in saturated fats and low in fruit and vegetable content. This approach provides evidence for a causal role for the microbiota in obesity and its attendant metabolic abnormalities. It also provides a method for defining unoccupied niches in disease-associated microbial communities, the role of dietary components in determining how these niches can be filled by human gut–derived bacterial taxa, and the effects of such occupancy on microbial and host metabolism. It also provides a way to identify health-promoting diets and next-generation probiotics representing naturally occurring members of our indigenous microbial communities that are well adapted to persist in a given body habitat. A key to this approach is the ability to harvest a microbial community from a donor representing a physiology, disease state, lifestyle, or geography of interest; to preserve the donor’s community by freezing it; and then to resurrect and replicate it in multiple recipient gnotobiotic animals that can be reared under conditions where environmental and host variables can be controlled and manipulated to a degree not achievable in clinical studies. Since these mice can be followed as a function of time prior to and after transplantation, in essence, a snapshot of a donor’s community can be converted into a movie. Transplantation of intact uncultured human (fecal) microbiota samples from multiple donors representing the phenotype of interest, with administration of the donors’ diets (or derivatives of those diets) to different groups of mice, is one way to assess whether transmissible responses are shared features of the microbiota or are highly donor specific. A second step is to determine whether the culturable component of a representative microbiota sample can transmit the phenotype(s) observed with the intact uncultured sample. Possession of a collection of cultured organisms that have co-evolved in a given donor’s body habitat sets the stage
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PART 3 Genes, the Environment, and Disease
for the selection of subsets of the collection for testing in gnotobiotic mice, the determination of which members are responsible for effecting the phenotype, and the elucidation of the mechanisms underlying these effects. The models used may inform the design and interpretation of clinical studies of the very individuals and populations whose microbiota are selected for creating these models. Human-to-human fecal microbiota transplantation (FMT) is currently the most direct way to establish proof-of-concept for a causal role for the microbiota in disease pathogenesis. A human donor’s feces are provided to a recipient via nasogastric tube or another technique. Numerous small trials have documented the effects of FMT from healthy donors to recipients with diseases ranging from C. difficile infection to Crohn’s disease, ulcerative colitis, and type 2 diabetes. Only a few of these studies have used a double-blind, placebo-controlled design. In a double-blind, controlled trial involving men 21–65 years old with a body mass index of >30 kg/m2 and documented insulin resistance, FMT was performed using a microbiota from metabolically healthy lean donors or from the study participants themselves. A microbiota from lean donors significantly improved peripheral insulin sensitivity over that in controls. This change was associated with an increase in the relative abundance of the butyrate-producing bacteria related to Roseburia intestinalis (in the feces) and Eubacterium hallii (in the small intestine). The efficacy of FMT for the treatment of recurrent C. difficile infection has been assessed in a number of small trials. One unblinded, placebo-controlled trial assessed the use of FMT in 42 patients with recurrent C. difficile infection (defined as at least one relapse after treatment with vancomycin or metronidazole for ≥10 d). Patients were pretreated with oral vancomycin. The experimental group then received FMT via nasoduodenal tube from healthy volunteer donors (1% for sustained periods, and a large number of IM injections (>80–100) was required to access a large muscle mass. Intravascular vector delivery has been used to access large areas of skeletal muscle in animal models of hemophilia and will likely be tested for this and other disorders in upcoming trials. The first trial of an AAV vector expressing factor IX delivered to the liver in humans with hemophilia B resulted in therapeutic circulating levels at the highest dose tested, but expression at these levels (>5%) lasted for only 6–10 weeks before declining to baseline (10 years ago continuing to manifest electroretinal and behavioral evidence of visual function. As is the case for X-linked SCID, gene transfer must occur relatively early in life to achieve optimal correction of the genetic disease, although the exact limitations imposed by age have not yet been defined. AAV-RPE65 trials carried out in both the United States and the United Kingdom have shown restoration of visual and retinal function in over 30 subjects, with the most marked improvement occurring in the younger subjects. Trials for other inherited retinal degenerative disorders such as choroideremia are under way, as are studies for certain complex acquired disorders such as age-related macular degeneration, which affects several million people worldwide. The neovascularization that occurs in age-related macular degeneration can be inhibited by expression of vascular endothelial growth factor (VEGF) inhibitors such as angiostatin or through the use of RNA interference (RNAi)-mediated knockdown of VEGF. Early-phase trials of siRNAs that target VEGF RNA are under way, but these require repeated intravitreal injection of the siRNAs; an AAV vector–mediated approach, which would allow long-term inhibition of the biological effects of VEGF through a soluble VEGF receptor, is now in clinical testing.
GENE THERAPY FOR CANCER The majority of clinical gene transfer experience has been in subjects with cancer (Fig. 91e-1). As a general rule, a feature that distinguishes gene therapies from conventional cancer therapeutics is that the former are less toxic, in some cases because they are delivered locally (e.g., intratumoral injections), and in other cases because they are targeted specifically to elements of the tumor (immunotherapies, antiangiogenic approaches). Because cancer is a disease of aging, and many elderly are frail, the development of therapeutics with milder side effects is an important goal. LOCAL APPROACHES Cancer gene therapies can be divided into local and systemic approaches (Table 91e-3). Some of the earliest cancer gene therapy trials focused Table 91e-3 Gene Therapy Strategies in Cancer Local/regional approaches Suicide gene/prodrug Suppressor oncogene Oncolytic virus Systemic approaches Chemoprotection Immunomodulation Antiangiogenesis
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CHAPTER 91e Gene Therapy in Clinical Medicine
Recombinant adeno-associated viral (AAV) vectors have emerged as attractive gene delivery vehicles for genetic disease. Engineered from a small replication-defective DNA virus, they are devoid of viral coding sequences and trigger very little immune response in experimental animals. They are capable of transducing nondividing target cells, and the donated DNA is stabilized primarily in an episomal form, thus minimizing risks arising from insertional mutagenesis. Because the vector has a tropism for certain long-lived cell types, such as skeletal muscle, the central nervous system (CNS), and hepatocytes, long-term expression can be achieved even in the absence of integration.
A memory T cell response to viral capsid, present in humans but not in other animal species (which are not natural hosts for the virus), likely led to the loss of expression (Table 91e-2). In response to these findings, a second trial included a short course of prednisolone, to be administered if factor IX levels began to decline. This approach resulted in long-term expression of factor IX, in the range of 2–5%, in men with severe hemophilia B. Current efforts are focused on expanding these trials, and extending the approach to hemophilia A.
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on local delivery of a prodrug or a suicide gene that would increase sensitivity of tumor cells to cytotoxic drugs. A frequently used strategy has been intratumoral injection of an adenoviral vector expressing the thymidine kinase (TK) gene. Cells that take up and express the TK gene can be killed after the administration of ganciclovir, which is phosphorylated to a toxic nucleoside by TK. Because cell division is required for the toxic nucleoside to affect cell viability, this strategy was initially used in aggressive brain tumors (glioblastoma multiforme) where the cycling tumor cells were affected but the nondividing normal neurons were not. More recently, this approach has been explored for locally recurrent prostate, breast, and colon tumors, among others. Another local approach uses adenoviral-mediated expression of the tumor suppressor p53, which is mutated in a wide variety of cancers. This strategy has resulted in complete and partial responses in squamous cell carcinoma of the head and neck, esophageal cancer, and non-small-cell lung cancer after direct intratumoral injection of the vector. Response rates (~15%) are comparable to those of other single agents. The use of oncolytic viruses that selectively replicate in tumor cells but not in normal cells has also shown promise in squamous cell carcinoma of the head and neck and in other solid tumors. This approach is based on the observation that deletion of certain viral genes abolishes their ability to replicate in normal cells but not in tumor cells. An advantage of this strategy is that the replicating vector can proliferate and spread within the tumor, facilitating eventual tumor clearance. However, physical limitations to viral spread, including fibrosis, intermixed normal cells, basement membranes, and necrotic areas within the tumor, may limit clinical efficacy. Oncolytic viruses are licensed and available in some countries but not in the United States.
PART 4 Regenerative Medicine
SYSTEMIC APPROACHES Because metastatic disease rather than uncontrolled growth of the primary tumor is the source of mortality for most cancers, there has been considerable interest in developing systemic gene therapy approaches. One strategy has been to promote more efficient recognition of tumor cells by the immune system. Approaches have included transduction of tumor cells with immune-enhancing genes encoding cytokines, chemokines, or co-stimulatory molecules; and ex vivo manipulation of dendritic cells to enhance the presentation of tumor antigens. Recently, considerable success has been achieved using lentiviral transduction of autologous lymphocytes with a cDNA encoding a chimeric antigen receptor (CAR). The CAR moiety consists of a tumor antigenbinding domain (e.g., an antibody to the B cell antigen CD19) fused to an intracellular signaling domain that allows T cell activation. The transduced lymphocytes can then recognize and destroy cells bearing the antigen. This CAR–T cell approach has proven extraordinarily successful in the setting of refractory chronic lymphocytic leukemia and pre-B-cell acute lymphoblastic leukemia. Infusion of gene-modified T cells engineered to recognize the B cell antigen CD19 has resulted in >1000-fold expansion in vivo, trafficking of the T cells to the bone marrow, and complete remission in a subset of patients who had failed multiple chemotherapy regimens. The cells persist as memory CAR+ T cells, providing ongoing antitumor functionality. Some patients experience a delayed tumor lysis syndrome requiring intensive medical management. This approach also causes an on-target toxicity, leading to B cell aplasia that necessitates lifelong IgG infusions. Current results indicate that long-lasting remissions can be achieved and the strategy can theoretically be extended to other tumor types if a tumor antigen can be identified. Gene transfer strategies have also been developed for inhibiting tumor angiogenesis. These have included constitutive expression of angiogenesis inhibitors such as angiostatin and endostatin; use of siRNA to reduce levels of VEGF or VEGF receptor; and combined approaches in which autologous T cells are genetically modified to recognize antigens specific to tumor vasculature. These studies are still in early-phase testing. Another novel systemic approach is the use of gene transfer to protect normal cells from the toxicities of chemotherapy. The most
extensively studied of these approaches has been transduction of hematopoietic cells with genes encoding resistance to chemotherapeutic agents, including the multidrug resistance gene MDRI or the gene encoding O6-methylguanine DNA methyltransferase (MGMT). Ex vivo transduction of hematopoietic cells, followed by autologous transplantation, is being investigated as a strategy for allowing administration of higher doses of chemotherapy than would otherwise be tolerated.
GENE THERAPY FOR VASCULAR DISEASE The third major category addressed by gene transfer studies is cardiovascular disease. Initial experience was in trials designed to increase blood flow to either skeletal (critical limb ischemia) or cardiac muscle (angina/myocardial ischemia). First-line treatment for both of these groups includes mechanical revascularization or medical management, but a subset of patients are not candidates for or fail these approaches. These patients formed the first cohorts for evaluation of gene transfer to achieve therapeutic angiogenesis. The major transgene used has been VEGF, attractive because of its specificity for endothelial cells; other transgenes have included fibroblast growth factor (FGF) and hypoxia-inducible factor 1, α subunit (HIF-1α). The design of most of the trials has included direct IM (or myocardial) injection of either a plasmid or an adenoviral vector expressing the transgene. Both of these vectors are likely to result in only short-term expression of VEGF, which may be adequate because there is no need for continued transgene expression once the new vessels have formed. Direct injection favors local expression, which should help to avoid systemic effects such as retinal neovascularization or new vessel formation in a nascent tumor. Initial trials of adeno-VEGF or plasmid-VEGF injection resulted in improvement over baseline in angiographically detectable vasculature, but no change in amputation frequency or cardiovascular mortality. Studies using different routes of administration or different transgenes are currently under way. More recent studies have used AAV vectors to develop a therapeutic approach for individuals with refractory congestive heart failure. In preclinical studies, a vector encoding sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) demonstrated positive left ventricular inotropic effects in a swine model of volume-overloaded heart failure. Results of a phase II study in which vector was infused via the coronary arteries in patients with congestive heart failure demonstrated safety and some indications of efficacy; larger studies are now planned.
OTHER APPROACHES This chapter has focused on gene addition therapy, in which a normal gene is transferred to a target tissue to drive expression of a gene product with therapeutic effects. Another powerful technique under development is genome editing, in which a mutation is corrected in situ, generating a wild-type copy under the control of the endogenous regulatory signals. This approach makes use of novel reagents including zinc finger nucleases, TALENs and CRISPR, which introduce double-stranded breaks into the DNA near the site of the mutation and then rely on a donated repair sequence and cellular mechanisms for repair of double-strand breaks to reconstitute a functioning gene. Another strategy recently introduced into clinical trials is the use of siRNAs or short hairpin RNAs as transgenes to knock down expression of deleterious genes (e.g., mutant huntingtin in Huntington’s disease or genes of the hepatitis C genome in infected individuals).
SUMMARY The power and versatility of gene transfer approaches are such that there are few serious disease entities for which gene transfer therapies are not under development. The development of new classes of therapeutics typically takes two to three decades; monoclonal antibodies and recombinant proteins are recent examples. Gene therapeutics, which entered clinical testing in the early 1990s, traversed the same time course. Examples of clinical success are now abundant, and gene therapy approaches are likely to become increasingly important as a
Table 91e-4 Taking History from Subjects Enrolled in Gene Transfer Studies Elements of History for Subjects Enrolled in Gene Transfer Trials 1. What vector was administered? Is it predominantly integrating (retroviral, lentiviral, herpesvirus [latency and reactivation]) or nonintegrating (plasmid, adenoviral, adeno-associated viral)? 2. What was the route of administration of the vector? 3. What was the target tissue? 4. What gene was transferred in? A disease-related gene? A marker? 5. Were there any adverse events noted after gene transfer? Screening Questions for Long-Term Follow-Up in Gene Transfer Subjectsa 1. Has a new malignancy been diagnosed? 2. Has a new neurologic/ophthalmologic disorder, or exacerbation of a preexisting disorder, been diagnosed? 3. Has a new autoimmune or rheumatologic disorder been diagnosed? 4. Has a new hematologic disorder been diagnosed?
therapeutic modality in the twenty-first century. A central question to be addressed is the long-term safety of gene transfer, and regulatory agencies have mandated a 15-year follow-up for subjects enrolled in gene therapy trials (Table 91e-4). Realization of the therapeutic benefits of modern molecular medicine will depend on continued progress in gene transfer technology.
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Factors influencing long-term risk include: integration of the vector into the genome, vector persistence without integration, and transgene-specific effects.
a
CHAPTER 91e Gene Therapy in Clinical Medicine
92e
Tissue Engineering Anthony Atala
Tissue engineering is a field that applies principles of regenerative medicine to restore the function of various organs by combining cells with biomaterials. It is multidisciplinary, often combining the skills of physicians, cell biologists, bioengineers, and material scientists, to recapitulate the native three-dimensional architecture of an organ, the appropriate cell types, and the supportive nutrients and growth factors that allow normal cell growth, differentiation, and function. Tissue engineering is a relatively new field, originating in the late 1970s. Early studies focused on efforts to create skin substitutes using biomaterials and epithelial skin cells with a goal of providing barrier protection for patients with burns. The early strategies employed a tissue biopsy, followed by ex vivo expansion of cells seeded on scaffolds. The cell– scaffold composite was later implanted back into the same patient, where the new tissue would mature. However, there were many hurdles to overcome. The three major challenges in the field of tissue engineering involved: (1) the ability to grow and expand normal primary human cells in large quantities; (2) the identification of appropriate biomaterials; and (3) the requirement for adequate vascularization and innervation of the engineered constructs.
VASCULARIZATION AND INNERVATION Implanted tissue-engineered constructs require adequate vascularity and innervation. Judah Folkman, a pioneer in the field of angiogenesis, made the observation that cells could survive in volumes up to 3 mm3 via nutrient diffusion alone, but larger cell volumes required vascularization for survival. Adequate vascularity was also essential for normal innervation to occur. This was a major challenge in the field of tissue engineering, which largely depended on the patient’s native angiogenesis and innervation. Even if sufficient cell quantities are available, there is a theoretical limit on the types of tissue constructs that could be created. In response to this challenge, material scientists designed scaffolds with much greater porosity and architecture. Scaffold designs included the creation of thin, porous sponges comprised of 95% air, markedly increasing the surface area for the resident cells. These properties promoted increased vascularity and innervation. The addition of growth factors, such as vascular endothelial growth factor and nerve growth factor, has been used to enhance angiogenesis and innervation. LEVEL OF COMPLEXITY FOR THE ENGINEERING OF TISSUES AND ORGANS All human tissues are complex. However, from an architectural aspect, tissues can be categorized under four levels. Flat tissue structures, such as skin, are the least complex (level 1), comprised predominantly of a single epithelial cell type. Tubular structures, such as blood vessels and the trachea, are more complex architecturally (level 2) and must be constructed to ensure that the structure does not collapse over time. These tissues typically have two major cell types. They are designed to act as a conduit for air or fluid at a steady state within a defined physiologic range. Hollow nontubular organs, such as the stomach, bladder, or uterus, are more complex architecturally (level 3). The cells are functionally more complex, and these cell types often have a functional interdependence. By far, the most complex are the solid organs (level 4), because the amount of cells per cm2 are exponentially greater than any of the other tissue types. For the first three tissue levels (1–3), when the constructs are initially implanted, the cell layering on the scaffolds is thin, not unlike that seen in tissue culture matrices. The cell layering continues to
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CHAPTER 92e Tissue Engineering
ISOLATION AND GROWTH OF CELLS The original model for tissue engineering focused largely on the isolation of tissue from the organ of interest, the growth and expansion of the tissue-specific cells, and the seeding of these cells onto threedimensional scaffolds. Just a few decades ago, most primary cultures of human cells could not be grown and expanded in large quantities, representing a major impediment to the engineering of human tissues. However, the identification of specific tissue progenitor cells in the 1990s allowed expansion of multiple cell types, and progress has occurred steadily since then. Some cell types are more amenable to expansion than others, reflecting in part their native regenerative capacity but also varying requirements for nutrients, growth factors, and cell–cell contacts. As an example of progress, after years of effort, protocols for the growth and expansion of human cardiomyocytes are now available. However, there are still many tissue-specific cell types that cannot be expanded from tissue sources, including the pancreas, liver, and nerves. The discovery of pluripotent or highly multipotent stem cells (Chap. 88) may ultimately allow most human cell types to be used for tissue engineering. The stem cell characteristics depend on their origin and their degree of plasticity, with cells from the earliest developmental stages, such as embryonic stem cells, having the greatest plasticity. Induced pluripotent stem cells have the advantage that they can be derived from individual patients, allowing autologous transplants. They can also be differentiated, in vitro, along cell-specific lineages, although these protocols are still at an early stage of development. Human embryonic and induced pluripotent stem cells have a very high replicative potential, but they also have the potential for rejection and tumor formation (e.g., teratomas). The more recently described amniotic fluid and placental stem cells have a high replicative potential but without an apparent propensity for tumor formation. Moreover, they have the potential to be used in an autologous manner without rejection. Adult stem cells, such as those derived from bone marrow, also have less propensity for tumor formation and, if used in an autologous manner, will not be rejected, but their replicative potential is limited, especially for endoderm and ectoderm cells. Stem cells can be derived from autologous or heterologous sources. Heterologous cells can be used when only temporary coverage is needed, such as replacing skin after a burn or wound. However, if a more permanent construct is required, autologous cells are preferred to avoid rejection. There are also practical issues related to tissue sources. For example, if a patient presents with end-stage heart disease, obtaining a cardiac tissue biopsy for cell expansion is unlikely to be feasible, and bone marrow–derived mesenchymal cells may provide an alternative.
BIOMATERIALS AS SCAFFOLDS FOR TISSUE ENGINEERING The biomaterials used to create the scaffolds for tissue engineering require specific properties to enhance the long-term success of the implanted constructs. Ideally, the biomaterials should be biocompatible; elicit minimal inflammatory responses; have appropriate biomechanical properties; and promote cell attachment, viability, proliferation, and differentiated function. Ideally, the scaffolds should replicate the biomechanical and structural properties of the tissue being replaced. In addition, biodegradation should be controlled such that the scaffold retains its structural integrity until the cells deposit their own matrix. If the scaffolds degrade too quickly, the constructs may collapse. If the scaffolds degrade too slowly, fibrotic tissue may form. Also, the degradation of the scaffolds should not alter the local environment unfavorably, because this can impair the function of cells or newly formed tissue. The first scaffolds designed for tissue regeneration were naturally derived materials, such as collagen. The first artificially derived material for tissue engineering used a biodegradable scaffold made of polyglycolic acid. Naturally derived scaffolds have properties very similar to the native matrix, but there is an inherent batch-to-batch variability, whereas the production of artificially derived biomaterials can be better controlled, allowing for more uniform results. More recently, combination scaffolds, made of both naturally and artificially derived biomaterials, have been used for tissue engineering. An emerging area is the use of peptide nanostructures to facilitate tissue engineering. Some of these are self-assembling peptide amphiphiles that allow scaffolds to form in vivo, for example at sites of spinal cord injury where they have been used experimentally to prevent scar formation and facilitate nerve and blood vessel regeneration. Peptide nanostructures can be combined with other biomaterials, and they can be linked to growth factors, antibodies, and various signaling molecules that can modulate cell behavior during organ regeneration.
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mature, in concert with the recipient’s native angiogenesis and neoinnervation. For level 4 (solid) organs, the vascularity requirements are substantial, and native tissue angiogenesis is not sufficient. The engineering strategies for tissues vary according to their complexity level.
PART 4 Regenerative Medicine
tissue regeneration, either alone or with the use of scaffolds. For example, gene transcription factors used in the mouse pancreas led to tissue regeneration. Surgically implanted decellularized heart valve scaffolds, coated with proteins that attract vascular stem cells, led to the creation of in situ cell-seeded functional heart valves in STRATEGIES FOR TISSUE ENGINEERING sheep. Drugs that induce muscle regeneration are being tested clinThe basic principles of tissue engineering involve the use of the relically. Small molecules that induce tissue regeneration are currently evant cell populations, where the cell biology is well understood and under investigation for multiple applications, including growth of the cells can be reproducibly retrieved and expanded, and the use skin and hair and for musculoskeletal applications. of optimized biomaterials and scaffold designs. Cell seeding can be 3. The most common strategy for the engineering of tissues uses performed using various techniques, including static or flow-based scaffolds seeded with cells. The most direct and established type of systems that use bioreactors. tissue engineering uses flat scaffolds, either artificial or naturally Most techniques for the engineering of tissues fall under one of five derived, that are seeded with cells and used for the replacement or strategies (Fig. 92e-1): repair of flat tissue structures. The flat scaffolds can also be sized and molded at the time of surgical implantation, or they can be 1. Scaffolds can be used alone, without cells, and implanted, where shaped prior to cell seeding, for example, for tubular organs such they depend on native cell migration onto the scaffold from the as blood vessels or nontubular hollow tissues such as bladders. adjacent tissue for regeneration. The first use of decellularized scafBioreactors are often used to expose the cell–scaffold construct to folds for tissue regeneration was for urethral reconstruction. These mechanical forces, such as, stress, strain, and pulsatile flow that aid techniques are most optimal when the size of the defect is relatively in the normal development of the cells into tissues (Video 92e-1, small, usually 35 proportions of older people (5% or lower). 30-35 Based on estimates from the United Nations 25-30 20-25 Population Division, 809 million people were 15-20 age 60 years or older in 2012, of whom 279 mil10-15 lion lived in more developed countries and 530 5-10 35 and survival at older ages. Countries vary in 30-35 the extent to which the “future elderly” cohorts 25-30 20-25 will be more educated. China in particular will 15-20 have a much more educated elderly popula10-15 tion in 2050 (with more than two-thirds of the 5-10 35) leads to a 29% increased risk of dying, people with BMI in the overweight range seem to have reduced mortality, at least in population studies of middle-aged and older subjects. People with a BMI in the overweight range seem more able to counteract and respond to disease, trauma, and infection, whereas caloric restriction impairs healing and immune responses. On the other hand, BMI is an insufficient denominator of body and body fat composition. A well-trained athlete may have a similar BMI as an overweight person because of the higher muscle mass density. The waist-to-hip ratio is a much better indicator for body fat and an excellent and stringent predictor of the risk of dying from cardiovascular disease: the lower the waist-to-hip ratio, the lower is the risk. Periodic fasting How can caloric restriction be translated to humans in a socially and medically feasible way? A whole series of periodic fasting regimens are asserting themselves as suitable strategies, among them the alternate-day fasting diet, the “five:two” intermittent fasting diet, and a 48-h fast once or twice each month. Periodic fasting is psychologically more viable, lacks some of the negative side effects, and is only accompanied by minimal weight loss. It is striking that many cultures implement periodic fasting rituals, for example Buddhists, Christians, Hindus, Jews, Muslims, and some African animistic religions. It could be speculated that a selective advantage of fasting versus nonfasting populations is conferred by health-promoting attributes of religious routines that periodically limit caloric intake. Indeed, several lines of evidence indicate that intermittent fasting regimens exert antiaging effects. For example improved morbidity and longevity were observed among Spanish home nursing residents who underwent alternate-day fasting. Even rats subjected to alternate-day fasting live up to 83% longer than normally fed control animals, and one 24-h fasting period every 4 days is sufficient to generate lifespan extension Repeated fasting and eating cycles may circumvent the negative side effects of sustained caloric restriction. This strategy may even yield effects despite extreme overeating during the nonfasting periods. In a spectacular experiment, mice fed a high-fat diet in a time-restricted manner, i.e., with regular fasting breaks, showed reduced inflammation markers and no fatty liver and were slim in comparison to mice with equivalent total calorie consumption but ad libitum. From an evolutionary point of view, this kind of feeding pattern may reflect mammalian adaptation to food availability: overeating in times of nutrient availability (e.g., after a hunting success) and starvation in between. This is how some indigenous peoples who have avoided
Western lifestyles live today; those who have been investigated show limited signs of age-induced diseases such as cancer, neurodegeneration, diabetes, cardiovascular disease, and hypertension. Fasting exerts beneficial effects on healthspan by minimizing the risk of developing age- related diseases including hypertension, neurodegeneration, cancer, and cardiovascular diseases. The most effective and rapid repercussion of fasting is reduction in hypertension. Two weeks of water-only fasting resulted in a blood pressure below 120/80 mmHg in 82% of subjects with borderline hypertension. Ten days of fasting cured all hypertensive patients who had been taking antihypertensive medication previously. Periodic fasting dampens the consequences of many age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and frontotemporal dementia, but not amyotrophic lateral sclerosis in mouse models). Fasting cycles are as effective as chemotherapy against certain tumors in mice. In combination with chemotherapy, fasting protected mice against the negative side effects of chemotherapeutic drugs, while it enhanced their efficacy against tumors. Combining fasting and chemotherapy rendered 20–60% of mice cancer-free when inoculated with highly aggressive tumors like glioblastoma or pancreatic tumors, which have 100% mortality even with chemotherapy. This approach has been attempted in people with some indication that toxicities of chemotherapy are reduced. Pharmacologic Interventions to Delay Aging and Increase Lifespan Virtually all obese people know that stable weight reduction will reduce their elevated risk of cardiometabolic disease and enhance their overall survival, yet only 20% of overweight individuals are able to lose 10% of their weight for a period of at least 1 year. Even in the most motivated people (such as the “Cronies” who deliberately attempt long-term caloric restriction in order to extend their lives), long-term caloric restriction is extremely difficult. Thus, focus has been directed at the possibility of developing medicines that replicate the beneficial effects of caloric restriction without the need for reducing food intake (“CR-mimetics,” Fig. 94e-5): • Resveratrol. Resveratrol, an agonist of SIRT1, is a polyphenol that is found in grapes and in red wine. The potential of resveratrol to promote lifespan was first identified in yeast, and it has gathered fame since, at least in part because it might be responsible for the so-called French paradox whereby wine reduces some of the cardiometabolic risks of a high-fat diet. Resveratrol has been reported to increase lifespan in many lower order species such as yeast, fruit flies, worms, and mice on high-fat diets. In monkeys fed a diet high in sugar and fat, resveratrol had beneficial outcomes related to inflammation and cardiometabolic parameters. Some studies in humans have also shown improvements in cardiometabolic function, whereas HO O OH
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Figure 94e-5 Chemical structures of four agents (resveratrol, rapamycin, spermidine, and metformin) that have been shown to delay aging in experimental animal models.
sarcopenia (age-related muscle wasting). Even moderate or low levels of exercise (30 min walking per day) have significant protective effects in obese subjects. In older people, regular physical activity has been found to increase the duration of independent living. While clearly promoting health and thus quality of life, regular exercise does not extend lifespan. Furthermore, the combination of exercise with caloric restriction has no additive effect on maximal lifespan in rodents. On the other hand, alternate-day fasting with exercise is more beneficial for the muscle mass than single treatments alone. In nonobese humans, exercise combined with caloric restriction has synergistic effects on insulin sensitivity and inflammation. From the evolutionary perspective, the responses to hunger and exercise are linked: when food is scarce, increased activity is required to hunt and gather.
Exercise and Physical Activity In humans and animals, regular exercise reduces the risk of morbidity and mortality. Given that cardiovascular diseases are the dominant cause of aging in humans but not in mice, the effects on human health may be even stronger than those seen in mouse experiments. An increase in aerobic exercise capacity, which declines during aging, is associated with favorable effects on blood pressure, lipids, glucose tolerance, bone density, and depression in older people. Likewise, exercise training protects against aging disorders such as cardiovascular diseases, diabetes mellitus, and osteoporosis. Exercise is the only treatment that can prevent or even reverse
CONCLUSIONS Clinicians need to understand aging biology in order to better manage people who are elderly now. Moreover there is an urgent need to develop strategies based on aging biology that delay aging, reduce or postpone the onset of age-related disorders, and increase functional life and healthspan for future generations. Interventions related to nutritional interventions and drugs that act on nutrient-sensing pathways are being developed and, in some cases, are already being studied in humans. Whether these interventions are universally effective or species/individual specific needs to be determined.
Hormesis The term hormesis describes the, at first sight paradoxic, protective effects conferred by the exposure to low doses of stressors or toxins (or as Nietzsche stated, “What does not kill him makes him stronger”). Adaptive stress responses elicited by noxious agents (chemical, thermal, or radioactive) precondition an organism, rendering it resistant to subsequent higher and otherwise lethal doses of the same trigger. Hormetic stressors have been found to influence aging and lifespan, presumably by increasing cellular resilience to factors that might contribute to aging such as oxidative stress. Yeast cells that have been exposed to low doses of oxidative stress exhibit a marked antistress response that inhibits death following exposure to lethal doses of oxidants. During ischemic preconditioning in humans, short periods of ischemia protect the brain and the heart against a more severe deprivation of oxygen and subsequent reperfusion-induced oxidative stress. Similarly, the lifelong and periodic exposure to various stressors can inhibit or retard the aging process. Consistent with this concept, heat or mild doses of oxidative stress can lead to lifespan extension in C. elegans. Caloric restriction can also be considered to be a type of hormetic stress that results in the activation of antistress transcription factors (Rim15, Gis1, and Msn2/Msn4 in yeast and FOXO in mammals) that enhance the expression of free radical–scavenging factors and heat shock proteins.
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Chapter 94e The Biology of Aging
others have been negative. Gene expression studies in animals and humans reveal that resveratrol mimics some of the metabolic and gene expression changes of caloric restriction. • Rapamycin. Rapamycin, an inhibitor of mTOR, was originally discovered on Easter Island (Rapa Nui; hence its name) as a bacterial secretion with antibiotic properties. Before its immersion in the antiaging field, rapamycin already had a longstanding career as an immunosuppressant and cancer chemotherapeutic in humans. Rapamycin extends lifespan in all organisms tested so far, including yeast, flies, worms, and mice. However, the potential utility of rapamycin for human lifespan extension is likely to be limited by adverse effects related to immunosuppression, wound healing, proteinuria, and hypercholesterolemia, among others. An alternative strategy may be intermittent rapamycin feeding, which was found to increase mouse lifespan. • Spermidine. Spermidine is a physiologic polyamine that induces autophagy-mediated lifespan extension in yeast, flies, and worms. Spermidine levels decrease during the life of virtually all organisms including humans, with the stunning exception of centenarians. Oral administration of spermidine and upregulation of bacterial polyamine production in the gut both lead to lifespan extension in short-lived mouse models. Spermidine has also been found to have beneficial effects on neurodegeneration probably by increasing transcription of genes involved in autophagy. • Metformin. Metformin, an activator of AMPK, is a biguanide first isolated from the French lilac that is widely used for the treatment of type 2 diabetes mellitus. Metformin decreases hepatic gluconeogenesis and increases insulin sensitivity. Metformin has other actions including inhibition of mTOR and mitochondrial complex I and activation of the transcription factor SKN-1/Nrf2. Metformin increases lifespan in different mouse strains including female mouse strains predisposed to high incidence of mammary tumors. At a biochemical level, metformin supplementation is associated with reduced oxidative damage and inflammation and mimics some of the gene expression changes seen with caloric restriction.
Part 6: Nutrition and Weight Loss
95e
Nutrient Requirements and Dietary Assessment Johanna Dwyer
ESSENTIAL NUTRIENT REQUIREMENTS Energy For weight to remain stable, energy intake must match energy output. The major components of energy output are resting energy expenditure (REE) and physical activity; minor components include the energy cost of metabolizing food (thermic effect of food, or specific dynamic action) and shivering thermogenesis (e.g., cold-induced thermogenesis). The average energy intake is ~2600 kcal/d for American men and ~1800 kcal/d for American women, though these estimates vary with body size and activity level. Formulas for roughly estimating REE are useful in assessing the energy needs of an individual whose weight is stable. Thus, for males, REE = 900 + 10m, and for females, REE = 700 + 7m, where is m mass in kilograms. The calculated REE is then adjusted for physical activity level by multiplying by 1.2 for sedentary, 1.4 for moderately active, or 1.8 for very active individuals. The final figure, the estimated energy requirement (EER), provides an approximation of total caloric needs in a state of energy balance for a person of a certain age, sex, weight, height, and physical activity level. For further discussion of energy balance in health and disease, see Chap. 97. Protein Dietary protein consists of both essential and nonessential amino acids that are required for protein synthesis. The nine essential amino acids are histidine, isoleucine, leucine, lysine, methionine/ cystine, phenylalanine/tyrosine, threonine, tryptophan, and valine. Certain amino acids, such as alanine, can also be used for energy and gluconeogenesis. When energy intake is inadequate, protein intake must be increased, because ingested amino acids are diverted into pathways of glucose synthesis and oxidation. In extreme energy deprivation, protein-calorie malnutrition may ensue (Chap. 97). For adults, the recommended dietary allowance (RDA) for protein is ~0.6 g/kg desirable body mass per day, assuming that energy needs are met and that the protein is of relatively high biologic value. Current recommendations for a healthy diet call for at least 10–14% of calories from protein. Most American diets provide at least those amounts. Biologic value tends to be highest for animal proteins, followed by proteins from legumes (beans), cereals (rice, wheat, corn), and roots.
Combinations of plant proteins that complement one another in biologic value or combinations of animal and plant proteins can increase biologic value and lower total protein requirements. In healthy people with adequate diets, the timing of protein intake over the course of the day has little effect. Protein needs increase during growth, pregnancy, lactation, and rehabilitation after injury or malnutrition. Tolerance to dietary protein is decreased in renal insufficiency (with consequent uremia) and in liver failure. Normal protein intake can precipitate encephalopathy in patients with cirrhosis of the liver. Fat and Carbohydrate Fats are a concentrated source of energy and constitute, on average, 34% of calories in U.S. diets. However, for optimal health, fat intake should total no more than 30% of calories. Saturated fat and trans fat should be limited to 70 y
700
75
20
15
90
*
1.1
1.1
14
1.5
400
2.4
5
*
*
30
425*
Children
PART 6
Males
Nutrition and Weight Loss
Females
h
Pregnant women 14–18 y
750
80
15
15
75*
1.4
1.4
18
1.9
600j
2.6
6*
30*
450*
19–30 y
770
85
15
15
90*
1.4
1.4
18
1.9
600j
2.6
6*
30*
450*
31–50 y
770
85
15
15
90*
1.4
1.4
18
1.9
600j
2.6
6*
30*
450*
Lactating women 14–18 y
1200
115
15
19
75*
1.4
1.6
17
2.0
500
2.8
7*
35*
550*
19–30 y
1300
120
15
19
90
*
1.4
1.6
17
2.0
500
2.8
*
*
550*
31–50 y
1300
120
15
19
90
*
1.4
1.6
17
2.0
500
2.8
*
550*
7
*
7
35 35
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake. As retinol activity equivalents (RAEs). 1 RAE = 1 μg retinol, 12 μg β-carotene, 24 μg α-carotene, or 24 μg β-cryptoxanthin. The RAE for dietary provitamin A carotenoids is twofold greater than the retinol equivalent (RE), whereas the RAE for preformed vitamin A is the same as the RE. bAs cholecalciferol. 1 μg cholecalciferol = 40 IU vitamin D. cUnder the assumption of minimal sunlight. dAs α-tocopherol. α-Tocopherol includes RRR-α-tocopherol, the only form of α-tocopherol that occurs naturally in foods, and the 2R-stereoisomeric forms of α-tocopherol (RRR-, RSR-, RRS-, and RSS-α-tocopherol) that occur in fortified foods and supplements. It does not include the 2S-stereoisomeric forms of α-tocopherol (SRR-, SSR-, SRS-, and SSS-α-tocopherol) also found in fortified foods and supplements. eAs niacin equivalents (NEs). 1 mg of niacin = 60 mg of tryptophan; 0–6 months = preformed niacin (not NE). fAs dietary folate equivalents (DFEs). 1 DFE = 1 μg food folate = 0.6 μg of folic acid from fortified food or as a supplement consumed with food = 0.5 μg of a supplement taken on an empty stomach. gAlthough AIs have been set for choline, there are few data to assess whether a dietary supply of choline is needed at all stages of the life cycle, and it may be that the choline requirement can be met by endogenous synthesis at some of these stages. hBecause 10–30% of older people may malabsorb food-bound B12, it is advisable for those >50 years of age to meet their RDA mainly by consuming foods fortified with B12 or a supplement containing B12. iIn view of evidence linking inadequate folate intake with neural tube defects in the fetus, it is recommended that all women capable of becoming pregnant consume 400 μg of folate from supplements or fortified foods in addition to intake of food folate from a varied diet. j It is assumed that women will continue consuming 400 μg from supplements or fortified food until their pregnancy is confirmed and they enter prenatal care, which ordinarily occurs after the end of the periconceptional period—the critical time for formation of the neural tube. a
Source: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx).
level (UL). The DRIs also include acceptable macronutrient distribution ranges (AMDRs) for protein, fat, and carbohydrate. The current DRIs for vitamins and elements are provided in Tables 95e-1 and 95e-2, respectively. Table 95e-3 provides DRIs for water and macronutrients. EERs are discussed in Chap. 97 on energy balance in health and disease. Estimated Average Requirement When florid manifestations of the classic dietary-deficiency diseases such as rickets (deficiency of vitamin D and calcium), scurvy (deficiency of vitamin C), xerophthalmia (deficiency of vitamin A), and protein-calorie malnutrition were common, nutrient adequacy was inferred from the absence of their clinical signs. Later, biochemical and other changes were found to be evident long before the deficiency became clinically apparent. Consequently, criteria of adequacy are now based on biologic markers when they are available. Priority is given to sensitive biochemical, physiologic, or behavioral tests that reflect early changes in regulatory processes;
maintenance of body stores of nutrients; or, if available, the amount of a nutrient that minimizes the risk of chronic degenerative disease. Current efforts focus on this last variable, but relevant markers often are not available. The EAR is the amount of a nutrient estimated to be adequate for half of the healthy individuals of a specific age and sex. The types of evidence and criteria used to establish nutrient requirements vary by nutrient, age, and physiologic group. The EAR is not an effective estimate of nutrient adequacy in individuals because it is a median requirement for a group; 50% of individuals in a group fall below the requirement and 50% fall above it. Thus, a person with a usual intake at the EAR has a 50% risk of inadequate intake. For these reasons, other standards, described below, are more useful for clinical purposes. Recommended Dietary Allowances The RDA is the average daily dietary intake level that meets the nutrient requirements of nearly all healthy persons of a specific sex, age, life stage, or physiologic condition
95e-3
Table 95e-2 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Elements LifeStage Group
Calcium Chromium Copper Fluoride Iodine Iron Magnesium Manganese Molybdenum Phosphorus Selenium Zinc Potassium Sodium Chloride (mg/d) (μg/d) (μg/d) (mg/d) (μg/d) (mg/d) (mg/d) (mg/d) (μg/d) (mg/d) (μg/d) (mg/d) (g/d) (g/d) (g/d)
Infants Birth to 6 mo
200*
0.2*
200*
0.01*
110*
6–12 mo
260*
5.5*
220*
0.5*
130*
0.27*
30*
0.003*
2*
100*
15*
2*
0.4*
0.12*
0.18*
11
75*
0.6*
3*
275*
20*
3
0.7*
0.37*
0.57*
Children 700
11*
340
0.7*
90
7
80
1.2*
17
460
20
3
3.0*
1.0*
1.5*
4–8 y
1000
*
15
440
1
*
90
10
130
*
1.5
22
500
30
5
3.8
*
*
1.2
1.9*
9–13 y
1300
25*
700
2*
120
8
240
1.9*
34
1250
40
8
4.5*
1.5*
2.3*
14–18 y
1300
35*
890
3*
150
11
410
2.2*
43
1250
55
11
4.7*
1.5*
2.3*
19–30 y
1000
35*
900
4*
150
8
400
2.3*
45
700
55
11
4.7*
1.5*
2.3*
31–50 y
1000
35*
900
4*
150
8
420
2.3*
45
700
55
11
4.7*
1.5*
2.3*
51–70 y
1000
*
900
4
*
150
8
420
*
45
700
55
11
4.7
*
*
2.0*
>70 y
1200
*
30
900
4
*
150
8
420
*
2.3
45
700
55
11
4.7
*
*
1.2
1.8*
9–13 y
1300
21*
700
2*
120
8
240
1.6*
34
1250
40
8
4.5*
1.5*
2.3*
14–18 y
1300
24*
890
3*
150
15
360
1.6*
43
1250
55
9
4.7*
1.5*
2.3*
19–30 y
1000
25*
900
3*
150
18
310
1.8*
45
700
55
8
4.7*
1.5*
2.3*
31–50 y
1000
*
900
3
*
150
18
320
*
45
700
55
8
4.7
*
*
2.3*
51–70 y
1200
*
900
3
*
150
8
320
*
45
700
55
8
4.7
*
*
2.0*
>70 y
1200
*
20
900
3
*
150
8
320
*
1.8
45
700
55
8
4.7
*
*
1.2
1.8*
Males
30
2.3
1.3
Females
25 20
1.8 1.8
1.5 1.3
Pregnant women 14–18 y
1300
29*
1000
3*
220
27
400
2.0*
50
1250
60
12
4.7*
1.5*
2.3*
19–30 y
1000
30*
1000
3*
220
27
350
2.0*
50
700
60
11
4.7*
1.5*
2.3*
31–50 y
1000
30*
1000
3*
220
27
360
2.0*
50
700
60
11
4.7*
1.5*
2.3*
Lactating women 14–18 y
1300
44*
1300
3*
290
10
360
2.6*
50
1250
70
13
5.1*
1.5*
2.3*
19–30 y
1000
*
45
1300
3
*
290
9
310
*
2.6
50
700
70
12
5.1
*
*
1.5
2.3*
31–50 y
1000
45*
1300
3*
290
9
320
2.6*
50
700
70
12
5.1*
1.5*
2.3*
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake. Sources: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx), based on: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1997); Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998); Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000); and Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2001); Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005); and Dietary Reference Intakes for Calcium and Vitamin D (2011). These reports can be accessed via www.nap.edu.
(e.g., pregnancy or lactation). The RDA, which is the nutrient-intake goal for planning diets of individuals, is defined statistically as two standard deviations above the EAR to ensure that the needs of any given individual are met. The online tool at http://fnic.nal.usda.gov/ interactiveDRI/ allows health professionals to calculate individualized daily nutrient recommendations for dietary planning based on the DRIs for persons of a given age, sex, and weight. The RDAs are used to formulate food guides such as the U.S. Department of Agriculture (USDA) MyPlate Food Guide for individuals (www.supertracker.usda .gov/default.aspx), to create food-exchange lists for therapeutic diet planning, and as a standard for describing the nutritional content of foods and nutrient-containing dietary supplements. The risk of dietary inadequacy increases as intake falls below the RDA. However, the RDA is an overly generous criterion for evaluating nutrient adequacy. For example, by definition, the RDA exceeds the actual requirements of all but ~2–3% of the population. Therefore, many people whose intake falls below the RDA may still be getting enough of the nutrient. On food labels, the nutrient content in a food is stated by weight or as a percent of the daily value (DV), a variant of the RDA used on the nutrition facts panel that, for an adult, represents the highest RDA for an adult consuming 2000 kcal. Adequate Intake It is not possible to set an RDA for some nutrients that do not have an established EAR. In this circumstance, the AI is
based on observed or experimentally determined approximations of nutrient intakes in healthy people. In the DRIs, AIs rather than RDAs are proposed for nutrients consumed by infants (up to age 1 year) as well as for chromium, fluoride, manganese, sodium, potassium, pantothenic acid, biotin, choline, and water consumed by persons of all ages. Vitamin D and calcium recommendations were recently revised, and more precise estimates are now available. Tolerable Upper Levels of Nutrient Intake Healthy individuals derive no established benefit from consuming nutrient levels above the RDA or AI. In fact, excessive nutrient intake can disturb body functions and cause acute, progressive, or permanent disabilities. The tolerable UL is the highest level of chronic nutrient intake (usually daily) that is unlikely to pose a risk of adverse health effects for most of the population. Data on the adverse effects of large amounts of many nutrients are unavailable or too limited to establish a UL. Therefore, the lack of a UL does not mean that the risk of adverse effects from high intake is nonexistent. Nutrients in commonly eaten foods rarely exceed the UL. However, highly fortified foods and dietary supplements provide more concentrated amounts of nutrients per serving and thus pose a potential risk of toxicity. Nutrient supplements are labeled with supplement facts that express the amount of nutrient in absolute units or as the percentage of the DV provided per recommended serving size. Total nutrient consumption, including that in foods, supplements,
CHAPTER 95e Nutrient Requirements and Dietary Assessment
1–3 y
95e-4
Table 95e-3 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Total Water and Macronutrients Total Watera Life-Stage Group (L/d) Infants Birth to 6 mo 0.7*
Carbohydrate (g/d)
Total Fiber (g/d)
60*
NDc
Fat (g/d)
Linoleic Acid (g/d)
α-Linolenic Acid (g/d)
PART 6 Nutrition and Weight Loss
4.6
0.5
9.1* 11.0
ND
7*
0.7*
13
ND
10
*
0.9*
19
ND
12*
1.2*
34
ND
16
*
1.6*
52
38*
ND
17*
1.6*
56
130
38*
ND
17*
1.6*
56
3.7*
130
30*
ND
14*
1.6*
56
>70 y
3.7*
130
30*
ND
14*
1.6*
56
Females 9–13 y
2.1*
130
26*
ND
10*
1.0*
34
14–18 y
2.3
*
130
26
*
ND
11
*
1.1*
46
19–30 y
2.7*
130
25*
ND
12*
1.1*
46
31–50 y
2.7*
130
25*
ND
12*
1.1*
46
51–70 y
2.7*
130
21*
ND
11*
1.1*
46
>70 y
2.7*
130
21*
ND
11*
1.1*
46
Pregnant women 14–18 y
3.0*
175
28*
ND
13*
1.4*
71
19–30 y
3.0*
175
28*
ND
13*
1.4*
71
31–50 y
3.0*
175
28*
ND
13*
1.4*
71
Lactating women 14–18
3.8*
210
29*
ND
13*
1.3*
71
19–30 y
3.8*
210
29*
ND
13*
1.3*
71
31–50 y
*
210
*
ND
*
*
71
6–12 mo
0.8
*
Children 1–3 y
*
31*
4.4*
0.5*
*
*
*
Proteinb (g/d)
95
ND
30
1.3*
130
19*
4–8 y
1.7
*
130
25
*
Males 9–13 y
2.4*
130
31*
14–18 y
3.3
*
130
38
*
19–30 y
3.7*
130
31–50 y
3.7*
51–70 y
3.8
29
13
1.3
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those groups, but lack of data or uncertainty in the data make it impossible to specify with confidence the percentage of individuals covered by this intake. a Total water includes all water contained in food, beverages, and drinking water. bBased on grams of protein per kilogram of body weight for the reference body weight (e.g., for adults: 0.8 g/kg body weight for the reference body weight). cNot determined.
Source: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx), based on: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (2002/2005) and Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005). These reports can be accessed via www.nap.edu.
and over-the-counter medications (e.g., antacids), should not exceed RDA levels.
and health often decline with age, energy needs of older persons, especially those over 70, tend to be lower than those of younger persons.
Acceptable Macronutrient Distribution Ranges The AMDRs are not experimentally determined but are rough ranges for energy-providing macronutrient intakes (protein, carbohydrate, and fat) that the Institute of Medicine’s Food and Nutrition Board considers to be healthful. These ranges are 10–35% of calories for protein, 20–35% of calories for fat, and 45–65% of calories for carbohydrate. Alcohol, which also provides energy, is not a nutrient; therefore, no recommendations are not provided.
Dietary Composition Dietary composition affects the biologic availability and use of nutrients. For example, the absorption of iron may be impaired by large amounts of calcium or lead; likewise, non-heme iron uptake may be impaired by a lack of ascorbic acid and amino acids in the meal. Protein use by the body may be decreased when essential amino acids are not present in sufficient amounts—a rare scenario in U.S. diets. Animal foods, such as milk, eggs, and meat, have high biologic values, with most of the needed amino acids present in adequate amounts. Plant proteins in corn (maize), soy, rice, and wheat have lower biologic values and must be combined with other plant or animal proteins or fortified with the amino acids that are deficient to achieve optimal use by the body.
FACTORS ALTERING NUTRIENT NEEDS The DRIs are affected by age, sex, rate of growth, pregnancy, lactation, physical activity level, concomitant diseases, drugs, and dietary composition. If requirements for nutrient sufficiency are close to levels indicating excess of a nutrient, dietary planning is difficult. Physiologic Factors Growth, strenuous physical activity, pregnancy, and lactation all increase needs for energy and several essential nutrients. Energy needs rise during pregnancy due to the demands of fetal growth and during lactation because of the increased energy required for milk production. Energy needs decrease with loss of lean body mass, the major determinant of REE. Because lean tissue, physical activity,
Route of Intake The RDAs apply only to oral intakes. When nutrients are administered parenterally, similar values can sometimes be used for amino acids, glucose (carbohydrate), fats, sodium, chloride, potassium, and most vitamins because their intestinal absorption rate is nearly 100%. However, the oral bioavailability of most mineral elements may be only half that obtained by parenteral administration. For some nutrients that are not readily stored in the body or that cannot be stored in large amounts, timing of administration may also
be important. For example, amino acids cannot be used for protein synthesis if they are not supplied together; instead, they will be used for energy production, although in healthy individuals eating adequate diets, the distribution of protein intake over the course of the day has little effect on health.
DIETARY ASSESSMENT In clinical situations, nutritional assessment is an iterative process that involves: (1) screening for malnutrition, (2) assessing the diet and other data to establish either the absence or the presence of malnutrition and its possible causes, (3) planning and implementing the most appropriate nutritional therapy, and (4) reassessing intakes to make sure that they have been consumed. Some disease states affect the bioavailability, requirements, use, or excretion of specific nutrients. In these circumstances, specific measurements of various nutrients or their biomarkers may be required to ensure adequate replacement (Chap. 96e). Most health care facilities have nutrition-screening processes in place for identifying possible malnutrition after hospital admission. Nutritional screening is required by the Joint Commission, which accredits and certifies health care organizations in the United States. However, there are no universally recognized or validated standards. The factors that are usually assessed include abnormal weight for height or body mass index (e.g., BMI 25); reported weight change (involuntary loss or gain of >5 kg in the past 6 months) (Chap. 56); diagnoses with known nutritional implications (e.g., metabolic disease, any disease affecting the gastrointestinal tract, alcoholism); present therapeutic dietary prescription; chronic poor appetite; presence of chewing and swallowing problems or major food intolerances; need for assistance with preparing or shopping for food, eating, or other aspects of self-care; and social isolation. The nutritional status of hospitalized patients should be reassessed periodically—at least once every week. A more complete dietary assessment is indicated for patients who exhibit a high risk of or frank malnutrition on nutritional screening. The type of assessment varies with the clinical setting, the severity of the patient’s illness, and the stability of the patient’s condition. Acute-Care Settings In acute-care settings, anorexia, various other diseases, test procedures, and medications can compromise dietary intake. Under such circumstances, the goal is to identify and avoid inadequate intake and to assure appropriate alimentation. Dietary assessment focuses on what patients are currently eating, whether or not they are able and willing to eat, and whether or not they experience any problems with eating. Dietary intake assessment is based on information from observed intakes; medical records; history; clinical examination; and anthropometric, biochemical, and functional status
Ambulatory Settings The aim of dietary assessment in the outpatient setting is to determine whether or not the patient’s usual diet is a health risk in itself or if it contributes to existing chronic disease-related problems. Dietary assessment also provides the basis for planning a diet that fulfills therapeutic goals while ensuring patient adherence. The outpatient dietary assessment should review the adequacy of present and usual food intakes, including vitamin and mineral supplements, oral nutritional supplements, medical foods, other dietary supplements, medications, and alcohol, because all of these may affect the patient’s nutritional status. The assessment should focus on the dietary constituents that are most likely to be involved or compromised by a specific diagnosis as well as on any comorbidities that are present. More than one day’s intake should be reviewed to provide a better representation of the usual diet. There are many ways to assess the adequacy of a patient’s habitual diet. These include use of a food guide, a food-exchange list, a diet history, or a food-frequency questionnaire. A commonly used food guide for healthy persons is the USDA’s Choose My Plate, which is useful as a rough guide for avoiding inadequate intakes of essential nutrients as well as likely excesses in the amounts of fat (especially saturated and trans fats), sodium, sugar, and alcohol consumed (Table 95e-4). The Choose My Plate graphic emphasizes a balance between calories and nutritional needs, encouraging increased intake of fruits and vegetables, whole grains, and low-fat milk in conjunction with reduced intake of sodium and high-calorie sugary drinks. The Web version of the guide provides a calculator that tailors the number of servings suggested for healthy patients of different weights, sexes, ages, and life-cycle stages to help them to meet their needs while avoiding excess (http://www.supertracker.usda.gov/default.aspx and www .ChooseMyPlate.gov). Patients who follow ethnic or unusual dietary patterns may need extra instruction on how foods should be categorized and on the appropriate portion sizes that constitute a serving. The process of reviewing the guide with patients helps them transition
95e-5
CHAPTER 95e Nutrient Requirements and Dietary Assessment
Disease Dietary deficiency diseases include protein-calorie malnutrition, iron-deficiency anemia, goiter (due to iodine deficiency), rickets and osteomalacia (vitamin D deficiency), and xeropthalmia (vitamin A deficiency), megaloblastic anemia (vitamin B12 or folic acid deficiency), scurvy (vitamin C/ascorbic acid deficiency), beriberi (thiamin deficiency), and pellagra (niacin and tryptophan deficiency) (Chaps. 96e and 97). Each deficiency disease is characterized by imbalances at the cellular level between the supply of nutrients or energy and the body’s nutritional needs for growth, maintenance, and other functions. Imbalances and excesses in nutrient intakes are recognized as risk factors for certain chronic degenerative diseases, such as saturated fat and cholesterol in coronary artery disease; sodium in hypertension; obesity in hormone-dependent endometrial and breast cancers; and ethanol in alcoholism. Because the etiology and pathogenesis of these disorders are multifactorial, diet is only one of many risk factors. Osteoporosis, for example, is associated with calcium deficiency, sometimes secondary to vitamin D deficiency, as well as with risk factors related to environment (e.g., smoking, sedentary lifestyle), physiology (e.g., estrogen deficiency), genetic determinants (e.g., defects in collagen metabolism), and drug use (chronic steroid and aromatase inhibitors) (Chap. 425).
evaluations. The objective is to gather enough information to establish the likelihood of malnutrition due to poor dietary intake or other causes in order to assess whether nutritional therapy is indicated (Chap. 98e). Simple observations may suffice to suggest inadequate oral intake. These include dietitians’ and nurses’ notes; observation of a patient’s frequent refusal to eat or the amount of food eaten on trays; the frequent performance of tests and procedures that are likely to cause meals to be skipped; adherence to nutritionally inadequate diet orders (e.g., clear liquids or full liquids) for more than a few days; the occurrence of fever, gastrointestinal distress, vomiting, diarrhea, or a comatose state; and the presence of diseases or use of treatments that involve any part of the alimentary tract. Acutely ill patients with diet-related diseases such as diabetes need assessment because an inappropriate diet may exacerbate these conditions and adversely affect other therapies. Abnormal biochemical values (serum albumin levels 30, and emergency exchange transfusion if arterial saturation drops to 50–60% are often fatal. Congenital methemoglobinemia arises from globin mutations that stabilize iron in the ferric state (e.g., HbM Iwata [α87His→Tyr], Table 127-3) or from mutations that impair the enzymes that reduce methemoglobin to hemoglobin (e.g., methemoglobin reductase, NADP diaphorase). Acquired methemoglobinemia is caused by toxins that oxidize heme iron, notably nitrate and nitrite-containing compounds, including drugs commonly used in cardiology and anesthesiology. DIAGNOSIS AND MANAGEMENT OF PATIENTS WITH UNSTABLE HEMOGLOBINS, HIGH-AFFINITY HEMOGLOBINS, AND METHEMOGLOBINEMIA Unstable hemoglobin variants should be suspected in patients with nonimmune hemolytic anemia, jaundice, splenomegaly, or premature biliary tract disease. Severe hemolysis usually presents during infancy as neonatal jaundice or anemia. Milder cases may present in adult life with anemia or only as unexplained reticulocytosis, hepatosplenomegaly, premature biliary tract disease, or leg ulcers. Because spontaneous
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THALASSEMIA SYNDROMES The thalassemia syndromes are inherited disorders of α- or β-globin biosynthesis. The reduced supply of globin diminishes production of hemoglobin tetramers, causing hypochromia and microcytosis. Unbalanced accumulation of α and β subunits occurs because the synthesis of the unaffected globins proceeds at a normal rate. Unbalanced chain accumulation dominates the clinical phenotype. Clinical severity varies widely, depending on the degree to which the synthesis of the affected globin is impaired, altered synthesis of other globin chains, and coinheritance of other abnormal globin alleles. CLINICAL MANIFESTATIONS OF β THALASSEMIA SYNDROMES Mutations causing thalassemia can affect any step in the pathway of globin gene expression: transcription, processing of the mRNA precursor, translation, and posttranslational metabolism of the β-globin
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637
Figure 127-5 β Thalassemia intermedia. Microcytic and ypochromic red blood cells are seen that resemble the red h blood cells of severe iron-deficiency anemia. Many elliptical and teardrop-shaped red blood cells are noted. polypeptide chain. The most common forms arise from mutations that derange splicing of the mRNA precursor or prematurely terminate translation of the mRNA. Hypochromia and microcytosis characterize all forms of β thalassemia because of the reduced amounts of hemoglobin tetramers (Fig. 127-5). In heterozygotes (β thalassemia trait), this is the only abnormality seen. Anemia is minimal. In more severe homozygous states, unbalanced α- and β-globin accumulation causes accumulation of highly insoluble unpaired α chains. They form toxic inclusion bodies that kill developing erythroblasts in the marrow. Few of the proerythroblasts beginning erythroid maturation survive. The surviving RBCs bear a burden of inclusion bodies that are detected in the spleen, shortening the RBC life span and producing severe hemolytic anemia. The resulting profound anemia stimulates erythropoietin release and compensatory erythroid hyperplasia, but the marrow response is sabotaged by the ineffective erythropoiesis. Anemia persists. Erythroid hyperplasia can become exuberant and produce masses of extramedullary erythropoietic tissue in the liver and spleen. Massive bone marrow expansion deranges growth and development. Children develop characteristic “chipmunk” facies due to maxillary marrow hyperplasia and frontal bossing. Thinning and pathologic fracture of long bones and vertebrae may occur due to cortical invasion by erythroid elements and profound growth retardation. Hemolytic anemia causes hepatosplenomegaly, leg ulcers, gallstones, and highoutput congestive heart failure. The conscription of caloric resources to support erythropoiesis leads to inanition, susceptibility to infection, endocrine dysfunction, and in the most severe cases, death during the first decade of life. Chronic transfusions with RBCs improve oxygen delivery, suppress the excessive ineffective erythropoiesis, and prolong life, but the inevitable side effects, notably iron overload, often prove fatal by age 30 years. Severity is highly variable. Known modulating factors are those that ameliorate the burden of unpaired α-globin inclusions. Alleles associated with milder synthetic defects and coinheritance of α thalassemia trait reduce clinical severity by reducing accumulation of excess α globin. HbF persists to various degrees in β thalassemias. γ-Globin gene chains can substitute for β chains, generating more hemoglobin and reducing the burden of α-globin inclusions. The terms β thalassemia major and β thalassemia intermedia are used to reflect the clinical heterogeneity. Patients with β thalassemia major require intensive transfusion support to survive. Patients with β thalassemia intermedia have a somewhat milder phenotype and can survive without transfusion. The terms β thalassemia minor and β thalassemia trait describe asymptomatic heterozygotes for β thalassemia.
Chapter 127 Disorders of Hemoglobin
mutation is common, family history of anemia may be absent. The peripheral blood smear often shows anisocytosis, abundant cells with punctate inclusions, and irregular shapes (i.e., poikilocytosis). The two best tests for diagnosing unstable hemoglobins are the Heinz body preparation and the isopropanol or heat stability test. Many unstable Hb variants are electrophoretically silent. A normal electrophoresis does not rule out the diagnosis. Mass spectroscopy or direct gene analysis will provide a definitive diagnosis. Severely affected patients may require transfusion support for the first 3 years of life, because splenectomy before age 3 is associated with a significantly higher immune deficit. Splenectomy is usually effective thereafter, but occasional patients may require lifelong transfusion support. After splenectomy, patients can develop cholelithiasis and leg ulcers, hypercoagulable states, and susceptibility to overwhelming sepsis. Splenectomy should thus be avoided or delayed unless it is the only alternative. Precipitation of unstable hemoglobins is aggravated by oxidative stress, e.g., infection and antimalarial drugs, which should be avoided where possible. High-O2 affinity hemoglobin variants should be suspected in patients with erythrocytosis. The best test for confirmation is measurement of the P50. A high-O2 affinity hemoglobin causes a significant left shift (i.e., lower numeric value of the P50); confounding conditions, e.g., tobacco smoking or carbon monoxide exposure, can also lower the P50. High-affinity hemoglobins are often asymptomatic; rubor or plethora may be telltale signs. When the hematocrit approaches 60%, symptoms of high blood viscosity and sluggish flow (headache, lethargy, dizziness, etc.) may be present. These persons may benefit from judicious phlebotomy. Erythrocytosis represents an appropriate attempt to compensate for the impaired oxygen delivery by the abnormal variant. Overzealous phlebotomy may stimulate increased erythropoiesis or aggravate symptoms by thwarting this compensatory mechanism. The guiding principle of phlebotomy should be to improve oxygen delivery by reducing blood viscosity and increasing blood flow rather than restoration of a normal hematocrit. Phlebotomy-induced modest iron deficiency may aid in control. Low-affinity hemoglobins should be considered in patients with cyanosis or a low hematocrit with no other reason apparent after thorough evaluation. The P50 test confirms the diagnosis. Counseling and reassurance are the interventions of choice. Methemoglobin should be suspected in patients with hypoxic symptoms who appear cyanotic but have a Pao2 sufficiently high that hemoglobin should be fully saturated with oxygen. A history of nitrite or other oxidant ingestions may not always be available; some exposures may be inapparent to the patient, and others may result from suicide attempts. The characteristic muddy appearance of freshly drawn blood can be a critical clue. The best diagnostic test is methemoglobin assay, which is usually available on an emergency basis. Methemoglobinemia often causes symptoms of cerebral ischemia at levels >15%; levels >60% are usually lethal. Intravenous injection of 1 mg/kg of methylene blue is effective emergency therapy. Milder cases and follow-up of severe cases can be treated orally with methylene blue (60 mg three to four times each day) or ascorbic acid (300–600 mg/d).
THALASSEMIA SYNDROMES The four classic α thalassemias, most common in Asians, are α thalassemia-2 trait, in which one of the four α-globin loci is deleted;
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Patients with β thalassemia intermedia exhibit similar stigmata but can surHemoglobin Hemoglobin H Hemoglobin Level, vive without chronic hypertransfusion. Condition A, % (β4), % g/L (g/dL) MCV, fL Management is particularly challenging Normal 97 0 150 (15) 90 because a number of factors can aggraSilent thalassemia: −α/αα 98–100 0 150 (15) 90 vate the anemia, including infection, Thalassemia trait: 85–95 Rare red blood cell 120–130 (12–13) 70–80 onset of puberty, and development of −α/−α homozygous α-thal-2a inclusions splenomegaly and hypersplenism. Some or patients may eventually benefit from −−/αα heterozygous α-thal-1a splenectomy. The expanded erythron can cause absorption of excessive dietary Hemoglobin H disease: 70–95 5–30 60–100 (6–10) 60–70 −−/−α heterozygous α-thaliron and hemosiderosis, even without 1/α-thal-2 transfusion. Some patients eventually Hydrops fetalis: −−/−− 0 5–10b Fatal in utero or at become transfusion dependent. homozygous α-thal-1 birth β Thalassemia minor (i.e., thalasa When both α alleles on one chromosome are deleted, the locus is called α-thal-1; when only a single α allele on one chromosemia trait) usually presents as profound some is deleted, the locus is called α-thal-2. b90–95% of the hemoglobin is hemoglobin Barts (tetramers of γ chains). microcytosis and hypochromia with target cells, but only minimal or mild anemia. The mean corpuscular volume is α thalassemia-1 trait, with two deleted loci; HbH disease, with three rarely >75 fL; the hematocrit is rarely 50%. Folic acid supplements lent in the United States as a result of immigration of Asian may be useful. Vaccination with Pneumovax in anticipation of eventual splenectomy is advised, as is close monitoring for infection, leg persons, especially in California, where HbE is the most common variulcers, and biliary tract disease. Many patients develop endocrine ant detected. HbE is mildly unstable but not enough to affect RBC life deficiencies as a result of iron overload. Early endocrine evaluation span significantly. Heterozygotes resemble individuals with a mild is required for glucose intolerance, thyroid dysfunction, and delayed β-thalassemia trait. Homozygotes have somewhat more marked abnormalities but are asymptomatic. Compound heterozygotes for onset of puberty or secondary sexual characteristics.
638 TABLE 127-4 The α Thalassemias
PART 7 Oncology and Hematology
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HbE and a β thalassemia gene can have β thalassemia intermedia or β thalassemia major, depending on the severity of the coinherited thalassemic gene. The βE allele contains a single base change in codon 26 that causes the amino acid substitution. This mutation also activates a cryptic RNA splice site, generating a structurally abnormal globin mRNA that cannot be translated, from about 50% of the initial pre-mRNA molecules. The remaining 40–50% are normally spliced and generate functional mRNA that is translated into βE-globin because the mature mRNA carries the base change that alters codon 26. Genetic counseling of the persons at risk for HbE should focus especially on the interaction of HbE with β thalassemia, because HbE homozygosity is a condition associated with mildly asymptomatic microcytosis, hypochromia, and hemoglobin levels rarely 100 methyltransferase reactions (Fig. 128-1). During thymidylate synthesis, 5,10-methylene-THF is oxidized to DHF (dihydrofolate). The enzyme DHF reductase converts this to THF. The drugs methotrexate, pyrimethamine, and (mainly in bacteria) trimethoprim inhibit DHF reductase and so prevent formation of active THF coenzymes from DHF. A small fraction of the folate coenzyme is not recycled during thymidylate synthesis but is degraded at the C9-N10 bond.
COBALAMIN-FOLATE RELATIONS Folate is required for many reactions in mammalian tissues. Only two reactions in the body are known to require cobalamin. Methylmalonyl CoA isomerization requires adocobalamin, and the methylation of homocysteine to methionine requires both methylcobalamin and 5-MTHF (Fig. 128-1). This reaction is the first step in the pathway by which 5-MTHF, which enters bone marrow and other cells from plasma, is converted into all the intracellular folate coenzymes. The coenzymes are all polyglutamated (the larger size aiding retention in the cell), but the enzyme folate polyglutamate synthase can use only THF, not MTHF, as substrate. In cobalamin deficiency, MTHF accumulates in plasma, and intracellular folate concentrations fall due to failure of formation of THF, the substrate on which folate polyglutamates are built. This has been termed THF starvation, or the methylfolate trap. This theory explains the abnormalities of folate metabolism that occur in cobalamin deficiency (high serum folate, low cell folate, positive purine precursor aminoimidazole carboxamide ribonucleotide [AICAR] excretion; Table 128-2) and also why the anemia of cobalamin deficiency responds to folic acid in large doses.
CLINICAL FEATURES Many symptomless patients are detected through the finding of a raised mean corpuscular volume (MCV) on a routine blood count. The main clinical features in more severe cases are those of anemia. Anorexia is
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642
Methylated product (e.g., methylated lipids, myelin basic protein, DOPA, DNA)
GSH Pyruvate
S-Adenosylmethionine (SAM)
S-Adenosylhomocysteine (SAH)
Cysteine
THE METHYLATION CYCLE
Cystathionine Cystathionine synthase vitamin B6
Substrate
Methyltransferases
Homocysteine
ATP
Methionine
Polyglutamate synthase + glutamates
Methionine synthase methylcobalamin Tetrahydrofolate
5-Methyl tetrahydrofolate
Cell
PART 7
Glycine
5,10-Methylenetetrahydrofolate reductase
Oncology and Hematology
5, 10-Methylene tetrahydrofolate
5-Methyl tetrahydrofolate (monoglutamate)
Plasma
Deoxyuridine monophosphate Folic acid
DHF reductase
Serine Purines
Formate Dihydrofolate 10-Formyl tetrahydrofolate
DNA CYCLE (CELL REPLICATION)
Deoxythymidine monophosphate Folic acid
Figure 128-1 The role of folates in DNA synthesis and in formation of S-adenosylmethionine (SAM), which is involved in numerous methylation reactions. DHF, dihydrofolate; GSH, glutathione. (Reprinted from AV Hoffbrand et al [eds]: Postgraduate Haematology, 5th ed. Oxford, UK, Blackwell Publishing, 2005; with permission.) usually marked, and there may be weight loss, diarrhea, or constipation. Glossitis, angular cheilosis, a mild fever in more severely anemic patients, jaundice (unconjugated), and reversible melanin skin hyperpigmentation also may occur with a deficiency of either folate or cobalamin. Thrombocytopenia sometimes leads to bruising, and this may be aggravated by vitamin C deficiency or alcohol in malnourished patients. The anemia and low leukocyte count may predispose to infections, particularly of the respiratory and urinary tracts. Cobalamin deficiency has also been associated with impaired bactericidal function of phagocytes. GENERAL TISSUE EFFECTS OF COBALAMIN AND FOLATE DEFICIENCIES Epithelial Surfaces After the marrow, the next most frequently affected tissues are the epithelial cell surfaces of the mouth, stomach, and small intestine and the respiratory, urinary, and female genital tracts. The cells show macrocytosis, with increased numbers of multinucleate and dying cells. The deficiencies may cause cervical smear abnormalities. Complications of Pregnancy The gonads are also affected, and infertility is common in both men and women with either deficiency. Maternal folate deficiency has been implicated as a cause of prematurity, and both folate deficiency and cobalamin deficiency have been implicated in recurrent fetal loss and neural tube defects, as discussed below.
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Neural Tube Defects Folic acid supplements at the time of conception and in the first 12 weeks of pregnancy reduce by ~70% the incidence of neural tube defects (NTDs) (anencephaly, meningomyelocele, encephalocele, and spina bifida) in the fetus. Most of this protective effect can be achieved by taking folic acid, 0.4 mg daily, at the time of conception. The incidence of cleft palate and harelip also can be reduced by prophylactic folic acid. There is no clear simple relationship between maternal folate status and these fetal abnormalities, although overall the lower the maternal folate, the greater the risk to the fetus. NTDs also can be caused by antifolate and antiepileptic drugs. An underlying maternal folate metabolic abnormality has also been postulated. One abnormality has been identified: reduced activity of the enzyme 5,10-methylene-THF reductase (MTHFR) (Fig. 128-1) caused by a common C677T polymorphism in the MTHFR gene. In one study, the prevalence of this polymorphism was found to be higher than in controls in the parents of NTD fetuses and in the fetuses themselves: homozygosity for the TT mutation was found in 13% of cases compared with 5% of control subjects. The polymorphism codes for a thermolabile form of MTHFR. The homozygous state results in a lower mean serum and red cell folate level compared with control subjects, as well as significantly higher serum homocysteine levels. Tests for mutations in other enzymes possibly associated with NTDs,
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e.g., methionine synthase and serine–glycine hydroxymethylase, have been negative. Serum vitamin B12 levels are also lower in the sera of mothers of NTD infants than in controls. In addition, maternal TC II receptor polymorphisms are associated with increased risk of NTD births. There are, however, no studies showing dietary fortification with vitamin B12 reduces the incidence of NTDs.
Malignancy Prophylactic folic acid in pregnancy has been found in some but not all studies to reduce the subsequent incidence of acute lymphoblastic leukemia (ALL) in childhood. A significant negative association has also been found with the MTHFR C677T polymorphism and leukemias with mixed lineage leukemia (MLL) translocations, but a positive association with hyperdiploidy in infants with ALL or acute myeloid leukemia or with childhood ALL. A second polymorphism in the MTHFR gene, A1298C, is also strongly associated with hyperdiploid leukemia. There are various positive and negative associations between polymorphisms in folate-dependent enzymes and the incidence of adult ALL. The C677T polymorphism is thought to lead to increased thymidine pools and “better quality” of DNA synthesis by shunting one-carbon groups toward thymidine and purine synthesis. This may explain its reported association with a lower risk for colorectal cancer. Most but not all studies suggest that prophylactic folic acid also protects against colon adenomas. Other tumors that have been associated with folate polymorphisms or status include follicular lymphoma, breast cancer, and gastric cancer. A meta-analysis of 50,000 individuals given folic acid or placebo in cardiovascular or colon adenoma prevention trials found that folic acid supplementation did not substantially increase or decrease the incidence of site-specific cancer during the first 5 years of treatment. Because folic acid may “feed” tumors, it probably should be avoided in those with established tumors unless there is severe megaloblastic anemia due to folate deficiency. Neurologic Manifestations Cobalamin deficiency may cause a bilateral peripheral neuropathy or degeneration (demyelination) of the posterior and pyramidal tracts of the spinal cord and, less frequently, optic atrophy or cerebral symptoms. The patient, more frequently male, presents with paresthesias, muscle weakness, or difficulty in walking and sometimes dementia, psychotic disturbances, or visual impairment. Long-term nutritional cobalamin deficiency in infancy leads to poor brain development and impaired intellectual development. Folate deficiency has been suggested to cause organic nervous disease, but this is uncertain, although methotrexate injected into the cerebrospinal fluid may cause brain or spinal cord damage. An important clinical problem is the nonanemic patient with neurologic or psychiatric abnormalities and a low or borderline serum cobalamin level. In such patients, it is necessary to try to establish whether there is significant cobalamin deficiency, e.g., by careful examination of the blood film, tests for serum gastrin level and for antibodies to IF or parietal cells, along with serum methylmalonic acid
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HEMATOLOGIC FINDINGS PERIPHERAL BLOOD Oval macrocytes, usually with considerable anisocytosis and poikilocytosis, are the main feature (Fig. 128-2A). The MCV is usually >100 fL unless a cause of microcytosis (e.g., iron deficiency or thalassemia trait) is present. Some of the neutrophils are hypersegmented (more than five nuclear lobes). There may be leukopenia due to a reduction in granulocytes and lymphocytes, but this is usually >1.5 × 109/L; the platelet count may be moderately reduced, rarely to 258 pmol/L (>350 ng/L), have this pattern of raised metabolite levels. These findings bring into question the exact cutoff points for normal MMA and homocysteine levels. It is also unclear at present whether these mildly raised metabolite levels have clinical consequences. Serum homocysteine is raised in both early cobalamin and folate deficiency but may be raised in other conditions, e.g., chronic renal disease, alcoholism, smoking, pyridoxine deficiency, hypothyroidism, and therapy with steroids, cyclosporine, and other drugs. Levels are also higher in serum than in plasma, in men than in premenopausal women, in women taking hormone replacement therapy or in oral contraceptive users, and in elderly persons and patients with several inborn errors of metabolism affecting enzymes in trans-sulfuration pathways of homocysteine metabolism. Thus, homocysteine levels must be carefully interpreted for diagnosis of cobalamin or folate deficiency.
Chapter 128 Megaloblastic Anemias
Inflammatory Conditions Chronic inflammatory diseases such as tuberculosis, rheumatoid arthritis, Crohn’s disease, psoriasis, exfoliative dermatitis, bacterial endocarditis, and chronic bacterial infections cause deficiency by reducing the appetite and increasing the demand for folate. Systemic infections also may cause malabsorption of folate. Severe deficiency is virtually confined to the patients with the most active disease and the poorest diet.
COBALAMIN DEFICIENCY 647 Serum Cobalamin This is measured by an automated enzyme-linked immunosorbent assay (ELISA) or competitive-binding luminescence assay (CBLA). Normal serum levels range from 118–148 pmol/L (160–200 ng/L) to ~738 pmol/L (1000 ng/L). In patients with megaloblastic anemia due to cobalamin deficiency, the level is usually 800 × 109/L. COBALAMIN DEFICIENCY It is usually necessary to treat patients who have developed cobalamin deficiency with lifelong regular cobalamin injections. In the UK, the form used is hydroxocobalamin; in the United States, cyanocobalamin. In a few instances, the underlying cause of cobalamin deficiency can be permanently corrected, e.g., fish tapeworm, tropical sprue, or an intestinal stagnant loop that is amenable to surgery. The indications for starting cobalamin therapy are a well-documented megaloblastic anemia or other hematologic abnormalities and neuropathy due to the deficiency. Patients with borderline serum cobalamin levels but no hematologic or other abnormality may be followed to make sure that the cobalamin deficiency does not progress (see below). If malabsorption of cobalamin or rises in serum MMA levels have been demonstrated, however, these patients also should be given regular maintenance cobalamin therapy. Cobalamin should be given routinely to all patients who have had a total gastrectomy or ileal resection. Patients who have undergone gastric reduction for control of obesity or who are receiving longterm treatment with proton pump inhibitors should be screened and, if necessary, given cobalamin replacement. Replenishment of body stores should be complete with six 1000-μg IM injections of hydroxocobalamin given at 3- to 7-day intervals. More frequent doses are usually used in patients with cobalamin neuropathy, but there is no evidence that they produce a better response. Allergic reactions are rare and may require desensitization or antihistamine or glucocorticoid cover. For maintenance therapy, 1000 μg hydroxocobalamin IM once every 3 months is satisfactory. Because of the poorer retention of cyanocobalamin, protocols generally use higher and more frequent doses, e.g., 1000 μg IM, monthly, for maintenance treatment. Because a small fraction of cobalamin can be absorbed passively through mucous membranes even when there is complete failure of physiologic IF-dependent absorption, large daily oral doses (1000– 2000 μg) of cyanocobalamin have been used in PA for replacement
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and maintenance of normal cobalamin status in, e.g., food malabsorption of cobalamin. Sublingual therapy has also been proposed for those in whom injections are difficult because of a bleeding tendency and who may not tolerate oral therapy. If oral therapy is used, it is important to monitor compliance, particularly with elderly, forgetful patients. This author prefers parenteral therapy for initial treatment, particularly in severe anemia or if a neuropathy is present, and for maintenance. For treatment of patients with subnormal serum vitamin B12 (B12) levels with a normal MCV and no hypersegmentation of neutrophils, a negative IF antibody test in the absence of tests of B12 absorption is problematic. Some (perhaps 15%) cases may be due to TC I (HC) deficiency. Homocysteine and/or MMA measurements may help, but in the absence of these tests and with otherwise normal gastrointestinal function, repeat serum B12 assay after 6–12 months may help one decide whether to start cobalamin therapy. Vitamin B12 injections are used in a wide variety of diseases, often neurologic, despite normal serum B12 and folate levels and a normal blood count and in the absence of randomized, double-blind, controlled trials. These conditions include multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis (ME). It seems probable that any benefit is due to the placebo effect of a usually painless, pink injection. In ME, oral B12 therapy, despite providing equally large amounts of B12, has not been beneficial, supporting the view of the effect of the injections being placebo only. FOLATE DEFICIENCY Oral doses of 5–15 mg folic acid daily are satisfactory, as sufficient folate is absorbed from these extremely large doses even in patients with severe malabsorption. The length of time therapy must be continued depends on the underlying disease. It is customary to continue therapy for about 4 months, when all folate-deficient red cells will have been eliminated and replaced by new folate-replete populations. Before large doses of folic acid are given, cobalamin deficiency must be excluded and, if present, corrected; otherwise cobalamin neuropathy may develop despite a response of the anemia of cobalamin deficiency to folate therapy. Studies in the United States, however, suggest that there is no increase in the proportion of individuals with low serum cobalamin levels and no anemia since food fortification with folic acid, but it is unknown if there has been a change in incidence of cobalamin neuropathy. Long-term folic acid therapy is required when the underlying cause of the deficiency cannot be corrected and the deficiency is likely to recur, e.g., in chronic dialysis or hemolytic anemias. It may also be necessary in gluten-induced enteropathy that does not respond to a gluten-free diet. Where mild but chronic folate deficiency occurs, it is preferable to encourage improvement in the diet after correcting the deficiency with a short course of folic acid. In any patient receiving long-term folic acid therapy, it is important to measure the serum cobalamin level at regular (e.g., once-yearly) intervals to exclude the coincidental development of cobalamin deficiency. Folinic Acid (5-Formyl-THF) This is a stable form of fully reduced folate. It is given orally or parenterally to overcome the toxic effects of methotrexate or other DHF reductase inhibitors, e.g., trimethoprim or cotrimoxazole. PROPHYLACTIC FOLIC ACID Prophylactic folic acid is used in chronic dialysis patients and in parenteral feeds. Prophylactic folic acid has been used to reduce homocysteine levels to prevent cardiovascular disease and for cognitive function in the elderly, but there are no firm data to show any benefit. Pregnancy In over 70 countries (but none in Europe), food is fortified with folic acid (in grain or flour) to reduce the risk of NTDs. Nevertheless, folic acid, 400 μg daily, should be given as a supplement before and throughout pregnancy to prevent megaloblastic
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anemia and reduce the incidence of NTDs, even in countries with fortification of the diet. The levels of fortification provide up to 400 μg daily on average in Chile, but in most countries, it is nearer to 200 μg, so periconceptual folic acid is still needed. Studies in early pregnancy show significant lack of compliance with the folic acid supplements, emphasizing the benefit of food fortification. Supplemental folic acid reduces the incidence of birth defects in babies born to diabetic mothers. In women who have had a previous fetus with an NTD, 5 mg daily is recommended when pregnancy is contemplated and throughout the subsequent pregnancy.
MEGALOBLASTIC ANEMIA NOT DUE TO COBALAMIN OR FOLATE DEFICIENCY OR ALTERED METABOLISM This may occur with many antimetabolic drugs (e.g., hydroxyurea, cytosine arabinoside, 6-mercaptopurine) that inhibit DNA replication. Antiviral nucleoside analogues used in treatment of HIV infection may also cause macrocytosis and megaloblastic marrow changes. In the rare disease orotic aciduria, two consecutive enzymes in purine synthesis are defective. The condition responds to therapy with uridine, which bypasses the block. In thiamine-responsive megaloblastic anemia, there is a genetic defect in the high-affinity thiamine transport (SLC19A2) gene. This causes defective RNA ribose synthesis through impaired activity of transketolase, a thiamine-dependent enzyme in the pentose cycle. This leads to reduced nucleic acid production. It may be associated with diabetes mellitus and deafness and the presence of many ringed sideroblasts in the marrow. The explanation is unclear for megaloblastic changes in the marrow in some patients with acute myeloid leukemia and myelodysplasia.
129
Hemolytic Anemias and Anemia Due to Acute Blood Loss Lucio Luzzatto
DEFINITIONS A finite life span is a distinct characteristic of red cells. Hence, a logical, time-honored classification of anemias is in three groups: (1) decreased production of red cells, (2) increased destruction of red cells, and (3) acute blood loss. Decreased production is covered in Chaps. 126, 128, and 130; increased destruction and acute blood loss are covered in this chapter. All patients who are anemic as a result of either increased destruction of red cells or acute blood loss have one important element in common: the anemia results from overconsumption of red cells from the peripheral blood, whereas the supply of cells from the bone marrow is normal (indeed, it is usually increased). On the other hand, these two groups differ in that physical loss of red cells from the bloodstream or from the body itself, as in acute hemorrhage, is fundamentally different from destruction of red cells within the body, as in hemolytic anemias.
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Hereditary
Acquired
Intracorpuscular Defects Hemoglobinopathies Enzymopathies Membrane-cytoskeletal defects Paroxysmal nocturnal hemoglobinuria (PNH)
Extracorpuscular Factors Familial (atypical) hemolyticuremic syndrome Mechanical destruction (microangiopathic) Toxic agents Drugs Infectious Autoimmune
Hereditary causes correlate with intracorpuscular defects, because these defects are due to inherited mutations; the one exception is PNH, because the defect is due to an acquired somatic mutation. Similarly, acquired causes correlate with extracorpuscular factors, because mostly these factors are exogenous; the one exception is familial hemolyticuremic syndrome (HUS; often referred to as atypical HUS), because here an inherited abnormality allows complement activation to be excessive, with bouts of production of membrane attack complex capable of destroying normal red cells.
a
Therefore, the clinical aspects and pathophysiology of anemia in these two groups of patients are quite different, and they will be considered separately. HEMOLYTIC ANEMIAS With respect to primary etiology, anemias due to increased destruction of red cells, which we know as hemolytic anemias (HAs), may be inherited or acquired; from a clinical point of view, they may be more acute or more chronic, and they may vary from mild to very severe; the site of hemolysis may be predominantly intravascular or extravascular. With respect to mechanisms, HAs may be due to intracorpuscular causes or to extracorpuscular causes (Table 129-1). But before reviewing the individual types of HA, it is appropriate to consider what they have in common. GENERAL CLINICAL AND LABORATORY FEATURES The clinical presentation of a patient with anemia is greatly influenced in the first place by whether the onset is abrupt or gradual, and HAs are no exception. A patient with autoimmune HA or with favism may be a medical emergency, whereas a patient with mild hereditary spherocytosis or with cold agglutinin disease may be diagnosed after years. This is due in large measure to the remarkable ability of the body to adapt to anemia when it is slowly progressing (Chap. 77). What differentiates HAs from other anemias is that the patient has signs and symptoms arising directly from hemolysis (Table 129-2). At the clinical level, the main sign is jaundice; in addition, the patient may report discoloration of the urine. In many cases of HA, the spleen is enlarged, because it is a preferential site of hemolysis; and in some cases, the liver may be enlarged as well. In all severe congenital forms of HA, there may also be skeletal changes due to overactivity of the bone marrow (although they are never as severe as they are in thalassemia).
Chapter 129 Hemolytic Anemias and Anemia Due to Acute Blood Loss
Infancy and Childhood The incidence of folate deficiency is so high in the smallest premature babies during the first 6 weeks of life that folic acid (e.g., 1 mg daily) should be given routinely to those weighing pyruvate kinase > glucose-6-phosphate isomerase > rare deficiencies of other enzymes in the pathway. The more common enzyme deficiencies are encircled.
If the hemolytic event is transient, it does not usually cause any longterm consequences, except for an increased requirement for erythropoietic factors, particularly folic acid. However, if hemolysis is recurrent or persistent, the increased bilirubin production favors the formation of gallstones. If a considerable proportion of hemolysis takes place in the spleen, as is often the case, splenomegaly may become increasingly a feature, and hypersplenism may develop, with consequent neutropenia and/or thrombocytopenia. The increased red cell turnover also has metabolic consequences. In normal subjects, the iron from effete red cells is very efficiently recycled by the body; however, with chronic intravascular hemolysis, the persistent hemoglobinuria will cause considerable iron loss, needing replacement. With chronic extravascular hemolysis, the opposite problem, iron overload, is more common, especially if the patient needs frequent blood transfusions. Chronic iron overload will cause secondary hemochromatosis; this will cause damage particularly to the liver, eventually leading to cirrhosis, and to the heart muscle, eventually causing heart failure. Compensated Hemolysis Versus Hemolytic Anemia Red cell destruction is a potent stimulus for erythropoiesis, which is mediated by erythropoietin (EPO) produced by the kidney. This mechanism is so effective that
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in many cases the increased output of red cells from the bone marrow can fully balance an increased destruction of red cells. In such cases, we say that hemolysis is compensated. The pathophysiology of compensated hemolysis is similar to what we have just described, except there is no anemia. This notion is important from the diagnostic point of view, because a patient with a hemolytic condition, even an inherited one, may present without anemia; and it is also important from the point of view of management, because compensated hemolysis may become “decompensated,” i.e., anemia may suddenly appear, in certain circumstances, for instance in pregnancy, folate deficiency, or renal failure interfering with adequate EPO production. Another general feature of chronic HAs is seen when any intercurrent condition, such as an acute infection, depresses erythropoiesis. When this happens, in view of the increased rate of red cell turnover, the effect will be predictably much more marked than in a person who does not have hemolysis. The most dramatic example is infection by parvovirus B19, which may cause a rather precipitous fall in hemoglobin—an occurrence sometimes referred to as aplastic crisis.
Hemolytic Anemias due to Abnormalities of the Membrane-Cytoskeleton Complex The detailed architecture of the red cell membrane is complex, but its basic design is relatively simple (Fig. 129-2). The lipid bilayer incorporates phospholipids and cholesterol, and it is spanned by a number of proteins that have their hydrophobic transmembrane domain(s) embedded in the membrane; most of these proteins also extend to both the outside (extracellular domains) and the inside of the cell (cytoplasmic domains). Other proteins are tethered to the membrane through a glycosylphosphatidylinositol (GPI) anchor; these have only an extracellular domain, and they include ion channels, receptors for complement components, and receptors for other ligands. The most abundant red cell membrane proteins are glycophorins and the so-called band 3, an anion transporter. The extracellular domains of many of these proteins are heavily glycosylated, and they carry antigenic
Hereditary spherocytosis (HS) This is a relatively common type of genetically determined HA, with an estimated frequency of at least 1 in 5000. Its identification is credited to Minkowksy and Chauffard, who, at the end of the nineteenth century, reported families who had the presence of numerous spherocytes in the peripheral blood (Fig 129-4A). In vitro studies revealed that the red cells were abnormally susceptible to lysis in hypotonic media; indeed, the presence of osmotic fragility became the main diagnostic test for HS. Today we know that HS, thus defined, is genetically heterogeneous; i.e., it can arise from a variety of mutations in one of several genes (Table 129-3). It has been also recognized that the inheritance of HS is not always autosomal dominant (with the patient being heterozygous); indeed, some of the most severe forms are instead autosomal recessive (with the patient being homozygous). Clinical presentation and diagnosis The spectrum of clinical severity of HS is broad. Severe cases may present in infancy with severe anemia, whereas mild cases may present in young adults or even later in life. The main clinical findings are jaundice, an enlarged spleen, and often gallstones; indeed, it may be the finding of gallstones in a young person that triggers diagnostic investigations.
CD55
RhAG CD59 –
AChE Rh Band 3
Chapter 129 Hemolytic Anemias and Anemia Due to Acute Blood Loss
INHERITED HEMOLYTIC ANEMIAS There are three essential components in the red cell: (1) hemoglobin, (2) the membrane-cytoskeleton complex, and (3) the metabolic machinery necessary to keep hemoglobin and the membrane-cytoskeleton complex in working order. Diseases caused by abnormalities of hemoglobin, or hemoglobinopathies, are covered in Chap. 127. Here we will deal with diseases of the other two components.
determinants that correspond to blood groups. Underneath the mem- 651 brane, and tangential to it, is a network of other proteins that make up the cytoskeleton. The main cytoskeletal protein is spectrin, the basic unit of which is a dimer of α-spectrin and β-spectrin. The membrane is physically linked to the cytoskeleton by a third set of proteins (including ankyrin and the so-called band 4.1 and band 4.2), which thus make these two structures intimately connected to each other. The membrane-cytoskeleton complex is so integrated that, not surprisingly, an abnormality of almost any of its components will be disturbing or disruptive, causing structural failure, which results ultimately in hemolysis. These abnormalities are almost invariably inherited mutations; thus, diseases of the membrane-cytoskeleton complex belong to the category of inherited HAs. Before the red cells lyse, they often exhibit more or less specific morphologic changes that alter the normal biconcave disk shape. Thus, the majority of the diseases in this group have been known for over a century as hereditary spherocytosis and hereditary elliptocytosis. Over the past 20 years, their molecular basis has been elucidated; it has emerged that both conditions can arise from mutations in several genes with considerable overlap (Fig. 129-3).
GPC
CD47 4.2
Ankyrin
Band 3 GPA
β-Spectrin
Adducin
p55
α-Spectrin Dematin
4.1R
Tropomyosin Self-association site
α β
Actin protofilament
Tropomodulin
Figure 129-2 The red cell membrane. In this figure, one sees, within the lipid bilayer, several membrane proteins, of which band 3 (anion exchanger 1 [AE1]) is the most abundant; the α-β spectrin dimers that associate to form most of the cytoskeleton; and several proteins (e.g., ankyrin) that connect the membrane to the cytoskeleton. In addition, as examples of glycosylphosphatidylinositol (GPI)-linked proteins, one sees acetylcholinesterase (AChE) and the two complement-regulatory proteins CD59 and CD55. The (nonrealistic) shapes of the protein moieties of the GPI-linked proteins are meant to indicate that they can be very different from each other and that, unlike with the other membrane proteins shown, the entire polypeptide chain is extracellular. Branched lines symbolize carbohydrate moiety of proteins. The molecules are obviously not drawn to the same scale. Additional explanations can be found in the text. (From N Young et al: Clinical Hematology. Copyright Elsevier, 2006; with permission.)
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652
ANK1 EPB42
HS SPTB
SPTA1
SLC4A1
EPB41 HE
RHAG PIEZ01 SLC2A1
HSt
PART 7
Figure 129-3 Hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary stomatocytosis (HSt) are three morphologically distinct forms of congenital hemolytic anemia. It has emerged that each one can arise from mutation of one of several genes and that different mutations of the same gene can give one or another form. (See also Table 129-3.)
Oncology and Hematology
The variability in clinical manifestations that is observed among patients with HS is largely due to the different underlying molecular lesions (Table 129-3). Not only are mutations of several genes involved, but also individual mutations of the same gene can also give very different clinical manifestations. In milder cases, hemolysis is often compensated (see above), and this may cause variation in time even in the same patient, due to the fact that intercurrent conditions (e.g., pregnancy, infection) may cause decompensation. The anemia is usually normocytic, with the characteristic morphology that gives the disease its name. An increased mean corpuscular hemoglobin concentration (MCHC) on an ordinary blood count report should raise the suspicion of HS, because HS is almost the only condition in which this abnormality occurs. It has been apparent for a long time that the spleen plays a special role in HS through a dual mechanism. On one hand, like in many other HAs, the spleen itself is a major site of destruction; on the other hand, transit through the splenic circulation makes the defective red cells more spherocytic and, therefore, accelerates their demise, even though that may take place elsewhere. When there is a family history, it is usually easy to make a diagnosis based on features of HA and typical red cell morphology. However, there may be no family history for at least two reasons. First, the patient may have a de novo mutation, i.e., a mutation that has taken place in a germ cell of one of his parents or early after zygote formation. Second, the patient may have a recessive form of HS (Table 129-3). In such cases, more extensive laboratory investigations are required, including osmotic fragility, the acid glycerol lysis test, the eosin-5′-maleimide (EMA)–binding test, and SDS-gel electrophoresis of membrane proteins; these tests are usually carried out in laboratories with special expertise in this area. Sometimes a definitive diagnosis can be obtained only by molecular studies demonstrating a mutation in one of the genes underlying HS (Table 129-3). TREATMENT
Hereditary Spherocytosis
We do not have a causal treatment for HS; i.e., no way has yet been found to correct the basic defect in the membrane-cytoskeleton structure. Given the special role of the spleen in HS (see above), it has long been thought that an almost obligatory therapeutic measure was splenectomy. Because this operation may have more than trivial consequences, today we have more articulate recommendations, based on disease severity (having found out, whenever possible, about the outcome of splenectomy in the patient’s relatives with HS), as follows. In mild cases, avoid splenectomy. Delay splenectomy until puberty in moderate cases or until 4–6 years of age in severe cases. Antipneumococcal vaccination before splenectomy
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Figure 129-4 Peripheral blood smear from patients with membrane-cytoskeleton abnormalities. A. Hereditary spherocytosis. B. Hereditary elliptocytosis, heterozygote. C. Elliptocytosis, with both alleles of the α-spectrin gene mutated. is imperative, whereas penicillin prophylaxis after splenectomy is controversial. Along with splenectomy, cholecystectomy should not be regarded as automatic; it should be carried out, usually by the laparoscopic approach, when clinically indicated.
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653
TABLE 129-3 Inherited Diseases of the Red Cell Membrane-Cytoskeleton Complex Gene SPTA1
Chromosomal Location 1q22-q23
Protein Produced α-Spectrin
Disease(s) with Certain Mutations (Inheritance) HS (recessive) HE (dominant)
SPTB
14q23-q24.1
β-Spectrin
HS (dominant) HE (dominant)
ANK1 SLC4A1
8p11.2 17q21
Ankyrin Band 3; also known as AE (anion exchanger) or AE1
HS (dominant) HS (dominant) Southeast Asia ovalocytosis (dominant) Stomatocytosis
1p33-p34.2
Band 4.1
HE (dominant)
EPB42 RHAG
15q15-q21 6p21.1-p11
Band 4.2 Rhesus antigen
HS (recessive) Chronic nonspherocytic hemolytic anemia (recessive)
PIEZO1
16q23-q24
PIEZO1
Dehydrated hereditary stomatocytosis (dominant)
Polymorphic mutation (deletion of 9 amino acids); clinically asymptomatic; protective against Plasmodium falciparum. Certain specific missense mutations shift protein function from anion exchanger to cation conductance. Mutations of this gene account for about 5% of HE, mostly with prominent morphology but no hemolysis in heterozygotes; severe hemolysis in homozygotes. Mutations of this gene account for about 3% of HS. Very rare; associated with total loss of all Rh antigens. A specific mutation causes overhydrated stomatocytosis. Also known as xerocytosis with pseudohyperkalemia. Patients may present with perinatal edema. PIEZO1 is a mechanosensitive cation channel.
Abbreviations: HE, hereditary elliptocytosis; HS, hereditary spherocytosis.
Hereditary elliptocytosis (HE) HE is at least as heterogeneous as HS, both from the genetic point of view (Table 129-3, Fig. 129-3) and from the clinical point of view. Again, it is the shape of the red cells (Fig. 129-4B) that gives the name to the condition, but there is no direct correlation between the elliptocytic morphology and clinical severity. In fact, some mild or even asymptomatic cases may have nearly 100% elliptocytes, whereas in severe cases, all kinds of bizarre poikilocytes can predominate. Clinical features and recommended management are similar to those outlined above for HS. Although the spleen may not have the specific role it has in HS, in severe cases, splenectomy may be beneficial. The prevalence of HE causing clinical disease is similar to that of HS. However, an in-frame deletion of nine amino acids in the SLC4A1 gene encoding band 3, causing the so-called Southeast Asia ovalocytosis, has a frequency of up to 7% in certain populations, presumably as a result of malaria selection; it is asymptomatic in heterozygotes and probably lethal in homozygotes. Disorders of Cation Transport These rare conditions with autosomal dominant inheritance are characterized by increased intracellular sodium in red cells, with concomitant loss of potassium; indeed, they are sometimes discovered through the incidental finding, in a blood test, of a high serum K+ (pseudohyperkalemia). In patients from some families, the cation transport disturbance is associated with gain of water; as a result, the red cells are overhydrated (low MCHC), and on a blood smear, the normally round-shaped central pallor is replaced by a linear-shaped central pallor, which has earned this disorder the name stomatocytosis (Fig. 129-3). In patients from other families, instead, the red cells are dehydrated (high MCHC), and their consequent rigidity has earned this disorder the name xerocytosis. One would surmise that in these disorders the primary defect may be in a cation transporter; indeed, xerocytosis results from mutations in PIEZO1. In other patients with stomatocytosis, mutations are found in other genes also related to solute transport (Table 129-3), including SLC4A1 (encoding band 3), the Rhesus gene RHAG, and the glucose transporter gene SLC2A1 responsible for a special form called cryohydrocytosis. Hemolysis can vary from relatively mild to quite severe. From the practical point of view, it is important to know that in stomatocytosis, splenectomy is strongly contraindicated because it has been followed in a significant proportion of cases by severe thromboembolic complications.
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Enzyme Abnormalities When there is an important defect in the membrane or in the cytoskeleton, hemolysis is a direct consequence of the fact that the very structure of the red cell is abnormal. Instead, when one of the enzymes is defective, the consequences will depend on the precise role of that enzyme in the metabolic machinery of the red cell, which, in first approximation, has two important functions: (1) to provide energy in the form of ATP and (2) to prevent oxidative damage to hemoglobin and to other proteins by providing sufficient reductive potential; the key molecule for this is NADPH. Abnormalities of the glycolytic pathway Because red cells, in the course of their differentiation, have sacrificed not only their nucleus and their ribosomes, but also their mitochondria, they rely exclusively on the anaerobic portion of the glycolytic pathway for producing energy in the form of ATP. Most of the ATP is required by the red cell for cation transport against a concentration gradient across the membrane. If this fails, due to a defect of any of the enzymes of the glycolytic pathway (Table 129-4), the result will be hemolytic disease.
Chapter 129 Hemolytic Anemias and Anemia Due to Acute Blood Loss
EPB41
Comments Rare Mutations of this gene account for about 65% of HE. More severe forms may be due to coexistence of an otherwise silent mutant allele. Rare Mutations of this gene account for about 30% of HE, including some severe forms. May account for majority of HS. Mutations of this gene may account for about 25% of HS.
Pyruvate kinase deficiency Abnormalities of the glycolytic pathway are all inherited and all rare. Among them, deficiency of pyruvate kinase (PK) is the least rare, with an estimated prevalence in most populations of the order of 1:10,000. However, very recently, a polymorphic PK mutation (E277K) was found in some African populations, with heterozygote frequencies of 1–7%, suggesting that this may be another malaria-related polymorphism. The clinical picture of homozygous (or compound biallelic) PK deficiency is that of an HA that often presents in the newborn with neonatal jaundice; the jaundice persists, and it is usually associated with a very high reticulocytosis. The anemia is of variable severity; sometimes it is so severe as to require regular blood transfusion treatment, whereas sometimes it is mild, bordering on a nearly compensated hemolytic disorder. As a result, the diagnosis may be delayed, and in some cases, it is made, for instance, in a young woman during her first pregnancy, when the anemia may get worse. The delay in diagnosis may be also helped by the fact that the anemia is remarkably well tolerated, because the metabolic block at the last step in glycolysis causes an increase in bisphosphoglycerate (or DPG; Fig. 129-1), a major effector of the hemoglobin-oxygen dissociation curve; thus, the oxygen delivery to the tissues is enhanced, a remarkable compensatory feat.
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654 TABLE 129-4 Red Cell Enzyme Abnormalities Causing Hemolysis Enzyme (Acronym)
Chromosomal Location
Prevalence Clinical of Enzyme Manifestations Deficiency (Rank) Extra-Red Cell
Comments
Glycolytic Pathway Hexokinase (HK) Glucose 6-phosphate isomerase (G6PI) Phosphofructokinase (PFK) Aldolase Triose phosphate isomerase (TPI) Glyceraldehyde 3-phosphate dehydrogenase (GAPD) Diphosphoglycerate mutase (DPGM)
10q22 19q31.1 12q13 16q22-24 12p13 12p13.31-p13.1
Very rare Rare (4)a Very rare Very rare Very rare Very rare
Other isoenzymes known
7q31-q34
Very rare
Phosphoglycerate kinase (PGK) Pyruvate kinase (PK)
Xq13 1q21
Very rare Rare (2)a
CNS, NM
Glucose 6-phosphate dehydrogenase (G6PD) Glutathione synthase γ-Glutamylcysteine synthase Cytochrome b5 reductase
Xq28
Common (1)a
20q11.2 6p12 22q13.31-qter
Very rare Very rare Rare
Very rarely granulocytes CNS CNS CNS
9q34.1 3q11-q12
Very rare Rare (3)a
NM, CNS Myopathy CNS (severe), NM Myopathy Erythrocytosis rather than hemolysis May benefit from splenectomy May benefit from splenectomy
Redox In almost all cases, only AHA from exogenous trigger
PART 7
Methemoglobinemia rather than hemolysis
Nucleotide Metabolism Adenylate kinase (AK)
Oncology and Hematology
Pyrimidine 5′-nucleotidase (P5N)
CNS May benefit from splenectomy
The numbers from (1) to (4) indicate the ranking order of these enzymopathies in terms of frequency.
a
Abbreviations: AHA, acquired hemolytic anemia; CNS, central nervous system; NM, neuromuscular.
TREATMENT
Pyruvate Kinase Deficiency
The management of PK deficiency is mainly supportive. In view of the marked increase in red cell turnover, oral folic acid supplements should be given constantly. Blood transfusion should be used as necessary, and iron chelation may have to be added if the blood transfusion requirement is high enough to cause iron overload. In these patients, who have more severe disease, splenectomy may be beneficial. There is a single case report of curative treatment of PK deficiency by bone marrow transplantation from an HLA-identical PK-normal sibling. This seems a viable option for severe cases when a sibling donor is available. Rescue of inherited PK deficiency through lentiviral-mediated human PK gene transfer has been successful in mice. Prenatal diagnosis has been carried out in a mother who had already had an affected child. Other glycolytic enzyme abnormalities All of these defects are rare to very rare (Table 129-4), and all cause hemolytic anemia with varying degrees of severity. It is not unusual for the presentation to be in the guise of severe neonatal jaundice, which may require exchange transfusion; if the anemia is less severe, it may present later in life, or it may even remain asymptomatic and be detected incidentally when a blood count is done for unrelated reasons. The spleen is often enlarged. When other systemic manifestations occur, they can involve the central nervous system (sometimes entailing severe mental retardation, particularly in the case of triose phosphate isomerase deficiency), the neuromuscular system, or both. This is not altogether surprising, if we consider that these are housekeeping genes. The diagnosis of hemolytic anemia is usually not difficult, thanks to the triad of normomacrocytic anemia, reticulocytosis, and hyperbilirubinemia. Enzymopathies should be considered in the differential diagnosis of any chronic Coombs-negative hemolytic anemia. Unlike with membrane disorders where the red cells show characteristic morphologic abnormalities, in most cases of glycolytic enzymopathies, these are conspicuous by their absence. A definitive diagnosis can be made only by demonstrating the deficiency of an individual enzyme by quantitative assays; these
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are carried out in only a few specialized laboratories. If a particular molecular abnormality is already known in the family, then one could test directly for that defect at the DNA level, thus bypassing the need for enzyme assays. Of course the time may be getting nearer when a patient will present with her or his exome already sequenced, and we will need to concentrate on which genes to look up within the file. The principles for the management of these conditions are similar as for PK deficiency. In one case of phosphoglycerate kinase deficiency, allogeneic bone marrow transplantation (BMT) effectively controlled the hematologic manifestations but did not reverse neurologic damage. Abnormalities of redox metabolism Glucose 6-phosphate dehydrogenase (G6PD) deficiency G6PD is a housekeeping enzyme critical in the redox metabolism of all aerobic cells (Fig. 129-1). In red cells, its role is even more critical, because it is the only source of NADPH, which directly and via glutathione (GSH) defends these cells against oxidative stress (Fig. 129-5). G6PD deficiency is a prime example of an HA due to interaction between
G6P 6PG
NADP
GSH
H 2 O2
NADPH GSSG H2 O G6PD Glutathione Glutathione reductase peroxidase
Catalase
Oxidative agents
Hb(Fe2+) MetHb(Fe3+)
Figure 129-5 Diagram of redox metabolism in the red cell. 6PG, 6-phosphogluconate; G6P, glucose 6-phosphate; G6PD, glucose 6-phosphate dehydrogenase; GSH, reduced glutathione; GSSG, oxidized glutathione; Hb, hemoglobin; MetHb, methemoglobin; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate.
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an intracorpuscular cause and an extracorpuscular cause, because in the majority of cases hemolysis is triggered by an exogenous agent. Although a decrease in G6PD activity is present in most tissues of G6PD-deficient subjects, in other cells, the decrease is much less marked than in red cells, and it does not seem to impact on clinical expression.
Epidemiology G6PD deficiency is widely distributed in tropical and subtropical parts of the world (Africa, Southern Europe, the Middle East, Southeast Asia, and Oceania) (Fig. 129-6) and wherever people from those areas have migrated. A conservative estimate is that at least 400 million people have a G6PD deficiency gene. In several of these areas, the frequency of a G6PD deficiency gene may be as high as 20% or more. It would be quite extraordinary for a trait that causes significant pathology to spread widely and reach high frequencies in many populations without conferring some biologic advantage. Indeed, G6PD is one of the best-characterized examples of genetic polymorphisms in the human species. Clinical field studies and
Clinical manifestations The vast majority of people with G6PD deficiency remain clinically asymptomatic throughout their lifetime; however, all of them have an increased risk of developing neonatal jaundice (NNJ) and a risk of developing acute HA (AHA) when challenged by a number of oxidative agents. NNJ related to G6PD deficiency is very rarely present at birth; the peak incidence of clinical onset is between day 2 and day 3, and in most cases, the anemia is not severe. However, NNJ can be very severe in some G6PD-deficient babies, especially in association with prematurity, infection, and/or environmental factors (such as naphthalene-camphor balls, which are used in babies’ bedding and clothing), and the risk of severe NNJ is also increased by the coexistence of a monoallelic or biallelic mutation in the uridyl transferase gene (UGT1A1; the same mutations are associated with Gilbert’s syndrome). If inadequately managed, NNJ associated with G6PD deficiency can produce kernicterus and permanent neurologic damage. AHA can develop as a result of three types of triggers: (1) fava beans, (2) infections, and (3) drugs (Table 129-5). Typically, a hemolytic attack starts with malaise, weakness, and abdominal or lumbar pain. After an interval of several hours to 2–3 days, the patient develops jaundice and often dark urine. The onset can be extremely abrupt, especially with favism in children. The anemia is moderate to extremely severe, usually normocytic and normochromic, and due partly to intravascular hemolysis; hence, it is associated with hemoglobinemia, hemoglobinuria, high LDH, and low or absent plasma haptoglobin. The blood film shows anisocytosis, polychromasia, and spherocytes typical of hemolytic anemias. The most typical feature of G6PD deficiency is the presence of bizarre poikilocytes, with red cells that appear to have unevenly distributed hemoglobin (“hemighosts”) and red cells that appear to have had parts of them bitten away (“bite cells” or “blister cells”) (Fig. 129-7). A classical test, now rarely carried out, is supravital staining with methyl violet, which, if done promptly, reveals the presence of Heinz bodies (consisting of precipitates of denatured hemoglobin and hemichromes), which are regarded as a signature of oxidative damage to red cells (they are also seen with unstable hemoglobins). LDH is high, and so is the unconjugated
Chapter 129 Hemolytic Anemias and Anemia Due to Acute Blood Loss
GENETIC CONSIDERATIONS The G6PD gene is X-linked, and this has important implications. First, because males have only one G6PD gene (i.e., they are hemizygous for this gene), they must be either normal or G6PD deficient. By contrast, females, who have two G6PD genes, can be either normal or deficient (homozygous) or intermediate (heterozygous). As a result of the phenomenon of X chromosome inactivation, heterozygous females are genetic mosaics, with a highly variable ratio of G6PDnormal to G6PD-deficient cells and an equally variable degree of clinical expression; some heterozygotes can be just as affected as hemizygous males. The enzymatically active form of G6PD is either a dimer or a tetramer of a single protein subunit of 514 amino acids. G6PDdeficient subjects have been found invariably to have mutations in the coding region of the G6PD gene (Fig. 129-5). Almost all of the approximately 180 different mutations known are single missense point mutations, entailing single amino acid replacements in the G6PD protein. In most cases, these mutations cause G6PD deficiency by decreasing the in vivo stability of the protein; thus, the physiologic decrease in G6PD activity that takes place with red cell aging is greatly accelerated. In some cases, an amino acid replacement can also affect the catalytic function of the enzyme. Among these mutations, those underlying chronic nonspherocytic hemolytic anemia (CNSHA; see below) are a discrete subset. This much more severe clinical phenotype can be ascribed in some cases to adverse qualitative changes (for instance, a decreased affinity for the substrate, glucose 6-phosphate) or simply to the fact that the enzyme deficit is more extreme, because of a more severe instability of the enzyme. For instance, a cluster of mutations map at or near the dimer interface, and clearly they compromise severely the formation of the dimer.
in vitro experiments strongly support the view that G6PD deficiency 655 has been selected by Plasmodium falciparum malaria, by virtue of the fact that it confers a relative resistance against this highly lethal infection. Different G6PD variants underlie G6PD deficiency in different parts of the world. Some of the more widespread variants are G6PD Mediterranean on the shores of that sea, in the Middle East, and in India; G6PD A– in Africa and in Southern Europe; G6PD Vianchan and G6PD Mahidol in Southeast Asia; G6PD Canton in China; and G6PD Union worldwide. The heterogeneity of polymorphic G6PD variants is proof of their independent origin, and it supports the notion that they have been selected by a common environmental agent, in keeping with the concept of convergent evolution (Fig. 129-6).
Figure 129-6 Epidemiology of glucose 6-phosphate dehydrogenase (G6PD) deficiency throughout the world. The different shadings indicate increasingly high levels of prevalence, up to about 20%; the different colored symbols indicate individual genetic variants of G6PD, each one having a different mutation. (From L Luzzatto et al, in C Scriver et al [eds]: The Metabolic & Molecular Bases of Inherited Disease, 8th ed. New York, McGraw-Hill, 2001.)
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656 TABLE 129-5 Drugs That Carry Risk of Clinical Hemolysis in Persons with Glucose 6-Phosphate Dehydrogenase Deficiency Antimalarials Sulphonamides/sulphones
Antibacterial/antibiotics
Antipyretic/analgesics
Other
Definite Risk Primaquine Dapsone/chlorproguanila Sulfamethoxazole Others Dapsone Cotrimoxazole Nalidixic acid Nitrofurantoin Niridazole Acetanilide Phenazopyridine
Possible Risk Chloroquine
Doubtful Risk Quinine
Sulfasalazine Sulfadimidine
Sulfisoxazole Sulfadiazine
Ciprofloxacin Norfloxacin
Chloramphenicol p-Aminosalicylic acid
Acetylsalicylic acid high dose (>3 g/d)
Naphthalene Methylene blue Rasburicase
Vitamin K analogues Ascorbic acid (>1 g)
Acetylsalicylic acid (50 years old or has comorbid disease, add ampicillin (2 g q4h) for Listeria coverage. Dexamethasone (10 mg q6h × 4 days) improves outcome in adults with meningitis (especially pneumococcal) and cloudy CSF, positive CSF Gram’s stain, or a CSF leukocyte count >1000/mL. Urgent surgical evaluation is critical. If a penicillin- or oxacillin-sensitive strain is isolated, these agents are superior to vancomycin (penicillin, 4 mU q4h; or oxacillin, 2 g q4h). Do not use glucocorticoids. Use IV quinidine if IV quinine is not available. During IV quinidine treatment, blood pressure and cardiac function should be monitored continuously and blood glucose periodically. Surgical evaluation is essential. If a penicillin- or oxacillin-sensitive strain is isolated, these agents are superior to vancomycin (penicillin, 4 mU q4h; or oxacillin, 2 g q4h).
164
Rickettsia rickettsii
Doxycycline (100 mg bid)
Purpura fulminans
S. pneumoniae, H. influenzae, N. meningitidis Group A Streptococcus, Staphylococcus aureus
Ceftriaxone (2 g q12h) plus vancomycin (15 mg/kg q12h)b Vancomycin (15 mg/kg q12h)b plus clindamycin (600 mg q8h
Sepsis with Soft Tissue Findings Necrotizing fasciitis Group A Streptococcus, mixed aerobic/anaerobic flora, CA-MRSAe Clostridial myonecrosis Clostridium perfringens
Infectious Diseases
Comments
Rocky Mountain spotted fever (RMSF)
Erythroderma: toxic shock syndrome
PART 8
Treatment
Neurologic Infections Bacterial meningitis S. pneumoniae, N. meningitidis
Brain abscess, Streptococcus spp., suppurative intracranial Staphylococcus spp., infections anaerobes, gram-negative bacilli Cerebral malaria Plasmodium falciparum
Spinal epidural abscess
Focal Infections Acute bacterial endocarditis
Vancomycin (15 mg/kg q12h)b plus metronidazole (500 mg q8h) plus ceftriaxone (2 g q12h) Artesunate (2.4 mg/kg IV at 0, 12, and 24 h; then once daily)f or quinine (IV loading dose of 20 mg salt/kg; then 10 mg/kg q8h)
Staphylococcus spp., gram-negative bacilli
Vancomycin (15 mg/kg q12h)b plus ceftriaxone (2 g q24h)
S. aureus, β-hemolytic streptococci, HACEK group,g Neisseria spp., S. pneumoniae
Ceftriaxone (2 g q12h) plus vancomycin (15 mg/kg q12h)b
Adjust treatment when culture data become available. Surgical evaluation is essential.
211
171, 180, 182, 325 172, 173
164
246e, 248
456
155
These empirical regimens include coverage for gram-positive pathogens that are resistant to β-lactam antibiotics. Local resistance patterns should be considered and may alter the need for empirical vancomycin. bA vancomycin loading dose of 20–25 mg/kg can be considered in critically ill patients. cβ-Lactam antibiotics may exhibit unpredictable pharmacodynamics in sepsis. Prolonged or continuous infusions can be considered. dThe optimal dose of IV immunoglobulin has not been determined, but the median dose in observational studies is 2 g/kg (total dose administered for 1–5 days). eCommunity-acquired methicillin-resistant S. aureus. fIn the United States, artesunate must be obtained through the Centers for Disease Control and Prevention. For patients diagnosed with severe malaria, full doses of parenteral antimalarial treatment should be started with whichever recommended antimalarial agent is first available. gHaemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. a
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bacterial meningitis must be given before or at the time of the first dose of antibiotic. Glucocorticoids can also be harmful, sometimes resulting in worse outcomes—e.g., when given in the setting of cerebral malaria or viral hepatitis.
SPECIFIC PRESENTATIONS The infections considered below according to common clinical presentation can have rapidly catastrophic outcomes, and their immediate recognition and treatment can be life-saving. Recommended empirical therapeutic regimens are presented in Table 147-1. SEPSIS WITHOUT AN OBVIOUS FOCUS OF PRIMARY INFECTION Patients initially have a brief prodrome of nonspecific symptoms and signs that progresses quickly to hemodynamic instability with hypotension, tachycardia, tachypnea, respiratory distress, and altered mental status. Disseminated intravascular coagulation (DIC) with clinical evidence of a hemorrhagic diathesis is a poor prognostic sign.
Overwhelming Infection in Asplenic Patients (See also Chap. 325) Patients without splenic function are at risk for overwhelming bacterial sepsis. Asplenic adult patients succumb to sepsis at 58 times the rate of the general population. Most infections are thought to occur within the first 2 years after splenectomy, with a mortality rate of ~50%, but the increased risk persists throughout life. In asplenia, encapsulated bacteria cause the majority of infections. Adults, who are more likely to have antibody to these organisms, are at lower risk than children. Streptococcus pneumoniae is the most common isolate, causing 50–70% of cases, but the risk of infection with Haemophilus influenzae or Neisseria meningitidis is also high. Severe clinical manifestations of infections due to E. coli, S. aureus, group B streptococci, P. aeruginosa, Bordetella holmesii, and Capnocytophaga, Babesia, and Plasmodium species have been described. Babesiosis (See also Chap. 249) A history of recent travel to endemic areas raises the possibility of infection with Babesia. Between 1 and 4 weeks after a tick bite, the patient experiences chills, fatigue, anorexia, myalgia, arthralgia, shortness of breath, nausea, and headache; ecchymosis and/or petechiae are occasionally seen. The tick that most commonly transmits Babesia, Ixodes scapularis, also transmits Borrelia burgdorferi (the agent of Lyme disease) and Anaplasma; coinfection can occur, resulting in more severe disease. Infection with the European species Babesia divergens is more frequently fulminant than that due to the U.S. species Babesia microti. B. divergens causes a febrile syndrome with hemolysis, jaundice, hemoglobinemia, and renal failure and is associated with a mortality rate of >40%. Severe babesiosis
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Other Sepsis Syndromes Tularemia (Chap. 195) is seen throughout the United States but occurs primarily in Arkansas, Missouri, South Dakota, and Oklahoma. This disease is associated with wild rabbit, tick, and tabanid fly contact. It can be transmitted by arthropod bite, handling of infected animal carcasses, consumption of contaminated food and water, or inhalation. The typhoidal form can be associated with gram-negative septic shock and a mortality rate of >30%, especially in patients with underlying comorbid or immunosuppressive conditions. Plague occurs infrequently in the United States (Chap. 196), primarily after contact with ground squirrels, prairie dogs, or chipmunks, but is endemic in other parts of the world, with >90% of all cases occurring in Africa. The septic form is particularly rare and is associated with shock, multiorgan failure, and a 30% mortality rate. These infections should be considered in the appropriate epidemiologic setting. The Centers for Disease Control and Prevention lists Francisella tularensis and Yersinia pestis (the agents of tularemia and plague, respectively) along with Bacillus anthracis (the agent of anthrax) as important organisms that might be used for bioterrorism (Chap. 261e). SEPSIS WITH SKIN MANIFESTATIONS (See also Chap. 24) Maculopapular rashes may reflect early meningococcal or rickettsial disease but are usually associated with nonemergent infections. Exanthems are usually viral. Primary HIV infection commonly presents with a rash that is typically maculopapular and involves the upper part of the body but can spread to the palms and soles. The patient is usually febrile and can have lymphadenopathy, severe headache, dysphagia, diarrhea, myalgias, and arthralgias. Recognition of this syndrome provides an opportunity to prevent transmission and to institute treatment and monitoring early on. Petechial rashes caused by viruses are seldom associated with hypotension or a toxic appearance, although there can be exceptions (e.g., severe measles or arboviral infection). Petechial rashes limited to the distribution of the superior vena cava are rarely associated with severe disease. In other settings, petechial rashes require more urgent attention. Meningococcemia (See also Chap. 180) Almost three-quarters of patients with N. meningitidis bacteremia have a rash. Meningococcemia most often affects young children (i.e., those 6 months to 5 years old). In sub-Saharan Africa, the high prevalence of serogroup A meningococcal disease has been a threat to public health for more than a century. Thousands of deaths occur annually in this area, which is known as the “meningitis belt,” and large epidemic waves occur approximately every 8–12 years. Serogroups W135 and X are also important emerging pathogens in Africa. In the United States, sporadic cases and outbreaks occur in day-care centers, schools (grade school through college, particularly among college freshmen living in residential halls), and army barracks. Household contacts of index cases are at 400–800 times greater risk of disease than the general population. Patients may exhibit fever, headache, nausea, vomiting, myalgias, changes in mental status, and meningismus. However, the rapidly progressive form of disease is not usually associated with meningitis. The rash is initially pink, blanching, and maculopapular, appearing on the trunk and extremities, but then becomes hemorrhagic, forming petechiae. Petechiae are first seen at the ankles, wrists, axillae, mucosal surfaces, and palpebral and bulbar conjunctiva, with subsequent spread on the lower extremities and to the trunk. A cluster of petechiae may be seen at pressure points—e.g., where a blood pressure cuff has been inflated. In rapidly progressive meningococcemia (10–20% of cases), the petechial rash quickly becomes purpuric (see Fig. 70-5), and patients develop DIC, multiorgan failure, and shock; 50–60% of these patients die, and survivors often require extensive debridement or amputation of gangrenous extremities.
CHAPTER 147 Approach to the Acutely Ill Infected Febrile Patient
Septic Shock (See also Chap. 325) Patients with bacteremia leading to septic shock may have a primary site of infection (e.g., pneumonia, pyelonephritis, or cholangitis) that is not evident initially. Elderly patients with comorbid conditions, hosts compromised by malignancy and neutropenia, and patients who have recently undergone a surgical procedure or hospitalization are at increased risk for an adverse outcome. Gram-negative bacteremia with organisms such as Pseudomonas aeruginosa or Escherichia coli and gram-positive infection with organisms such as Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]) or group A streptococci can present as intractable hypotension and multiorgan failure. Treatment can usually be initiated empirically on the basis of the presentation, host factors (Chap. 325), and local patterns of bacterial resistance. Outcomes are worse when antimicrobial treatment is delayed or when the responsible pathogen ultimately proves not to be susceptible to the initial regimen. Broad-spectrum antimicrobial agents are therefore recommended and should be instituted rapidly, preferably within the first hour after presentation. Risk factors for fungal infection should be assessed, as the incidence of fungal septic shock is increasing. Biomarkers such as C-reactive protein and procalcitonin have not proved reliable diagnostically but, when measured over time, can facilitate appropriate de-escalation of therapy. Glucocorticoids should be considered only for patients with severe sepsis who do not respond to fluid resuscitation and vasopressor therapy.
is especially common in asplenic hosts but does occur in hosts with 781 normal splenic function, particularly those >60 years of age and those with underlying immunosuppressive conditions such as HIV infection or malignancy. Complications include renal failure, acute respiratory failure, and DIC.
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782 Hypotension with petechiae for 70 years old, and persons with underlying immunosuppression also are at increased risk of death. Other rickettsial diseases cause significant morbidity and mortality worldwide. Mediterranean spotted fever caused by Rickettsia conorii is found in Africa, southwestern and southcentral Asia, and southern Europe. Patients have fever, flu-like symptoms, and an inoculation eschar at the site of the tick bite. A maculopapular rash develops within 1–7 days, involving the palms and soles but sparing the face. Elderly patients or those with diabetes, alcoholism, uremia, or congestive heart failure are at risk for severe disease characterized by neurologic involvement, respiratory distress, and gangrene of the digits. Mortality rates associated with this severe form of disease approach 50%. Epidemic typhus, caused by Rickettsia prowazekii, is transmitted in louse-infested environments and emerges in conditions of extreme poverty, war, and natural disaster. Patients experience a sudden onset of high fevers, severe headache, cough, myalgias, and abdominal pain. A maculopapular rash develops (primarily on the trunk) in more than half of patients and can progress to petechiae and purpura. Serious signs include delirium, coma, seizures, noncardiogenic pulmonary edema, skin necrosis, and peripheral gangrene. Mortality rates approached 60% in the preantibiotic era and continue to exceed 10–15% in contemporary outbreaks. Scrub typhus, caused by Orientia tsutsugamushi (a separate genus in the family Rickettsiaceae), is transmitted by larval mites or chiggers and is one of the most common infections in southeastern Asia and the western Pacific. The organism is found in areas of heavy scrub vegetation (e.g., along riverbanks). Patients may have an inoculation eschar and may develop a maculopapular rash. Severe cases progress to pneumonia, meningoencephalitis, DIC, and renal failure. Mortality rates range from 1% to 35%. If recognized in a timely fashion, rickettsial disease is very responsive to treatment. Doxycycline (100 mg twice daily for 3–14 days) is the treatment of choice for both adults and children. The newer macrolides and chloramphenicol may be suitable alternatives, but mortality rates are higher when a tetracycline-based treatment is not given. Purpura Fulminans (See also Chaps. 180 and 325) Purpura fulminans is the cutaneous manifestation of DIC and presents as large ecchymotic areas and hemorrhagic bullae. Progression of petechiae to
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purpura, ecchymoses, and gangrene is associated with congestive heart failure, septic shock, acute renal failure, acidosis, hypoxia, hypotension, and death. Purpura fulminans has been associated primarily with N. meningitidis but, in splenectomized patients, may be associated with S. pneumoniae, H. influenzae, and S. aureus. Ecthyma Gangrenosum Septic shock caused by P. aeruginosa or Aeromonas hydrophila can be associated with ecthyma gangrenosum (see Figs. 189-1 and 25e-35): hemorrhagic vesicles surrounded by a rim of erythema with central necrosis and ulceration. These gramnegative bacteremias are most common among patients with neutropenia, extensive burns, and hypogammaglobulinemia. Other Emergent Infections Associated with Rash Vibrio vulnificus and other noncholera Vibrio bacteremic infections (Chap. 193) can cause focal skin lesions and overwhelming sepsis in hosts with chronic liver disease, iron storage disorders, diabetes, renal insufficiency, or other immunocompromising conditions. After ingestion of contaminated raw shellfish, typically oysters from the Gulf Coast, there is a sudden onset of malaise, chills, fever, and hypotension. The patient develops bullous or hemorrhagic skin lesions, usually on the lower extremities, and 75% of patients have leg pain. The mortality rate can be as high as 50–60%, particularly when the patient presents with hypotension. Outcomes are improved when patients are treated with tetracycline-containing regimens. Other infections, caused by agents such as Aeromonas, Klebsiella, and E. coli, can cause hemorrhagic bullae and death due to overwhelming sepsis in cirrhotic patients. Capnocytophaga canimorsus can cause septic shock in asplenic patients. Infection typically follows a dog bite. Patients present with fever, chills, myalgia, vomiting, diarrhea, dyspnea, confusion, and headache. Findings can include an exanthem or erythema multiforme (see Figs. 70-9 and 25e-25), cyanotic mottling or peripheral cyanosis, petechiae, and ecchymosis. About 30% of patients with this fulminant form die of overwhelming sepsis and DIC, and survivors may require amputation because of gangrene. Erythroderma TSS (Chaps. 172 and 173) is usually associated with erythroderma. The patient presents with fever, malaise, myalgias, nausea, vomiting, diarrhea, and confusion. There is a sunburn-type rash that may be subtle and patchy but is usually diffuse and is found on the face, trunk, and extremities. Erythroderma, which desquamates after 1–2 weeks, is more common in Staphylococcus-associated than in Streptococcus-associated TSS. Hypotension develops rapidly—often within hours—after the onset of symptoms. Multiorgan failure occurs. Early renal failure may precede hypotension and distinguishes this syndrome from other septic shock syndromes. There may be no indication of a primary focal infection, although possible cutaneous or mucosal portals of entry for the organism can be ascertained when a careful history is taken. Colonization rather than overt infection of the vagina or a postoperative wound, for example, is typical with staphylococcal TSS, and the mucosal areas appear hyperemic but not infected. Streptococcal TSS is more often associated with skin or soft tissue infection (including necrotizing fasciitis), and patients are more likely to be bacteremic. TSS caused by Clostridium sordellii is associated with childbirth or with skin injection of black-tar heroin. The diagnosis of TSS is defined by the clinical criteria of fever, rash, hypotension, and multiorgan involvement. The mortality rate is 5% for menstruationassociated TSS, 10–15% for nonmenstrual TSS, 30–70% for streptococcal TSS, and up to 90% for obstetric C. sordellii TSS. Viral Hemorrhagic Fevers Viral hemorrhagic fevers (Chaps. 233 and 234) are zoonotic illnesses caused by viruses that reside in either animal reservoirs or arthropod vectors. These diseases occur worldwide and are restricted to areas where the host species live. They are caused by four major groups of viruses: Arenaviridae (e.g., Lassa fever in Africa), Bunyaviridae (e.g., Rift Valley fever in Africa; hantavirus hemorrhagic fever with renal syndrome in Asia; or Crimean-Congo hemorrhagic fever, which has an extensive geographic distribution), Filoviridae (e.g., Ebola and Marburg virus infections in Africa), and Flaviviridae (e.g., yellow fever in Africa and South America and dengue in Asia, Africa, and the Americas). Lassa fever
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and Ebola and Marburg virus infections are also transmitted from person to person. The vectors for most viral fevers are found in rural areas; dengue and yellow fever are important exceptions. After a prodrome of fever, myalgias, and malaise, patients develop evidence of vascular damage, petechiae, and local hemorrhage. Shock, multifocal hemorrhaging, and neurologic signs (e.g., seizures or coma) predict a poor prognosis. Dengue (Chap. 233) is the most common arboviral disease worldwide. More than half a million cases of dengue hemorrhagic fever occur each year, with at least 12,000 deaths. Patients have a triad of symptoms: hemorrhagic manifestations, evidence of plasma leakage, and platelet counts of 65% for spontaneous myonecrosis, which is often associated with Clostridium septicum or C. tertium and underlying malignancy. The mortality rates associated with trunk and limb infection are 63% and 12%, respectively, and any delay in surgical treatment increases the risk of death. NEUROLOGIC INFECTIONS WITH OR WITHOUT SEPTIC SHOCK Bacterial Meningitis (See also Chap. 164) Bacterial meningitis is one of the most common infectious disease emergencies involving the central nervous system. Although hosts with cell-mediated immune deficiency (including transplant recipients, diabetic patients, elderly patients, and cancer patients receiving certain chemotherapeutic
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Suppurative Intracranial Infections (See also Chap. 164) In suppurative intracranial infections, rare intracranial lesions present along with sepsis and hemodynamic instability. Rapid recognition of the toxic patient with central neurologic signs is crucial to improvement of the dismal prognosis of these entities. Subdural empyema arises from the paranasal sinus in 60–70% of cases. Microaerophilic streptococci and staphylococci are the predominant etiologic organisms. The patient is toxic, with fever, headache, and nuchal rigidity. Of all patients, 75% have focal signs and 6–20% die. Despite improved survival rates, 15–44% of patients are left with permanent neurologic deficits. Septic cavernous sinus thrombosis follows a facial or sphenoid sinus infection; 70% of cases are due to staphylococci (including MRSA), and the remainder are due primarily to aerobic or anaerobic streptococci. A unilateral or retroorbital headache progresses to a toxic appearance and fever within days. Three-quarters of patients have unilateral periorbital edema that becomes bilateral and then progresses to ptosis, proptosis, ophthalmoplegia, and papilledema. The mortality rate is as high as 30%. Septic thrombosis of the superior sagittal sinus spreads from the ethmoid or maxillary sinuses and is caused by S. pneumoniae, other streptococci, and staphylococci. The fulminant course is characterized by headache, nausea, vomiting, rapid progression to confusion and coma, nuchal rigidity, and brainstem signs. If the sinus is totally thrombosed, the mortality rate exceeds 80%. Brain Abscess (See also Chap. 164) Brain abscess often occurs without systemic signs. Almost half of patients are afebrile, and presentations are more consistent with a space-occupying lesion in the brain; 70% of patients have headache and/or altered mental status, 50% have focal neurologic signs, and 25% have papilledema. Abscesses can present as single or multiple lesions resulting from contiguous foci or hematogenous infection, such as endocarditis. The infection progresses over several days from cerebritis to an abscess with a mature capsule. More than half of infections are polymicrobial, with an etiology consisting of aerobic bacteria (primarily streptococcal species) and anaerobes. Abscesses arising hematogenously are especially apt to rupture into the ventricular space, causing a sudden and severe deterioration in clinical status and a high mortality rate. Otherwise, mortality is low but morbidity is high (30–55%). Patients presenting with stroke and a parameningeal infectious focus, such as sinusitis or otitis, may have a brain abscess, and physicians must maintain a high level of suspicion. Prognosis worsens in patients with a fulminant course, delayed diagnosis, abscess rupture into the ventricles, multiple abscesses, or abnormal neurologic status at presentation.
CHAPTER 147 Approach to the Acutely Ill Infected Febrile Patient
Necrotizing Fasciitis This infection is characterized by extensive necrosis of the subcutaneous tissue and fascia. It may arise at a site of minimal trauma or postoperative incision and may also be associated with recent varicella, childbirth, or muscle strain. The most common causes of necrotizing fasciitis are group A streptococci alone (Chap. 173), the incidence of which has been increasing for the past two decades, and a mixed facultative and anaerobic flora (Chap. 156). Diabetes mellitus, IV drug use, chronic liver or renal disease, and malignancy are associated risk factors. Physical findings are initially minimal compared with the severity of pain and the degree of fever. The examination is often unremarkable except for soft tissue edema and erythema. The infected area is red, hot, shiny, swollen, and exquisitely tender. In untreated infection, the overlying skin develops blue-gray patches after 36 h, and cutaneous bullae and necrosis develop after 3–5 days. Necrotizing fasciitis due to a mixed flora, but not that due to group A streptococci, can be associated with gas production. Without treatment, pain decreases because of thrombosis of the small blood vessels and destruction of the peripheral nerves—an ominous sign. The mortality rate is 15–34% overall, >70% in association with TSS, and nearly 100% without surgical intervention. Necrotizing fasciitis may also be due to Clostridium perfringens (Chap. 179); in this condition, the patient is extremely toxic and the mortality rate is high. Within 48 h, rapid tissue invasion and systemic toxicity associated with hemolysis and death ensue. The distinction between this entity and clostridial myonecrosis is made by muscle biopsy. Necrotizing fasciitis caused by community-acquired MRSA also has been reported.
agents) are at particular risk for Listeria monocytogenes meningitis, 783 most cases in adults are due to S. pneumoniae (30–60%) and N. meningitidis (10–35%). The classic presentation of fever, meningismus, and altered mental status is seen in only one-half to two-thirds of patients. The elderly can present without fever or meningeal signs. Cerebral dysfunction is evidenced by confusion, delirium, and lethargy that can progress to coma. In some cases, the presentation is fulminant, with sepsis and brain edema; papilledema at presentation is unusual and suggests another diagnosis (e.g., an intracranial lesion). Focal signs, including cranial nerve palsies (IV, VI, VII), can be seen in 10–20% of cases; 50–70% of patients have bacteremia. A poor outcome is associated with coma, hypotension, a pneumococcal etiology, respiratory distress, a CSF glucose level of 90%. The vaccine is recommended for persons staying >1 month in rural endemic areas or for shorter periods if their activities (e.g., camping, bicycling, hiking) in these areas will increase exposure risk.
CHAPTER 149 Health Recommendations for International Travel
Japanese encephalitis (Ixiaro)
Intervals of 3–5 months, depending on initial dose >1 year after primary series (optimal booster schedule not yet determined) >3 years (optimal booster schedule not yet determined)
Recommended Immunizations • Hepatitis A and B Hepatitis A (Chap. 795 360) is one of the most common vaccine-preventable infections of travelers. The risk is six times greater for travelers who stray from the usual tourist routes. The mortality rate for hepatitis A increases with age, reaching almost 2% among individuals over age 50. Of the four hepatitis A vaccines currently available in North America (two in the United States), all are interchangeable and have an efficacy of >95%. Hepatitis A vaccine is currently given to all children in the United States. Since the most frequently identified risk factor for hepatitis A in the United States is international travel, and since morbidity and mortality increase with age, it seems appropriate that all adults be immune prior to travel. Long-stay overseas workers appear to be at considerable risk for hepatitis B infection (Chap. 360). The recommendation that all travelers be immunized against hepatitis B before departure is supported by two studies showing that 17% of the assessed travelers who received health care abroad had some type of injection; according to the World Health Organization, nonsterile equipment is used for up to 75% of all injections given in parts of the developing world. A 3-week accelerated schedule of the combined hepatitis A and B vaccine has been approved in the United States. Although no data are available on the specific risk of infection with hepatitis B virus among U.S. travelers, ~240 million people in the world have chronic infection. All children and adolescents in the United States are immunized against this illness. Hepatitis B vaccination should be considered for all travelers.
Cholera The risk of cholera (Chap. 193) is extremely low, with ~1 case per 500,000 journeys to endemic areas. Cholera vaccine, not currently available in the United States, was rarely recommended but was considered for aid and health care workers in refugee camps or in disaster-stricken/war-torn areas. A more effective oral cholera vaccine is available in other countries.
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796 Rabies Domestic animals, primarily dogs, are the major transmit-
ters of rabies in developing countries (Chap. 232). Several studies have shown that the risk of rabies posed by a dog bite in an endemic area translates into 1–3.6 cases per 1000 travelers per month of stay. Countries where canine rabies is highly endemic include Mexico, the Philippines, Sri Lanka, India, Thailand, China, and Vietnam. The two vaccines available in the United States provide >90% protection. Rabies vaccine is recommended for long-stay travelers, particularly children (who tend to play with animals and may not report bites), and for persons who may be occupationally exposed to rabies in endemic areas; however, in a large-scale study, almost 50% of potential exposures occurred within the first month of travel. Even after receipt of a preexposure rabies vaccine series, two postexposure doses are required. Travelers who have had the preexposure series do not require rabies immune globulin (which is often unavailable in developing countries) if they are exposed to the disease.
PART 8 Infectious Diseases
PREVENTION OF MALARIA AND OTHER INSECT-BORNE DISEASES It is estimated that more than 30,000 American and European travelers develop malaria each year (Chap. 248). The risk to travelers is highest in Oceania and sub-Saharan Africa (estimated at 1:5 and 1:50 per month of stay, respectively, among persons not using chemoprophylaxis); intermediate in malarious areas on the Indian subcontinent and in Southeast Asia (1:250–1:1000 per month); and low in South and Central America (1:2500–1:10,000 per month). Of the 1925 cases of malaria reported in 2011 in the United States (the highest figure in 40 years), 90% of those due to Plasmodium falciparum occurred in travelers returning or emigrating from Africa and Oceania. VFRs are at the highest risk of acquiring malaria and may die of the disease if their immunity has waned after living outside an endemic area for a number of years. According to data from the CDC, VFRs accounted for 59% of severe malaria cases in the United States in 2011. With the worldwide increase in chloroquine- and multidrug-resistant falciparum malaria, decisions about chemoprophylaxis have become more difficult. The case-fatality rate for falciparum malaria in the United States is 4%; however, in only one-third of patients who die is the diagnosis of malaria considered before death. Several studies indicate that fewer than 50% of travelers adhere to basic recommendations for malaria prevention. Keys to the prevention of malaria include both personal protection measures against mosquito bites (especially between dusk and dawn) and malaria chemoprophylaxis. The former measures entail the use of DEET-containing insect repellents, permethrin-impregnated bed nets and clothing, screened sleeping accommodations, and protective clothing. Thus, in regions where infections such as malaria are transmitted, DEET products (25–50%) are recommended, even for children and infants at birth. Studies suggest that concentrations of DEET above ~50% do not offer a marked increase in protection time against mosquitoes. The CDC also recommends picaridin, oil of lemon eucalyptus (PMD, paramenthane-3,8-diol), and IR3535 (3-[N-butyl-N-acetyl]-aminopropionic acid, ethyl ester). In general, higher concentrations of any active ingredient provide a longer duration of protection. Personal protection measures also help prevent other insect-transmitted illnesses, such as dengue fever (Chap. 233). Over the past decade, the incidence of dengue has markedly increased, particularly in the Caribbean region, Latin America, Southeast Asia, and (more recently) Africa. Chikungunya, another mosquito-borne infection that clinically resembles dengue fever but with arthralgia and arthritis instead of myalgia, has recently crossed to the Western Hemisphere; many thousands of cases are now occurring in the Caribbean. Both dengue and chikungunya viruses are transmitted by an urban-dwelling mosquito that bites primarily at dawn and dusk. Table 149-2 lists the currently recommended drugs of choice for prophylaxis of malaria, by destination. PREVENTION OF GASTROINTESTINAL ILLNESS Diarrhea, the leading cause of illness in travelers (Chap. 160), is usually a short-lived, self-limited condition. However, 40% of affected individuals need to alter their scheduled activities, and another 20% are confined to bed. The most important determinant of risk is the destination. Incidence rates per 2-week stay have been reported to be
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Table 149-2 Malaria Chemosuppressive Regimens, According to Geographic Areaa Geographic Area Central America (north of Panama), Iraq, Turkey, northern Argentina, and Paraguay
Drug of Choiceb Chloroquine
South America (but not northern Argentina or Paraguay, where chloroquine may be used); Central America (only Panama east of the Canal); Asia (including Southeast Asia); Africa; and Oceania Thai-Myanmar and Thai-Cambodian borders, central Vietnam
Doxycycline Atovaquone-proguanilc Mefloquine
Alternatives Atovaquoneproguanilc Doxycycline Mefloquine Primaquine
Atovaquone-proguanilc Doxycycline
a See CDC’s Health Information for International Travel 2014 (www.cdc.gov/travel). bIn all areas where chloroquine can still be used, the other drugs listed may be used as alternatives. c Malarone.
Note: See also Chap. 248.
as low as 8% in industrialized countries and as high as 55% in parts of Africa, Central and South America, and Southeast Asia. Infants and young adults are at particularly high risk for gastrointestinal illness and for complications such as dehydration. Recent reviews suggest that there is little correlation between dietary indiscretions and the occurrence of travelers’ diarrhea. Earlier studies of U.S. students in Mexico showed that eating meals in restaurants and cafeterias or consuming food from street vendors was associated with increased risk. For further discussion, see “Precautions,” below. Etiology (See also Table 160-3) The most frequently identified pathogens causing travelers’ diarrhea are enterotoxigenic and enteroaggregative Escherichia coli (Chap. 186), although in some parts of the world (notably northern Africa and Southeast Asia) Campylobacter infections (Chap. 192) appear to predominate. Other common causative organisms include Salmonella (Chap. 190), Shigella (Chap. 191), rotavirus (Chap. 227), and norovirus (Chap. 227). The latter virus has caused numerous outbreaks on cruise ships. Except for giardiasis (Chap. 254), parasitic infections are uncommon causes of travelers’ diarrhea in short-term travelers. A growing problem for travelers is the development of antibiotic resistance among many bacterial pathogens. Examples include strains of Campylobacter resistant to quinolones and strains of E. coli, Shigella, and Salmonella resistant to trimethoprimsulfamethoxazole E. coli. O157 is very rarely a cause of travelers’ diarrhea. Precautions Some experts think that it is not only what travelers eat but also where they eat that puts them at risk of illness. Food sold by street vendors can carry a high risk, and restaurant hygiene can be a major problem over which the traveler has no control. In addition to discretion in choosing the source of food and water, general precautions include eating foods piping hot; avoiding foods that are raw or poorly cooked; and drinking only boiled or commercially bottled beverages, particularly those that are carbonated. Heating kills diarrhea-causing organisms, whereas freezing does not; therefore, ice cubes made from unpurified water should be avoided. In spite of these recommendations, the literature has repeatedly documented dietary indiscretions by 98% of travelers within the first 72 h after arrival at their destination. The maxim “Boil it, cook it, peel it, or forget it!” is easy to remember but apparently difficult to follow. Self-Treatment (See also Table 160-5) As travelers’ diarrhea often occurs despite rigorous food and water precautions, travelers should carry medications for self-treatment. An antibiotic is useful in reducing the frequency of bowel movements and the duration of illness in moderate to severe diarrhea. The standard regimen is a 3-day course of a quinolone taken twice daily (or, in the case of some newer
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formulations, once daily). However, studies have shown that one double dose of a quinolone may be equally effective. For diarrhea acquired in areas such as Thailand, where >90% of Campylobacter infections are quinolone resistant, azithromycin may be a better alternative. Rifaximin, a poorly absorbed rifampin derivative, is highly effective against noninvasive bacterial pathogens such as enterotoxigenic and enteroaggregative E. coli. The current approach to self-treatment of travelers’ diarrhea for the typical short-term traveler is to carry three once-daily doses of an antibiotic and to use as many doses as necessary to resolve the illness. If neither high fever nor blood in the stool accompanies the diarrhea, loperamide should be taken in combination with the antibiotic; studies have shown that this combination is more effective than an antibiotic alone and does not prolong illness. Prophylaxis Prophylaxis of travelers’ diarrhea with bismuth subsalicylate is widely used but only ~60% effective. For certain individuals (e.g., athletes, persons with a repeated history of travelers’ diarrhea, and persons with chronic diseases), a single daily dose of a quinolone, azithromycin, or rifaximin during travel of 10,500 m (>35,000 ft) should pose
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798 no problem for the healthy pregnant traveler. Since each airline has
a policy regarding pregnancy and flying, it is best to check with the specific carrier when booking reservations. Domestic air travel is usually permitted until the 36th week, whereas international air travel is generally curtailed after the 32nd week. There are no known risks for pregnant women who travel to highaltitude destinations and stay for short periods. However, there are likewise no data on the safety of pregnant women at altitudes of >4500 m (15,000 ft).
PART 8
THE HIV-INFECTED TRAVELER (See also Chap. 226) The HIV-infected traveler is at special risk of serious infections due to a number of pathogens that may be more prevalent at travel destinations than at home. However, the degree of risk depends primarily on the state of the immune system at the time of travel. For persons whose CD4+ T cell counts are normal or >500/ μL, data suggest no greater risk during travel than for persons without HIV infection. Individuals with AIDS (CD4+ T cell counts of 3 months or who intend to work or study abroad. Some countries will accept an HIV serologic test done within 6 months of departure, whereas others will not accept a blood test done at any time in the traveler’s home country. Border officials often have the authority to make inquiries of individuals entering a country and to check the medications they are carrying. If antiretroviral drugs are identified, the person may be barred from entering the country. Information on testing requirements for specific countries is available from consular offices but is subject to frequent change.
Infectious Diseases
Immunizations All of the HIV-infected traveler’s routine immunizations should be up to date (Chap. 148). The response to immunization may be impaired at CD4+ T cell counts of 80% among persons with asymptomatic HIV infection and 2 × ULN, defer treatment and reevaluate. Isoniazid Determine whether hepatic risk factors are presIf ALT is 5 × ULN (or 3 × ULN with symptoms)c or if bilirubin reaches jaundice levels ent. If so, obtain baseline and periodic ALT and (usually >2 × ULN), interrupt treatment. With normalization, consider an alternative bilirubin values. agent. Rifampin Same as above Same as above TB Treatment Check ALT, bilirubin, platelets, creatinine, and hepatitis panel for all patients at baseline. If hepatic risk factors are present, check ALT and bilirubin monthly. Isoniazid If ALT is >5 × ULN (or >3 × ULN with hepatitis Obtain history of alcohol consumption and concomitant drug use. symptoms)c In most instances, discontinue isoniazid, pyrazinamide, rifampin, and other hepatotoxic drugs. Consider alternative agents. Obtain viral hepatitis serologies. Rechallenge: With normalization of liver enzymes, rifampin and isoniazid may be sequentially reintroduced. With no recurrence of hepatotoxicity, pyrazinamide is not resumed in many cases. Alternative rechallenge protocols have been used. Rifampin If primary elevation is in bilirubin and alkaline Discontinue rifampin if total bilirubin reaches jaundice levels (usually >2 × ULN). phosphatase, most likely due to rifampin May try to reintroduce; if not tolerated, may substitute fluoroquinolone Ethambutol Decrease in visual acuity or color vision or appear- Discontinue ethambutol and repeat ocular exam. Peripheral neuropathy may be a ance on monthly screening precursor of ocular toxicity; if it occurs, consider repeat ocular exam. Pyrazinamide If ALT is >5 × ULN (or >3 × ULN with symptoms)c Same as for isoniazid Fluoroquinolone If QTc prolongation is discovered incidentally on Check audiometry and at least BUN and creatinine monthly. ECG Aminoglycoside Abnormal results on audiometry testing, BUN, Discontinue aminoglycoside if not MDR-TB. As appropriate, assess renal function, creatinine, electrolytes at baseline or on monthly correct electrolytes, or seek ENT consultation. check a All regimens require monthly clinical monitoring. bHepatic risk factors: chronic alcohol use, viral hepatitis, preexisting liver disease, pregnancy or ≤3 months postpartum, hepatotoxic medications. cRelevant manifestations include nausea, vomiting, abdominal pain, jaundice, or unexplained fatigue.
Abbreviations: ALT, alanine aminotransferase; BUN, blood urea nitrogen; ECG, electrocardiogram; ENT, ear, nose, and throat; LTBI, latent tuberculosis infection; MDR-TB, multidrug-resistant tuberculosis; ULN, upper limit of normal. Sources: JJ Saukkonen et al: Am J Respir Crit Care Med 174:935, 2006; American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Am J Respir Crit Care Med 167:603, 2003.
is inexpensive. In this setting, the drug is taken daily or intermittently (i.e., twice weekly) as DOT for 9 months. The 9-month course is more efficacious than the 6-month course (75–90% vs ≤65%), but extension of treatment to 12 months is not likely to provide further protection. A 6-month course of daily or intermittent isoniazid is considered second-line, but acceptable, therapy. A recent large open-label, multicenter, randomized, controlled trial showed that weekly DOT with isoniazid and rifapentine, administered over 3 months, was not inferior to daily isoniazid given for 9 months and had a higher treatment completion rate than the single-drug regimen. For treatment of TB disease, isoniazid is used in combination with other agents to ensure killing of both actively dividing M. tuberculosis and slowly growing "persister" organisms. Unless the organism is resistant, the standard regimen includes isoniazid, rifampin, ethambutol, and pyrazinamide (Table 205e-2). Isoniazid is often given together with 25–50 mg of pyridoxine daily to prevent drug-related peripheral neuropathy.
Pharmacology Isoniazid is the hydrazide of isonicotinic acid, a small, water-soluble molecule. The usual adult oral daily dose of 300 mg results in peak serum levels of 3–5 μg/mL within 30 min to 2 h after ingestion—well in excess of the MICs for most susceptible strains of M. tuberculosis. Both oral and IM preparations of isoniazid reach effective levels in the body, although antacids and high-carbohydrate meals may interfere with oral absorption. Isoniazid diffuses well throughout the body, reaching therapeutic concentrations in body cavities and fluids, with concentrations in cerebrospinal fluid (CSF) comparable to those in serum. Isoniazid is metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2) and hydrolysis. Both fast- and slowacetylation phenotypes occur; patients who are “fast acetylators” may have lower serum levels of isoniazid, whereas “slow acetylators” may have higher levels and experience more toxicity. Satisfactory isoniazid levels are attained in the majority of homozygous fast NAT2 acetylators given a dose of 6 mg/kg and in the majority of homozygous slow acetylators given only 3 mg/kg. Genotyping is increasingly being used to characterize isoniazid-related pharmacogenomic responses. Isoniazid’s interactions with other drugs are due primarily to its inhibition of the cytochrome P450 system. Among the drugs with significant isoniazid interactions are warfarin, carbamazepine, benzodiazepines, acetaminophen, clopidogrel, maraviroc, dronedarone, salmeterol, tamoxifen, eplerenone, and phenytoin. Dosing The recommended daily dose for the treatment of TB in the United States is 5 mg/kg for adults and 10–20 mg/kg for children, with a maximal daily dose of 300 mg for both. For intermittent therapy in adults (usually twice per week), the dose is 15 mg/kg, with a maximal daily dose of 900 mg. Isoniazid does not require dosage adjustment in patients with renal disease. When the 12-dose, 3-month weekly LTBI regimen is used, the dose of isoniazid is 15 mg/kg, with a maximal dose of 900 mg, and the drug is coadministered with rifapentine. Resistance Although isoniazid, along with rifampin, is the mainstay of TB treatment regimens, ~7% of clinical M. tuberculosis isolates in the United States are resistant. Rates of primary isoniazid resistance among untreated patients are significantly higher in many populations born outside the United States. Five separate pathways for isoniazid
Adverse effects Although isoniazid is generally well tolerated, druginduced liver injury and peripheral neuropathy are significant adverse effects associated with this agent. Isoniazid may cause asymptomatic transient elevation of aminotransferase levels (often termed hepatic adaptation) in up to 20% of recipients. Other adverse reactions include rash (2%), fever (1.2%), anemia, acne, arthritic symptoms, a systemic lupus erythematosus–like syndrome, optic atrophy, seizures, and psychiatric symptoms. Symptomatic hepatitis occurs in fewer than 0.1% of persons treated with isoniazid alone for LTBI, and fulminant hepatitis with hepatic failure occurs in fewer than 0.01%. Isoniazid-associated hepatitis is idiosyncratic, but its incidence increases with age, with daily alcohol consumption, and in women who are within 3 months postpartum. In patients who have liver disorders or HIV infection, who are pregnant or in the 3-month postpartum period, who have a history of liver disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), who use alcohol regularly, who have multiple medical problems, or who have other risk factors for chronic liver disease, the risks and benefits of treatment for LTBI should be weighed. If treatment is undertaken, these patients should have serum concentrations of alanine aminotransferase (ALT) determined at baseline. Routine baseline hepatic ALT testing based solely on an age of >35 years is optional and depends on individual concerns. Monthly biochemical monitoring during isoniazid treatment is indicated for patients whose baseline liver function tests yield abnormal results and for persons at risk for hepatic disease, including the groups just mentioned. Guidelines recommend that isoniazid be discontinued in the presence of hepatitis symptoms or jaundice and an ALT level three times the upper limit of normal or in the absence of symptoms with an ALT level five times the upper limit of normal (Table 205e-3). Peripheral neuropathy associated with isoniazid occurs in up to 2% of patients given 5 mg/kg. Isoniazid appears to interfere with pyridoxine (vitamin B6) metabolism. The risk of isoniazid-related neurotoxicity is greatest for patients with preexisting disorders that also pose a risk of neuropathy, such as HIV infection; for those with diabetes mellitus, alcohol abuse, or malnutrition; and for those simultaneously receiving other potentially neuropathic medications, such as stavudine. These patients should be given prophylactic pyridoxine (25–50 mg/d). Rifampin Rifampin is a semisynthetic derivative of Amycolatopsis rifamycinica (formerly known as Streptomyces mediterranei). The most active antimycobacterial agent available, rifampin is the keystone of first-line treatment for TB. Introduced in 1968, this drug eventually permitted dramatic shortening of the TB treatment course. Rifampin has both sterilizing and bactericidal activity against dividing and nondividing M. tuberculosis. The drug is also active against an array of other organisms, including some gram-positive and gram-negative bacteria, Legionella, M. kansasii, and Mycobacterium marinum. Rifampin, administered for 4 months, is also an alternative agent to isoniazid for the treatment of LTBI, although efficacy data are scant at this time. A 3-month course of rifampin alone has been found to be similar in efficacy to a 6-month course of isoniazid. Although the efficacy of the 4-month regimen of rifampin is under study, comparison of this regimen with 9 months of isoniazid in randomized safety and tolerability studies suggests fewer adverse events, including hepatotoxicity; less treatment interruption; a higher completion rate; and greater cost-effectiveness.
205e-3
CHAPTER 205e Antimycobacterial Agents
Mechanism of action Isoniazid is a prodrug activated by the mycobacterial KatG catalase-peroxidase; isoniazid is coupled with reduced nicotinamide adenine dinucleotide (NADH). The resulting isonicotinic acyl–NADH complex blocks the mycobacterial ketoenoylreductase known as InhA, binding to its substrate and inhibiting fatty acid synthase and ultimately mycolic acid synthesis. Mycolic acids are essential components of the mycobacterial cell wall. KatG activation of isoniazid also results in the release of free radicals that have antimycobacterial activity, including nitric oxide. The minimal inhibitory concentrations (MICs) of isoniazid for wild-type (untreated) susceptible strains are 95% of cases of early syphilis, although clinical relapse can follow treatment, particularly in patients with concurrent HIV infection. Because the risk of neurologic relapse may be higher in HIV-infected patients, CSF examination is recommended in HIV-seropositive individuals with syphilis of any stage, particularly those with a serum RPR titer of ≥1:32 or a
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1139
TABLE 206-2 Recommendations for the Treatment of Syphilisa Stage of Syphilis Primary, secondary, or early latent
Patients without Penicillin Allergy CSF normal or not examined: Penicillin G benzathine (single dose of 2.4 mU IM) CSF abnormal: Treat as neurosyphilis Late latent (or latent of uncertain duration), CSF normal or not examined: Penicillin G benzathine cardiovascular, or benign tertiary (2.4 mU IM weekly for 3 weeks) CSF abnormal: Treat as neurosyphilis
Neurosyphilis (asymptomatic or symptomatic)
Syphilis in pregnancy
Aqueous crystalline penicillin G (18–24 mU/d IV, given as 3–4 mU q4h or continuous infusion) for 10–14 days or Aqueous procaine penicillin G (2.4 mU/d IM) plus oral probenecid (500 mg qid), both for 10–14 days According to stage
Patients with Confirmed Penicillin Allergyb CSF normal or not examined: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 2 weeks CSF abnormal: Treat as neurosyphilis CSF normal and patient not infected with HIV: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 4 weeks CSF normal and patient infected with HIV: Desensitization and treatment with penicillin if compliance cannot be ensured CSF abnormal: Treat as neurosyphilis Desensitization and treatment with penicillinc
Desensitization and treatment with penicillin
See Table 206-1 and text for indications for CSF examination. bBecause of the documented presence of macrolide resistance in many T. pallidum strains in North America, Europe, and China, azithromycin or other macrolides should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used for men who have sex with men or for pregnant women. cLimited data suggest that ceftriaxone (2 g/d either IM or IV for 10–14 days) can be used; however, cross-reactivity between penicillin and ceftriaxone is possible. a
Abbreviations: CSF, cerebrospinal fluid; mU, million units. Source: Adapted from the 2010 Sexually Transmitted Diseases Treatment Guidelines from the Centers for Disease Control and Prevention.
CD4+ T cell count of ≤350/μL. Therapy appropriate for neurosyphilis should be given if there is any evidence of CNS infection.
Syphilis in Penicillin-Allergic Patients For penicillin-allergic patients with syphilis, a 2-week (early syphilis) or 4-week (late or late latent syphilis) course of therapy with doxycycline or tetracycline is recommended (Table 206-2). These regimens appear to be effective in early syphilis but have not been tested for late or late latent syphilis, and compliance may be problematic. Limited studies suggest that ceftriaxone (1 g/d, given IM or IV for 8–10 days) is effective for early syphilis. These nonpenicillin regimens have not been carefully evaluated in HIV-infected individuals and should be used with caution. If compliance and follow-up cannot be ensured, penicillinallergic HIV-infected persons with late latent or late syphilis should be desensitized and treated with penicillin. Neurosyphilis Penicillin G benzathine, given in total doses of up to 7.2 million units, does not produce detectable concentrations of penicillin G in CSF and should not be used for treatment of neurosyphilis. Asymptomatic neurosyphilis may relapse as symptomatic disease after treatment with benzathine penicillin, and the risk of relapse may be higher in HIV-infected patients. Both symptomatic and asymptomatic neurosyphilis should be treated with aqueous penicillin (Table 206-2). Administration either of IV aqueous crystalline penicillin G or of IM aqueous procaine penicillin G plus oral probenecid in recommended doses is thought to ensure treponemicidal concentrations of penicillin G in CSF. The clinical response to penicillin therapy for meningeal syphilis is dramatic, but treatment of neurosyphilis with existing parenchymal damage may only arrest disease progression. No data suggest
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Management of Syphilis in Pregnancy Every pregnant woman should undergo a nontreponemal test at her first prenatal visit and, if at high risk of exposure, again in the third trimester and at delivery. In the untreated pregnant patient with presumed syphilis, expeditious treatment appropriate to the stage of the disease is essential. Patients should be warned of the risk of a Jarisch-Herxheimer reaction, which may be associated with mild premature contractions but rarely results in premature delivery. Penicillin is the only recommended agent for the treatment of syphilis in pregnancy. If the patient has a documented penicillin allergy, desensitization and penicillin therapy should be undertaken according to the CDC’s 2010 guidelines. After treatment, a quantitative nontreponemal test should be repeated monthly throughout pregnancy to assess therapeutic efficacy. Treated women whose antibody titers rise by fourfold or whose titers do not decrease by fourfold over a 3-month period should be re-treated.
Syphilis
Tertiary Syphilis CSF examination should be performed. If the CSF is normal, the recommended treatment is penicillin G benzathine (7.2 million units total; Table 206-2). If CSF abnormalities are found, the patient should be treated for neurosyphilis. The clinical response to treatment for benign tertiary syphilis is usually impressive. However, responses to therapy for cardiovascular syphilis are not dramatic because aortic aneurysm and aortic regurgitation cannot be reversed by antibiotics.
CHAPTER 206
Late Latent Syphilis or Syphilis of Unknown Duration If the CSF is normal or is not examined, the recommended treatment is penicillin G benzathine (7.2 million units total; Table 206-2). If CSF abnormalities are found, the patient should be treated for neurosyphilis.
that additional therapy (e.g., penicillin G benzathine for 3 weeks) is beneficial after treatment for neurosyphilis. The use of antibiotics other than penicillin G for the treatment of neurosyphilis has not been studied, although very limited data suggest that ceftriaxone may be used. In patients with penicillin allergy demonstrated by skin testing, desensitization and treatment with penicillin are recommended.
EVALUATION AND MANAGEMENT OF CONGENITAL SYPHILIS Whether or not they are infected, newborn infants of mothers with reactive serologic tests may themselves have reactive tests because of transplacental transfer of maternal IgG antibody. For asymptomatic infants born to women treated adequately with penicillin during the first or second trimester of pregnancy, monthly quantitative nontreponemal tests may be performed to monitor for appropriate reduction in antibody titers. Rising or persistent titers indicate infection, and the infant should be treated. Detection of neonatal IgM antibody may be useful, but no commercially available test is currently recommended. An infant should be treated at birth if the treatment status of the seropositive mother is unknown; if the mother has received inadequate or nonpenicillin therapy; if the mother received penicillin therapy in the third trimester; or if the infant may be difficult to follow. The CSF should be examined to obtain baseline values before treatment. Penicillin is the only recommended drug for the treatment of syphilis in infants. Specific recommendations for the treatment of infants and older children are included in the CDC’s 2010 treatment guidelines.
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1140 JARISCH-HERXHEIMER REACTIoN
A dramatic although usually mild reaction consisting of fever, chills, myalgias, headache, tachycardia, increased respiratory rate, increased circulating neutrophil count, and vasodilation with mild hypotension may follow the initiation of treatment for syphilis. This reaction is thought to be a response to lipoproteins released by dying T. pallidum organisms. The Jarisch-Herxheimer reaction occurs in 50% of patients with primary syphilis, 90% of those with secondary syphilis, and a lower proportion of persons with laterstage disease. Defervescence takes place within 12–24 h. In patients with secondary syphilis, erythema and edema of the mucocutaneous lesions may increase. Patients should be warned to expect such symptoms, which can be managed with symptom-based treatment. Steroid or other anti-inflammatory therapy is not required for this mild transient reaction.
and the duration of infection before treatment. Both humoral and cellular responses are considered to be of major importance in immunity and in the healing of early lesions. Cellular infiltration, predominantly by T lymphocytes and macrophages, produces a TH1 cytokine milieu consistent with the clearance of organisms by activated macrophages. Specific antibody enhances phagocytosis and is required for macrophage-mediated killing of T. pallidum. Recent studies demonstrate antigenic variation of the TprK protein, which may lead to persistence of infection and determine susceptibility to reinfection with another strain. Comparative genomic studies have revealed some sequence variations among T. pallidum strains, which can be differentiated by molecular typing methods. Possible correlations between molecular type and clinical manifestations are being examined.
PART 8 Infectious Diseases
FoLLoW-UP EVALUATIoN oF RESPoNSES To THERAPY Efficacy of treatment should be assessed by clinical evaluation and monitoring of the quantitative VDRL or RPR titer for a fourfold decline (e.g., from 1:32 to 1:8). Patients with primary or secondary syphilis should be examined 6 and 12 months after treatment and persons with latent or late syphilis at 6, 12, and 24 months. More frequent clinical and serologic examination (3, 6, 9, 12, and 24 months) is recommended for patients concurrently infected with HIV, regardless of the stage of syphilis. After successful treatment of seropositive first-episode primary or secondary syphilis, the VDRL or RPR titer progressively declines, becoming negative by 12 months in 40–75% of seropositive primary cases and in 20–40% of secondary cases. Patients with HIV infection or a history of prior syphilis are less likely to become nonreactive in the VDRL or RPR test. Rates of decline of serologic titers appear to be slower, and serologically defined treatment failures more common, among HIV-infected patients than among those without HIV co-infection; however, effective antiretroviral therapy may reduce these differences. Re-treatment should be considered if serologic responses are not adequate or if clinical signs persist or recur. Because it is difficult to differentiate treatment failure from reinfection, the CSF should be examined, with treatment for neurosyphilis if CSF is abnormal and treatment for late latent syphilis if CSF is normal. A minority of patients treated for early syphilis may experience a one-dilution titer increase within 14 days after treatment; however, this early elevation does not significantly affect the serologic outcome at 6 months after treatment. Patients treated for late latent syphilis frequently have low initial VDRL or RPR titers and may not have a fourfold decline after therapy with penicillin. In such patients, re-treatment is not warranted unless the titer rises or signs and symptoms of syphilis appear. Because treponemal tests may remain reactive despite treatment for seropositive syphilis, these tests are not useful in following the response to therapy. The activity of neurosyphilis (symptomatic or asymptomatic) correlates best with CSF pleocytosis, and this measure provides the most sensitive index of response to treatment. Repeat CSF examinations should be performed every 6 months until the cell count is normal. An elevated CSF cell count falls to normal in 3–12 months in adequately treated HIV-uninfected patients. The persistence of mild pleocytosis in HIV-infected patients may be due to the presence of HIV in CSF; this scenario may be difficult to distinguish from treatment failure. Elevated levels of CSF protein fall more slowly, and the CSF VDRL titer declines gradually over several years. In patients treated for neurosyphilis, a fourfold reduction in serum RPR titer has been positively correlated with normalization of CSF abnormalities; this correlation is stronger in HIV-uninfected patients and in HIV-infected patients receiving effective antiretroviral therapy.
IMMUNITY To SYPHILIS The rate of development of acquired resistance to T. pallidum after natural or experimental infection is related to the size of the antigenic stimulus, which depends on both the size of the infecting inoculum
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207e
Endemic Treponematoses Sheila A. Lukehart
The endemic treponematoses are chronic diseases that are transmitted by direct contact, usually during childhood, and, like syphilis, can cause severe late manifestations years after initial infection. These diseases are caused by very close relatives of Treponema pallidum subspecies pallidum, the etiologic agent of venereal syphilis (Chap. 206). Yaws, pinta, and endemic syphilis are traditionally distinguished from venereal syphilis by mode of transmission, age of acquisition, geographic distribution, and clinical features; however, there is some overlap for each of these factors. Generally, yaws flourishes in moist tropical areas of several regions, endemic syphilis is found primarily in arid climates, and pinta is found in temperate foci in the Americas (Fig. 207e-1). These infections are usually limited to rural areas of developing nations and are seen in developed countries only among recent immigrants from endemic regions. Our “knowledge” about the endemic treponematoses is based on observations by health care workers who have visited endemic areas; virtually no well-designed studies of the natural history, diagnosis, or treatment of these infections have been conducted. The treponemal infections are compared and contrasted in Table 207e-1.
MICROBIOLOGY The etiologic agents of the endemic treponematoses are listed in Table 207e-1. These little-studied organisms are morphologically identical to T. pallidum subspecies pallidum (the agent of venereal syphilis), and no definitive antigenic differences among them have been identified to date. A controversy has existed about whether the pathogenic treponemes are truly separate organisms, as genome sequencing indicates that yaws and syphilis treponemes are 99.8% identical. Three of the four organisms are classified as subspecies of T. pallidum; the fourth (T. carateum) remains a separate species simply because no organisms have been available for genetic studies. Based on analysis of the small number of strains currently available, molecular signatures—assessed by polymerase chain reaction (PCR) amplification of tpr genes and restriction digestion—have been identified that can differentiate the T. pallidum subspecies. Whether these genetic differences are related to distinct clinical characteristics of these diseases has not been determined. Full genome sequencing of an unclassified strain (Fribourg-Blanc) isolated from a baboon in 1966 shows a very high degree of homology with available strains of T. pallidum subspecies pertenue. This observation is consistent with an earlier report that the Fribourg-Blanc strain can cause experimental infection of humans. Molecular analyses of additional samples from affected baboons suggests that the nonhuman primate samples diverge from the evolutionary tree prior to the clade that contains the human isolates, but uncertainty remains about the importance of the nonhuman primate reservoir for human infection.
CLINICAL FEATURES All of the treponemal infections, including syphilis, are chronic and are characterized by defined disease stages, with a localized primary lesion, disseminated secondary lesions, periods of latency, and possible late lesions. Primary and secondary stages are more frequently overlapping in yaws and endemic syphilis than in venereal syphilis, and the late manifestations of pinta are very mild relative to the destructive lesions of the other treponematoses. The current preference is to divide the clinical course of the endemic treponematoses into “early” and “late” stages. The major clinical distinctions made between venereal syphilis and the nonvenereal infections are the apparent lack of congenital transmission and of central nervous system (CNS) involvement in the nonvenereal infections. It is not known whether these distinctions are entirely accurate. Because of the high degree of genetic relatedness among the organisms, there is little biological reason to think that T. pallidum subspecies endemicum and T. pallidum subspecies pertenue would be unable to cross the blood-brain barrier or to invade the placenta. These organisms are like T. pallidum subspecies pallidum in that they obviously disseminate from the site of initial infection and can persist for decades. The lack of recognized congenital infection may be due to the fact that childhood infections often reach the latent stage (low bacterial load) before girls reach sexual maturity. Neurologic involvement may go unrecEndemic syphilis Pinta Yaws ognized because of the lack of trained Figure 207e-1 Geographic distribution of endemic treponematoses. (Courtesy of the World medical personnel in endemic regions, Health Organization; updated from www.who.int/yaws/epidemiology/Map_yaws_90s.jpg.) the delay of many years between infection
207e-1
CHAPTER 207e Endemic Treponematoses
EPIDEMIOLOGY In a World Health Organization (WHO)–sponsored mass eradication campaign from 1952 to 1969, more than 160 million people in Africa, Asia, and South America were examined for treponemal infections, and more than 50 million cases, contacts, and persons with latent infections were treated. This campaign reduced the prevalence of active yaws from >20% to 10% in some regions of northern Ghana, Mali, Niger, Burkina Faso, and Senegal. In Asia and the Pacific Islands, reports suggest active outbreaks of yaws in Indonesia, Papua New Guinea, the Solomon Islands, East Timor, Vanuatu, Laos, and Kampuchea. India actively renewed its focus on yaws control in 1996, achieved zero-case status in 2003, and declared elimination in 2006. In the Americas, foci of yaws
are thought to persist in Haiti and other Caribbean islands, Peru, Colombia, Ecuador, Brazil, Guyana, and Surinam, although recent data are lacking. Pinta is limited to Central America and northern South America, where it is found rarely and only in very remote villages. Evidence of yaws-like and venereal diseases, with treponemal seroreactivity, in wild gorillas and baboons in Africa has led to speculation that there may be an animal reservoir for yaws.
207e-2
TABLE 207e-1 Comparison of the Treponemes and Associated Diseases Feature Organism Common modes of transmission Usual age of acquisition Primary lesion
Venereal Syphilis T. pallidum subsp. pallidum Sexual, transplacental
Yaws T. pallidum subsp. pertenue Skin-to-skin
Sexual maturity or in utero Cutaneous ulcer (chancre)
Early childhood Papilloma, often ulcerative
Common location Secondary lesions
Genital, oral, anal Mucocutaneous lesions; condylomata lata
Extremities Cutaneous papulosquamous lesions; condylomata lata, osteoperiostitis
Infectious relapses Late complications
~25% Gummas, cardiovascular and central nervous system involvementa
Common Destructive gummas of skin, bone, cartilage
Endemic Syphilis T. pallidum subsp. endemicum Mouth-to-mouth or via shared drinking/eating utensils Early childhood Mucosal papule, rarely seen Oral Mucocutaneous lesions (mucous patch, split papule, condylomata lata); osteoperiostitis Unknown Destructive gummas of skin, bone, cartilage
Pinta T. carateum Skin-to-skin Late childhood Nonulcerating papule with satellites, pruritic Extremities, face Pintides, pigmented, pruritic
Unknown Nondestructive, dyschromic, achromic macules
Central nervous system involvement and congenital infection in the endemic treponematoses have been postulated by some investigators (see text).
a
and possible CNS manifestations, or a low rate of symptomatic CNS disease. Some published evidence supports congenital transmission as well as cardiovascular, ophthalmologic, and CNS involvement in yaws and endemic syphilis. Although the reported studies have been small, have failed to control for other causes of CNS abnormalities, and in some instances have not included serologic confirmation, it may be erroneous to accept unquestioningly the frequently repeated belief that these organisms fail to cause such manifestations.
PART 8 Infectious Diseases
Yaws Also known as pian, framboesia, or bouba, yaws is characterized by the development of one or several primary lesions (“mother yaw”) followed by multiple disseminated skin lesions. All early skin lesions are infectious and may persist for many months; cutaneous relapses are common during the first 5 years. Late manifestations, affecting ~10% of untreated persons, are destructive and can involve skin, bone, and joints. The infection is transmitted by direct contact with infectious lesions, often during play or group sleeping, and may be enhanced by disruption of the skin by insect bites or abrasions. After an average of 3–4 weeks, the first lesion begins as a papule—usually on an extremity— and then enlarges (particularly during moist warm weather) to become papillomatous or “raspberry-like” (thus the name “framboesia”) (Fig. 207e-2A). Regional lymphadenopathy develops, and the lesion usually heals within 6 months; dissemination is thought to occur during the early weeks of infection. A generalized secondary eruption (Fig. 207e-2B), accompanied by generalized lymphadenopathy, appears either concurrent with or after the primary lesion; may take several forms (macular, papular, or papillomatous); and may become
A
B
secondarily infected with other bacteria. Painful papillomatous lesions on the soles of the feet result in a crablike gait (“crab yaws”), and periostitis may result in nocturnal bone pain and polydactylitis. Late yaws is manifested by gummas of the skin and long bones, hyperkeratoses of the palms and soles, osteitis and periostitis, and hydrarthrosis. The late gummatous lesions are characteristically extensive. Destruction of the nose, maxilla, palate, and pharynx is termed gangosa and is similar to the destructive lesions seen in leprosy and leishmaniasis. Endemic Syphilis The early lesions of endemic syphilis (bejel, siti, dichuchwa, njovera, skerljevo) are localized primarily to mucocutaneous and mucosal surfaces. The infection is reportedly transmitted by direct contact, by kissing, by premastication of food, or by sharing of drinking and eating utensils. A role for insects in transmission has been suggested but is unproven. The initial lesion, usually an intraoral papule, often goes unrecognized and is followed by mucous patches (Fig. 207e-2C) on the oral mucosa and mucocutaneous lesions resembling the condylomata lata of secondary syphilis. This eruption may last for months or even years, and treponemes can readily be demonstrated in early lesions. Periostitis and regional lymphadenopathy are common. After a variable period of latency, late manifestations may appear, including osseous and cutaneous gummas. Destructive gummas, osteitis, and gangosa are more common in endemic syphilis than in yaws. Pinta Pinta (mal del pinto, carate, azul, purupuru) is the most benign of the treponemal infections. This disease has three stages that are characterized by marked changes in skin color (Fig. 207e-2D), but pinta does not appear to cause destructive lesions or to involve
C
D
Figure 207e-2 Clinical manifestations of endemic treponematoses. A. Papillomatous initial lesion of early yaws. B. Disseminated lesions of early yaws. C. Mucous patches of endemic syphilis. D. Pigmented macules of pinta. (Photos published with permission from Dr. David Fegan, Brisbane, Australia [A and B]; and from PL Perine et al: Handbook of Endemic Treponematoses, Geneva, World Health Organization, 1984 [C and D].)
tissues other than the skin. The initial papule is most often located on the extremities or face and is pruritic. After one to many months of infection, numerous disseminated secondary lesions (pintides) appear. These lesions are initially red but become deeply pigmented, ultimately turning a dark slate blue. The secondary lesions are infectious and highly pruritic and may persist for years. Late pigmented lesions are called dyschromic macules and contain treponemes. Over time, most pigmented lesions show varying degrees of depigmentation, becoming brown and eventually white and giving the skin a mottled appearance. White achromic lesions are characteristic of the late stage. DIAGNOSIS Diagnosis of the endemic treponematoses is based on clinical manifestations and, when available, dark-field microscopy and serologic testing. The same serologic tests that are used for venereal syphilis (Chap. 206) become reactive during all treponemal infections. Although several targets have been evaluated for specific serodiagnosis, to date there is no antibody test that can discriminate among the different infections. The nonvenereal treponemal infections should be considered in the evaluation of a reactive syphilis serology in any person who has emigrated from an endemic area. Sensitive PCR assays can be used to confirm treponemal infection and to identify the etiologic agent in research laboratories. TREATMENT
Endemic Treponematoses
CONTROL Buoyed by the successful elimination of yaws in India in 2006 and the availability of an inexpensive, single-dose oral drug for treatment, in 2012 the WHO renewed its efforts to eradicate yaws globally by 2020. Enthusiasm is high; several planning meetings have been held to develop country-specific plans of action; and resources are being sought. Some caution is warranted: The possible animal reservoir will need to be evaluated. There may be only a window of time during which countries can successfully use azithromycin for yaws eradication before resistance begins to appear in yaws organisms. Given the ongoing lower-dose azithromycin mass treatment campaigns against trachoma, often in populations also at high risk for yaws, development of macrolide resistance is likely at some point. Complete drug coverage and continued careful surveillance by health centers (the weak link in prior control efforts) will be essential for success.
207e-3
CHAPTER 207e Endemic Treponematoses
The WHO-recommended therapy for patients and their contacts is benzathine penicillin G (1.2 million units IM for adults; 600,000 units for children 40, altered mental status, acute renal failure, respiratory insufficiency, hypotension, and arrhythmias. The classic presentation, often referred to as Weil's syndrome, encompasses the triad of hemorrhage, jaundice, and acute kidney injury. Patients die of septic shock with multiorgan failure and/or severe bleeding complications that most commonly involve the lungs (pulmonary hemorrhage), gastrointestinal tract (melena, hemoptysis), urogenital tract (hematuria), and skin (petechiae, ecchymosis, and bleeding from venipuncture sites). Pulmonary hemorrhage (with or without jaundice) is now recognized as a widespread public health problem, presenting with cough, chest pain, respiratory distress, and hemoptysis that may not be apparent until patients are intubated. Jaundice occurs in 5–10% of all patients with leptospirosis; it can be profound and give an orange cast to the skin but usually is not associated with fulminant hepatic necrosis. Physical examination may reveal an enlarged and tender liver. Acute kidney injury is common in severe disease, presenting after several days of illness, and can be either nonoliguric or oliguric. Typical electrolyte abnormalities include hypokalemia and
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hyponatremia. Loss of magnesium in the urine is uniquely associated with leptospiral nephropathy. Hypotension is associated with acute tubular necrosis, oliguria, or anuria, requiring fluid resuscitation and sometimes vasopressor therapy. Hemodialysis can be life-saving, with renal function typically returning to normal in survivors. Other syndromes include (necrotizing) pancreatitis, cholecystitis, skeletal muscle involvement, rhabdomyolysis (with moderately elevated serum creatine kinase levels), and neurologic manifestations including aseptic meningitis. Cardiac involvement is commonly reflected on the electrocardiogram as nonspecific ST- and T-wave changes. Repolarization abnormalities and arrhythmias are considered poor prognostic factors. Myocarditis has been described. Rare hematologic complications include hemolysis, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome. Long-term symptoms following severe leptospirosis include fatigue, myalgia, malaise, and headache and may persist for years. Autoimmune-associated uveitis, a potentially chronic condition, is a recognized sequela of leptospirosis. DIAGNOSIS The clinical diagnosis of leptospirosis should be based on an appropriate exposure history combined with any of the protean manifestations of the disease. Returning travelers from endemic areas usually have a history of recreational freshwater activities or other mucosal or percutaneous contact with contaminated surface waters or soil. For nontravelers, recreational water contact and occupational hazards that involve direct or indirect animal contact should be explored (see “Epidemiology,” above). Although biochemical, hematologic, and urinalysis findings in acute leptospirosis are nonspecific, certain patterns may suggest the diagnosis. Laboratory results usually show signs of a bacterial infection, including leukocytosis with a left shift and elevated markers of inflammation (C-reactive protein level and erythrocyte sedimentation rate). Thrombocytopenia (platelet count ≤100 × 109/L) is common and is associated with bleeding and renal failure. In severe disease, signs of coagulation activation may be present, varying from borderline abnormalities to a serious derangement compatible with DIC as defined by international criteria. The kidneys are invariably involved in leptospirosis. Related findings range from urinary sediment changes (leukocytes, erythrocytes, and hyaline or granular casts) and mild proteinuria in mild disease to renal failure and azotemia in severe leptospirosis. Nonoliguric hypokalemic renal insufficiency (see “Clinical Manifestations,” above) is characteristic of early leptospirosis. Serum bilirubin levels may be high, whereas rises in aminotransferase and alkaline phosphatase levels are usually moderate. Although clinical symptoms of pancreatitis are not a common finding, amylase levels are often elevated. When symptoms of aseptic meningitis develop, examination of the CSF shows pleocytosis that can range from a few cells to >1000 cells/μL, with a polymorphonuclear cell predominance. The protein concentration in the CSF may be elevated; CSF glucose levels are normal. In severe leptospirosis, pulmonary radiographic abnormalities are more common than would be expected on the basis of physical examination (Fig. 208-4). The most common radiographic finding is a patchy bilateral alveolar pattern that corresponds to scattered alveolar hemorrhage. These abnormalities predominantly affect the lower lobes. Other findings include pleura-based densities (representing areas of hemorrhage) and diffuse ground-glass attenuation typical of acute respiratory distress syndrome (ARDS). A definitive diagnosis of leptospirosis is based on isolation of the organism from the patient, on a positive result in the polymerase chain reaction (PCR), or on seroconversion or a rise in antibody titer. In cases with strong clinical evidence of infection, a single antibody titer of 1:200–1:800 (depending on whether the case occurs in a lowor high-endemic area) in the microscopic agglutination test (MAT) is required. Preferably, a fourfold or greater rise in titer is detected between acute- and convalescent-phase serum specimens. Antibodies generally do not reach detectable levels until the second week of illness. The antibody response can be affected by early treatment with antibiotics.
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The MAT, which uses a battery of live leptospiral strains, and the enzyme-linked immunosorbent assay (ELISA), which uses a broadly reacting antigen, are the standard serologic procedures. The MAT usually is available only in specialized laboratories and is used for determination of the antibody titer and for tentative identification of the involved leptospiral serogroup—and, when epidemiologic background information is available, the putative serovar. This point underscores the importance of testing antigens representative of the serovars prevalent in the particular geographic area. However, cross-reactions occur frequently, and thus definitive identification of the infecting serovar or serogroup is not possible without isolation of the causative organism. Because serologic testing lacks sensitivity in the early acute phase of the disease (up to day 5), it cannot be used as the basis for a timely decision about whether to start treatment. In addition to the MAT and the ELISA, various rapid tests with diagnostic value have been developed, and some of these are commercially available. These rapid tests mainly apply lateral flow, (latex) agglutination, or ELISA methodology and are reasonably sensitive and specific, although results reported in the literature vary, probably as a consequence of differences in test interpretation, (re)exposure risks, serovar distribution, and the use of biased serum panels. These methods do not require culture or MAT facilities and are useful in settings that lack a strong medical infrastructure. PCR methodologies, notably real-time PCR, have become increasingly widely implemented. Compared with serology, PCR offers a great advantage: the capacity to confirm the diagnosis of leptospirosis with a high degree of accuracy during the first 5 days of illness.
Leptospirosis
Severe leptospirosis should be treated with IV penicillin (Table 208-1) as soon as the diagnosis is considered. Leptospires are highly susceptible to a broad range of antibiotics, and early intervention may prevent the development of major organ system failure or lessen its severity. Although studies supporting antibiotic therapy have produced conflicting results, clinical trials are difficult to perform in settings where patients frequently present for medical care with late stages of disease. Antibiotics are less likely to benefit patients in whom organ damage has already occurred. Two open-label randomized studies comparing penicillin with parenteral cefotaxime, parenteral ceftriaxone, and doxycycline showed no significant differences among the antibiotics with regard to complications and mortality risk. Thus ceftriaxone, cefotaxime, or doxycycline is a satisfactory alternative to penicillin for the treatment of severe leptospirosis. In mild cases, oral treatment with doxycycline, azithromycin, ampicillin, or amoxicillin is recommended. In regions where rickettsial diseases are coendemic, doxycycline or azithromycin is the drug of choice. In rare instances, a Jarisch-Herxheimer reaction develops within hours after the initiation of antimicrobial therapy.
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Moderate/severe leptospirosis
Regimen Doxycyclineb (100 mg PO bid) or Amoxicillin (500 mg PO tid) or Ampicillin (500 mg PO tid) Penicillin (1.5 million units IV or IM q6h) or Ceftriaxone (2 g/d IV) or Cefotaxime (1 g IV q6h) or Doxycycline (loading dose of 200 mg IV, then 100 mg IV q12h)
Chemoprophylaxisc Doxycyclineb (200 mg PO once a week) or Azithromycin (250 mg PO once or twice a week) All regimens are given for 7 days. bDoxycycline should not be given to pregnant women or children. c The efficacy of doxycycline prophylaxis in endemic or epidemic settings remains unclear. Experiments in animal models and a cost-effectiveness model indicate that azithromycin has a number of characteristics that may make it efficacious in treatment and prophylaxis.
a
Aggressive supportive care for leptospirosis is essential and can be life-saving. Patients with nonoliguric renal dysfunction require aggressive fluid and electrolyte resuscitation to prevent dehydration and precipitation of oliguric renal failure. Peritoneal dialysis or hemodialysis should be provided to patients with oliguric renal failure. Rapid initiation of hemodialysis has been shown to reduce mortality risk and typically is necessary only for short periods. Patients with pulmonary hemorrhage may have reduced pulmonary compliance (as seen in ARDS) and may benefit from mechanical ventilation with low tidal volumes to avoid high ventilation pressures. Evidence is contradictory for the use of glucocorticoids and desmopressin as adjunct therapy for pulmonary involvement associated with severe leptospirosis. PROGNOSIS Most patients with leptospirosis recover. However, post-leptospirosis symptoms, mainly of a depression-like nature, may occur and persist for years after the acute disease. Mortality rates are highest among patients who are elderly and those who have severe disease (pulmonary hemorrhage, Weil’s syndrome). Leptospirosis during pregnancy is associated with high fetal mortality rates. Long-term follow-up of patients with renal failure and hepatic dysfunction has documented good recovery of renal and hepatic function.
Leptospirosis
TREATMENT
Indication Treatment Mild leptospirosis
CHAPTER 208
DIFFERENTIAL DIAGNOSIS The differential diagnosis of leptospirosis is broad, reflecting the diverse clinical presentations of the disease. Although leptospirosis transmission is more common in tropical and subtropical regions, the absence of a travel history does not exclude the diagnosis. When fever, headache, and myalgia predominate, influenza and other common and less common (e.g., dengue and chikungunya) viral infections should be considered. Malaria, typhoid fever, ehrlichiosis, viral hepatitis, and acute HIV infection may mimic the early stages of leptospirosis and are important to recognize. Rickettsial diseases, hantavirus infections (hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome), and dengue share epidemiologic and clinical features with leptospirosis. Dual infections have been reported. In this light, it is advisable to conduct serologic testing for hantavirus, rickettsiae, and dengue virus when leptospirosis is suspected. When bleeding is detected, dengue hemorrhagic fever and other viral hemorrhagic fevers, including hantavirus infection, yellow fever, Rift Valley fever, filovirus infections, and Lassa fever, should be considered.
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TABLE 208-1 Treatment and Chemoprophylaxis of Leptospirosis in Adultsa
PREVENTION Individuals who may be exposed to Leptospira through their occupations or their involvement in recreational freshwater activities should be informed about the risks. Measures for controlling leptospirosis include avoidance of exposure to urine and tissues from infected animals through proper eyewear, footwear, and other protective equipment. Targeted rodent control strategies could be considered. Vaccines for agricultural and companion animals are generally available, and their use should be encouraged. The veterinary vaccine used in a given area should contain the serovars known to be present in that area. Unfortunately, some vaccinated animals still excrete leptospires in their urine. Vaccination of humans against a specific serovar prevalent in an area has been undertaken in some European and Asian countries and has proved effective. Although a large-scale trial of vaccine in humans has been reported from Cuba, no conclusions can be drawn about efficacy and adverse reactions because of insufficient details on study design. The efficacy of chemoprophylaxis with doxycycline (200 mg once a week) or azithromycin (in pregnant women and children) is being disputed, but focused preand postexposure administration is indicated in instances of welldefined short-term exposure (Table 208-1).
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209
10- to 20-μm-long Borrelia cells, with a diameter of 0.1–0.2 μm, are too narrow to be seen by bright-field microscopy of Gram-stained specimens.
Relapsing Fever Alan G. Barbour
PART 8
Relapsing fever is caused by infection with any of several species of Borrelia spirochetes. Physicians in ancient Greece distinguished relapsing fever from other febrile disorders by its characteristic clinical presentation: two or more fever episodes separated by varying periods of well-being. In the nineteenth century, relapsing fever was one of the first diseases to be associated with a specific microbe by virtue of its characteristic laboratory finding: the presence of large numbers of spirochetes of the genus Borrelia in the blood. The host responds with systemic inflammation that results in an illness ranging from a flulike syndrome to sepsis. Other manifestations are the consequences of central nervous system (CNS) involvement and coagulopathy. Antigenic variation of the spirochetes’ surface proteins accounts for the infection’s relapsing course. Acquired immunity follows the serial development of antibodies to each of the several variants appearing during an infection. Treatment with antibiotics results in rapid cure but at the risk of a moderate to severe JarischHerxheimer reaction. Louse-borne relapsing fever caused large epidemics well into the twentieth century and currently occurs in northeastern Africa. At present, however, most cases of relapsing fever are tick-borne in origin. Sporadic cases and small outbreaks are focally distributed on most continents, with Africa most affected. In North America, the majority of reports of relapsing fever have been from the western United States and Canada. Nevertheless, the recent discovery that another species in the relapsing fever group causes human disease in the same geographic distribution as Lyme disease (Chap. 210) confounds epidemiologic distinctions between the two major types of Borrelia infection.
Infectious Diseases
ETIOLOGIC AGENT Coiled, thin microscopic filaments that swim in one direction and then coil up before heading in another were first observed in the blood of patients with relapsing fever in the 1880s (www.youtube .com/watch?v=VxDPV2lBd9U). These microbes were categorized as spirochetes and grouped as several species in the genus Borrelia. It was not until the 1960s that the organisms were isolated in pure culture. The breakthrough cultivation medium and its derivatives are rich in their ingredients, ranging from simple (e.g., amino acids and N-acetylglucosamine) to more complex (e.g., serum and protein hydrolysates). The limited biosynthetic capacity of Borrelia cells is accounted for by a genome content one-quarter that of Escherichia coli. Like other spirochetes, the helix-shaped Borrelia cells have two membranes, the outer of which is more loosely secured than in other double-membrane bacteria, such as E. coli. As a consequence, fixed organisms with damaged membranes can assume a variety of morphologies in smears and histologic preparations. The flagella of spirochetes run between the two membranes and are not on the cell surface. Although technically gram-negative in their staining properties, the
EPIDEMIOLOGY The several species of Borrelia that cause relapsing fever have restricted geographic distributions (Table 209-1). The exception is Borrelia recurrentis, which is also the only species transmitted by the louse. Louse-borne relapsing fever (LBRF) is usually acquired from a body louse (Pediculus humanus corporis), with humans serving as the reservoir. Acquisition occurs not from the bite itself but from either rubbing the insect’s feces into the bite site with the fingers in response to irritation or inoculation of feces into the conjunctivae or an open wound. Although LBRF transmission is currently limited to Ethiopia and adjacent countries, the disease has had a global distribution in the past, and that potential remains. Epidemics with thousands of cases of LBRF can occur under circumstances of famine, natural disaster, refugee migration, and war. All other known species of relapsing fever agents are tick-borne—in most cases, by soft ticks of the genus Ornithodoros (Fig. 209-1). Tickborne relapsing fever (TBRF) is found on most continents but is absent or rare in tropical, low-desert, arctic, or alpine environments. For most species, the reservoirs of infection are small to medium-sized mammals, usually rodents but sometimes pigs and other domestic animals living in or around human habitats. However, one species, Borrelia duttonii in sub-Saharan Africa, is largely maintained by tick transmission between human hosts. In North America, TBRF occurs as single cases or small case clusters through transient exposure of persons to infested buildings or caves in less populated areas where the rodent reservoirs have nests. The two main Borrelia species involved in North America are Borrelia hermsii (in the mountainous west) and Borrelia turicatae (in the southwestern and south-central regions). The soft tick vectors typically feed for no more than 30 min, usually without being noticed, while the victim is sleeping. Transovarial transmission from one generation of ticks to the next means that infection risk may persist in an area long after incriminated mammalian reservoirs have been eradicated. A newly recognized pathogen, Borrelia miyamotoi, belongs to the clade of relapsing fever species but is transmitted to humans from other mammals by hard ticks (e.g., Ixodes scapularis in the eastern United States) that also transmit Lyme disease, babesiosis, anaplasmosis, ehrlichiosis, and arboviral encephalitis. B. miyamotoi is acquired through outdoor activities and through contact with ticks in forested and shrubby areas during recreation, work, or activities around the home. In residents of areas where B. miyamotoi and Borrelia burgdorferi coexist, the prevalence of antibodies to the former is about onethird of that to the latter. PATHOGENESIS AND IMMUNITY Unlike LBRF spirochetes, TBRF spirochetes enter the body in the tick’s saliva with the onset of feeding. From an inoculum of a few cells, the spirochetes proliferate in the blood, doubling every 6 h to numbers of 106–107/mL or more. Borrelia species are extracellular pathogens; their
TABLE 209-1 Relapsing Fever Borrelia Species, by Geographic Region, Vector, and Primary Reservoir Species B. crocidurae B. duttonii B. hermsii B. hispanica B. miyamotoi B. persica B. recurrentis B. turicatae B. venezuelensis
Region(s) Africa Africa North America Europe, North Africa Eurasia, North America Eurasia Africa, globala North America Central and South America
Arthropod Vector(s) Ornithodoros erraticus, O. sonrai (soft ticks) O. moubata O. hermsi O. erraticus complex Ixodes species (hard ticks) O. tholozani Pediculus humanus corporis (human body louse) O. turicata O. rudis
Primary Reservoir Mammals Humans Mammals Mammals Mammals Mammals Humans Mammals Mammals
Although transmission is currently limited to Ethiopia and adjacent countries, B. recurrentis infection has had a global distribution in the past, and that potential remains.
a
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Figure 209-1 Ornithodoros turicata soft ticks of different ages.
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Relapsing Fever
CLINICAL MANIFESTATIONS Relapsing fever presents with the sudden onset of fever. Febrile periods are punctuated by intervening afebrile periods of a few days; this pattern occurs at least twice. The patient’s temperature is ≥39°C and may be as high as 43°C. The first fever episode often ends in a crisis lasting ~15–30 min and consisting of rigors, a further elevation in temperature, and increases in pulse and blood pressure. The crisis phase is followed by profuse diaphoresis, falling temperature, and hypotension, which usually persist for several hours. In LBRF, the first episode of fever is unremitting for 3–6 days; it is usually followed by a single milder episode. In TBRF, multiple febrile periods last 1–3 days each. In both forms, the interval between fevers ranges from 4 to 14 days, sometimes with symptoms of malaise and fatigue. The symptoms that accompany the fevers are usually nonspecific. Headache, neck stiffness, arthralgia, myalgia, and nausea may accompany the first and subsequent febrile episodes. An enlarging spleen and liver cause abdominal pain. A nonproductive cough is common during LBRF and—in combination with fever and myalgias—may suggest influenza. Acute respiratory distress syndrome may occur during TBRF. On physical examination, the patient may be delirious or apathetic. There may be body lice in the patient’s clothes or signs of insect bites. In regions with B. miyamotoi infection, a hard tick may be embedded in the skin. Epistaxis, petechiae, and ecchymoses are common during LBRF but not in TBRF. Splenomegaly or spleen tenderness is common in both forms of relapsing fever. The majority of patients with LBRF and ~10% of patients with TBRF have discernible hepatomegaly. Localizing neurologic findings are more common in TBRF than in LBRF. In North America, B. turicatae infection has neurologic manifestations more often than B. hermsii infection. Meningoencephalitis can result in residual hemiplegia or aphasia. Myelitis and radiculopathy
DIAGNOSIS Relapsing fever should be considered in a patient with the characteristic fever pattern and a history of recent exposure—i.e., within 1–2 weeks before illness onset—to body lice or soft-bodied ticks in geographic areas with documented current or past transmission. Because of the longevity of the ticks and the transovarial transmission of the pathogen in the ticks, a case of relapsing fever may be diagnosed many years after the last case reported in that locale. The bedrock for laboratory diagnosis remains the same as it has been for a century: direct detection of the spirochetes by microscopy of the blood. Manual differential counts of white blood cells by Wright or Giemsa stain usually reveal spirochetes in thin blood smears if their concentration is ≥105/mL and several oil-immersion fields are examined (Fig. 209-2). The preferred time to obtain a blood specimen is between the fever’s onset and its peak. Lower concentrations of spirochetes may be revealed by a thick blood smear that is either directly stained with acridine orange and then examined by fluorescence microscopy or treated with 0.5% acetic acid before Giemsa or Wright staining. An alternative to a fixed blood smear is a wet mount of anticoagulated blood mixed with saline and examined by phase-contrast or dark-field microscopy for motile spirochetes. Polymerase chain reaction (PCR) and similar DNA amplification procedures are increasingly used for examination of an extract of blood. PCR may reveal spirochetes between febrile episodes, since there are already escape variants in the population when the first wave of bacteria is neutralized. Culture of blood or CSF in Barbour-Stoenner-Kelly broth medium is an option for isolation of Borrelia species except for B. miyamotoi, which is noncultivable or poorly cultivable. However, few laboratories offer this service. An alternative for tick-borne Borrelia species, including B. miyamotoi, is inoculation of blood or CSF into immunodeficient mice and examination of the animal’s blood after a few days. Options for serologic confirmation of infection are limited. Most assays that are available commercially or in reference laboratories are based on whole cells of a single Borrelia species. These assays may not detect the major variant antigens to which the patient is mainly responding or may yield false-positive results due to antibodies to crossreactive antigens of related bacteria, including B. burgdorferi. The most
CHAPTER 209
presence inside cells likely represents a dead end for the bacteria after phagocytosis. Binding of the spirochetes to erythrocytes leads to aggregation of red blood cells, their sequestration in the spleen and liver, and hepatosplenomegaly and anemia. A bleeding disorder is probably the consequence of thrombocytopenia, impaired hepatic production of clotting factors, and/or blockage of small vessels by aggregates of spirochetes, erythrocytes, and platelets. Some species are neurotropic and frequently enter the brain, where they are comparatively sheltered from host immunity. Relapsing fever spirochetes can cross the maternal-fetal barrier and cause placental damage and inflammation, leading to intrauterine growth retardation and congenital infection. Although Borrelia species do not have potent exotoxins or a lipopolysaccharide endotoxin, they have abundant membrane-associated lipoproteins whose recognition and binding by Toll-like receptors on host cells can lead to a proinflammatory process similar to that in endotoxemia, with elevations of tumor necrosis factor α, interleukin 6, and interleukin 8 concentrations. IgM antibodies specific for the serotype-defining surface lipoprotein appear after a few days of infection and soon reach a concentration that causes lysis of bacteria in the blood through either direct bactericidal action or opsonization. The release of large amounts of lipoproteins and other bacterial products from dying bacteria provokes a “crisis,” during which there can be an increase in temperature, hypotension, and other signs of shock. A similar phenomenon occurring in some patients soon after the initiation of antibiotic treatment is characterized by the abrupt worsening of the condition, which is called a Jarisch-Herxheimer reaction (JHR).
may develop. Unilateral or bilateral Bell’s palsy and deafness from sev- 1147 enth or eighth cranial nerve involvement are the most common forms of cranial neuritis and typically present in the second or third febrile episode, not the first. Visual impairment from unilateral or bilateral iridocyclitis or panophthalmitis may be permanent. In LBRF, neurologic manifestations such as altered mental state or stiff neck are thought to be secondary to spirochetemia and systemic inflammation rather than to direct invasion of the nervous system. Myocarditis appears to be common in both forms of relapsing fever and accounts for some deaths. Most commonly, myocarditis is evidenced by gallops on cardiac auscultation, a prolonged QTc interval, and cardiomegaly and pulmonary edema on chest radiography. General laboratory studies are not specific. Mild to moderate normocytic anemia is common, but frank hemolysis and hemoglobinuria do not develop. Leukocyte counts are usually in the normal range or only slightly elevated, and leukopenia can occur during the crisis. Platelet counts can fall below 50,000/µL. Laboratory evidence of hepatitis can be found, with elevated serum concentrations of unconjugated bilirubin and aminotransferases; the prothrombin and partial thromboplastin times may be moderately prolonged. Analysis of the cerebrospinal fluid (CSF) is indicated in cases of suspected relapsing fever with signs of meningitis or meningoencephalitis. The presence of mononuclear pleocytosis and mildly to moderately elevated protein levels justifies intravenous antibiotic therapy in TBRF. The manifestations and course of B. miyamotoi infection remain incompletely characterized, but reports to date indicate that the sign most often reported by patients at presentation is fever without respiratory symptoms starting 1–2 weeks after a tick bite and recurring once or twice in some cases. Meningoencephalitis with spirochetes in the CSF was documented in one immunodeficient adult.
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Tick-borne relapsing fever
Louse-borne relapsing fever
Meningitis/encephalitis Oral therapy
Intravenous ceftriaxone 2 g qd or Na penicillin G, 5 million U q6h for 14 days
First choice Age ≥9 years, not pregnant: doxcycline, 100 mg bid Age 800, further investigation is warranted. Some authorities recommend that patients with valvulopathy and acute Q fever receive doxycycline and hydroxychloroquine to prevent chronic Q fever. For women who exhibit a serologic profile of chronic Q fever after childbirth, hydroxychloroquine and doxycycline should be given for 1 year. BIOLOGIC MODIFYING AGENTS Interferon γ was successful in the treatment of a 3-year-old boy with prolonged fever, abdominal pain, and thrombocytopenia due to C. burnetii that had not been eradicated with conventional antibiotic therapy. Many patients with granulomatous hepatitis due to Q fever have a prolonged febrile illness that is unresponsive to antibiotics. For these individuals, treatment with prednisone (0.5 mg/kg) has resulted in defervescence within 2–15 days. After defervescence, the glucocorticoid dose is tapered over the next month.
Q Fever
ANTIBIOTICS Treatment of acute Q fever with doxycycline (100 mg twice daily for 14 days) is usually successful. Quinolones also are effective. When Q fever is diagnosed during pregnancy, treatment with trimethoprimsulfamethoxazole (TMP-SMX) is recommended for the duration of the pregnancy. One study showed no intrauterine fetal deaths and substantial reduction of obstetric complications in a group of Q fever patients treated with TMP-SMX. The treatment of chronic Q fever is difficult and requires careful follow-up. Addition of hydroxychloroquine (to alkalinize the phagolysosome) renders doxycycline bactericidal against C. burnetii, and this combination is currently the favored regimen. Treatment with doxycycline (100 mg bid) and hydroxychloroquine (200 mg tid; plasma concentration maintained at 0.8–1.2 μg/mL) for 18 months is superior to a regimen of doxycycline and ofloxacin. Among 21 patients who received doxycycline and hydroxychloroquine, 1 died of a surgical complication, 2 were still being treated at the end of the study, 1 was still being evaluated, and 17 were cured. The mean duration of treatment was 31 months. In the ofloxacin and doxycycline group of 14 patients, 1 had died, 1 was still being treated, 7 had relapsed, and 5 had been cured by the end of the study. Optimal management of Q fever endocarditis entails determining the MIC of doxycycline for the patient’s isolate and measuring
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Prevention A whole-cell vaccine (Q-Vax) licensed in Australia effectively prevents Q fever in abattoir workers. Before administration of the vaccine, skin testing with intradermal diluted C. burnetii vaccine is performed, serologic testing is undertaken, and a history of possible Q fever is sought. Vaccine is given only to patients with no history of Q fever and negative results in serologic and skin testing. Good animal-husbandry practices are important in preventing widespread contamination of the environment by C. burnetii. These practices include isolating aborting animals for up to 14 days, raising feed bunks to prevent contamination of feed by excreta, destroying aborted materials (by burning and burying fetal membranes and stillborn animals), and wearing masks and gloves when handling aborted materials. Vaccination of sheep and goats and a culling program were effective in the Netherlands outbreak. Only seronegative pregnant animals should be used in research settings, and only seronegative animals should be permitted in petting zoos. During an outbreak of Q fever and for 4 weeks after it ceases, blood donations should not be accepted from individuals who live in the affected area. Acknowledgment The contributions of Didier Raoult, MD, to this chapter in previous editions are gratefully acknowledged.
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212
Infections Due to Mycoplasmas R. Doug Hardy
MYCOPLASMA PNEUMONIAE
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CLINICAL MANIFESTATIONS Upper Respiratory Tract Infections and Pneumonia Acute M. pneumoniae infections generally manifest as pharyngitis, tracheobronchitis, reactive airway disease/wheezing, or a nonspecific upper respiratory syndrome. Little evidence supports the commonly held belief that this organism is an important cause of otitis media, with or without bullous myringitis. Pneumonia develops in 3–13% of infected individuals; its onset is usually gradual, occurring over several days, but may be more abrupt. Although Mycoplasma pneumonia may begin with a sore throat, the most common presenting symptom is cough. The cough is typically nonproductive, but some patients produce sputum. Headache, malaise, chills, and fever are noted in the majority of patients. On physical examination, wheezes or rales are detected in ∼80% of patients with M. pneumoniae pneumonia. In many patients, however, pneumonia can be diagnosed only by chest radiography. The most common radiographic pattern is that of peribronchial pneumonia with thickened bronchial markings, streaks of interstitial infiltration, and areas of subsegmental atelectasis. Segmental or lobar consolidation is not uncommon. While clinically evident pleural effusions are infrequent, lateral decubitus views reveal that up to 20% of patients have pleural effusions. Overall, the clinical presentation of pneumonia in an individual patient is not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia. The possibility of M. pneumoniae infection deserves particular consideration when community-acquired pneumonia fails to respond to treatment with a penicillin or a cephalosporin—antibiotics that are ineffective against mycoplasmas. Symptoms usually resolve within 2–3 weeks after the onset of illness. Although M. pneumoniae pneumonia is generally selflimited, appropriate antimicrobial therapy significantly shortens the duration of clinical illness. Infection uncommonly results in critical illness and only rarely in death. In some patients, long-term recurrent wheezing or reactive airway disease may follow the resolution of acute pneumonia. The significance of chronic infection, especially as it relates to asthma, is an area of active investigation.
Infections Due to Mycoplasmas
PATHOGENESIS M. pneumoniae is generally thought to act as an extracellular pathogen. Although the organism has been shown to exist and replicate within human cells, it is not known whether these intracellular events contribute to the pathogenesis of disease. M. pneumoniae attaches to ciliated respiratory epithelial cells by means of a complex terminal organelle at the tip of one end of the organism. Cytoadherence is mediated by interactive adhesins and accessory proteins clustered on this organelle. After extracellular attachment, M. pneumoniae causes injury to host respiratory tissue. The mechanism of injury is thought to be mediated by the production of hydrogen peroxide and of a recently identified ADP-ribosylating and vacuolating cytotoxin of M. pneumoniae that has many similarities to pertussis toxin. Because mycoplasmas lack a cell wall, they also lack cell wall–derived stimulators of the innate immune system, such as lipopolysaccharide, lipoteichoic acid, and murein (peptidoglycan) fragments. However, lipoproteins from the mycoplasmal cell membrane appear to have inflammatory properties, probably acting through Toll-like receptors (primarily TLR2) on macrophages and other cells. Lung biopsy specimens from patients with M. pneumoniae respiratory tract infection reveal an inflammatory process involving the trachea, bronchioles, and peribronchial tissue, with a monocytic infiltrate coinciding with a luminal exudate of polymorphonuclear leukocytes. Experimental evidence indicates that innate immunity provides most of the host’s defense against mycoplasmal infection in the lungs, whereas cellular immunity may actually play an immunopathogenic role, exacerbating mycoplasmal lung disease. Humoral immunity appears to provide protection against dissemination of M. pneumoniae infection; patients with humoral immunodeficiencies do not have more severe lung disease than do immunocompetent patients in the early stages of infection but more often develop disseminated infection resulting in syndromes such as arthritis, meningitis, and osteomyelitis. The immunity that follows severe M. pneumoniae infections is more protective and longer-lasting than that following mild infections.
EPIDEMIOLOGY M. pneumoniae infection occurs worldwide. It is likely that the incidence of upper respiratory illness due to M. pneumoniae is up to 20 times that of pneumonia caused by this organism. Infection is spread from one person to another by respiratory droplets expectorated during coughing and results in clinically apparent disease in an estimated 80% of cases. The incubation period for M. pneumoniae is 2–4 weeks; therefore, the time-course of infection in a specific population may be several weeks long. Intrafamilial attack rates are as high as 84% among children and 41% among adults. Outbreaks of M. pneumoniae illness often occur in institutional settings such as military bases, boarding schools, and summer camps. Infections tend to be endemic, with sporadic epidemics every 4–7 years. There is no seasonal pattern. Most significantly, M. pneumoniae is a major cause of communityacquired respiratory illness in both children and adults and is often grouped with Chlamydia pneumoniae and Legionella species as being among the most important bacterial causes of “atypical” communityacquired pneumonia. For community-acquired pneumonia in adults, M. pneumoniae is the most frequently detected “atypical” organism. Analysis of 13 studies of community-acquired pneumonia published since 1995 (which included 6207 ambulatory and hospitalized adults) showed that the overall prevalence of M. pneumoniae was 22.7%; by comparison, the prevalence of C. pneumoniae was 11.7%, and that of Legionella species was 4.6%. M. pneumoniae pneumonia is also referred to as Eaton agent pneumonia (the organism having first been isolated in the early 1940s by Monroe Eaton), primary atypical pneumonia, and “walking” pneumonia.
CHAPTER 212
Mycoplasmas are prokaryotes of the class Mollicutes. Their size (150–350 nm) is closer to that of viruses than to that of bacteria. Unlike viruses, however, mycoplasmas grow in cell-free culture media; in fact, they are the smallest organisms capable of independent replication. The entire genomes of many Mycoplasma species have been sequenced and have been found to be among the smallest of all prokaryotic genomes. Sequencing information for these genomes has helped define the minimal set of genes necessary for cellular life. The absence of genes related to the synthesis of amino acids, fatty acid metabolism, and cholesterol dictates the mycoplasmas’ parasitic or saprophytic dependence on a host for exogenous nutrients and necessitates the use of complex fastidious media to culture these organisms. Mycoplasmas lack a cell wall and are bound only by a cell membrane. The absence of a cell wall explains the inactivity of β-lactam antibiotics (penicillins and cephalosporins) against infections caused by these organisms. At least 13 Mycoplasma species, two Acholeplasma species, and two Ureaplasma species have been isolated from humans. Most of these species are thought to be normal inhabitants of oral and urogenital mucous membranes. Only four species—M. pneumoniae, M. hominis, U. urealyticum, and U. parvum—have been shown conclusively to be pathogenic in immunocompetent humans. M. pneumoniae primarily infects the respiratory tract, while M. hominis, U. urealyticum, and U. parvum are associated with a variety of genitourinary tract disorders and neonatal infections. Some data indicate that M. genitalium may be a cause of disease in humans. Other mycoplasmas may cause disease in immunocompromised persons.
Genuine second attacks of M. pneumoniae pneumonia have been 1163 reported infrequently.
Extrapulmonary Manifestations An array of extrapulmonary manifestations may develop during M. pneumoniae infection. The most significant are neurologic, dermatologic, cardiac, rheumatologic, and
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1164 hematologic in nature. Extrapulmonary manifestations can be a
PART 8
result of disseminated infection, especially in patients with humoral immunodeficiencies (e.g., septic arthritis); postinfectious autoimmune phenomena (e.g., Guillain-Barré syndrome); or possibly ADPribosylating toxin. Overall, these manifestations are uncommon, given the frequency of M. pneumoniae infection. Notably, many patients with extrapulmonary M. pneumoniae disease do not have respiratory disease. Skin eruptions described with M. pneumoniae infection include erythematous (macular or maculopapular), vesicular, bullous, petechial, and urticarial rashes. In some reports, 17% of patients with M. pneumoniae pneumonia have had an exanthem. Erythema multiforme major (Stevens-Johnson syndrome) is the most clinically significant skin eruption associated with M. pneumoniae infection; it appears to occur more commonly with M. pneumoniae than with other infectious agents. A wide spectrum of neurologic manifestations has been reported with M. pneumoniae infection. The most common are meningoencephalitis, encephalitis, Guillain-Barré syndrome, and aseptic meningitis. M. pneumoniae has been implicated as a likely etiologic agent in 5–7% of cases of encephalitis. Other neurologic manifestations may include cranial neuropathy, acute psychosis, cerebellar ataxia, acute demyelinating encephalomyelitis, cerebrovascular thromboembolic events, and transverse myelitis. Hematologic manifestations of M. pneumoniae infection include hemolytic anemia, aplastic anemia, cold agglutinins, disseminated intravascular coagulation, and hypercoagulopathy. When anemia does occur, it generally develops in the second or third week of illness. In addition, hepatitis, glomerulonephritis, pancreatitis, myocarditis, pericarditis, rhabdomyolysis, and arthritis (septic and reactive) have been convincingly ascribed to M. pneumoniae infection. Septic arthritis has been described most commonly in hypogammaglobulinemic patients.
DIAGNOSIS
Infectious Diseases
Clinical findings, nonmicrobiologic laboratory tests, and chest radiography are not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia. In addition, since M. pneumoniae lacks a cell wall, it is not visible on Gram’s stain. Although of historical interest, the measurement of cold agglutinin titers is no longer recommended for the diagnosis of M. pneumoniae infection because the findings are nonspecific and assays specific for M. pneumoniae are now available. Acute M. pneumoniae infection can be diagnosed by polymerase chain reaction (PCR) detection of the organism in respiratory tract secretions or by isolation of the organism in culture (Table 212-1). Oropharyngeal, nasopharyngeal, and pulmonary specimens are all acceptable for diagnosing M. pneumoniae pneumonia. Other bodily fluids, such cerebrospinal fluid, are acceptable for extrapulmonary infection. M. pneumoniae culture (which requires special media) is not recommended for routine diagnosis because the organism may take weeks to grow and is often difficult to isolate from clinical specimens. In contrast, PCR allows rapid, specific diagnosis earlier in the course of clinical illness. The diagnosis can also be established by serologic tests for IgM and IgG antibodies to M. pneumoniae in paired (acute- and convalescent-phase) serum samples; enzyme-linked immunoassay is
TABLE 212-1 Diagnostic Tests for Respiratory Mycoplasma pneumoniae Infectiona Test Respiratory culture Respiratory PCR Serologic studiesb
Sensitivity, % ≤60 65–90 55–100
the recommended serologic method. An acute-phase sample alone is not adequate for diagnosis, as antibodies to M. pneumoniae may not develop until 2 weeks into the illness; therefore, it is important to test paired samples. In addition, IgM antibody to M. pneumoniae can persist for up to 1 year after acute infection. Thus its presence may indicate recent rather than acute infection. The combination of PCR of respiratory tract secretions and serologic testing constitutes the most sensitive and rapid approach to the diagnosis of M. pneumoniae infection. TREATMENT
Although in the majority of untreated cases symptoms resolve within 2–3 weeks without significant associated morbidity, M. pneumoniae pneumonia can be a serious illness that responds to appropriate antimicrobial therapy (Table 212-2). Randomized, double-blind, placebo-controlled trials in adults have demonstrated that antimicrobial treatment significantly decreases the duration of fever, cough, malaise, hospitalization, and radiologic abnormalities in M. pneumoniae pneumonia. Treatment options for acute M. pneumoniae infection include macrolides (e.g., oral azithromycin, 500 mg on day 1, then 250 mg/d on days 2–5), tetracyclines (e.g., oral doxycycline, 100 mg twice daily for 10–14 days), and respiratory fluoroquinolones. However, ciprofloxacin and ofloxacin are not recommended because of their high minimal inhibitory concentrations against M. pneumoniae isolates and their poor performance in experimental studies. A 10- to 14-day course of quinolone therapy appears adequate. In Japan and China, very high levels (up to ≥90%) of M. pneumoniae resistance to macrolides have been reported. In Europe and to a lesser degree in the United States, macrolide-resistant M. pneumoniae is emerging. In investigated outbreaks of respiratory illness due to M. pneumoniae in the United States, macrolide resistance has been reported in 8–27% of isolates. Clinical studies have demonstrated that, when treated with macrolides, patients with community-acquired pneumonia due to macrolideresistant M. pneumoniae experience a significantly longer duration of symptoms than do patients infected with macrolide-sensitive organisms; thus macrolide resistance in M. pneumoniae does appear to have clinical significance. If macrolide resistance is prominent in a particular geographic locale or is suspected, then a nonmacrolide antibiotic should be considered for treatment; in addition, culture of M. pneumoniae may prove useful in these instances, providing an isolate for susceptibility testing. Clinical observations and experimental data suggest that the addition of glucocorticoids to an antibiotic regimen may be of value for the treatment of severe or refractory M. pneumoniae pneumonia. However, relevant clinical experience is limited. Even though appropriate antibiotic therapy significantly reduces the duration of respiratory illness, it does not appear to shorten the duration of detection of M. pneumoniae by culture or PCR; therefore, a test of cure or eradication is not suggested. The roles of antimicrobial drugs, glucocorticoids, and IV immunoglobulin in the treatment of neurologic disease due to M. pneumoniae remain unknown. TABLE 212-2 Antimicrobial Agents of Choice for Mycoplasma Infectionsa Organism M. pneumoniae
Specificity, % 100 90–100 55–100
U. urealyticum, U. parvum
A combination of PCR and serology is suggested for routine diagnosis. If macrolide resistance is suspected, M. pneumoniae culture may prove useful, providing an isolate for susceptibility testing. bAcute- and convalescent-phase serum samples are recommended.
a
Abbreviation: PCR, polymerase chain reaction.
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Mycoplasma pneumoniae Infections
M. hominis M. genitalium
Drug(s) Azithromycin, clarithromycin, erythromycin, doxycycline, levofloxacin, moxifloxacin, gemifloxacin (not ciprofloxacin or ofloxacin) Azithromycin, clarithromycin, erythromycin, doxycycline Doxycycline, clindamycin Azithromycin
Antimicrobial resistance has been reported in mycoplasmas, as described in the text.
a
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UROGENITAL MYCOPLASMAS (SEE ALSO CHAP. 163) EPIDEMIOLOGY M. hominis, M. genitalium, U. urealyticum, and U. parvum can cause urogenital tract disease. The significance of isolation of these organisms in a variety of other syndromes is unknown and in some cases is being investigated. M. fermentans has not been shown convincingly to cause human disease. While urogenital mycoplasmas may be transmitted to a fetus during passage through a colonized birth canal, sexual contact is the major mode of transmission, and the risk of colonization increases dramatically with increasing numbers of sexual partners. In asymptomatic women, these mycoplasmas may be found throughout the lower urogenital tract. The vagina yields the largest number of organisms; next most densely colonized are the periurethral area and the cervix. Ureaplasmas are isolated less often from urine than from the cervix, but M. hominis is found with approximately the same frequency at these two sites. Ureaplasmas are isolated from the vagina of 40–80% of sexually active, asymptomatic women and M. hominis from 21–70%. The two microorganisms are found concurrently in 31–60% of women. In men, colonization with each organism is less prevalent. Mycoplasmas have been isolated from urine, semen, and the distal urethra of asymptomatic men.
Postpartum and Postabortal Infection Studies implicate M. hominis as the primary pathogen in ∼5–10% of women who have postpartum or postabortal fever; ureaplasmas have been implicated to a lesser degree. These infections are generally self-limited; however, if symptoms persist, specific antimicrobial therapy should be given. Ureaplasmas also appear to play a role in occasional postcesarean wound infections. Non-urogenital Infection In rare instances, M. hominis causes nonurogenital infections, such as brain abscess, wound infection, poststernotomy mediastinitis, endocarditis, and neonatal meningitis. These infections are most common among immunocompromised and hypogammaglobulinemic patients. Ureaplasmas and M. hominis can cause septic arthritis in immunodeficient patients. Ureaplasmas probably cause neonatal pneumonitis; their significant role in the development of bronchopulmonary dysplasia—the chronic lung disease of premature infants—has been documented in a number of studies. It is unclear whether ureaplasmas and M. hominis cause
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TREATMENT
Urogenital Mycoplasma Infections
Because colonization with urogenital mycoplasmas is common, it appears at present that their isolation from the urogenital tract in the absence of disease generally does not warrant treatment. Macrolides and doxycycline are considered the antimicrobial agents of choice for Ureaplasma infections (Table 212-2). Ureaplasma resistance to macrolides, doxycycline, quinolones, and chloramphenicol has been reported. M. hominis is resistant to macrolides. Doxycycline is generally the drug of choice for M. hominis infections, although resistance has been reported. Clindamycin is generally active against M. hominis. Quinolones are active in vitro against M. hominis. For M. genitalium, the agent of choice appears to be azithromycin; treatment failures have been reported with other macrolides as well as with quinolones.
213
Chlamydial Infections Charlotte A. Gaydos, Thomas C. Quinn
Chlamydiae are obligate intracellular bacteria that cause a wide variety of diseases in humans and animals.
ETIOLOGIC AGENTS The chlamydiae were originally classified as four species in the genus Chlamydia: C. trachomatis, C. pneumoniae, C. psittaci, and C. pecorum (the last species being found in ruminants). The C. psittaci group has been separated into three species: C. psittaci, C. felis, and C. abortus. The mouse pneumonitis strain (MoPn) is now classified as C. muridarum, and the guinea pig inclusion conjunctivitis strain (GPIC) is now designated C. caviae. C. trachomatis is divided into two biovars: trachoma and LGV (lymphogranuloma venereum). The trachoma biovar causes two major types of disease in humans: ocular trachoma, the leading infectious cause of preventable blindness in the developing world; and urogenital infections, which are sexually or neonatally transmitted. The 18 serovars of C. trachomatis fall into three groups: the trachoma serovars A, B, Ba, and C; the oculogenital serovars D–K; and the LGV serovars L1–L3. Serovars can be distinguished by serologic typing with monoclonal antibodies or by molecular gene typing. However, serovar identification usually is not important clinically since the antibiotic susceptibility pattern is the same for all three groups. The one exception applies when LGV is suspected on clinical grounds; in this situation, serovar determination is important because a longer treatment duration is required for LGV strains.
Chlamydial Infections
Pelvic Inflammatory Disease M. hominis can cause pelvic inflammatory disease. In most episodes, M. hominis occurs as part of a polymicrobial infection, but the organism may play an independent role in a limited number of cases. Some data also support an association of M. genitalium with pelvic inflammatory disease. Ureaplasmas are not thought to cause pelvic inflammatory disease.
DIAGNOSIS Culture and PCR are both appropriate methods for the isolation of urogenital mycoplasmas. Culture of these organisms, however, requires special techniques and media that generally are available only at larger medical centers and reference laboratories. Serologic testing is not recommended for the clinical diagnosis of urogenital Mycoplasma infections.
CHAPTER 213
CLINICAL MANIFESTATIONS Urethritis, Pyelonephritis, and Urinary Calculi In many episodes of Chlamydia-negative nongonococcal urethritis, ureaplasmas may be the causative agent. These organisms may also cause chronic voiding symptoms in women. The common presence of ureaplasmas in the urethra of asymptomatic men suggests either that only certain serovars are pathogenic or that predisposing factors, such as lack of immunity, must exist in persons who develop symptomatic infection. Alternatively, disease may develop only upon initial exposure to ureaplasmas. Ureaplasmas have been implicated in epididymitis. M. genitalium also appears to cause urethritis. M. genitalium and ureaplasmas do not have a known role in prostatitis. M. hominis does not appear to play a primary etiologic role in urethritis, epididymitis, or prostatitis. Evidence suggests that M. hominis causes up to 5% of cases of acute pyelonephritis. Ureaplasmas have not been associated with this disease. Ureaplasmas play a limited role in the production of urinary calculi. The frequency with which ureaplasmas reach the kidney, the predisposing factors that allow them to do so, and the relative frequency of urinary tract calculi induced by this organism (compared with other organisms) are not known.
infertility, spontaneous abortion, premature labor, low birth weight, 1165 or chorioamnionitis.
BIOLOGY, GROWTH CYCLE, AND PATHOGENESIS BIOLOGY During their intracellular growth, chlamydiae produce characteristic intracytoplasmic inclusions that can be visualized by direct fluorescent antibody (DFA) or Giemsa staining of infected clinical material, such as conjunctival scrapings or cervical or urethral epithelial
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1166 cells. Chlamydiae are nonmotile, gram-negative, obligate intracellular
bacteria that replicate within the cytoplasm of host cells, forming the characteristic membrane-bound inclusions that are the basis for some diagnostic tests. Originally considered to be large viruses, chlamydiae differ from viruses in possessing RNA and DNA as well as a cell wall that is quite similar in structure to the cell wall of typical gram-negative bacteria. However, chlamydiae lack peptidoglycan; their structural integrity depends on disulfide binding of outer-membrane proteins.
PART 8
GROWTH CYCLE Among the defining characteristics of chlamydiae is a unique growth cycle that involves alternation between two highly specialized morphologic forms (Figs. 213-1 and 213-2): the elementary body (EB), which is the infectious form and is specifically adapted for extracellular survival, and the metabolically active and replicating reticulate body (RB), which is not infectious, is adapted for an intracellular environment, and does not survive well outside the host cell. The biphasic growth cycle begins with attachment of the EB (diameter, 0.25–0.35 μm) at specific sites on the surface of the host cell. The EB enters the cell through a process similar to receptor-mediated endocytosis and resides in an inclusion, where the entire growth cycle is completed. The chlamydiae prevent phagosome-lysosome fusion. The inclusion membrane is modified by insertion of chlamydial antigens. Once the EB has entered the cell, it reorganizes into an RB, which is larger (0.5–1 μm) and contains more RNA. After ~8 h, the RB starts to divide by binary fission. The intracytoplasmic, membrane-bound inclusion body containing the RBs increases in size as the RBs multiply. Approximately 18–24 h after infection of the cell, these RBs begin to become EBs by a reorganization or condensation process that is poorly understood. After rupture of the inclusion body, the EBs are released to initiate another cycle of infection. Chlamydiae are susceptible to many broad-spectrum antibiotics and possess a number of enzymes, but they have a very restricted
Infectious Diseases Figure 213-1 Chlamydial intracellular inclusions filled with smaller dense elementary bodies and larger reticulate bodies. (Reprinted with permission from WE Stamm: Chlamydial infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, 2008, p 1070.)
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2. Initial inclusions 3. Fusion of inclusions; appearance of RBs
1. Uptake of chlamydial EBs
Cell cytoplasm Cell membrane Cell nucleus 6. Release of EBs
4. Multiplication of RBs; enlargement of inclusion 5. Conversion of RBs to EBs
8. Return to normal cycle with IFN-γ removal 7. Persistence associated with IFN-γ exposure; large aberrant RBs
Figure 213-2 Chlamydial life cycle. EBs, elementary bodies; RBs, reticulate bodies; IFN-γ, interferon γ. (Reprinted with permission from WE Stamm: Chlamydial infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, 2008, p 1071.) metabolic capacity. None of these metabolic reactions results in the production of energy. Chlamydiae have thus been considered to be energy parasites that use the ATP produced by the host cell for their own metabolic functions. Many aspects of chlamydial molecular biology are not well understood, but the sequencing of several chlamydial genomes and new proteomics research have provided researchers with many relevant tools for elucidating the biology of the life cycle. PATHOGENESIS Genital infections are mostly caused by C. trachomatis serovars D–K, with serovars D, E, and F involved most often. Molecular typing of the major outer-membrane protein gene (omp1) from which serovar differences arise has been used to demonstrate that polymorphisms can occur in isolates from patients who are exposed frequently to multiple infections, while less variation is observed in isolates from less sexually active populations. Polymorphisms in the major outer-membrane protein may provide antigenic variation, and the different forms allow persistence in the community because immunity to one is not protective against the others. The trachoma biovar is essentially a parasite of squamocolumnar epithelial cells; the LGV biovar is more invasive and involves lymphoid cells. As is typical of chlamydiae, C. trachomatis strains are capable of causing chronic, clinically inapparent, asymptomatic infections. Because the duration of the chlamydial growth cycle is ~48–72 h, the incubation period of sexually transmitted chlamydial infections is relatively long—generally 1–3 weeks. C. trachomatis causes cell death as a result of its replicative cycle and can induce cell damage whenever it persists. However, few toxic effects are demonstrated, and cell death because of chlamydial replication is not sufficient to account for disease manifestations, the majority of which are due to immunopathologic mechanisms or nonspecific host responses to the organism or its byproducts. In recent years, the entire genomes of various chlamydial species have been sequenced, the field of proteomics has become established, host innate immunity has been more precisely delineated, and innovative host cell–chlamydial interaction studies have been conducted. As a result, many insights have been gained into how chlamydiae adapt and replicate in their intracellular environment and produce disease. These insights into pathogenesis include information
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on the regulation of gene expression, protein localization, the type III secretion system, the roles of CD4+ and CD8+ T lymphocytes in the host response, and T lymphocyte trafficking. The chlamydial heat-shock protein, which shares antigenic epitopes with similar proteins of other bacteria and with human heat-shock protein, may sensitize the host, and repeated infections may cause host cell damage. Persistent or recurrent chlamydial infections are associated with fibrosis, scarring, and complications following simple epithelial infections. A common endpoint of these late consequences is scarring of mucous membranes. Genital complications can lead to pelvic inflammatory disease (PID) and its late consequences of infertility, ectopic pregnancy, and chronic pelvic pain, while ocular infections may lead to blinding trachoma. High levels of antibody to human heatshock protein have been associated with tubal factor infertility and ectopic pregnancy. Without adequate therapy, chlamydial infections may persist for several years, although symptoms—if present—usually abate. The pathogenic mechanisms of C. pneumoniae have yet to be completely elucidated. The same is true for C. psittaci, except that this agent infects cells very efficiently and causes disease that may reflect direct cytopathic effects.
CHLAMYDIA TRACHOMATIS INFECTIONS
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Clinical Manifestations • Nongonococcal and postgonococcal urethritis C. trachomatis is the most common cause of nongonococcal urethritis (NGU) and postgonococcal urethritis (PGU). The designation PGU refers to NGU developing in men 2–3 weeks after treatment of gonococcal urethritis with single doses of agents such as penicillin or cephalosporins, which lack antimicrobial activity against chlamydiae. Since current treatment regimens for gonorrhea have evolved and now include combination therapy with tetracycline, doxycycline, or azithromycin—all of which are effective against concomitant chlamydial infection—both the incidence of PGU and the causative role of C. trachomatis in this syndrome have declined. In the United States, most of the estimated 2 million cases of acute urethritis are NGU, and C. trachomatis is implicated in 30–50% of these cases. The cause of most of the remaining cases of NGU is uncertain, but recent evidence suggests that Ureaplasma urealyticum, Mycoplasma genitalium, Trichomonas vaginalis, and herpes simplex virus (HSV) cause some cases. The rate of involvement of C. trachomatis in urethral infection ranges from 3–7% among asymptomatic men to 15–20% among symptomatic men attending STD clinics. A multisite study of men in Baltimore, Seattle, Denver, and San Francisco reported an overall chlamydial prevalence of 7% in urine samples assessed by nucleic acid amplification tests (NAATs). As in women, infection in men is age related, with young age as the greatest risk factor for chlamydial urethritis. The prevalence among men is highest at 20–24 years of age. In STD clinics, urethritis is usually less prevalent among men who have sex with men (MSM) than among heterosexual men and is almost always much more common among African-American men than among Caucasian men. One study reported prevalences of 19% and 9% among nonwhite and white heterosexual men, respectively.
Chlamydial Infections
Epidemiology C. trachomatis genital infections are global in distribution. The World Health Organization (WHO) estimated in 2008 that >106.4 million cases occur annually worldwide. This figure makes chlamydial infection the most prevalent sexually transmitted bacterial infection in the world. The associated morbidity is substantial, and economic costs are high. In the United States, chlamydial infections are the most commonly reported of all infectious diseases. In 2012, 1.3 million cases were reported to the U.S. Centers for Disease Control and Prevention (CDC); however, the CDC estimates that 2–3 million new cases occur per year, with substantial underreporting due to lack of screening in some populations. Rates of infection have increased every year; higher rates among women than among men reflect the focus on expansion of screening programs for women during the past 20 years, the use of increasingly sensitive diagnostic tests, an increased emphasis on case reporting, and improvements in the information systems used for reporting. The CDC and other professional organizations recommend annual screening of all sexually active women ≤25 years of age as well as rescreening of previously infected individuals at 3 months. Young women have the highest infection rates; in 2012, the figures were 3416.5 and 3722.5 cases per 100,000 population at 15–19 and 20–24 years of age, respectively. Age-specific rates among men, while much lower than those among women, were highest in the 20- to
CHAPTER 213
GENITAL INFECTIONS Spectrum Although chlamydiae cause a number of human diseases, localized lower genital tract infections caused by C. trachomatis and the sequelae of such infections are the most important in terms of medical and economic impact. Oculogenital infections due to C. trachomatis serovars D–K are transmitted during sexual contact or from mother to baby during childbirth and are associated with many syndromes, including cervicitis, salpingitis, acute urethral syndrome, endometritis, ectopic pregnancy, infertility, and PID in female patients; urethritis, proctitis, and epididymitis in male patients; and conjunctivitis and pneumonia in infants. Women bear the greatest burden of morbidity because of the serious sequelae of these infections. Untreated infections lead to PID, and multiple episodes of PID can lead to tubal factor infertility and chronic pelvic pain. Studies estimate that up to 80–90% of women and >50% of men with C. trachomatis genital infections lack symptoms; other patients have very mild symptoms. Thus a large reservoir of infected persons continues to transmit infection to sexual partners. As their designations reflect, the LGV serovars (L1, L2, and L3) cause LGV, an invasive sexually transmitted disease (STD) characterized by acute lymphadenitis with bubo formation and/or acute hemorrhagic proctitis (see “Lymphogranuloma Venereum,” below).
24-year-old age group, at 1343.3 cases per 100,000. In 2012, rates 1167 increased for all racial and ethnic groups, with the highest rates among African Americans. For example, the rate of chlamydial infection among African-American girls 15–19 years of age was 7507.1 cases per 100,000—almost six times the rate among Caucasian girls in the same age group (1301.5/100,000). The rate among African-American women 20–24 years old was 4.8 times the rate among Caucasian women in the same age group. Similar racial disparities in reported rates of chlamydial infection exist among men. For boys 15–19 years of age, the rate among African Americans was 11.1 times the rate among Caucasians. The rate among Native Americans/Alaska Natives was more than four times the rate among Caucasians (648.3), and the rate among Latinos (383.6) was two times higher than that among Caucasians. These disparities are important reflections of health inequities in the United States. The above statistics are based on case reporting. Studies based on screening surveys estimate that the U.S. prevalence of C. trachomatis cervical infection is 5% among asymptomatic female college students and prenatal patients, >10% among women seen in family planning clinics, and >20% among women seen in STD clinics. The prevalence of genital C. trachomatis infections varies substantially by geographic locale, with the highest rates in the southeastern United States. However, asymptomatic infections have been detected in >8–10% of young female military recruits from all parts of the country. The prevalence of C. trachomatis in the cervix of pregnant women is 5–10 times higher than that of Neisseria gonorrhoeae. The prevalence of genital infection with either agent is highest among women who are between the ages of 18 and 24, single, and non-Caucasian (e.g., AfricanAmerican, Latina, Asian, Pacific Islander). Infections recur frequently in these same risk groups and are often acquired from untreated sexual partners. The use of oral contraception and the presence of cervical ectopy also confer an increased risk. The proportion of infections that are asymptomatic appears to be higher for C. trachomatis than for N. gonorrhoeae, and symptomatic C. trachomatis infections are clinically less severe. Mild or asymptomatic C. trachomatis infections of the fallopian tubes nonetheless cause ongoing tubal damage and infertility. The costs of C. trachomatis infections and their complications to the U.S. health care system have recently been estimated to exceed $516.7 million annually.
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PART 8
NGU is diagnosed by documentation of a leukocytic urethral exudate and by exclusion of gonorrhea by Gram’s staining or culture. C. trachomatis urethritis is generally less severe than gonococcal urethritis, although in any individual patient these two forms of urethritis cannot reliably be differentiated solely on clinical grounds. Symptoms include urethral discharge (often whitish and mucoid rather than frankly purulent), dysuria, and urethral itching. Physical examination may reveal meatal erythema and tenderness as well as a urethral exudate that is often demonstrable only by stripping of the urethra. At least one-third of male patients with C. trachomatis urethral infection have no evident signs or symptoms of urethritis. The availability of NAATs for first-void urine specimens has facilitated broaderbased testing for asymptomatic infection in male patients. As a result, asymptomatic chlamydial urethritis has been demonstrated in 5–10% of sexually active male adolescents screened at school-based clinics or community centers. Such patients generally have pyuria (≥15 leukocytes per 400× microscopic field in the sediment of first-void urine), a positive leukocyte esterase test, or an increased number of leukocytes on a Gram-stained smear prepared from a urogenital swab inserted 1–2 cm into the anterior urethra. To differentiate between true urethritis and functional symptoms in symptomatic patients or to make a presumptive diagnosis of C. trachomatis infection in high-risk but asymptomatic men (e.g., male patients in STD clinics, sex partners of women with nongonococcal salpingitis or mucopurulent cervicitis, fathers of children with inclusion conjunctivitis), the examination of an endourethral specimen for increased leukocytes is useful if specific diagnostic tests for chlamydiae are not available. Alternatively, urethritis can be assayed noninvasively by examination of a first-void urine sample for pyuria, either by microscopy or by the leukocyte esterase test. Urine (or a urethral swab) can also be tested directly for chlamydiae by DNA amplification methods, as described below (see “Detection Methods”).
Infectious Diseases
Epididymitis Chlamydial urethritis may be followed by acute epididymitis, but this condition is rare, generally occurring in sexually active patients 80% of affected patients have
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the HLA-B27 phenotype and since other mucosal infections produce an identical syndrome, chlamydial infection is thought to initiate an aberrant hyperactive immune response that produces inflammation of the involved target organs in these genetically predisposed individuals. Evidence of exaggerated cell-mediated and humoral immune responses to chlamydial antigens in reactive arthritis supports this hypothesis. The finding of chlamydial EBs and DNA in joint fluid and synovial tissue from patients with reactive arthritis suggests that chlamydiae may actually spread from genital to joint tissues in these patients—perhaps in macrophages. NGU is the initial manifestation of reactive arthritis in 80% of patients, typically occurring within 14 days after sexual exposure. The urethritis may be mild and may even go unnoticed by the patient. Similarly, gonococcal urethritis may precede reactive arthritis, but coinfection with an agent of NGU is difficult to rule out. The urethral discharge may be purulent or mucopurulent, and patients may or may not report dysuria. Accompanying prostatitis, usually asymptomatic, has been described. Arthritis usually begins ~4 weeks after the onset of urethritis but may develop sooner or, in a small percentage of cases, may actually precede urethritis. The knees are most frequently involved; next most commonly affected are the ankles and small joints of the feet. Sacroiliitis, either symmetrical or asymmetrical, is documented in twothirds of patients. Mild bilateral conjunctivitis, iritis, keratitis, or uveitis is sometimes present but lasts for only a few days. Finally, dermatologic manifestations occur in up to 50% of patients. The initial lesions— usually papules with a central yellow spot—most often involve the soles and palms and, in ~25% of patients, eventually epithelialize and thicken to produce keratoderma blenorrhagicum. Circinate balanitis is usually painless and occurs in fewer than half of patients. The initial episode of reactive arthritis usually lasts 2–6 months. Proctitis Primary anal or rectal infections with C. trachomatis have been described in women and MSM who practice anal intercourse. In these infections, rectal involvement is initially characterized by severe anorectal pain, a bloody mucopurulent discharge, and tenesmus. Oculogenital serovars D–K and LGV serovars L1, L2, and L3 have been found to cause proctitis. The LGV serovars are far more invasive and cause much more severely symptomatic disease, including severe ulcerative proctocolitis that can be clinically confused with HSV proctitis. Histologically, LGV proctitis may resemble Crohn’s disease in that giant cell formation and granulomas are detected. In the United States and Europe, cases of LGV proctitis occur almost exclusively in MSM, many of whom are positive for HIV infection. The less invasive non-LGV serovars of C. trachomatis cause mild proctitis. Many infected individuals are asymptomatic, and in these cases infection is diagnosed only by routine culture or NAAT of rectal swabs. The number of fecal leukocytes is usually abnormal in both asymptomatic and symptomatic cases. Sigmoidoscopy may yield normal findings or may reveal mild inflammatory changes or small erosions or follicles in the lower 10 cm of the rectum. Histologic examination of rectal biopsies generally shows anal crypts and prominent follicles as well as neutrophilic infiltration of the lamina propria. Chlamydial proctitis is best diagnosed by isolation of C. trachomatis from the rectum and documentation of a response to appropriate therapy. NAATs are reportedly more sensitive than culture for diagnosis and are also specific. Mucopurulent cervicitis Although many women with chlamydial infections of the cervix have no symptoms, almost half generally have local signs of infection on examination. Cervicitis is usually characterized by the presence of a mucopurulent discharge, with >20 neutrophils per microscopic field visible in strands of cervical mucus in a thinly smeared, gram-stained preparation of endocervical exudate. Hypertrophic ectopy of the cervix may also be evident as an edematous area near the cervical os that is congested and bleeds easily on minor trauma (e.g., when a specimen is collected with a swab). A Papanicolaou smear shows increased numbers of neutrophils as well as a characteristic pattern of mononuclear inflammatory cells including plasma cells, transformed lymphocytes, and histiocytes. Cervical biopsy shows a predominantly mononuclear cell infiltrate of
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may develop in some women with chlamydial infection, the major- 1169 ity of women attending STD clinics for urethral chlamydial infection do not have dysuria or frequency. Even in women with chlamydial urethritis causing the acute urethral syndrome, signs of urethritis such as urethral discharge, meatal redness, and swelling are uncommon. However, mucopurulent cervicitis in a woman presenting with dysuria and frequency strongly suggests C. trachomatis urethritis. Other correlates of chlamydial urethral syndrome include a duration of dysuria of >7–10 days, lack of hematuria, and lack of suprapubic tenderness. Abnormal urethral Gram’s stains showing >10 PMNs per 1000× field in women with dysuria but without coliform bacteriuria support the diagnosis of chlamydial urethritis. Other possible diagnoses include gonococcal or trichomonal infection of the urethra.
Pelvic inflammatory disease Inflammation of sections of the fallopian tube is often referred to as salpingitis or PID. The proportion of acute salpingitis cases caused by C. trachomatis varies geographically and with the population studied. It has been estimated that C. trachomatis causes up to 50% of PID cases in the United States. PID occurs via ascending intraluminal spread of C. trachomatis or N. gonorrhoeae from the lower genital tract. Mucopurulent cervicitis is often followed by endometritis, endosalpingitis, and finally pelvic peritonitis. Evidence of mucopurulent cervicitis is often found in women with laparoscopically verified salpingitis. Similarly, endometritis, demonstrated by an endometrial biopsy showing plasma cell infiltration of the endometrial epithelium, is documented in most women with laparoscopy-verified chlamydial (or gonococcal) salpingitis. Chlamydial endometritis can also occur in the absence of clinical evidence of salpingitis. Histologic evidence of endometritis has been correlated with a syndrome consisting of vaginal bleeding, lower abdominal pain, and uterine tenderness in the absence of adnexal tenderness. Chlamydial salpingitis produces milder symptoms than gonococcal salpingitis and may be associated with less marked adnexal tenderness. Thus, mild adnexal or uterine tenderness in a sexually active woman with cervicitis suggests chlamydial PID. Chronic untreated endometrial and tubal inflammation can result in tubal scarring, impaired tubal function, tubal occlusion, and infertility, even among women who report no prior treatment for PID. C. trachomatis has been implicated particularly often in “subclinical” PID on the basis of (1) a lack of history of PID among Chlamydiaseropositive women with tubal damage or (2) detection of chlamydial DNA or antigen among asymptomatic women with tubal infertility. These data suggest that the best method to prevent PID and its sequelae is surveillance and control of lower genital tract infections along with diagnosis and treatment of sex partners and prevention of reinfections. Promotion of early symptom recognition and health care presentation may reduce the frequency and severity of sequelae of PID.
Infection in pregnancy and the neonatal period Infections during pregnancy can be transmitted to infants during delivery. Approximately 20–30% of infants exposed to C. trachomatis in the birth canal develop conjunctivitis, and 10–15% subsequently develop pneumonia. Consequently, all newborn infants receive ocular prophylaxis at birth to prevent ophthalmia neonatorum. Without treatment, conjunctivitis usually develops at 5–19 days of life and often results in a profuse mucopurulent discharge. Roughly half of infected infants develop clinical evidence of inclusion conjunctivitis. However, it is impossible to differentiate chlamydial conjunctivitis from other forms of neonatal conjunctivitis (e.g., that due to N. gonorrhoeae, Haemophilus influenzae, Streptococcus pneumoniae, or HSV) on clinical grounds; thus laboratory diagnosis is required. Inclusions within epithelial cells are often detected in Giemsa-stained conjunctival smears, but these smears are considerably less sensitive than cultures or NAATs for chlamydiae. Gram-stained smears may show gonococci or occasional small gramnegative coccobacilli in Haemophilus conjunctivitis, but smears should be accompanied by cultures or NAATs for these agents. C. trachomatis has also been isolated frequently and persistently from the nasopharynx, rectum, and vagina of infected infants—occasionally for >1 year in the absence of treatment. In some cases, otitis media results from perinatally acquired chlamydial infection. Pneumonia may develop in infants from 2 weeks to 4 months of age. C. trachomatis is estimated to cause 20–30% of pneumonia cases in infants 30 polymorphonuclear neutrophils (PMNs) per 1000× field in a gram-stained smear of cervical mucus correlates best with chlamydial or gonococcal cervicitis. Clinical recognition of chlamydial cervicitis depends on a high index of suspicion and careful cervical examination. No genital symptoms are specifically correlated with chlamydial cervical infection. The differential diagnosis of a mucopurulent discharge from the endocervical canal in a young, sexually active woman includes gonococcal endocervicitis, salpingitis, endometritis, and intrauterine contraceptive device–induced inflammation. Diagnosis of cervicitis is based on the presence of PMNs on a cervical swab as noted above; the presence of chlamydiae is confirmed by either culture or NAAT.
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As NAATs for C. trachomatis are being used more often, increasing numbers of cases of LGV proctitis are being recognized in MSM. Such patients present with anorectal pain and mucopurulent, bloody rectal discharge. Sigmoidoscopy reveals ulcerative proctitis or proctocolitis, with purulent exudate and mucosal bleeding. Histopathologic findings in the rectal mucosa include granulomas with giant cells, crypt abscesses, and extensive inflammation. These clinical, sigmoidoscopic, and histopathologic findings may closely resemble those of Crohn’s disease of the rectum. The most common presenting picture in heterosexual men and women is the inguinal syndrome, which is characterized by painful inguinal lymphadenopathy beginning 2–6 weeks after presumed exposure; in rare instances, the onset comes after a few months. The inguinal adenopathy is unilateral in two-thirds of cases, and palpable enlargement of the iliac and femoral nodes is often evident on the same side as the enlarged inguinal nodes. The nodes are initially discrete, but progressive periadenitis results in a matted mass of nodes that becomes fluctuant and suppurative. The overlying skin becomes fixed, inflamed, and thin, and multiple draining fistulas finally develop. Extensive enlargement of chains of inguinal nodes above and below the inguinal ligament (“the sign of the groove”) is not specific and, although not uncommon, is documented in only a minority of cases. Spontaneous healing usually takes place after several months; inguinal scars or granulomatous masses of various sizes persist for life. Massive pelvic lymphadenopathy may lead to exploratory laparotomy.
Constitutional symptoms are common during the stage of regional lymphadenopathy and, in cases of proctitis, may include fever, chills, headache, meningismus, anorexia, myalgias, and arthralgias. Other systemic complications are infrequent but include arthritis with sterile effusion, aseptic meningitis, meningoencephalitis, conjunctivitis, hepatitis, and erythema nodosum (Fig. 25e-40). Complications of untreated anorectal infection include perirectal abscess; anal fistulas; and rectovaginal, rectovesical, and ischiorectal fistulas. Secondary bacterial infection probably contributes to these complications. Rectal stricture is a late complication of anorectal infection and usually develops 2–6 cm from the anal orifice—i.e., at a site within reach on digital rectal examination. A small percentage of cases of LGV in men present as chronic progressive infiltrative, ulcerative, or fistular lesions of the penis, urethra, or scrotum. Associated lymphatic obstruction may produce elephantiasis. When urethral stricture occurs, it usually involves the posterior urethra and causes incontinence or difficulty with urination. Diagnosis • Detection methods Historically, chlamydiae were cultivated in the yolk sac of embryonated eggs. The organisms can be grown more easily in tissue culture, but cell culture—once considered the diagnostic gold standard—has been replaced by nonculture assays (Table 213-1). In general, culture for chlamydiae in clinical specimens is now performed only in specialized laboratories. The first nonculture assays, such as DFA staining of clinical material and enzyme immunoassay (EIA), have been replaced by NAATS, which are molecular
TABLE 213-1 Diagnostic Tests for Sexually Transmitted and Perinatal Chlamydia trachomatis Infection
PART 8 Infectious Diseases
Infection Men NGU, PGU
Suggestive Signs/Symptoms
Presumptive Diagnosisa
Confirmatory Test of Choice
Discharge, dysuria
Urine or urethral NAAT for C. trachomatis
Epididymitis
Unilateral intrascrotal swelling, pain, tenderness; fever; NGU
Gram’s stain with >4 neutrophils per oil-immersion field; no gonococci Gram’s stain with >4 neutrophils per oil-immersion field; no gonococci; urinalysis with pyuria
Women Cervicitis
Salpingitis
Urethritis
Mucopurulent cervical discharge, bleeding and edema of the zone of cervical ectopy Lower abdominal pain, cervical motion tenderness, adnexal tenderness or masses Dysuria and frequency without hematuria
Adults of Either Sex Proctitis Rectal pain, discharge, tenesmus, bleeding; history of receptive anorectal intercourse Reactive arthritis NGU, arthritis, conjunctivitis, typical skin lesions LGV
Neonates Conjunctivitis
Infant pneumonia
Regional adenopathy, primary lesion, proctitis, systemic symptoms
Purulent conjunctival discharge 6–18 days after delivery Afebrile; staccato cough, diffuse rales, bilateral hyperinflation, interstitial infiltrates
Cervical Gram’s stain with ≥20 neutrophils per oil-immersion field in cervical mucus C. trachomatis always potentially present in salpingitis
Urine or urethral NAAT for C. trachomatis
Urine, cervical, or vaginal NAAT for C. trachomatis
Urine, cervical, or vaginal NAAT for C. trachomatis
MPC; sterile pyuria; negative routine urine culture
Urine or urethral NAAT for C. trachomatis
Negative gonococcal culture and Gram’s stain; at least 1 neutrophil per oil-immersion field in rectal Gram’s stain Gram’s stain with >4 neutrophils per oil-immersion field; lack of gonococci indicative of NGU None
Rectal NAAT for C. trachomatis or culture
Negative culture and Gram’s stain for gonococci, Haemophilus spp., pneumococci, staphylococci None
Urine or urethral NAAT for C. trachomatis
Culture of LGV strain from node or rectum, occasionally from urethra or cervix; NAAT for C. trachomatis from these sites; LGV CF titer, ≥1:64; micro-IF titer, ≥1:512 Conjunctival NAAT for C. trachomatis; FA-stained scraping of conjunctival material Chlamydial culture or NAAT of sputum, pharynx, eye, rectum; micro-IF antibody to C. trachomatis—fourfold change in IgG or IgM antibody titer
A presumptive diagnosis of chlamydial infection is often made in the syndromes listed when gonococci are not found. A positive test for Neisseria gonorrhoeae does not exclude the involvement of C. trachomatis, which often is present in patients with gonorrhea.
a
Abbreviations: CF, complement-fixing; FA, fluorescent antibody; LGV, lymphogranuloma venereum; micro-IF, microimmunofluorescence; MPC, mucopurulent cervicitis; NAAT, nucleic acid amplification test; NGU, nongonococcal urethritis; PGU, postgonococcal urethritis. Source: Reprinted with permission from WE Stamm: Chlamydial infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al (eds). New York, McGraw-Hill, 2008, p 1075.
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tests that amplify the nucleic acids in clinical specimens. NAATS are currently recommended by the CDC as the diagnostic assays of choice; four or five NAAT assays approved by the U.S. Food and Drug Administration (FDA) are commercially available, some as highthroughput robotic platforms. Point-of-care diagnostic assays (including NAATs), by which patients can be treated before leaving the clinic, are of increasing interest and are becoming available. Choice of specimen Cervical and urethral swabs have traditionally been used for the diagnosis of STDs in female and male patients, respectively. However, given the greatly increased sensitivity and specificity of NAATs, less invasive samples (e.g., urine for both sexes and vaginal swabs for women) can be used. For screening of asymptomatic women, the CDC now recommends that self-collected or clinician-collected vaginal swabs, which are slightly more sensitive than urine, be used. Urine screening tests are often used in outreach screening programs, however. For symptomatic women undergoing a pelvic examination, cervical swab samples are desirable because they have slightly higher chlamydial counts. For male patients, a urine specimen is the sample of choice, but self-collected penile-meatal swabs have been explored. Alternative specimen types Ocular samples from babies and adults can be assessed by NAATs. However, since commercial NAATs for this purpose have not yet been approved by the FDA, laboratories must perform their own verification studies. Samples from rectal and pharyngeal sites have been used successfully to detect chlamydiae, but laboratories must verify test performance.
TREATMENT
C. trachomatis Genital Infections
A 7-day course of tetracycline (500 mg four times daily), doxycycline (100 mg twice daily), erythromycin (500 mg four times daily), or a fluoroquinolone (ofloxacin, 300 mg twice daily; or levofloxacin, 500 mg/d) can be used for treatment of uncomplicated chlamydial infections. A single 1-g oral dose of azithromycin is as effective as a 7-day
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Chlamydial Infections
Serology Serologic testing may be helpful in the diagnosis of LGV and neonatal pneumonia caused by C. trachomatis. The serologic test of choice is the microimmunofluorescence (MIF) test, in which hightiter purified EBs mixed with embryonated chicken yolk-sac material are affixed to a glass microscope slide to which dilutions of serum are applied. After incubation and washing, fluorescein-conjugated IgG or IgM antibody is applied. The test is read with an epifluorescence microscope, with the highest dilution of serum producing visible fluorescence designated as the titer. The MIF test is not widely available and is highly labor intensive. Although the complement fixation (CF) test also can be used, it employs only lipopolysaccharide (LPS) as the antigen and therefore identifies the pathogen only to the genus level. Single-point titers of >1:64 support a diagnosis of LGV, in which it is difficult to demonstrate rising antibody titers; i.e., paired serum samples are difficult to obtain since, by its very nature, the disease results in the patient’s being seen by the physician after the acute stage. Any antibody titer of >1:16 is considered significant evidence of exposure to chlamydiae. However, serologic testing is never recommended for diagnosis of uncomplicated genital infections of the cervix, urethra, and lower genital tract or for C. trachomatis screening of asymptomatic individuals.
SEX PARTNERS The continued high prevalence of chlamydial infections in most parts of the United States is due primarily to the failure to diagnose—and therefore treat—patients with symptomatic or asymptomatic infection and their sex partners. Urethral or cervical infection with C. trachomatis has been well documented in a high proportion of the sex partners of patients with NGU, epididymitis, reactive arthritis, salpingitis, and endocervicitis. If possible, confirmatory laboratory tests for chlamydiae should be undertaken in these individuals, but even those without positive tests or evidence of clinical disease who have recently been exposed to proven or possible chlamydial infection (e.g., NGU) should be offered therapy. A novel approach is partner-delivered therapy, in which infected patients receive treatment and are also provided with single-dose azithromycin to give to their sex partner(s).
CHAPTER 213
Other diagnostic issues Because NAATs detect nucleic acids instead of live organisms, they should be used with caution as test-of-cure assays. Residual nucleic acid from cells rendered noninfective by antibiotics may continue to yield a positive result in NAATs until as long as 3 weeks after therapy, when viable organisms have actually been eradicated. Therefore, clinicians should not use NAATs for test of cure until after 3 weeks. The CDC currently does not recommend a test of cure after treatment for infection with C. trachomatis. However, because incidence studies have demonstrated that previous chlamydial infection increases the probability of becoming reinfected, the CDC does recommend that previously infected individuals be rescreened 3 months after treatment.
course of doxycycline for the treatment of uncomplicated genital 1171 C. trachomatis infections in adults. Azithromycin causes fewer adverse gastrointestinal reactions than do older macrolides such as erythromycin. The single-dose regimen of azithromycin has great appeal for the treatment of patients with uncomplicated chlamydial infection (especially those without symptoms and those with a likelihood of poor compliance) and of the sexual partners of infected patients. These advantages must be weighed against the considerably greater cost of azithromycin. Whenever possible, the single 1-g dose should be given as directly observed therapy. Although not approved by the FDA for use in pregnancy, this regimen appears to be safe and effective for this purpose. However, amoxicillin (500 mg three times daily for 7 days) also can be given to pregnant women. The fluoroquinolones are contraindicated in pregnancy. A 2-week course of treatment is recommended for complicated chlamydial infections (e.g., PID, epididymitis) and at least a 3-week course of doxycycline (100 mg orally twice daily) or erythromycin base (500 mg orally four times daily) for LGV. Failure of treatment with a tetracycline in genital infections usually indicates poor compliance or reinfection rather than involvement of a drug-resistant strain. To date, clinically significant drug resistance has not been observed in C. trachomatis. Treatment or testing for chlamydiae should be considered among N. gonorrhoeae–infected patients because of the frequency of co-infection. Systemic treatment with erythromycin has been recommended for ophthalmia neonatorum and for C. trachomatis pneumonia in infants. For the treatment of adult inclusion conjunctivitis, a single 1-g dose of azithromycin is as effective as standard 10-day treatment with doxycycline. Recommended treatment regimens for both bubonic and anogenital LGV include tetracycline, doxycycline, or erythromycin for 21 days.
NEONATES AND INFANTS In neonates with conjunctivitis or infants with pneumonia, erythromycin ethylsuccinate or estolate can be given orally at a dosage of 50 mg/kg per day, preferably in four divided doses, for 2 weeks. Careful attention must be given to compliance with therapy—a frequent problem. Relapses of eye infection are common after topical treatment with erythromycin or tetracycline ophthalmic ointment and may also follow oral erythromycin therapy. Thus follow-up cultures should be performed after treatment. Both parents should be examined for C. trachomatis infection and, if diagnostic testing is not readily available, should be treated with doxycycline or azithromycin. Prevention Since many chlamydial infections are asymptomatic, effective control and prevention must involve periodic screening of individuals at risk. Selective cost-effective screening criteria have been developed. Among women, young age (generally 60% and a plasma half-life of 7–9 h. The drug is excreted unmetabolized, primarily by the kidneys. Zanamivir has low oral bioavailability and is administered orally via a hand-held inhaler. By this route, ~15% of the dose is deposited in the lower respiratory tract, and low plasma levels of the drug are detected. The toxicities most frequently encountered with orally administered oseltamivir are nausea, gastrointestinal discomfort, and (less commonly) vomiting. Gastrointestinal discomfort is usually transient and is less likely if the drug is administered with food. Neuropsychiatric events (delirium, self-injury) have been reported in children who have been taking oseltamivir, primarily in Japan. Zanamivir is orally inhaled and is generally well tolerated, although exacerbations of asthma may occur. An IV formulation of zanamivir is under development and is available from GlaxoSmithKline as part of clinical trials. Inhaled zanamivir and orally administered oseltamivir have been effective in the treatment of naturally occurring, uncomplicated influenza A or B in otherwise healthy adults. In placebo-controlled studies, illness has been shortened by 1.0–1.5 days of therapy with either of these drugs when treatment is administered within 2 days of onset of symptoms. Pooled analyses of clinical studies of oseltamivir suggest that treatment may reduce the likelihood of hospitalizations and of certain respiratory tract complications associated with influenza, and observational studies suggest that oseltamivir may reduce mortality rates associated with influenza A outbreaks (Chap. 224). Once-daily inhaled zanamivir or once-daily orally administered oseltamivir can provide prophylaxis against laboratory-documented influenza A– and influenza B–associated illness. Resistance to the neuraminidase inhibitors may develop by changes in the viral neuraminidase enzyme, by changes in the hemagglutinin that make it more resistant to the actions of the neuraminidase, or by both mechanisms. Isolates that are resistant to oseltamivir—most commonly through the H275Y mutation, which leads to a change from histidine to tyrosine at that residue in the neuraminidase—remain sensitive to zanamivir. Certain mutations impart resistance to both oseltamivir and zanamivir (e.g., I223R, which leads to a change from isoleucine to arginine). Because the mechanisms of action of the neuraminidase inhibitors differ from those of the adamantanes (see below), zanamivir and oseltamivir are active against strains of influenza A virus that are resistant to amantadine and rimantadine. Appropriate use of antiviral agents against influenza viruses depends on a knowledge of the resistance patterns of circulating viruses. As of this writing, currently circulating influenza A/H1N1 and H3N2 viruses (2013–2014) were sensitive to zanamivir and oseltamivir, with a few exceptions for oseltamivir. Up-to-date information on patterns of resistance to antiviral drugs is available from the Centers for Disease Control and Prevention (CDC) at www.cdc.gov/flu.
215e-1
CHAPTER 215e Antiviral Chemotherapy, Excluding Antiretroviral Drugs
The field of antiviral therapy—both the number of antiviral drugs and our understanding of their optimal use—historically has lagged behind that of antibacterial treatment, but significant progress has been made in recent years on new drugs for several viral infections. The development of antiviral drugs poses several challenges. Viruses replicate intracellularly and often use host cell enzymes, macromolecules, and organelles for synthesis of viral particles. Therefore, useful antiviral compounds must discriminate between host and viral functions with a high degree of specificity; agents without such selectivity are likely to be too toxic for clinical use. Significant progress has also been made in the development of laboratory assays to assist clinicians in the appropriate use of antiviral drugs. Phenotypic and genotypic assays for resistance to antiviral drugs are becoming more widely available, and correlations of laboratory results with clinical outcomes are being better defined. Of particular note has been the development of highly sensitive and specific methods that measure the concentration of virus in blood (virus load) and permit direct assessment of the antiviral effect of a given drug regimen in that host site. Virus load measurements have been useful in recognizing the risk of disease progression in patients with viral infections and in identifying patients for whom antiviral chemotherapy might be of greatest benefit. As with any in vitro laboratory test, results are highly dependent on and likely vary with the laboratory techniques used. Information regarding the pharmacodynamics of antiviral drugs, and particularly the relationship of concentration effects to efficacy, has been slow to develop but is also expanding. However, assays to measure concentrations of antiviral drugs, especially of their active moieties within cells, are still primarily research procedures not widely available to clinicians. Thus, there are limited guidelines for adjusting dosages of antiviral agents to maximize antiviral activity and minimize toxicity. Consequently, clinical use of antiviral drugs must be accompanied by particular vigilance for unanticipated adverse effects. Like that of other infections, the course of viral infections is profoundly affected by interplay between the pathogen and a complex set of host defenses. The presence or absence of preexisting immunity, the ability to mount humoral and/or cell-mediated immune responses, and the stimulation of innate immunity are important determinants of the outcome of viral infections. The state of the host’s defenses needs to be considered when antiviral agents are used or evaluated. As with any therapy, the optimal use of antiviral compounds requires a specific and timely diagnosis. For some viral infections, such as herpes zoster, the clinical manifestations are so characteristic that a diagnosis can be made on clinical grounds alone. For other viral infections, such as influenza A, epidemiologic information (e.g., the documentation of a community-wide influenza outbreak) can be used to make a presumptive diagnosis with a high degree of accuracy. However, for most of the remaining viral infections, including herpes simplex encephalitis, cytomegaloviral infections other than retinitis, and enteroviral infections, diagnosis on clinical grounds alone cannot be accomplished with certainty. For such infections, rapid viral diagnostic techniques are of great importance. Considerable progress has also been made in recent years in the development of such tests, which are now widely available for a number of viral infections. Despite these complexities, the efficacy of a number of antiviral compounds has been clearly established in rigorously conducted and controlled studies. As summarized in Table 215e-1, this chapter reviews the antiviral drugs that are currently approved or are likely to be considered for approval in the near future for use against viral infections other than those caused by HIV. Antiretroviral drugs are reviewed in Chap. 226.
ANTIVIRAL DRUGS ACTIVE AGAINST RESPIRATORY INFECTIONS (SEE ALSO CHAPS. 223 AND 224)
215e-2
TABLE 215e-1 Antiviral Chemotherapy and Chemoprophylaxis Infection Influenza A and B: treatment
Drug Oseltamivir
Route Oral
Dosage Adults: 75 mg bid × 5 d Children 1–12 years: 30–75 mg bid, depending on weight,a × 5 d
Zanamivir
Inhaled orally
Adults and children ≥7 years: 10 mg bid × 5 d
Amantadineb
Oral
Adults: 100 mg qd or bid × 5–7 d Children 1–9 years: 5 mg/kg per day (maximum, 150 mg/d) × 5–7 d
Rimantadineb
Oral
100 mg qd or bid × 5–7 d in adults
Oseltamivir
Oral
Adults: 75 mg/d Children ≥1 year: 30–75 mg/d, depending on weighta
Zanamivir
Inhaled orally
Adults and children ≥5 years: 10 mg/d
Influenza A: prophylaxis
Amantadineb or rimantadineb
Oral
RSV infection
Ribavirin
Small-particle aerosol
Adults: 200 mg/d Children 1–9 years: 5 mg/kg per day (maximum, 150 mg/d) Administered 12–18 h/d from a reservoir containing 20 mg/mL × 3–6 d
CMV disease
Ganciclovir
IV
5 mg/kg bid × 14–21 d; then 5 mg/kg per day as maintenance dose
Valganciclovir
Oral
900 mg bid × 21 d; then 900 mg/d as maintenance dose
Foscarnet
IV
Cidofovir
IV
Fomivirsen
Intravitreal
60 mg/kg q8h × 14–21 d; then 90–120 mg/kg per day as maintenance dose 5 mg/kg once weekly × 2 weeks, then once every other week; given with probenecid and hydration 330 mg on days 1 and 15 followed by 330 mg monthly as maintenance
Acyclovir
Oral
20 mg/kg (maximum, 800 mg) 4 or 5 times daily × 5 d
Valacyclovir
Oral
Influenza A: treatment
Influenza A and B: prophylaxis
PART 8 Infectious Diseases
Varicella: immunocompetent host
Varicella: Acyclovir immunocompromised host Herpes simplex Acyclovir encephalitis
IV
Children 2–18 years: 20 mg/kg tid (not to exceed 1 g tid) × 5 d 10 mg/kg q8h × 7 d
IV
10 mg/kg q8h × 14–21 d
Neonatal herpes simplex
IV
20 mg/kg q8h × 14–21 d
Acyclovir
Comment When started within 2 d of onset in uncomplicated disease, zanamivir and oseltamivir reduce symptom duration by 1.0–1.5 and 1.3 d, respectively. Their effectiveness in prevention or treatment of complications is unclear, although some analyses suggest that oseltamivir may reduce the frequency of respiratory tract complications and hospitalizations. Oseltamivir's side effects of nausea and vomiting can be reduced in frequency by drug administration with food. Zanamivir may exacerbate bronchospasm in patients with asthma. Amantadine and rimantadine are not recommended for routine use unless antiviral susceptibilities are known because of widespread resistance in A/H3N2 viruses since 2005–2006 and in pandemic A/H1N1 viruses in 2009–2010. Their efficacy in treatment of uncomplicated disease caused by sensitive viruses has been similar to that of neuraminidase inhibitors. Prophylaxis must be continued for the duration of exposure and can be administered simultaneously with inactivated vaccine. Unless the sensitivity of isolates is known, neither amantadine nor rimantadine is currently recommended for prophylaxis or therapy.
Use of ribavirin is to be considered for treatment of infants and young children hospitalized with RSV pneumonia and bronchiolitis, according to the American Academy of Pediatrics. Ganciclovir, valganciclovir, foscarnet, and cidofovir are approved for treatment of CMV retinitis in patients with AIDS. They are also used for colitis, pneumonia, or “wasting” syndrome associated with CMV and for prevention of CMV disease in transplant recipients. Valganciclovir has largely supplanted oral ganciclovir and is frequently used in place of IV ganciclovir. Foscarnet is not myelosuppressive and is active against acyclovir- and ganciclovir-resistant herpesviruses.
Fomivirsen has reduced the rate of progression of CMV retinitis in patients in whom other regimens have failed or have not been well tolerated. The major form of toxicity is ocular inflammation. Treatment confers modest clinical benefit when administered within 24 h of rash onset.
A change to oral valacyclovir can be considered once fever has subsided if there is no evidence of visceral involvement. Results are optimal when therapy is initiated early. Some authorities recommend treatment for 21 d to prevent relapses. Serious morbidity is common despite therapy. Prolonged oral administration after initial IV therapy has been suggested because of long-term sequelae associated with cutaneous recurrences of HSV infection. (Continued)
215e-3
TABLE 215e-1 Antiviral Chemotherapy and Chemoprophylaxis (continued) Infection Genital herpes simplex, primary: treatment
Genital herpes simplex, recurrent: treatment
Genital herpes simplex, recurrent: suppression
Drug Acyclovir
Route IV
Dosage 5 mg/kg q8h × 5–10 d
Oral
400 mg tid or 200 mg 5 times daily × 7–10 d
Topical
5% ointment; 4–6 applications daily × 7–10 d
Valacyclovir
Oral
1 g bid × 7–10 d
Famciclovir
Oral
250 mg tid × 7–10 dc
Acyclovir
Oral
Famciclovir
Oral
Valacyclovir
Oral
Acyclovir Valacyclovir
Oral Oral
Famciclovir
Oral
400 mg tid × 5 d or 800 mg tid ×2d 125 mg bid × 5 d, 1000 mg bid × 1 d, or 500 mg once, then 250 mg PO bid × 3 doses 500 mg bid × 3 d or 1 g once a day × 5 d 400 mg bid 500–1000 mg/d or 250–500 mg bid 250 mg bid
Valacyclovir Famciclovir Acyclovir
Mucocutaneous herpes simplex in immunocompromised host: prevention Valacyclovir of recurrence during intense Famciclovir immunosuppression Herpes simplex Penciclovir orolabialis, recurrente Valacyclovir
Herpes simplex keratitis
Herpes zoster: immunocompetent host
IV Oral Topical Oral Oral Oral IV Oral Oral Topical Oral
5 mg/kg q8h × 7–14 d 400 mg 5 times daily × 10–14 d 5% ointment; 4–6 applications daily × 7 d or until healed 1 g tid × 7–10 dc 500 mg bid × 7–10 dd 400 mg 2–5 times daily or 800 mg bid 5 mg/kg q12h 500 mg to 1 g bid or tid 500 mg bidc 1.0% cream applied q2h during waking hours × 4 d 2 g q12h × 1 d
Famciclovirc
Oral
Docosanolf
Topical
Trifluridine
Topical
Vidarabine
Topical
Valacyclovir
Oral
1500 mg once or 750 mg bid × 1d 10% cream 5 times daily until healed 1 drop of 1% ophthalmic solution q2h while awake (maximum, 9 drops daily) 0.5-in. ribbon of 3% ophthalmic ointment 5 times daily 1 g tid × 7 d
Famciclovir
Oral
500 mg q8h × 7 d
Acyclovir
Oral
800 mg 5 times daily × 7–10 d
Suppressive therapy is recommended only for patients with at least 6–10 recurrences per year. “Breakthrough” occasionally takes place, and asymptomatic shedding of virus occurs. The need for suppressive therapy should be reevaluated after 1 year. Suppression with valacyclovir reduces transmission of genital HSV among virus-discordant couples. The choice of the IV or oral route and the duration of therapy depend on the severity of infection and the patient's ability to take oral medication. Oral or IV treatment has supplanted topical therapy except for small, easily accessible lesions. Foscarnet is used for acyclovir-resistant viruses. Treatment is administered during periods when intense immunosuppression is expected— e.g., during antitumor chemotherapy or after transplantation—and is usually continued for 2–3 months.
Treatment shortens healing time and symptom duration by 0.5–1.0 d (versus placebo). Therapy begun at earliest symptom reduces disease duration by 1 d. Therapy begun within 1 h of prodrome decreases time to healing by 1.8–2.2 d. Application at initial symptoms reduces healing time by 1 d. Therapy should be undertaken in consultation with an ophthalmologist.
Valacyclovir may be more effective than acyclovir for pain relief; otherwise, it has a similar effect on cutaneous lesions and should be given within 72 h of rash onset. The duration of postherpetic neuralgia is shorter than with placebo. Famciclovir showed overall efficacy similar to that of acyclovir in a comparative trial. It should be given ≤72 h after rash onset. Acyclovir causes faster resolution of skin lesions than placebo and provides some relief of acute symptoms if given within 72 h of rash onset. Combined with tapering doses of prednisone, acyclovir improves quality-of-life outcomes. (Continued)
CHAPTER 215e Antiviral Chemotherapy, Excluding Antiretroviral Drugs
Mucocutaneous Acyclovir herpes simplex in immunocompromised host: treatment
Comment The IV route is preferred for infections severe enough to warrant hospitalization or with neurologic complications. The oral route is preferred for patients whose condition does not warrant hospitalization. Adequate hydration must be maintained. Topical use—largely supplemented by oral therapy—may obviate systemic administration to pregnant women. Systemic symptoms and untreated areas are not affected. Valacyclovir appears to be as effective as acyclovir but can be administered less frequently. Famciclovir appears to be similar in effectiveness to acyclovir. The clinical effect is modest and is enhanced if therapy is initiated early. Treatment does not affect recurrence rates.
215e-4
TABLE 215e-1 Antiviral Chemotherapy and Chemoprophylaxis (continued) Route IV Oral Oral Oral Oral
Chronic hepatitis B
IFN-α2b
SC
Pegylated IFN-α2a
SC
180 μg weekly × 48 weeks
Lamivudine
Oral
100 mg/d × 12–18 months; 150 mg bid as part of therapy for HIV infection
Adefovir dipivoxil
Oral
10 mg/d × 48 weeks
Entecavir
Oral
0.5 mg/d × 48 weeks (1 mg/d if HBV is resistant to lamivudine)
Telbivudine
Oral
600 mg/d × 52 weeks
Tenofovir
Oral
300 mg/d × 48 weeks
IFN-α2a or IFN-α2b
SC
3 million units thrice weekly × 12–24 months
IFN-α2b/ribavirin
SC (IFN)/oral (ribavirin)
Pegylated IFN-α2b
SC
3 million units thrice weekly (IFN)/1000–1200 mg daily (ribavirin) × 6–12 months 1.5 μg weekly × 48 weeks
Pegylated IFN-α2a Pegylated IFN-α2b/ ribavirin
SC SC (IFN)/oral (ribavirin)
Pegylated IFN-α2a/ ribavirin
SC (IFN)/oral (ribavirin)
IFN-alfacon
SC
PART 8
Infection Drug Herpes zoster: Acyclovir immunocompromised host Valacyclovir Famciclovir Herpes zoster Acyclovir ophthalmicus Valacyclovir Famciclovir Condyloma IFN-α2b acuminatum IFN-αn3
Infectious Diseases Chronic hepatitis C
Oral Oral Intralesional Intralesional
Dosage 10 mg/kg q8h × 7 d 800 mg 5 times daily × 7 d 1 g tid × 7 dc 500 mg tid × 10 dc 600–800 mg 5 times daily × 10 d 1 g tid × 7 d 500 mg tid × 7 d 1 million units per wart (maximum of 5) thrice weekly × 3 weeks 250,000 units per wart (maximum of 10) twice weekly × up to 8 weeks 5 million units daily or 10 million units thrice weekly × 16–24 weeks
180 μg weekly × 48 weeks 1.5 μg/kg weekly (IFN)/ 800–1400 mg daily (ribavirin) × 24–48 weeks 180 μg weekly (IFN)/800–1200 mg daily (ribavirin) × 24–48 weeks 9–15 μg thrice weekly × 6–12 months
Comment Effectiveness in localized zoster is most marked when treatment is given early. Foscarnet may be used for acyclovir-resistant VZV infections.
Treatment reduces ocular complications, including ocular keratitis and uveitis.
Intralesional treatment frequently results in regression of warts, but lesions often recur. Parenteral administration may be useful if lesions are numerous. HBeAg and DNA are eliminated in 33–37% of cases. Histopathologic improvement is also seen. ALT levels return to normal in 39% of patients, and histologic improvement occurs in 38%. Lamivudine monotherapy is well tolerated and effective in reduction of HBV DNA levels, normalization of ALT levels, and improvement in histopathology. However, resistance develops in 24% of recipients when lamivudine is used as monotherapy for 1 year. A return of ALT levels to normal is documented in 48–72% of recipients and improved liver histopathology in 53–64%. Adefovir is effective in lamivudine-resistant hepatitis B. Renal function should be monitored. Normalization of ALT is seen in 68–78% of recipients and loss of HBeAg in 21%. Entecavir is active against lamivudine-resistant HBV. HBV DNA is reduced by >5 log10 copies/mL along with normalization of ALT levels in 74–77% of patients and improved histopathology in 65–67%. Resistance develops in 9–22% of patients after 2 years of therapy. Elevated CPK levels and myopathy may occur. ALT levels return to normal in 68–76% of patients, and liver histopathology improves in 72–74%. Resistance is uncommon with up to 2 years of therapy. SVRs are noted in 20–30% of patients. Normalization of ALT levels and improvements in liver histopathology are also seen. Combination therapy results in SVR in up to 40–50% of recipients. The slower clearance of pegylated IFNs than of standard IFNs permits once-weekly administration. Pegylated formulations appear to be superior to standard IFNs in efficacy, both as monotherapy and in combination with ribavirin, and have largely supplanted standard IFNs in treatment of hepatitis C. SVRs were seen in 42–51% of patients infected with HCV genotype 1 and in 76–82% of those infected with genotype 2 or 3. Doses of 9 and 15 μg are equivalent to IFN-α2a and IFN-α2b doses of 3 million units and 5 million units, respectively. (Continued)
TABLE 215e-1 Antiviral Chemotherapy and Chemoprophylaxis (continued) Infection
Chronic hepatitis D
Drug Sofosbuvirg
Route Oral
Simeprevirg
Oral
IFN-α2a or IFN-α2b Pegylated IFN-α2b Pegylated IFN-α2a
SC SC SC
215e-5
Dosage HCV genotypes 1, 4, 5, and 6: 400 mg qd with daily weight-based ribavirin (1000 mg [75 kg]) and weekly pegylated IFN for 12 weeks. Genotypes 2 and 3: 400 mg qd with daily weight-based ribavirin for 12 and 24 weeks, respectively
Comment Sofosbuvir is generally well tolerated, and most common side effects have been attributable to concomitantly administered IFN and ribavirin. Sofosbuvir is recommended in triple combination with pegylated IFN and ribavirin as first-line therapy for genotypes 1, 4, 5, and 6, with SVRs in 89–97% of treatment-naïve patients, and in double combination with ribavirin for genotypes 2 and 3. Alternative regimen for genotypes Simeprevir has supplanted the first-generation 1 and 4: 150 mg qd for 12 weeks protease inhibitors boceprevir and telaprevir. Its plus daily ribavirin and weekly metabolism by cytochrome CYP3A can result in pegylated IFN for 24 weeks and interactions with other drugs. Photosensitivity for 24–48 weeks, respectively and reversible hyperbilirubinemia are associated toxicities. Testing for the Q80K-resistant variant should be carried out since this variant is present in one-third of HCV genotype 1a infections. Triple combinations with pegylated IFN and ribavirin result in SVRs in 80% of genotype 1 infections without Q80K. 9 million units thrice weekly × 12 The overall efficacy and the optimal regimen months and duration of therapy are not fully established. Sustained SVRs have been seen in 25–30% of 1.5 μg weekly × 48 weeks patients for IFN-α and in 17–43% for pegylated 180 μg weekly × 48 weeks IFN-α.
For detailed weight recommendations and for children 80%). HSV has also been isolated from the lower respiratory tract of persons with acute respiratory distress syndrome and prolonged intubation. Most authorities believe that the presence of HSV in tracheal aspirates in such settings is due to reactivation of HSV in the tracheal region and localized tracheitis in persons with long-term intubation. Such patients should be evaluated for extension of HSV infection into the lung parenchyma. Controlled trials assessing the role of antiviral agents used against HSV in morbidity and mortality associated with acute respiratory distress syndrome have not been conducted. The role of lower respiratory tract HSV infection in overall rates of morbidity and mortality associated with these conditions is unclear. HSV is an uncommon cause of hepatitis in immunocompetent patients. HSV infection of the liver is associated with fever, abrupt elevations of bilirubin and serum aminotransferase levels, and leukopenia (90% of cases. Serum levels of aminotransferases and alkaline phosphatase are usually mildly elevated. The serum concentration of bilirubin is elevated in ~40% of cases.
Infectious Diseases
Complications Most cases of IM are self-limited. Deaths are very rare and are most often due to central nervous system (CNS) complications, splenic rupture, upper airway obstruction, or bacterial superinfection. When CNS complications develop, they usually do so during the first 2 weeks of EBV infection; in some patients, especially children, they are the only clinical manifestations of IM. Heterophile antibodies and atypical lymphocytes may be absent. Meningitis and encephalitis are the most common neurologic abnormalities, and patients may present with headache, meningismus, or cerebellar ataxia. Acute hemiplegia and psychosis also have been described. The cerebrospinal fluid contains mainly lymphocytes, with occasional atypical lymphocytes. Most cases resolve without neurologic sequelae. Acute EBV infection has also been associated with cranial nerve palsies (especially those involving cranial nerve VII), Guillain-Barré syndrome, acute transverse myelitis, and peripheral neuritis. Autoimmune hemolytic anemia occurs in ~2% of cases during the first 2 weeks. In most cases, the anemia is Coombs-positive, with cold agglutinins directed against the red blood cell antigen. Most patients with hemolysis have mild anemia that lasts for 1–2 months, but some patients have severe disease with hemoglobinuria and jaundice. Nonspecific antibody responses may also include rheumatoid factor, antinuclear antibodies, anti–smooth muscle antibodies, antiplatelet antibodies, and cryoglobulins. IM has been associated with red-cell aplasia, severe granulocytopenia, thrombocytopenia, pancytopenia, and hemophagocytic lymphohistiocytosis. The spleen ruptures in 6 months, with elevated levels of EBV DNA in the blood, high titers of antibody to EBV, and evidence of organ involvement, including hepatosplenomegaly, lymphadenopathy, and pneumonitis, uveitis, or neurologic disease. EBV is associated with several malignancies. About 15% of cases of Burkitt’s lymphoma in the United States and ~90% of those in Africa are associated with EBV (Chap. 134). African patients with Burkitt’s lymphoma have high levels of antibody to EBV, and their tumor tissue usually contains viral DNA. Malaria in African patients may impair cellular immunity to EBV and induce polyclonal B cell activation with an expansion of EBV-infected B cells. These changes may enhance the proliferation of B cells with elevated EBV DNA in the bloodstream, thereby increasing the likelihood of a c-myc translocation—the hallmark of Burkitt’s lymphoma. EBV-containing Burkitt’s lymphoma also occurs in patients with AIDS. Anaplastic nasopharyngeal carcinoma is common in southern China and is uniformly associated with EBV; the affected tissues
Figure 218-3 Oral hairy leukoplakia often presents as white plaques on the lateral surface of the tongue and is associated with Epstein-Barr virus infection.
2/9/15 6:22 PM
for the diagnosis of acute IM because it is present at elevated titers only 1189 during the first 2–3 months of the disease; in contrast, IgG antibody to VCA is usually not useful for diagnosis of IM but is often used to assess past exposure to EBV because it persists for life. Seroconversion to EBNA positivity also is useful for the diagnosis of acute infection with EBV. Antibodies to EBNA become detectable relatively late (3–6 weeks after the onset of symptoms) in nearly all cases of acute EBV infection and persist for the lifetime of the patient. These antibodies may be lacking in immunodeficient patients and in those with chronic active EBV infection. Titers of other antibodies also may be elevated in IM; however, these elevations are less useful for diagnosis. Antibodies to early antigens are detectable 3–4 weeks after the onset of symptoms in patients with IM. About 70% of individuals with IM have early antigen diffuse (EA-D) antibodies during the illness; the presence of EA-D antibodies is especially likely in patients with relatively severe disease. These antibodies usually persist for only 3–6 months. Levels of EA-D antibodies are also elevated in patients with nasopharyngeal carcinoma or chronic active EBV infection. Early antigen restricted (EA-R) antibodies are only occasionally detected in patients with IM but are often found at elevated titers in patients with African Burkitt’s lymphoma or chronic active EBV infection. IgA antibodies to EBV antigens have proved useful for the identification of patients with nasopharyngeal carcinoma and of persons at high risk for the disease. Other Studies Detection of EBV DNA, RNA, or proteins has been valuable in demonstrating the association of the virus with various malignancies. The polymerase chain reaction has been used to detect EBV DNA in the cerebrospinal fluid of some AIDS patients with lymphomas and to monitor the amount of EBV DNA in the blood of patients with lymphoproliferative disease. Detection of high levels of EBV DNA in blood for a few days to several weeks after the onset of IM may be useful if serologic studies yield equivocal results. Culture of EBV from throat washings or blood is not helpful in the diagnosis of acute infection, since EBV persists in the oropharynx and in B cells for the lifetime of the infected individual.
contain viral DNA and antigens. Patients with nasopharyngeal carcinoma often have elevated titers of antibody to EBV (Chap. 106). High levels of EBV plasma DNA before treatment or detectable levels of EBV DNA after radiation therapy correlate with lower rates of overall survival and relapse-free survival among patients with nasopharyngeal carcinoma. Worldwide, the most common EBV-associated malignancy is gastric carcinoma. About 9% of these tumors are EBV-positive. EBV has been associated with Hodgkin’s disease, especially the mixed-cellularity type (Chap. 134). Patients with Hodgkin’s disease often have elevated titers of antibody to EBV. In about half of cases in the United States, viral DNA and antigens are found in Reed-Sternberg cells. The risk of EBV-positive Hodgkin’s disease is significantly increased in young adults for several years after EBV-seropositive IM. About 50% of non-Hodgkin’s lymphomas in patients with AIDS are EBV-positive. EBV is present in B cells of lesions from patients with lymphomatoid granulomatosis. In some cases, EBV DNA has been detected in tumors from immunocompetent patients with angiocentric nasal NK/T cell lymphoma, T cell lymphoma, and CNS lymphoma. Studies have demonstrated viral DNA in leiomyosarcomas from AIDS patients and in smooth-muscle tumors from organ transplant recipients. Virtually all CNS lymphomas in AIDS patients are associated with EBV. Studies have found that a history of IM and higher levels of antibodies to EBV before the onset of disease is more common in persons with multiple sclerosis than in the general population; additional research on a possible causal relationship is needed.
D
A
- ssociated isease
EBV
N
TREATME T
Therapy for IM consists of supportive measures, with rest and analgesia. Excessive physical activity during the first month should be avoided to reduce the possibility of splenic rupture, which often necessitates splenectomy. Glucocorticoid therapy is not indicated for uncomplicated IM and in fact may predispose to bacterial superinfection. Prednisone (40–60 mg/d for 2–3 days, with subsequent tapering of the dose over 1–2 weeks) has been used for the prevention of airway obstruction in patients with severe tonsillar hypertrophy, for
1280
Antibody titer
640 320 Anti-VCA IgG
160
Anti-VCA IgM
Epstein-Barr Virus Infections, Including Infectious Mononucleosis
Differential Diagnosis Whereas ~90% of cases of IM are due to EBV, 5–10% of cases are due to cytomegalovirus (CMV) (Chap. 219). CMV is the most common cause of heterophile-negative mononucleosis; less common causes of IM and differences from IM due to EBV are shown in Table 218-2.
CHAPTER 218
DIAGNOSIS Serologic Testing (Fig. 218-4) The heterophile test is used for the diagnosis of IM in children and adults. In the test for this antibody, human serum is absorbed with guinea pig kidney, and the heterophile titer is defined as the greatest serum dilution that agglutinates sheep, horse, or cow erythrocytes. The heterophile antibody does not interact with EBV proteins. A titer of ≥40 is diagnostic of acute EBV infection in a patient who has symptoms compatible with IM and atypical lymphocytes. Tests for heterophile antibodies are positive in 40% of patients with IM during the first week of illness and in 80–90% during the third week. Therefore, repeated testing may be necessary, especially if the initial test is performed early. Tests usually remain positive for 3 months after the onset of illness, but heterophile antibodies can persist for up to 1 year. These antibodies usually are not detectable in children 1 month by seropositive mothers, 40–60% become infected. Iatrogenic transmission can result from blood transfusion; use of leukocyte-reduced or CMV-seronegative blood products for transfusion into low-birth-weight seronegative infants or seronegative pregnant women decreases risk. The great majority of infants infected at or after delivery remain asymptomatic. However, protracted interstitial pneumonitis has been associated with perinatally acquired CMV infection, particularly in premature infants, and occasionally has been accompanied by infection with Chlamydia trachomatis, Pneumocystis, or Ureaplasma urealyticum. Poor weight gain, adenopathy, rash, hepatitis, anemia, and atypical lymphocytosis may also be found, and CMV excretion often persists for months or years.
Population Fetus
Risk Factors Primary maternal infection/early pregnancy
Principal Syndromes Cytomegalic inclusion disease
Treatment Ganciclovir for symptomatic neonates
Organ transplant recipient
Seropositivity of donor and/or recipient; potent immunosuppressive regimen; treatment of rejection Graft-vs.-host disease; older age of recipient; seropositive recipient; viremia
Febrile leukopenia; gastrointestinal disease; pneumonia Pneumonia; gastrointestinal disease
Ganciclovir or valganciclovir
Hematopoietic stem cell transplant recipient Person with AIDS
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10% atypical lymphocytes. Total leukocyte counts may be low, normal, or markedly elevated. Although significant jaundice is uncommon, serum aminotransferase and alkaline phosphatase levels are often moderately elevated. Heterophile antibodies are absent; however, transient immunologic abnormalities are common and may include the presence of cryoglobulins, rheumatoid factors, cold agglutinins, and antinuclear antibodies. Hemolytic anemia, thrombocytopenia, and granulocytopenia complicate recovery in rare instances. Most patients recover without sequelae, although postviral asthenia may persist for months. The excretion of CMV in urine, genital secretions, and/or saliva often continues for months or years. Rarely, CMV infection is fatal in immunocompetent hosts; survivors can have recurrent episodes of fever and malaise, sometimes associated with autonomic nervous system dysfunction (e.g., attacks of sweating or flushing).
PART 8 Infectious Diseases
CMV Infection in the Immunocompromised Host (Table 219-1) CMV is the viral pathogen most commonly complicating organ transplantation (Chap. 169). In recipients of kidney, heart, lung, liver, pancreas, and vascularized composite (hand, face, other) transplants, CMV induces a variety of syndromes, including fever and leukopenia, hepatitis, colitis, pneumonitis, esophagitis, gastritis, and retinitis. CMV disease is an independent risk factor for both graft loss and death. Without prophylaxis, the period of maximal risk is between 1 and 4 months after transplantation. Disease likelihood and viral replication levels generally are greater after primary infection than after reactivation. Molecular studies indicate that seropositive transplant recipients are susceptible to infection with donor-derived, genotypically variant CMV, and such infection often results in disease. Reactivation infection, although common, is less likely than primary infection to be important clinically. The risk of clinical disease is related to various factors, such as degree of immunosuppression, use of antilymphocyte antibodies, lack of anti-CMV prophylaxis, and co-infection with other pathogens. The transplanted organ is particularly vulnerable as a target for CMV infection; thus there is a tendency for CMV hepatitis to follow liver transplantation and for CMV pneumonitis to follow lung transplantation. CMV viremia occurs in roughly one-third of hematopoietic stem cell transplant recipients; the risk of severe disease may be reduced by prophylaxis or preemptive therapy with antiviral drugs. The risk is greatest 5–13 weeks after transplantation, and identified risk factors include certain types of immunosuppressive therapy, an allogeneic (rather than an autologous) graft, acute graft-versus-host disease, older age, and pretransplantation recipient seropositivity. CMV is an important pathogen in patients with advanced HIV infection (Chap. 226), in whom it may cause retinitis or disseminated disease, particularly when peripheral-blood CD4+ T cell counts fall below 50–100/μL. As treatment for underlying HIV infection has improved, the incidence of serious CMV infections (e.g., retinitis) has decreased. However, during the first few weeks after institution of highly active antiretroviral therapy, acute flare-ups of CMV retinitis may occur secondary to an immune reconstitution inflammatory syndrome. Syndromes produced by CMV in immunocompromised hosts often begin with prolonged fatigue, fever, malaise, anorexia, night sweats, and arthralgias or myalgias. Liver function abnormalities, leukopenia, thrombocytopenia, and atypical lymphocytosis may be observed during these episodes. The development of tachypnea, hypoxemia,
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and unproductive cough signals respiratory involvement. Radiologic examination of the lung often shows bilateral interstitial or reticulonodular infiltrates that begin in the periphery of the lower lobes and spread centrally and superiorly; localized segmental, nodular, or alveolar patterns are less common. The differential diagnosis includes Pneumocystis infection; other viral, bacterial, or fungal infections; pulmonary hemorrhage; and injury secondary to irradiation or to treatment with cytotoxic drugs. Gastrointestinal CMV involvement may be localized or extensive and almost exclusively affects immunocompromised hosts. Colitis is the most common clinical manifestation in organ transplant recipients. Ulcers of the esophagus, stomach, small intestine, or colon may result in bleeding or perforation. CMV infection may lead to exacerbations of underlying ulcerative colitis. Hepatitis occurs frequently, particularly after liver transplantation. Acalculous cholecystitis and adrenalitis also have been described. CMV rarely causes meningoencephalitis in otherwise healthy individuals. Two forms of CMV encephalitis are seen in patients with AIDS. One resembles HIV encephalitis and presents as progressive dementia; the other is a ventriculoencephalitis characterized by cranial-nerve deficits, nystagmus, disorientation, lethargy, and ventriculomegaly. In immunocompromised patients, CMV can also cause subacute progressive polyradiculopathy, which is often reversible if recognized and treated promptly. CMV retinitis is an important cause of blindness in immunocompromised patients, particularly patients with advanced AIDS (Chap. 226). Early lesions consist of small, opaque, white areas of granular retinal necrosis that spread in a centrifugal manner and are later accompanied by hemorrhages, vessel sheathing, and retinal edema (Fig. 219-1). CMV retinopathy must be distinguished from that due to other conditions, including toxoplasmosis, candidiasis, and herpes simplex virus infection. Fatal CMV infections are often associated with persistent viremia and the involvement of multiple organ systems. Progressive pulmonary infiltrates, pancytopenia, hyperamylasemia, and hypotension are characteristic features that are frequently found in conjunction with a terminal bacterial, fungal, or protozoan superinfection. Extensive adrenal necrosis with CMV inclusions is often documented at autopsy, as is CMV involvement of many other organs. Diagnosis CMV infection usually cannot be diagnosed reliably on clinical grounds alone. Isolation of CMV or detection of its antigens or DNA in appropriate clinical specimens is the preferred approach. The most common method of detection is quantitative nucleic acid testing (QNAT) for CMV by polymerase chain reaction (PCR) technology,
Figure 219-1 Cytomegalovirus infection in a patient with AIDS may appear as an arcuate zone of retinitis with hemorrhages and optic disk swelling. Often CMV is confined to the retinal periphery, beyond view of the direct ophthalmoscope.
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Cytomegalovirus Infection
Ganciclovir is a guanosine derivative that has considerably more activity against CMV than its congener acyclovir. After intracellular conversion by a viral phosphotransferase encoded by CMV gene region UL97, ganciclovir triphosphate is a selective inhibitor of CMV DNA polymerase. Several clinical studies have indicated response rates of 70–90% among patients with AIDS who are given ganciclovir for the treatment of CMV retinitis or colitis. In severe infections (e.g., CMV pneumonia in hematopoietic stem cell transplant recipients), ganciclovir is often combined with CMV immune globulin. Prophylactic or suppressive ganciclovir may be useful in high-risk hematopoietic stem cell or organ transplant recipients (e.g., those who are CMV-seropositive before transplantation). In many patients with AIDS, persistently low CD4+ T cell counts, and CMV disease, clinical and virologic relapses occur promptly if treatment with ganciclovir is discontinued. Therefore, prolonged maintenance regimens are recommended for such patients. Resistance to ganciclovir is more common among patients treated for >3 months and is usually related to mutations in the CMV UL97 gene (or, less commonly, the UL54 gene). Valganciclovir is an orally bioavailable prodrug that is rapidly metabolized to ganciclovir in intestinal tissues and the liver. Approximately 60–70% of an oral dose of valganciclovir is absorbed. An oral valganciclovir dose of 900 mg results in ganciclovir blood levels similar to those obtained with an IV ganciclovir dose of 5 mg/kg. Valganciclovir appears to be as effective as IV ganciclovir for both CMV induction (treatment) and maintenance regimens, while providing the ease of oral dosing. Furthermore, the adverse-event profiles and rates of resistance for the two drugs are similar. Ganciclovir or valganciclovir therapy for CMV disease consists of a 14- to 21-day induction course (5 mg/kg IV twice daily for ganciclovir or 900 mg PO twice daily for valganciclovir), sometimes followed by maintenance therapy (e.g., valganciclovir, 900 mg/d). Peripheral-blood neutropenia develops in roughly one-quarter of treated patients but may be ameliorated by granulocyte colonystimulating factor or granulocyte-macrophage colony-stimulating factor. Whether to use maintenance therapy should depend on the overall level of immunocompromise and the risk of recurrent disease. Discontinuation of maintenance therapy should be considered in patients with AIDS who, while receiving antiretroviral therapy, have a sustained (3- to 6-month) increase in CD4+ T cell counts to >100/μL. For treatment of CMV retinitis, ganciclovir may also be administered via a slow-release pellet sutured into the eye. Although this intraocular device provides good local protection, contralateral eye disease and disseminated disease are not affected, and early retinal detachment is possible. A combination of intraocular and systemic therapy may be better than the intraocular implant alone. Foscarnet (sodium phosphonoformate) inhibits CMV DNA polymerase. Because this agent does not require phosphorylation to be active, it is also effective against most ganciclovir-resistant isolates. Foscarnet is less well tolerated than ganciclovir and causes considerable toxicity, including renal dysfunction, hypomagnesemia, hypokalemia, hypocalcemia, genital ulcers, dysuria, nausea, and paresthesia. Moreover, foscarnet administration requires the use of an infusion pump and close clinical monitoring. With aggressive hydration and dose adjustments for renal dysfunction, the toxicity of foscarnet can be reduced. The use of foscarnet should be avoided when a saline load cannot be tolerated (e.g., in cardiomyopathy). The approved induction regimen is 60 mg/kg every 8 h for 2 weeks, although 90 mg/kg every 12 h is equally effective and no more toxic. Maintenance infusions should deliver 90–120 mg/ kg once daily. No oral preparation is available. Foscarnet-resistant virus may emerge during extended therapy. This drug is used more frequently after hematopoietic stem cell transplantation than in other situations to avoid the myelosuppressive effects of ganciclovir; in
Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8
PREVENTION Prevention of CMV in organ and hematopoietic stem cell transplant recipients is usually based on one of two methods: universal prophylaxis or preemptive therapy. With universal prophylaxis, antiviral drugs are used for a defined period, often 3 or 6 months. One clinical trial demonstrated that, in CMV-seronegative recipients with seropositive donors, prophylaxis was more effective at prevention when given for 200 days rather than 100 days. With preemptive therapy, patients are monitored weekly for CMV viremia, and antiviral treatment is initiated once viremia is detected. Because of the bone marrow–suppressive effects of universal prophylaxis, preemptive therapy is more commonly employed in hematopoietic stem cell transplant recipients. For patients with advanced HIV infection (CD4+ T cell counts of 90% among the elderly. In pregnant
PATHOGENESIS B19V replicates primarily in erythroid progenitors. This specificity is due in part to the limited tissue distribution of the primary B19V receptor, blood group P antigen (globoside). Infection leads to hightiter viremia, with >1012 virus particles (or IU)/mL detectable in the blood at the apex (Fig. 221-1), and virus-induced cytotoxicity results in cessation of red cell production. In immunocompetent individuals, viremia and arrest of erythropoiesis are transient and resolve as the IgM and IgG antibody response is mounted. In individuals with normal erythropoiesis, there is only a minimal drop in hemoglobin levels; however, in those with increased erythropoiesis (especially with hemolytic anemia), this cessation of red cell production can induce a transient crisis with severe anemia (Fig. 221-1). Similarly, if an individual (or, after maternal infection, a fetus) does not mount a neutralizing antibody response and halt the lytic infection, erythroid production is compromised and chronic anemia develops (Fig. 221-1). The immune-mediated phase of illness, which begins 2–3 weeks after infection as the IgM response peaks, manifests as the rash of fifth disease together with arthralgia and/or frank arthritis. Low-level B19V DNA can be detected by polymerase chain reaction (PCR) in blood and tissues for months to years after acute infection. The B19V
Reticulocytes (g%)
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women, the estimated annual seroconversion rate is ~1%. Within 1195 households, secondary infection rates approach 50%. Detection of high-titer B19V in blood is not unusual (see “Pathogenesis,” below). Transmission can occur as a result of transfusion, most commonly of pooled components. To reduce the risk of transmission, plasma pools are screened by nucleic acid amplification technology, and high-titer pools are discarded. B19V is resistant to both heat and solvent-detergent inactivation.
Symptoms of anemia
2 6 10 20 Days Infection PRCA
Figure 221-1 Schematic of the time course of parvovirus B19V infection in (A) normals (erythema infectiosum), (B) transient aplastic crisis (TAC), and (C) chronic anemia/pure red-cell aplasia (PRCA). (Reprinted with permission from NS Young, KE Brown: N Engl J Med 350:586, 2004. © 2004 Massachusetts Medical Society. All rights reserved.)
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within a few weeks, but recurring symptoms can continue for months. The illness may mimic rheumatoid arthritis, and rheumatoid factor can often be detected in serum. B19V infection may trigger rheumatoid disease in some patients and has been associated with juvenile idiopathic arthritis.
1196
Transient Aplastic Crisis Asymptomatic transient reticulocytopenia occurs in most individuals with B19V infection. However, in patients who depend on continual rapid production of red cells, infection can cause transient aplastic crisis (TAC). Affected individuals include those with hemolytic disorders, hemoglobinopathies, red cell enzymopathies, and autoimmune hemolytic anemias. Patients present with symptoms of severe anemia (sometimes life-threatening) and a low reticulocyte count, and bone marrow examination reveals an absence of erythroid precursors and characteristic giant pronormoblasts. As its name indicates, the illness is transient, and anemia resolves with the cessation of cytopathic infection in the erythroid progenitors.
PART 8
Figure 221-2 Young child with erythema infectiosum, or fifth disease, showing typical “slapped-cheek” appearance.
Infectious Diseases
receptor is found in a variety of other cells and tissues, including megakaryocytes, endothelial cells, placenta, myocardium, and liver. Infection of these tissues by B19V may be responsible for some of the more unusual presentations of the infection. Rare individuals who lack P antigen are naturally resistant to B19V infection. CLINICAL MANIFESTATIONS Erythema Infectiosum Most B19V infections are asymptomatic or are associated with only a mild nonspecific illness. The main manifestation of symptomatic B19V infection is erythema infectiosum, also known as fifth disease or slapped-cheek disease (Fig. 221-2 and Fig. 25e-1A). Infection begins with a minor febrile prodrome ~7–10 days after exposure, and the classic facial rash develops several days later; after 2–3 days, the erythematous macular rash may spread to the extremities in a lacy reticular pattern. However, its intensity and distribution vary, and B19V-induced rash is difficult to distinguish from other viral exanthems. Adults typically do not exhibit the “slapped-cheek” phenomenon but present with arthralgia, with or without the macular rash. Polyarthropathy Syndrome Although uncommon among children, arthropathy occurs in ~50% of adults and is more common among women than among men. The distribution of the affected joints is often symmetrical, with arthralgia affecting the small joints of the hands and occasionally the ankles, knees, and wrists. Resolution usually occurs
Pure Red-Cell Aplasia/Chronic Anemia Chronic B19V infection has been reported in a wide range of immunosuppressed patients, including those with congenital immunodeficiency, AIDS (Chap. 226), lymphoproliferative disorders (especially acute lymphocytic leukemia), and transplantation (Chap. 169). Patients have persistent anemia with reticulocytopenia, absent or low levels of B19V IgG, high titers of B19V DNA in serum, and—in many cases—scattered giant pronormoblasts in bone marrow. Rarely, nonerythroid hematologic lineages are also affected. Transient neutropenia, lymphopenia, and thrombocytopenia (including idiopathic thrombocytopenic purpura) have been observed. B19V occasionally causes a hemophagocytic syndrome. Recent studies in Papua New Guinea and Ghana, where malaria is endemic, suggest that co-infection with Plasmodium and B19V plays a major role in the development of severe anemia in young children. Further studies must determine whether B19V infection contributes to severe anemia in other malarial regions. Hydrops Fetalis B19V infection during pregnancy can lead to hydrops fetalis and/or fetal loss. The risk of transplacental fetal infection is ~30%, and the risk of fetal loss (predominantly early in the second trimester) is ~9%. The risk of congenital infection is 104 IU/mL >104 IU/mL
Negative/positive
Positive
Negative/weakly positive
Negative/weakly positive
Positive
Fetus (1012 IU/mL, but rapidly decreases Often >1012 IU/mL, but should be >106 in the absence of treatment n/a
Abbreviations: IU, international units (1 IU equals ~1 genome); n/a, not applicable; PCR, polymerase chain reaction.
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by the third day of TAC in patients with hematologic disorders; these antibodies remain detectable for ~3 months. B19V IgG is detectable by the seventh day of illness and persists throughout life. Quantitative detection of B19V DNA should be used for the diagnosis of early TAC or chronic anemia. Although B19V levels fall rapidly with the development of the immune response, DNA can be detectable by PCR for months or even years after infection, even in healthy individuals; therefore, quantitative PCR should be used. In acute infection at the height of viremia, >1012 B19V DNA IU/mL of serum can be detected; however, titers fall rapidly within 2 days. Patients with aplastic crisis or B19V-induced chronic anemia generally have >105 B19V DNA IU/mL. TREATMENT
Parvovirus B19 Infection
PREVENTION No vaccine has been approved for the prevention of B19V infection, although vaccines based on B19V virus-like particles expressed in insect cells are known to be highly immunogenic. Phase 1 trials of a putative vaccine were discontinued because of adverse side effects.
DEFINITION The PARV4 viral sequence was initially detected in a patient with an acute viral syndrome. Similar sequences, including the related PARV5 sequence, have been detected in pooled plasma collections. The DNA sequence of PARV4/5 is distinctly different from that of all other parvoviruses, and this virus is now classified as a member of the newly described genus Tetraparvovirus. EPIDEMIOLOGY PARV4 DNA is commonly found in plasma pools but at lower concentrations than levels of B19V DNA found before in plasma pools prior to screening. The higher levels of PARV4 DNA and IgG antibody in tissues (bone marrow and lymphoid tissue) and sera from IV drug users than in the corresponding specimens from control patients suggest that the virus is transmitted predominantly by parenteral means in the United States and Europe. Evidence for nonparenteral transmission in other parts of the world is limited. CLINICAL MANIFESTATIONS To date, PARV4/5 infection has been associated only with mild clinical disease (rash and/or transient aminotransferase elevation).
HUMAN BOCAVIRUSES DEFINITION Animal bocaviruses are associated with mild respiratory symptoms and enteritis in young animals. HBoV1 was originally identified in the respiratory tract of young children with lower respiratory tract infections. More recently, HBoV1 and the related viruses HBoV2, HBoV3, and HBoV4 have all been identified in human fecal samples.
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Human Papillomavirus Infections Aaron C. Ermel, Darron R. Brown
Investigation of human papillomavirus (HPV) infection began in earnest in the 1980s after Harold zur Hausen postulated that infection with these viruses was associated with cervical cancer. It is now recognized that HPV infection of the human genital tract is extremely common and causes clinical states ranging from asymptomatic infection to genital warts (condylomata acuminata); dysplastic lesions or invasive cancers of the anus, penis, vulva, vagina, and cervix; and a subset of oropharyngeal cancers. This chapter describes the epidemiology of HPV in general and as a pathogen, the natural history of HPV infections and associated cancers, strategies to prevent HPV infection and HPV-associated disease, and treatment modalities. PATHOGENESIS Molecular Overview HPV is an icosahedral, nonenveloped, 8000-base-pair, double-stranded DNA virus with a diameter of 55 nm. Like those of other papillomaviruses, HPV’s genome consists of an early (E) gene region, a late (L) gene region, and a noncoding region that contains regulatory elements. The E1, E2, E5, E6, and E7 proteins are expressed early in the growth cycle and are necessary for viral replication and cellular transformation. The E6 and E7 proteins cause malignant transformation by targeting the human cell cycle– regulatory molecules p53 and Rb (retinoblastoma protein), respectively, for degradation. Translation of the L1 and L2 transcripts and splicing of an E1^E4 transcript occur later. The L1 gene encodes the 54-kDa major capsid protein that makes up the majority of the virus shell; the 77-kDa L2 minor protein constitutes a smaller percentage of the capsid mass. More than 125 HPV types have been identified and are numerically designated according to a unique L1 gene sequence. Approximately 40 HPV types are regularly found in the anogenital tract and are subdivided into high-risk and low-risk categories on the basis of the associated risk of cervical cancer. For example, HPV-6 and HPV-11 cause genital warts and ~10% of low-grade cervical lesions and are thus designated low risk. HPV-16 and HPV-18 cause dysplastic lesions and invasive cancers of the cervix and are considered high risk. HPV targets basal keratinocytes after microtrauma has exposed these cells to the virus. The HPV replication cycle is completed as keratinocytes undergo differentiation. Virions are assembled in the nuclei of differentiated keratinocytes and can be detected by electron microscopy. Infection is transmitted by contact with virus contained in these desquamated keratinocytes (or with free virus) from an infected individual.
Human Papillomavirus Infections
PARV4/5
CLINICAL MANIFESTATIONS HBoV1 DNA is found in respiratory secretions from 2–20% of children with acute respiratory infection, often in the presence of other pathogens; in these circumstances, the role of HBoV1 in disease pathogenesis is unknown. Clinical disease due to HBoV1 is associated with evidence of primary infection (IgG seroconversion or the presence of IgM), HBoV1 DNA in serum, or high-titer HBoV1 DNA (>104 genome copies/mL) in respiratory secretions. Symptoms are not dissimilar from those of other viral respiratory infections, and cough and wheezing are commonly reported. There is no specific treatment for bocavirus infection. The role of human bocaviruses in childhood gastroenteritis remains to be established.
CHAPTER 222
No antiviral drug effective against B19V is available, and treatment of B19V infection often targets symptoms only. TAC precipitated by B19V infection frequently necessitates symptom-based treatment with blood transfusions. In patients receiving chemotherapy, temporary cessation of treatment may result in an immune response and resolution. If this approach is unsuccessful or not applicable, commercial immune globulin (IVIg; Gammagard, Sandoglobulin) from healthy blood donors can cure or ameliorate persistent B19V infection in immunosuppressed patients. Generally, the dose used is 400 mg/kg daily for 5–10 days. Like patients with TAC, immunosuppressed patients with persistent B19V infection should be considered infectious. Administration of IVIg is not beneficial for erythema infectiosum or B19V-associated polyarthropathy. Intrauterine blood transfusion can prevent fetal loss in some cases of fetal hydrops.
EPIDEMIOLOGY 1197 Seroepidemiologic studies with HBoV virus-like particles suggest that human bocavirus infection is common. Worldwide, most individuals are infected before the age of 5 years.
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1198 Immune Response to HPV Infection A cell-mediated immune response
plays an important role in controlling the progression of natural HPV infection. Histologic examination of lesions in individuals who experience regression of genital warts demonstrates infiltration of T cells and macrophages. CD4+ T cell regulation is particularly important in controlling HPV infections, as evidenced by the higher rates of infection and disease among immunosuppressed individuals, particularly those who are infected with HIV. Specific T-cell responses may be measured against HPV proteins, the most important of which appear to be the E2 and E6 proteins. In women with HPV-16 cervical infection, a strong T-cell response to HPV-16-derived E2 protein is associated with a lack of progression of cervical disease. Natural HPV infection of the genital tract gives rise to a serum antibody response in only 60–70% of individuals because there is no viremic phase during infection. Significant, although incomplete, protection against type-specific reinfection is associated with the presence of neutralizing antibodies. Serum antibodies likely reach the cervical epithelium and secretions by transudation and exudation. Therefore, protection against infection is related to the amount of neutralizing antibody at the site of infection and lasts as long as levels of neutralizing antibodies are sufficient.
PART 8 Infectious Diseases
EPIDEMIOLOGY AND NATURAL HISTORY OF HPV-ASSOCIATED MALIGNANCY General Population HPV is transmitted by sexual intercourse, by oral sex, and possibly by touching of a partner’s genitalia. In cross-sectional and longitudinal studies, ~40% of young women have evidence of HPV infection, with peaks during the teens and early twenties—soon after first coitus. The number of lifetime sexual partners correlates with the likelihood of HPV infection and the subsequent risk of HPVassociated malignancy. HPV infection may develop in a monogamous person whose partner is infected. Most HPV infections become undetectable after 6–9 months. However, with prolonged follow-up and frequent sampling, the same HPV types may again be detected weeks or months after becoming undetectable. Whether such episodic detection indicates viral latency followed by reactivation or reinfection with an identical HPV type is still debated. Although HPV is the causative agent of several cancers, most attention has focused on cervical cancer—the second most common cancer among women worldwide, which affects more than 500,000 women and kills more than 275,000 women annually. More than 85% of all cervical cancer cases and deaths occur in women living in low-income countries, especially in sub-Saharan Africa, Asia, and South and Central America. A quarter-century of evidence shows that HPV causes nearly 100% of cervical cancers. HPV infection is the most significant risk factor for cervical cancer; relative risks range from 10 to 20 and exceed 100 in prospective and case-control studies, respectively. The time from HPV infection to cervical cancer diagnosis may exceed 20 years. Cervical cancer peaks in the fifth and sixth decades of life among women living in developed countries but as much as a decade earlier among women living in resource-poor countries. Persistent carriers of oncogenic HPV types are at greatest risk for high-grade cervical dysplasia and cancer. Why only certain HPV infections eventually lead to malignancy is not clear. Biomarkers that can predict which women will develop cervical cancer are not available. Immunosuppression in general plays a significant role in re-detection/reactivation of HPV infections, while other factors such as smoking, hormonal changes, Chlamydia infection, and nutritional deficits promote viral persistence and cancer. The International Agency for Research on Cancer concludes that HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 are carcinogenic in the uterine cervix. HPV-16 is particularly virulent and causes 50% of cervical cancers. Worldwide, HPV-16 and HPV-18 cause 70% of cervical squamous cell carcinomas and 85% of cervical adenocarcinomas. Oncogenic types other than HPV-16 and HPV-18 cause the remaining 30% of cervical cancers. HPV-16 and HPV-18 also cause nearly 90% of anal cancers worldwide. Although oncogenic HPV infection is necessary for the development of cervical malignancy, only
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~3–5% of infected women will ever develop this cancer, even in the absence of cytologic screening. In addition to cervical and anal cancer, other HPV-associated cancers include vulvar and vaginal cancer, which are associated with HPV in 50–70% of cases; penile cancer, which is caused by HPV in 50% of cases; and oropharyngeal squamous cell carcinoma (OPSCC). Over the past two decades, an epidemic of OPSCC related to oncogenic infection with HPV (primarily HPV-16) has developed. Annual rates of OPSCC among men in the United States have been increasing from a low of 0.27 case/100,000 in 1973 to 0.57 case/100,000 as of 2004; rates in women have remained relatively stable at ~0.17 case/100,000 per year. The increase in the incidence of OPSCC is greatest among white men 40–50 years of age. Nearly 14,000 new cases were diagnosed in the United States in 2013. Annual rates of OPSCCs of the base of the tongue and the tonsil have increased dramatically—i.e., by 1.3% and 0.6%, respectively. Fewer data are available from developing countries about OPSCCs. Effects of HIV on HPV-Associated Disease HIV infection accelerates the natural progression of HPV infections. HIV-infected persons are more likely than other individuals to develop genital warts and to have lesions that are more recalcitrant to treatment. HIV infection has been consistently associated with precancerous cervical lesions, including low-grade cervical intraepithelial neoplasia (CIN) and CIN 3, the immediate precursor to cervical cancer. Women with HIV/AIDS have significantly higher rates of cervical cancer and of subsets of some vulvar, vaginal, and oropharyngeal tumors than women in the general population. Studies indicate a direct relation between low CD4+ T lymphocyte counts and the risk of cervical cancer. Some studies show a reduced likelihood of HPV infection and precancerous lesions of the cervix in HIV-infected women receiving antiretroviral therapy (ART). The incidence of cervical cancer among HIV-infected women has not changed significantly since ART was introduced, possibly because of preexisting oncogenic HPV infections. The burden of HPV-related cancers is expected to increase in HIV-infected patients, given the prolonged life expectancies made possible by ART. For women living in developing countries where cervical cancer screening is not widely available, this situation may have significant consequences. Thus, elucidating the interactions of HIV infection and cervical cancer with cofactors such as diet, other sexually transmitted infections, and environmental exposures is a research focus with potentially enormous implications for women living in low- and middle-income countries. Similar to that of cervical cancer, the incidence of anal cancer is strongly influenced by HIV infection. HIV-infected men who have sex with men (MSM) and HIV-infected women have much higher rates of anal cancer than HIV-uninfected populations. Specifically, the incidence has been found to be as high as 130 cases/100,000 among HIV-positive MSM as opposed to only 5 cases/100,000 among HIVnegative MSM. The advent of ART has not impacted the incidence of anal cancer and high-grade anal intraepithelial neoplasia in the HIVinfected population. More information on screening, prevention, and treatment in the HIV-infected population can be found at the Department of Health and Human Services website (aidsinfo.nih.gov/guidelines). CLINICAL MANIFESTATIONS OF HPV INFECTION HPV infects the female vulva, vagina, and cervix and the male urethra, penis, and scrotum. Perianal, anal, and oropharyngeal infections occur in both genders. Figures 222-1, 222-2, and 222-3 show vulvar, penile, and perianal warts, respectively. Genital warts are caused primarily by HPV-6 or HPV-11; their surface is either smooth or rough. Penile genital warts are usually 2–5 mm in diameter and often occur in groups. A second type of penile lesion, keratotic plaques, is slightly raised above the normal epithelium and has a rough, often pigmented surface. Vulvar warts are soft, whitish papules that either are sessile or have multiple fine, finger-like projections. These lesions are most often located in the introitus and on the labia. In nonmucosal areas, lesions
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Figure 222-3 Perianal warts. (Reprinted from K Wolff, RA Johnson, AP Saavedra: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.)
PREVENTION OF HPV INFECTION: HPV VACCINES Vaccines effective in preventing HPV infection and HPV-associated disease represent a major development in the last decade. The vaccines use virus-like particles (VLPs) that consist of the HPV L1 major capsid protein. The L1 protein self-assembles into VLPs when expressed in eukaryotic cells (i.e., yeast for the Merck vaccine or insect cells for the GlaxoSmithKline vaccine; see below). These VLPs contain the same epitopes as the HPV virion. However, they do not contain genetic material and cannot transmit infection. The immunogenicity of HPV vaccines relies on the development of conformational neutralizing antibodies to epitopes displayed on viral capsids. Several large trials have demonstrated the high degree of safety and efficacy of HPV vaccines. The evidence to date has shown high and sustained efficacy against disease caused by those HPV types represented in the vaccines (HPV-6, -11, -16, and -18 in the Merck vaccine and HPV-16 and -18 in the GlaxoSmithKline vaccine). However, no therapeutic effect against active infection or disease has been found for either vaccine.
Figure 222-2 Condyloma acuminata of the shaft of the penis.
Bivalent Vaccine (Cervarix) A bivalent L1 VLP vaccine (HPV-16 and -18), marketed under the name Cervarix (GlaxoSmithKline), is administered by IM injection at months 0, 1, and 6. This vaccine was tested in 18,644 women 15–25 years of age who were residing in the United States, South America, Europe, and Asia. The primary endpoints of the study included vaccine efficacy against persistent infections with HPV16 and -18. Investigators also assessed the vaccine’s efficacy against CIN of grade 2 or higher due to HPV-16 and -18 in women who had no evidence of infection with these HPV types at baseline; in these women, vaccine efficacy was 94.9% (95% confidence interval [CI], 87.7 to 98.4) against CIN ≥2 related to HPV-16 or HPV-18, 91.7% (95% CI, 66.6 to 99.1) against CIN ≥3, and 100% (95% CI, –8.6 to 100) against adenocarcinoma in situ. Adverse events were evaluated in phase 3 trials in a subset of 3077 women who received the bivalent vaccine and 3080 women (controls) who received hepatitis A vaccine. Injection-site adverse events (pain, redness, and swelling) and systemic adverse events (fatigue, headache, and myalgia) were reported more frequently in the HPV vaccine group than in the control group. Serious adverse events (mainly injectionsite reactions), new-onset chronic disease, or medically significant conditions occurred in 3.5% of HPV vaccine recipients and in 3.5% of women receiving the control vaccine.
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Human Papillomavirus Infections
are similar in appearance to those in men: dry and keratotic. Vulvar lesions can appear as smooth, sometimes pigmented papules that may coalesce. Vaginal lesions appear as multiple areas of elongated papillae. Biopsy of vulvar or vaginal lesions may reveal malignancy, which is not always reliably identified by clinical examination. Subclinical cervical HPV infections are common, and the cervix may appear normal on examination. Cervical lesions often appear as papillary proliferations near the transformation zone. Irregular vascular loops are present beneath the surface epithelium. Patients who develop cervical cancer arising from HPV infection may present with a variety of symptoms. Early carcinomas appear eroded and bleed easily. More advanced carcinomas present as ulcerated lesions or as an exophytic cervical mass. Some cervical carcinomas are located in the cervical canal and may be difficult to see. Bleeding, symptoms of a mass lesion in late stages, and metastatic disease that may manifest as bowel or bladder obstruction due to direct extension of the tumor have also been described.
CHAPTER 222
Figure 222-1 Vulvar warts. (Downloaded from http://www2a.cdc .gov/stdtraining/ready-to-use/Manuals/HPV/hpv-slides-2013.pdf.)
Patients with squamous cell cancer of the anus have more variable presentations. The most common presentations include rectal bleeding and pain or a mass sensation. Of patients who are diagnosed with anal cancer, 20% may present with no specific symptoms at the time of diagnosis; rather, the lesion is found fortuitously.
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The bivalent vaccine is approved in the United States for prevention of cervical cancer, CIN ≥2, adenocarcinoma in situ, and CIN 1 caused by HPV-16 and -18. This vaccine is approved for administration to girls and women 9–25 years of age.
PART 8 Infectious Diseases
Quadrivalent Vaccine (Gardasil) A quadrivalent L1 VLP (HPV-6, -11, -16, and -18) vaccine, marketed under the name Gardasil (Merck), is administered IM at months 0, 2, and 6. A combined efficacy analysis based on data from four randomized double-blind clinical studies including more than 20,000 participants demonstrated that the vaccine’s efficacy against external genital warts was 98.9% (95% CI, 93.7 to 100). Its efficacy was 95.2% (95% CI, 87.2 to 98.7) in protecting against CIN, 100% (95% CI, 92.9 to 100) against HPV-16- or HPV-18-related CIN 2/3 or adenocarcinoma in situ, and 100% (95% CI, 55.5 to 100.0) against HPV-16- or HPV-18-related vulvar intraepithelial neoplasia grades 2 and 3 (VIN 2/3) and vaginal intraepithelial neoplasia grades 2 and 3 (VaIN 2/3). Safety data on the quadrivalent HPV vaccine are available from seven clinical trials including nearly 12,000 girls and women 9–26 years of age who received the vaccine and ~10,000 who received placebo. A larger proportion of young women reported injection-site adverse events in the vaccine groups than in the aluminum-containing or saline placebo groups. Systemic adverse events were reported by similar proportions of vaccine and placebo recipients and were described as mild or moderate by most participants. The types of serious adverse events reported were similar for the two groups. Ten persons who received the quadrivalent vaccine and seven persons who received placebo died during the course of the trials; no deaths were considered to be vaccine related. During the course of the quadrivalent vaccine trials, surveillance data on the development of new medical conditions were collected for up to 4 years after vaccination. No statistically significant differences in the incidence of any medical conditions between vaccine and placebo recipients were found; this result indicated a very good safety profile. A recent safety review by the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention (CDC) examined events related to Gardasil that had been reported to the Vaccine Adverse Events Reporting System. Adverse events were consistent with those seen in previous safety studies of the vaccine. It is noteworthy that rates of syncope and venous thrombotic events were higher with Gardasil than those that have usually been documented for other vaccines. The quadrivalent vaccine is approved for (1) vaccination of girls and women 9–26 years of age to prevent genital warts and cervical cancer caused by HPV-6, -11, -16, and -18; (2) vaccination of the same population to prevent precancerous or dysplastic lesions, including cervical adenocarcinoma in situ, CIN 2/3, VIN 2/3, VaIN 2/3, and CIN 1; (3) vaccination of boys and men 9–26 years of age to prevent genital warts caused by HPV-6 and -11; and (4) vaccination of individuals 9–26 years of age to prevent anal cancer and associated precancerous lesions due to HPV-6, -11, -16, and -18. Cross-Protection of HPV Vaccines Women vaccinated with either of the available vaccines produce neutralizing antibodies against types related to HPV-16 or -18. Analyses of data from clinical trials suggest that both vaccines may offer cross-protection against nonvaccine types. The bivalent vaccine appears more efficacious against HPV-31, -33, and -45 than the quadrivalent vaccine, but differences in study design make direct comparisons difficult. In addition, vaccine efficacy against persistent infections with HPV-31 and -45 appeared to wane over time in the bivalent vaccine trials, whereas efficacy against persistent infection with HPV-16 or -18 remained stable. Second-Generation Vaccines While HPV-16 and -18 cause the majority of cervical cancers worldwide, global data have shown that HPV-31, -33, -35, -45, -52, and -58 are the next most frequently detected types in invasive cervical cancers. Secondgeneration vaccines that are in development incorporate VLPs of additional oncogenic HPV types (other than HPV-16 and -18), including HPV-31, -33, -45, -52, and -58; efficacy studies are ongoing.
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If vaccines with these five additional oncogenic types prove to be effective, mathematical models estimate that the level of protection could be raised to 90% of all squamous cell cervical cancers worldwide. Recommendations for Vaccination The CDC’s Advisory Committee for Immunization Practice recommends administration of the quadrivalent HPV vaccine—with the schedule used in the vaccine trials—to all boys and girls 11–12 years of age as well as to boys/men and girls/ women 13–26 years of age who have not previously been vaccinated or who have not completed the full series. For women, Papanicolaou (Pap) smear testing and screening for HPV DNA are not recommended before vaccination. After vaccination, Pap testing is recommended to detect disease caused by other oncogenic HPV types. PREVENTION OF HPV-ASSOCIATED DISEASE After HPV infection occurs, prevention of HPV-associated disease relies on screening. Women residing in developing countries who lack access to cervical screening programs have a higher rate of cervical cancer and a lower rate of cancer-specific survival. Approximately 75% of women living in developed countries have been screened in the past 5 years, whereas the figure is only ~5% among women living in developing countries. Economic and logistic obstacles likely impede routine screening of these populations for cervical cancer. The primary method used for cancer screening is cervical cytology via Pap smear. The guidelines of the American Society of Colposcopy and Cervical Pathology recommend initiation of cervical cancer screening at age 21, regardless of the age of sexual debut. Women 21–29 years old with a normal Pap smear should have the test repeated every 3 years. Although adolescent and young women often test positive for HPV DNA, they are at very low risk of cervical cancer. Co-testing, or testing for HPV DNA at the time of the Pap smear, is not recommended for women in this age group because the presence of HPV DNA does not correlate with the presence of high-grade squamous intraepithelial neoplasia. Women 30–65 years of age should have a Pap smear every 3 years if testing for HPV DNA is not performed. The screening interval for women in this age group can be extended to every 5 years if co-testing results are negative. HPV testing is not recommended for partners of women with HPV or for screening for conditions other than cervical cancer. Currently, there is no clear consensus regarding screening for anal cancer and its precursors, including high-grade anal intraepithelial lesions. This lack of clarity is due to an inadequate understanding of optimal treatment for low- or high-grade anal dysplasia found during cytologic screening. The current HIV treatment guidelines suggest that there may be a benefit to screening, but an effect on the associated morbidity and mortality of anal squamous cell cancer has not been consistently demonstrated. TREATMENT
HPV-ASSOCIATED LESIONS
Overview and General Recommendations A variety of treatment modalities are available for various HPV infections, but none has been proven to eliminate HPV from tissue adjacent to the destroyed and infected tissue. Treatment efficacies are limited by frequent recurrences (presumably due to reinfection acquired from an infected partner), reactivation of latent virus, or autoinoculation from nearby infected cells. The goals of treatment include prevention of virus transmission, eradication of premalignant lesions, and reduction of symptoms. Treatment is generally successful in eliminating visible lesions and grossly diseased tissue. Different therapies are indicated for genital warts, vaginal and cervical disease, and perianal and anal disease. An optimal therapy for HPV-related genital tract disease that combines high efficacy, low toxicity, low cost, and low recurrence rate is not available. For genital warts of the penis or vulva, cryotherapy (see below) is safest, least expensive, and most effective. Guidelines for the treatment of genital warts can be found on the CDC website (www .cdc.gov/std/treatment/2010/genital-warts.htm). Women with vaginal
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lesions should be referred to a gynecologist experienced in colposcopy and treatment of these lesions. Treatment of cervical disease involves careful inspection, biopsy, and histopathologic grading to determine the severity and extent of disease. Women with evidence of cervical HPV infection should be referred to a gynecologist familiar with HPV and experienced in colposcopy. Optimal follow-up of these patients includes colposcopic examination of the cervix and vagina on a yearly basis. Guidelines from the American College of Gynecology and Obstetrics are available for the treatment of cervical dysplasia and cancer. For anal or perianal lesions, cryotherapy or surgical removal is safest and most effective. Anoscopy and/or sigmoidoscopy should be performed when patients have perianal lesions, and suspicious lesions should be biopsied to rule out malignancy. Therapeutic Options Tables 222-1 and 222-2 list the available patient-administered and physician-administered treatments, respectively. Podophyllotoxin Podophyllotoxin (0.05% solution or gel and 0.15% cream) induces necrosis of genital wart tissue that heals within a few days. It is relatively effective and can be self-administered. Podophyllotoxin is applied twice daily on three consecutive days of the week for a maximum of 4 weeks. Adverse effects are common and include pain, inflammation, erosion, and burning or itching. Podophyllotoxin should not be used to treat vaginal, cervical, or anal lesions. The safety of podophyllotoxin during pregnancy has not been established.
Cryotherapy Cryotherapy (liquid nitrogen) for HPV-associated lesions causes cellular death. Genital warts usually disappear after two or three weekly sessions but often recur. Cryotherapy, which
TABLE 222-1 Recommended Treatments That Can Be Self-Administered for Genital Warts Variable Effectiveness Recurrence Adverse effects Availability Cost
Podophyllotoxin Good Frequent Frequent, can be severe Good Inexpensive
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Sinecatechins Good Frequent Frequent, mild Fair Inexpensive
Imiquimod Good Frequent Frequent, mild to moderate Fair Expensive
Cryotherapy Good Frequent Mild, well tolerated
Availability Cost
Good Inexpensive
Surgical Removal Excellent Frequent Mild, well tolerated Good Moderately expensive
Laser Excellent Frequent Mild to moderate, well tolerated Fair Very expensive
Interferon Good Frequent Frequent, moderately severe Fair Very expensive
is nontoxic and is not associated with significant adverse reactions, can also be used for diseased cervical tissue. Local pain occurs frequently. Surgical Methods Exophytic lesions can be surgically removed after intradermal injection of 1% lidocaine. This treatment is well tolerated but can cause scarring and requires hemostasis. Genital warts can also be destroyed by electrocautery, in which no additional hemostasis is required. Laser Therapy Laser treatment affords destruction of exophytic lesions and other HPV-infected tissue while preserving normal tissue. Local anesthetics are generally adequate. Efficacy for genital lesions is at least equal to that of other therapies (60–90%), with low recurrence rates (5–10%). Complications include local pain, vaginal discharge, periurethral swelling, and penile or vulvar swelling. Laser therapy has also been used successfully to treat cervical dysplasia and anal disease caused by HPV. Interferon (IFN) Recombinant IFN-α is used for intralesional treatment of genital warts, including perianal lesions. The recommended dosage is 1.0 × 106 IU of IFN injected into each lesion three times weekly for 3 weeks. IFN therapy causes clearance of infected cells by immune-boosting effects. Adverse events include headache, nausea, vomiting, fatigue, and myalgia. IFN therapy is costly and should be reserved for severe cases that do not respond to cheaper treatments. IFN should not be used to treat vaginal, cervical, or anal lesions. Other Therapies Both trichloroacetic acid and bichloroacetic acid are caustic agents that destroy warts by coagulation of proteins. Neither of these agents is recommended for treatment.
Human Papillomavirus Infections
Imiquimod Imiquimod (5% or 3.75% cream) is a patient-applied topical immunomodulatory agent thought to activate immune cells by binding to a Toll-like receptor—an event that leads to an inflammatory response. Imiquimod 5% cream is applied to genital warts at bedtime three times per week for up to 16 weeks. Warts are cleared in ~56% of patients, more often in women than in men; recurrence rates approach 13%. Local inflammatory side effects are common. Rates of clearance of genital warts with the 3.75% formulation are not as high, but the duration of treatment is shorter (i.e., daily application for a maximum of 8 weeks), and fewer local and systemic adverse reactions occur. Imiquimod should not be used to treat vaginal, cervical, or anal lesions. The safety of imiquimod during pregnancy has not been established.
Variable Effectiveness Recurrence Adverse effects
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Sinecatechins Sinecatechins (15% ointment) is used to treat genital warts but should not be used to treat vaginal, cervical, or anal lesions. Sinecatechins causes an inflammatory response when applied topically three times a day for up to 4 months. Clearance rates approach 60% in some studies, and recurrence rates are 6–9%. Adverse effects (redness, burning, itching, and pain at the site of application) are generally mild. The safety of sinecatechins during pregnancy is unknown.
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TABLE 222-2 Recommended Treatments That Must Be Administered by a Clinician for Genital Warts and Other Human Papillomavirus–Associated Lesions
Counseling Most sexually active adults will be infected with HPV during their lives. For all patients (vaccinated or unvaccinated), certain behavioral interventions can reduce the risk of acquiring HPV. Physicians can provide their patients with measures that can reduce this risk. The only way to avoid acquiring an HPV infection is to abstain from sexual activity, including intimate touching and oral sex. Practicing safe sex (partner reduction, condom use) may lower the likelihood of HPV transmission. Most HPV infections are controlled by the immune system and cause no symptoms or disease. Some infections lead to genital warts and cervical precancers. Genital warts can be treated for cosmetic reasons and to prevent spread of infection to others. Even after resolution of genital warts, latent virus can persist in normalappearing skin or mucosa and thus theoretically can be transmitted to uninfected partners. Precancerous cervical lesions should be treated to prevent progression to cancer.
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Section 13 Infections Due to DNA and RNA Respiratory Viruses
223
Common Viral Respiratory Infections Raphael Dolin
GENERAL CONSIDERATIONS
PART 8 Infectious Diseases
Acute viral respiratory illnesses are among the most common of human diseases, accounting for one-half or more of all acute illnesses. The incidence of acute respiratory disease in the United States is 3–5.6 cases per person per year. The rates are highest among children 50 years and comorbidities such as cardiovascular disease, diabetes, and hepatitis. Illness in pregnant women may be particularly severe, but SARS-CoV infection appears to be milder in children than in adults. Information regarding the clinical manifestations of MERS-CoV is limited. The case–fatality rate has been high in the initial cases, but this may represent an ascertainment bias, and it is clear that mild cases occur as well. The median incubation period has been estimated to be 5.2 days, and a secondary case was estimated to have an incubation period of 9–12 days. Cases have been reported that begin with cough and fever and progress to acute respiratory distress and respiratory failure within a week. Other cases have manifested as mild upper respiratory symptoms only. Renal failure has been noted, and DPP-4, the host cell receptor for MERS-CoV, is expressed at high levels in the kidney; these findings suggest that direct viral infection of the kidney may lead to renal dysfunction. Diarrhea and vomiting are also common in MERS, and pericarditis has been reported. The clinical features of common colds caused by human coronaviruses are similar to those of illness caused by rhinoviruses. In studies of volunteers, the mean incubation period of colds induced by coronaviruses (3 days) is somewhat longer than that of illness caused by rhinoviruses, and the duration of illness is somewhat shorter (mean, 6–7 days). In some studies, the amount of nasal discharge was greater in colds induced by coronaviruses than in those induced by rhinoviruses. Coronaviruses other than SARS-CoV have been recovered occasionally from infants with pneumonia and from military recruits with lower respiratory tract disease and have been associated with worsening of chronic bronchitis. Two novel coronaviruses, HCoV-NL63 and HCoVHKU1, have been isolated from patients hospitalized with acute respiratory illness. Their overall role as causes of human respiratory disease remains to be determined. LABORATORY FINDINGS AND DIAGNOSIS Laboratory abnormalities in SARS include lymphopenia, which is documented in ~50% of cases and which mostly affects CD4+ T cells but also involves CD8+ T cells and natural killer cells. Total white blood cell counts are normal or slightly low, and thrombocytopenia may develop as the illness progresses. Elevated serum levels of aminotransferases, creatine kinase, and lactate dehydrogenase have been reported. A rapid diagnosis of SARS-CoV infection can be made by reversetranscription PCR (RT-PCR) of respiratory tract samples and plasma early in the illness and of urine and stool later on. SARS-CoV can also be grown from respiratory tract samples by inoculation into Vero E6 tissue culture cells, in which a cytopathic effect is seen within days. RT-PCR appears to be more sensitive than tissue culture, but only around one-third of cases are positive by PCR at initial presentation. Serum antibodies can be detected by ELISA or immunofluorescence, and nearly all patients develop detectable serum antibodies within 28 days after the onset of illness.
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Laboratory abnormalities in MERS-CoV infection include lymphopenia with or without neutropenia, thrombocytopenia, and elevated levels of lactate dehydrogenase. MERS-CoV can be isolated in tissue culture in Vero and LLC-MK2 cells, but PCR techniques are more sensitive and rapid and are the standard for laboratory diagnosis. Serologic tests using ELISA and immunofluorescence techniques have also been developed. Laboratory diagnosis of coronavirus-induced colds is rarely required. Coronaviruses that cause those illnesses are frequently difficult to cultivate in vitro but can be detected in clinical samples by ELISA or immunofluorescence assays or by RT-PCR for viral RNA. These research procedures can be used to detect coronaviruses in unusual clinical settings. TREATMENT
Coronavirus Infections
HUMAN RESPIRATORY SYNCYTIAL VIRUS INFECTIONS ETIOLOGIC AGENT Human respiratory syncytial virus (HRSV) is a member of the Paramyxoviridae family (genus Pneumovirus). It is an enveloped virus ~150–350 nm in diameter and is so named because its replication in
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Common Viral Respiratory Infections
PREVENTION The recognition of SARS led to a worldwide mobilization of public health resources to apply infection control practices to contain the disease. Case definitions were established, travel advisories were proposed, and quarantines were imposed in certain locales. As of this writing, no additional cases of SARS have been reported since 2004. However, it remains unknown whether the disappearance of cases is a result of control measures, whether it is part of a seasonal or otherwise unexplained epidemiologic pattern of SARS, or when or whether SARS might reemerge. The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) maintain recommendations for surveillance and assessment of potential cases of SARS (www.cdc.gov/sars/). The frequent transmission of the disease to health care workers makes it mandatory that strict infection-control practices be employed by health care facilities to prevent airborne, droplet, and contact transmission from any suspected cases of SARS. Health care workers who enter areas in which patients with SARS may be present should don gowns, gloves, and eye and respiratory protective equipment (e.g., an N95 filtering facepiece respirator certified by the National Institute for Occupational Safety and Health). Similarly, the WHO and the CDC have issued recommendations for identification, prevention, and control of MERS-CoV infections (www.cdc.gov/coronavirus/mers/index.html). Isolation precautions against airborne spread of infection should be instituted for patients hospitalized for suspected MERS, as described above for SARS. Vaccines have been developed against several animal coronaviruses but not against known human coronaviruses. The emergence of SARSCoV and MERS-CoV has stimulated interest in the development of vaccines against such agents.
EPIDEMIOLOGY HRSV is a major respiratory pathogen of young children and the foremost cause of lower respiratory disease in infants. Infection with HRSV is seen throughout the world in annual epidemics that occur in late fall, winter, or spring and last up to 5 months. The virus is rarely encountered during the summer. Rates of illness are highest among infants 1–6 months of age, peaking at 2–3 months of age. The attack rates among susceptible infants and children are extraordinarily high, approaching 100% in settings such as daycare centers where large numbers of susceptible infants are present. By age 2, virtually all children will have been infected with HRSV. HRSV accounts for 20–25% of hospital admissions of young infants and children for pneumonia and for up to 75% of cases of bronchiolitis in this age group. It has been estimated that more than half of infants who are at risk will become infected during an HRSV epidemic. In older children and adults, reinfection with HRSV is frequent, but disease is milder than in infancy. A common cold–like syndrome is the illness most commonly associated with HRSV infection in adults. It has been increasingly appreciated that severe lower respiratory tract disease with pneumonitis can occur in elderly (often institutionalized) adults, in individuals with cardiopulmonary disease, and in patients with immunocompromising disorders or treatment, including recipients of hematopoietic stem cell transplants (HSCTs) and solid-organ transplants (SOTs). HRSV is also an important nosocomial pathogen; during an outbreak, it can infect pediatric patients and up to 25–50% of the staff on pediatric wards. The spread of HRSV among families is efficient: up to 40% of siblings may become infected when the virus is introduced into the family setting. HRSV is transmitted primarily by close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. Virus may also be spread by coarse aerosols produced by coughing or sneezing, but it is inefficiently spread by fine-particle aerosols. The incubation period is ~4–6 days, and virus shedding may last for ≥2 weeks in children and for shorter periods in adults. In immunosuppressed patients, shedding can continue for weeks.
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There is no specific therapy for SARS with established efficacy. Although ribavirin has frequently been used, it has little if any activity against SARS-CoV in vitro, and no beneficial effect on the course of illness has been demonstrated. Because of suggestions that immunopathology may contribute to the disease, glucocorticoids have also been widely used, but their benefit, if any, likewise remains to be established. Supportive care to maintain pulmonary and other organ-system functions remains the mainstay of therapy. Similarly, there is no established antiviral therapy for MERS. Interferon α2b and ribavirin have displayed activity against MERS-CoV in vitro and in a rhesus macaque model, but data are not available on its use in human cases of MERS. The approach to the treatment of common colds caused by coronaviruses is similar to that discussed above for rhinovirus-induced illnesses.
vitro leads to the fusion of neighboring cells into large multinucleated 1205 syncytia. The single-stranded RNA genome codes for 11 virus-specific proteins. Viral RNA is contained in a helical nucleocapsid surrounded by a lipid envelope bearing two glycoproteins: the G protein, by which the virus attaches to cells, and the F (fusion) protein, which facilitates entry of the virus into the cell by fusing host and viral membranes. HRSV is considered to be of a single antigenic type, but two distinct subgroups (A and B) and multiple subtypes within each subgroup have now been described. Antigenic diversity is reflected by differences in the G protein, whereas the F protein is relatively conserved. Both antigenic groups can circulate simultaneously in outbreaks, although there are typically alternating patterns in which one subgroup predominates over 1- to 2-year periods.
PATHOGENESIS Little is known about the histopathology of minor HRSV infection. Severe bronchiolitis or pneumonia is characterized by necrosis of the bronchiolar epithelium and a peribronchiolar infiltrate of lymphocytes and mononuclear cells. Interalveolar thickening and filling of alveolar spaces with fluid can also be found. The correlates of protective immunity to HRSV are incompletely understood. Because reinfection occurs frequently and is often associated with illness, the immunity that develops after single episodes of infection clearly is not complete or long-lasting. However, the cumulative effect of multiple reinfections is to temper subsequent disease and to provide some temporary measure of protection against infection. Studies of experimentally induced disease in healthy volunteers indicate that the presence of nasal IgA neutralizing antibody correlates more closely with protection than does the presence of serum antibody. Studies in infants, however, suggest that maternally acquired antibody provides some protection from lower respiratory tract disease, although illness can be severe even in infants who have moderate levels of maternally derived serum antibody. The relatively severe disease observed in immunosuppressed
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1206 patients and experimental animal models indicates that cell-mediated immunity is an important mechanism of host defense against HRSV. Evidence suggests that major histocompatibility class I–restricted cytotoxic T cells may be particularly important in this regard.
PART 8
CLINICAL MANIFESTATIONS HRSV infection leads to a wide spectrum of respiratory illnesses. In infants, 25–40% of infections result in lower respiratory tract involvement, including pneumonia, bronchiolitis, and tracheobronchitis. In this age group, illness begins most frequently with rhinorrhea, low-grade fever, and mild systemic symptoms, often accompanied by cough and wheezing. Most patients recover gradually over 1–2 weeks. In more severe illness, tachypnea and dyspnea develop, and eventually frank hypoxia, cyanosis, and apnea can ensue. Physical examination may reveal diffuse wheezing, rhonchi, and rales. Chest radiography shows hyperexpansion, peribronchial thickening, and variable infiltrates ranging from diffuse interstitial infiltrates to segmental or lobar consolidation. Illness may be particularly severe in children born prematurely and in those with congenital cardiac disease, bronchopulmonary dysplasia, nephrotic syndrome, or immunosuppression. One study documented a 37% mortality rate among infants with HRSV pneumonia and congenital cardiac disease. In adults, the most common symptoms of HRSV infection are those of the common cold, with rhinorrhea, sore throat, and cough. Illness is occasionally associated with moderate systemic symptoms such as malaise, headache, and fever. HRSV has also been reported to cause lower respiratory tract disease with fever in adults, including severe pneumonia in the elderly—particularly in nursing-home residents, among whom its impact can rival that of influenza. HRSV pneumonia can be a significant cause of morbidity and death among patients undergoing stem cell and solid organ transplantation, in whom case– fatality rates of 20–80% have been reported. Sinusitis, otitis media, and worsening of chronic obstructive and reactive airway disease have also been associated with HRSV infection.
Infectious Diseases
LABORATORY FINDINGS AND DIAGNOSIS The diagnosis of HRSV infection can be suspected on the basis of a suggestive epidemiologic setting—that is, severe illness among infants during an outbreak of HRSV in the community. Infections in older children and adults cannot be differentiated with certainty from those caused by other respiratory viruses. The specific diagnosis is established by detection of HRSV in respiratory secretions, such as sputum, throat swabs, or nasopharyngeal washes. Virus can be isolated in tissue culture, but this method has been largely supplanted by rapid viral diagnostic techniques consisting of immunofluorescence or ELISA of nasopharyngeal washes, aspirates, and (less satisfactorily) nasopharyngeal swabs. With specimens from children, these techniques have sensitivities and specificities of 80–95%; they are somewhat less sensitive with specimens from adults. RT-PCR detection techniques have shown even higher rates of sensitivity and specificity, particularly in adults. Serologic diagnosis may be made by comparison of acute- and convalescent-phase serum specimens by ELISA or by neutralization or complement-fixation tests. These tests may be useful in older children and adults but are less sensitive in children 1 month) Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month’s duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis of any site, pulmonary,b disseminated, or extrapulmonary Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia Pneumonia, recurrentb Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain, onset at age >1 month Wasting syndrome attributed to HIV
CHAPTER 226
DEFINITION The current U.S. CDC classification system for HIV infection and AIDS categorizes people on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte measurement. A confirmed HIV case can be classified in one of five HIV infection stages (0, 1, 2, 3, or unknown). If there was a negative HIV test within 6 months of the first HIV infection diagnosis, the stage is 0, and remains 0 until 6 months after diagnosis. Advanced HIV disease (AIDS) is classified as stage 3 if one or more specific opportunistic illness has been diagnosed (Table 226-1). Otherwise, the stage is determined by CD4 test results and immunologic criteria (Table 226-2). If none of these criteria apply (e.g., because of missing information on CD4 test results), the stage is U (unknown). The definition and staging criteria of AIDS are complex and comprehensive and were established for surveillance purposes rather than for the practical care of patients. Thus, the clinician should not focus
a Only among children age 10 cGy, and for pregnant or lactating women with thyroid exposure >5 cGy; 65 mg/d for children and adolescents 3–18 with thyroid exposure >5 cGy; 32.5 mg/d for infants 1 mo to 3 y with thyroid exposure >5 cGy; 16 mg/d for neonates from birth to 1 mo with thyroid exposure >5 cGy IV 1 g in 250 mL NS or 5% glucose, given over 1–2 h or Up to 5 d as a bolus over 3–4 min Inhalation IM IV
1 g in 1:1 dilution with water or NS over 15–20 min 1 g; not recommended because of pain 1 g in 250 mL NS or 5% glucose, given over 1–2 h or as a bolus over 3–4 min
Inhalation IM IV
1 g in 1:1 dilution with water or NS over 15–20 min 1 g; not recommended because of pain 2 ampoules NaHCO3 (44.3 meq each, 7.5%) in 1000 mL NS, 125 mL/L; or 1 ampoule NaHCO3 (44.3 meq, 7.5%) in 500 mL NS, 500 mL/h
PO Prussian blue
137
PO
2 tablets q4 h until urine pH = 7–8, or 4 g (8 tablets) tid 1 g tid with 100–200 mL water, up to 10 g/d
Water Aluminum phosphate gel Aluminum hydroxide
Tritium (3H) Strontium
PO PO
>3–4 L/d 100 mL immediately after exposure
Strontium
PO
60–100 mL
Cs
Up to 5 d
Abbreviation: NS, normal saline.
Chelating agent
Chelating agent
Usually IV for the first Increased excretion 24 h, PO for addivia the kidneys tional 2 d; continuation of treatment for >3 d is rare and is based on titration of uranium amounts in the body
3 wk titrated by Ion exchanger urine and fecal bioassay and wholebody counting 3 wk Excretion of water Once Decreased gut absorption Once Decreased gut absorption
Except for KI and Prussian blue, these drugs had not been approved for this purpose by the U.S. Food and Drug Administration at the time of publication.
a
Mechanism of Action Blocking agent
MEDICAL ASSAY OF RADIATION IN THE EXPOSED PATIENT One of the major difficulties in treating victims exposed to radiation is determination of the amount of exposure. Immediately after a terrorist event, when victims are being triaged, information regarding source, dose, and exposure time is unlikely to be available. Clinical assessment of the patient is the best approach and includes history, physical examination, and observation for onset of the ARS prodrome. An early prodrome indicates high-level exposure to radiation. Victims who arrive at the hospital reporting severe weakness, nausea, vomiting, diarrhea, or seizures probably will not survive despite supportive
measures. A very limited number of tests can be performed to estimate radiation exposure and contamination. The Biodosimetry Assessment Tool (BAT) facilitates treatment decisions during radiation exposure incidents. Developed by the U.S. Armed Forces Radiobiology Research Institute (AFRRI), the BAT provides a method of estimating radiation exposure on the basis of a single lymphocyte count, the lymphocyte depletion rate, and the time from exposure to onset of emesis. The BAT algorithms are based on large datasets from human radiation exposure and are available at http://www.usuhs.mil/afrri/outreach/request.htm. The patient should be observed for clinical symptoms, and the severity and time of onset of nausea, vomiting, headache, anorexia, fever, hypotension, tachycardia, weakness, cognitive changes, skin desquamation, diarrhea, and bloody stools should be recorded. The AFRRI Biodosimetry Worksheet (http://www.usuhs.mil/afrri/outreach/pdf/ afrriform331.pdf ) is a useful resource for detailed recording. Baseline tests should include a complete blood count with differential and platelet count, renal evaluation, and determination of electrolytes, serum amylase, and serum C-reactive protein. Urine and stool samples should be obtained if internal contamination is suspected. Nasal swabs taken from each nostril within the first 1–2 h after the exposure may be useful for determination of radionuclide inhalation. After exhalation, each swab is labeled, sealed in a plastic bag, and sent for analysis to appropriate laboratories. Patients exposed to 0.7–4 Gy develop pancytopenia from as early as 10 days to as late as 8 weeks after exposure. Lymphocytes show the most rapid decline, whereas counts of other leukocytes and platelets decline less rapidly. Erythrocytes are the least vulnerable blood elements. Absolute lymphocyte counts should be repeated every 4–6 h for 5–6 days; they are the most valuable early indicator because they constitute a sensitive marker for radiation damage and correlate with both the exposure and the prognosis. A 50% drop in absolute lymphocyte count within the first 24 h indicates a significant injury. HLA typing is necessary whenever irreversible bone marrow damage is suspected. Lymphocyte chromosomal analysis can detect exposure to as little as 0.03–0.06 Gy, and 15 mL of blood for this purpose should be drawn as early as possible in a heparinized collection tube and kept cool. Radiation-induced chromosomal aberrations visible in peripheralblood lymphocytes include dicentric chromosomes and ring forms that last for a few weeks. Calibration of a dose-response curve makes it possible to assess the radiation dose on the basis of the presence of these aberrations. Dicentric quantification requires multiple days to perform and is available only in select centers. Another method for estimating exposure is the in vitro cytokinesis– block micronucleus assay. Micronuclei can be the result of small acentric chromosome fragments that arise during exposure to radiation. The technique to score the micronuclei in peripheral-blood lymphocytes has been standardized in the last few years. It can be a useful tool in small-scale exposures but is not feasible in a mass casualty setting. FOLLOW-UP It is desirable to continue follow-up over the long termin some circumstances. In general, only persons who are exposed to 92. Ca-DTPA is more effective than Zn-DTPA during the first 24 h after internal contamination, and the two drugs are equally effective after the initial 24 h. If both drugs are available, Ca-DTPA should be given as the first dose. If additional treatment is needed, treatment should be switched to Zn-DTPA. The dose is 1 g of Ca-DTPA or Zn-DTPA, dissolved in 250 mL of normal saline or 5% glucose and given intravenously over 1 h daily. The duration of chelation treatment depends on the amount of internal contamination and the individual response to treatment. DTPA also can be administrated by nebulized inhalation; 1 g is given in a 1:1 dilution with water or saline over 15–20 min. Nebulized Zn-DTPA is recommended if inhalation was the only route of internal contamination. The IV route is recommended and should be used if the route of internal contamination is not known or if multiple routes of internal contamination are likely. DTPA penta-ethyl ester is a prodrug that has a favorable oral-absorption profile and whose therapeutic effects have been demonstrated in initial efficacy studies. Because it can be given orally, this prodrug may ultimately prove more useful in the setting of mass casualties than IV or nebulized forms of the drug. Treating uranium contamination with DTPA is contraindicated due to synergistic damage to the kidneys. Lung lavage can reduce radiation-induced pneumonitis and is indicated only when a large amount of radionuclide enters the lungs and has the potential to cause acute radiation injury. The procedure requires anesthesia.
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Part 10: Disorders of the Cardiovascular System
1439
Section 1 Introduction to Cardiovascular Disorders
Joseph Loscalzo
NATURAL HISTORY Cardiovascular disorders often present acutely, as in a previously asymptomatic person who develops an acute myocardial infarction (Chap. 295), or a previously asymptomatic patient with hypertrophic cardiomyopathy (Chap. 287), or with a prolonged QT interval (Chap. 277) whose first clinical manifestation is syncope or even sudden death. However, the alert physician may recognize the patient at risk for these complications long before they occur and often can take measures to prevent their occurrence. For example, a patient with acute myocardial infarction will often have had risk factors for atherosclerosis for many years. Had these risk factors been recognized, their elimination or reduction might have delayed or even prevented the infarction. Similarly, a patient with hypertrophic cardiomyopathy may have had a heart murmur for years and a family history of this disorder. These findings could have led to an echocardiographic examination, recognition of the condition, and appropriate therapy long before the occurrence of a serious acute manifestation. Patients with valvular heart disease or idiopathic dilated cardiomyopathy, by contrast, may have a prolonged course of gradually increasing dyspnea and other manifestations of chronic heart failure that is punctuated by episodes of acute deterioration only late in the course of the disease. Understanding the natural history of various cardiac
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CARDIAC SYMPTOMS The symptoms caused by heart disease result most commonly from myocardial ischemia, disturbance of the contraction and/or relaxation of the myocardium, obstruction to blood flow, or an abnormal cardiac rhythm or rate. Ischemia, which is caused by an imbalance between the heart’s oxygen supply and demand, is manifest most frequently as chest discomfort (Chap. 19), whereas reduction of the pumping ability of the heart commonly leads to fatigue and elevated intravascular pressure upstream of the failing ventricle. The latter results in abnormal fluid accumulation, with peripheral edema (Chap. 50) or pulmonary congestion and dyspnea (Chap. 47e). Obstruction to blood flow, as occurs in valvular stenosis, can cause symptoms resembling those of myocardial failure (Chap. 279). Cardiac arrhythmias often develop suddenly, and the resulting symptoms and signs—palpitations (Chap. 52), dyspnea, hypotension, and syncope (Chap. 27)—generally occur abruptly and may disappear as rapidly as they develop. Although dyspnea, chest discomfort, edema, and syncope are cardinal manifestations of cardiac disease, they occur in other conditions as well. Thus, dyspnea is observed in disorders as diverse as pulmonary disease, marked obesity, and anxiety (Chap. 47e). Similarly, chest discomfort may result from a variety of noncardiac and cardiac causes other than myocardial ischemia (Chap. 19). Edema, an important finding in untreated or inadequately treated heart failure, also may occur with primary renal disease and in hepatic cirrhosis (Chap. 50). Syncope occurs not only with serious cardiac arrhythmias but in a number of neurologic conditions as well (Chap. 27). Whether heart disease is responsible for these symptoms frequently can be determined by carrying out a careful clinical examination (Chap. 267), supplemented by noninvasive testing using electrocardiography at rest and during exercise (Chap. 268), echocardiography, roentgenography, and other forms of myocardial imaging (Chap. 270e). Myocardial or coronary function that may be adequate at rest may be insufficient during exertion. Thus, dyspnea and/or chest discomfort that appear during activity are characteristic of patients with heart disease, whereas the opposite pattern, i.e., the appearance of these symptoms at rest and their remission during exertion, is rarely observed in such patients. It is important, therefore, to question the patient carefully about the relation of symptoms to exertion. Many patients with cardiovascular disease may be asymptomatic both at rest and during exertion but may present with an abnormal physical finding such as a heart murmur, elevated arterial pressure, or an abnormality of the electrocardiogram (ECG) or imaging test. It is important to assess the global risk of CAD in asymptomatic individuals, using a combination of clinical assessment and measurement of cholesterol and its fractions, as well as other biomarkers, such as C-reactive protein, in some patients (Chap. 291e). Since the first clinical manifestation of CAD may be catastrophic—sudden cardiac death, acute myocardial infarction, or stroke in previous asymptomatic persons—it is mandatory to identify those at high risk of such events and institute further testing and preventive measures.
Approach to the Patient with Possible Cardiovascular Disease
THE MAGNITUDE OF THE PROBLEM Cardiovascular diseases comprise the most prevalent serious disorders in industrialized nations and are a rapidly growing problem in developing nations (Chap. 266e). Age-adjusted death rates for coronary heart disease have declined by two-thirds in the last four decades in the United States, reflecting the identification and reduction of risk factors as well as improved treatments and interventions for the management of coronary artery disease, arrhythmias, and heart failure. Nonetheless, cardiovascular diseases remain the most common causes of death, responsible for 35% of all deaths, almost 1 million deaths each year. Approximately one-fourth of these deaths are sudden. In addition, cardiovascular diseases are highly prevalent, diagnosed in 80 million adults, or ~35% of the adult population. The growing prevalence of obesity (Chap. 416), type 2 diabetes mellitus (Chap. 417), and metabolic syndrome (Chap. 422), which are important risk factors for atherosclerosis, now threatens to reverse the progress that has been made in the age-adjusted reduction in the mortality rate of coronary heart disease. For many years cardiovascular disease was considered to be more common in men than in women. In fact, the percentage of all deaths secondary to cardiovascular disease is higher among women (43%) than among men (37%) (Chap. 6e). In addition, although the absolute number of deaths secondary to cardiovascular disease has declined over the past decades in men, this number has actually risen in women. Inflammation, obesity, type 2 diabetes mellitus, and the metabolic syndrome appear to play more prominent roles in the development of coronary atherosclerosis in women than in men. Coronary artery disease (CAD) is more frequently associated with dysfunction of the coronary microcirculation in women than in men. Exercise electrocardiography has a lower diagnostic accuracy in the prediction of epicardial obstruction in women than in men.
disorders is essential for applying appropriate diagnostic and therapeutic measures to each stage of the condition, as well as for providing the patient and family with the likely prognosis.
CHAPTER 264
264
Approach to the Patient with Possible Cardiovascular Disease
DIAGNOSIS As outlined by the New York Heart Association (NYHA), the elements of a complete cardiac diagnosis include the systematic consideration of the following: 1. The underlying etiology. Is the disease congenital, hypertensive, ischemic, or inflammatory in origin?
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1440 TABLE 264-1 New York Heart Association Functional Classification Class I No limitation of physical activity No symptoms with ordinary exertion Class II Slight limitation of physical activity Ordinary activity causes symptoms
Class III Marked limitation of physical activity Less than ordinary activity causes symptoms Asymptomatic at rest Class IV Inability to carry out any physical activity without discomfort Symptoms at rest
PART 10
Source: Modified from The Criteria Committee of the New York Heart Association.
Disorders of the Cardiovascular System
2. The anatomic abnormalities. Which chambers are involved? Are they hypertrophied, dilated, or both? Which valves are affected? Are they regurgitant and/or stenotic? Is there pericardial involvement? Has there been a myocardial infarction? 3. The physiologic disturbances. Is an arrhythmia present? Is there evidence of congestive heart failure or myocardial ischemia? 4. Functional disability. How strenuous is the physical activity required to elicit symptoms? The classification provided by the NYHA has been found to be useful in describing functional disability (Table 264-1). One example may serve to illustrate the importance of establishing a complete diagnosis. In a patient who presents with exertional chest discomfort, the identification of myocardial ischemia as the etiology is of great clinical importance. However, the simple recognition of ischemia is insufficient to formulate a therapeutic strategy or prognosis until the underlying anatomic abnormalities responsible for the myocardial ischemia, e.g., coronary atherosclerosis or aortic stenosis, are identified and a judgment is made about whether other physiologic disturbances that cause an imbalance between myocardial oxygen supply and demand, such as severe anemia, thyrotoxicosis, or supraventricular tachycardia, play contributory roles. Finally, the severity of the disability should govern the extent and tempo of the workup and strongly influence the therapeutic strategy that is selected. The establishment of a correct and complete cardiac diagnosis usually commences with the history and physical examination (Chap. 267). Indeed, the clinical examination remains the basis for the diagnosis of a wide variety of disorders. The clinical examination may then be supplemented by five types of laboratory tests: (1) ECG (Chap. 268), (2) noninvasive imaging examinations (chest roentgenogram, echocardiogram, radionuclide imaging, computed tomographic imaging, positron emission tomography, and magnetic resonance imaging) (Chap. 270e), (3) blood tests to assess risk (e.g., lipid determinations, C-reactive protein [Chap. 291e]) or cardiac function (e.g., brain natriuretic peptide [BNP] [Chap. 279]), (4) occasionally specialized invasive examinations (i.e., cardiac catheterization and coronary arteriography [Chap. 272]), and (5) genetic tests to identify monogenic cardiac diseases (e.g., hypertrophic cardiomyopathy [Chap. 287], Marfan’s syndrome [Chap. 427], and abnormalities of cardiac ion channels that lead to prolongation of the QT interval and an increase in the risk of sudden death [Chap. 276]). These tests are becoming more widely available. FAMILY HISTORY In eliciting the history of a patient with known or suspected cardiovascular disease, particular attention should be directed to the family history. Familial clustering is common in many forms of heart disease. Mendelian transmission of single-gene defects may occur, as in hypertrophic cardiomyopathy (Chap. 287), Marfan’s syndrome (Chap. 427), and sudden death associated with a prolonged QT syndrome (Chap. 277). Premature coronary disease and essential hypertension, type 2 diabetes mellitus, and hyperlipidemia (the most important risk factors for CAD) are usually polygenic disorders. Although familial transmission may be less obvious than in the monogenic disorders, it is helpful in assessing risk and prognosis in polygenic disorders, as well.
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Familial clustering of cardiovascular diseases not only may occur on a genetic basis but also may be related to familial dietary or behavior patterns, such as excessive ingestion of salt or calories and cigarette smoking. ASSESSMENT OF FUNCTIONAL IMPAIRMENT When an attempt is made to determine the severity of functional impairment in a patient with heart disease, it is helpful to ascertain the level of activity and the rate at which it is performed before symptoms develop. Thus, it is not sufficient to state that the patient complains of dyspnea. The breathlessness that occurs after running up two long flights of stairs denotes far less functional impairment than do similar symptoms that occur after taking a few steps on level ground. Also, the degree of customary physical activity at work and during recreation should be considered. The development of two-flight dyspnea in a well-conditioned marathon runner may be far more significant than the development of one-flight dyspnea in a previously sedentary person. The history should include a detailed consideration of the patient’s therapeutic regimen. For example, the persistence or development of edema, breathlessness, and other manifestations of heart failure in a patient who is receiving optimal doses of diuretics and other therapies for heart failure (Chap. 279) is far graver than are similar manifestations in the absence of treatment. Similarly, the presence of angina pectoris despite treatment with optimal doses of multiple antianginal drugs (Chap. 293) is more serious than it is in a patient on no therapy. In an effort to determine the progression of symptoms, and thus the severity of the underlying illness, it may be useful to ascertain what, if any, specific tasks the patient could have carried out 6 months or 1 year earlier that he or she cannot carry out at present. ELECTROCARDIOGRAM (See also Chap. 268) Although an ECG usually should be recorded in patients with known or suspected heart disease, with the exception of the identification of arrhythmias, conduction abnormalities, ventricular hypertrophy, and acute myocardial infarction, it generally does not establish a specific diagnosis. The range of normal electrocardiographic findings is wide, and the tracing can be affected significantly by many noncardiac factors, such as age, body habitus, and serum electrolyte concentrations. In general, electrocardiographic changes should be interpreted in the context of other abnormal cardiovascular findings. ASSESSMENT OF THE PATIENT WITH A HEART MURMUR (Fig. 264-1) The cause of a heart murmur can often be readily elucidated from a systematic evaluation of its major attributes: timing, duration, intensity, quality, frequency, configuration, location, and radiation when considered in the light of the history, general physical examination, and other features of the cardiac examination, as described in Chap. 267. The majority of heart murmurs are midsystolic and soft (grades I–II/VI). When such a murmur occurs in an asymptomatic child or young adult without other evidence of heart disease on clinical examination, it is usually benign and echocardiography generally is not required. By contrast, two-dimensional and Doppler echocardiography (Chap. 270e) are indicated in patients with loud systolic murmurs (grades ≥III/VI), especially those that are holosystolic or late systolic, and in most patients with diastolic or continuous murmurs. PITFALLS IN CARDIOVASCULAR MEDICINE Increasing subspecialization in internal medicine and the perfection of advanced diagnostic techniques in cardiology can lead to several undesirable consequences. Examples include the following: 1. Failure by the noncardiologist to recognize important cardiac manifestations of systemic illnesses. For example, the presence of mitral stenosis, patent foramen ovale, and/or transient atrial arrhythmia should be considered in a patient with stroke, or the presence of pulmonary hypertension and cor pulmonale should be considered in a patient with scleroderma or Raynaud’s syndrome. A cardiovascular examination should be carried out to identify and estimate
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EVALUATION OF HEART MURMUR PRESENCE OF CARDIAC MURMUR Systolic Murmur
Diastolic or Continuous Murmur
Grade III or >, holosystolic, or late systolic
Asymptomatic and no associated findings
Other signs or symptoms of cardiac disease Echocardiography
Normal ECG and chest X-ray
No further workup
Abnormal ECG or chest X-ray
Cardiac consult if appropriate
Figure 264-1 Approach to the evaluation of a heart murmur. ECG, electrocardiogram. (From RA O’Rourke, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman [eds]. Philadelphia, Saunders, 2003.) the severity of the cardiovascular involvement that accompanies many noncardiac disorders. 2. Failure by the cardiologist to recognize underlying systemic disorders in patients with heart disease. For example, hyperthyroidism should be considered in an elderly patient with atrial fibrillation and unexplained heart failure, and Lyme disease should be considered in a patient with unexplained fluctuating atrioventricular block. A cardiovascular abnormality may provide the clue critical to the recognition of some systemic disorders. For example, an unexplained pericardial effusion may provide an early clue to the diagnosis of tuberculosis or a neoplasm. 3. Overreliance on and overutilization of laboratory tests, particularly invasive techniques, for the evaluation of the cardiovascular system. Cardiac catheterization and coronary arteriography (chap. 272) provide precise diagnostic information that may be crucial in developing a therapeutic plan in patients with known or suspected CAD. Although a great deal of attention has been directed to these examinations, it is important to recognize that they serve to supplement, not supplant, a careful examination carried out with clinical and noninvasive techniques. A coronary arteriogram should not be performed in lieu of a careful history in patients with chest pain suspected of having ischemic heart disease. Although coronary arteriography may establish whether the coronary arteries are obstructed and to what extent, the results of the procedure by themselves often do not provide a definitive answer to the question of whether a patient’s complaint of chest discomfort is attributable to coronary atherosclerosis and whether or not revascularization is indicated.
1. In the absence of evidence of heart disease, the patient should be clearly informed of this assessment and not be asked to return at intervals for repeated examinations. If there is no evidence of disease, such continued attention may lead to the patient’s developing inappropriate concern about the possibility of heart disease. 2. If there is no evidence of cardiovascular disease but the patient has one or more risk factors for the development of ischemic heart disease (chap. 293), a plan for their reduction should be developed and the patient should be retested at intervals to assess compliance and efficacy in risk reduction. 3. Asymptomatic or mildly symptomatic patients with valvular heart disease that is anatomically severe should be evaluated periodically, every 6 to 12 months, by clinical and noninvasive examinations. Early signs of deterioration of ventricular function may signify the need for surgical treatment before the development of disabling symptoms, irreversible myocardial damage, and excessive risk of surgical treatment (chap. 283). 4. In patients with CAD (chap. 293), available practice guidelines should be considered in the decision on the form of treatment (medical, percutaneous coronary intervention, or surgical revascularization). Mechanical revascularization may be employed too frequently in the United States and too infrequently in Eastern Europe and developing nations. The mere presence of angina pectoris and/or the demonstration of critical coronary arterial narrowing at angiography should not reflexively evoke a decision to treat the patient by revascularization. Instead, these interventions should be limited to patients with CAD whose angina has not responded adequately to medical treatment or in whom revascularization has been shown to improve the natural history (e.g., acute coronary syndrome or multivessel CAD with left ventricular dysfunction).
ChaPter 265e Basic Biology of the Cardiovascular System
Grade I + II and midsystolic
available. Several examples may be used to demonstrate some of the 1441 principles of cardiovascular therapeutics:
Despite the value of invasive tests in certain circumstances, they entail some small risk to the patient, involve discomfort and substantial cost, and place a strain on medical facilities. Therefore, they should be carried out only if the results can be expected to modify the patient’s management. dISEASE PREVENTIoN ANd MANAgEMENT The prevention of heart disease, especially of CAD, is one of the most important tasks of primary care health givers as well as cardiologists. Prevention begins with risk assessment, followed by attention to lifestyle, such as achieving optimal weight, physical activity, and smoking cessation, and then aggressive treatment of all abnormal risk factors, such as hypertension, hyperlipidemia, and diabetes mellitus (chap. 417). After a complete diagnosis has been established in patients with known heart disease, a number of management options are usually
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265e
Basic Biology of the Cardiovascular System Joseph Loscalzo, Peter Libby, Jonathan A. Epstein
THE BLOOD VESSEL
A. Capillary
B. Vein
ORIGIN OF VASCULAR CELLS The intima in human arteries often contains occasional resident smooth-muscle cells beneath the monolayer of vascular endothelial cells. The embryonic origin of smooth-muscle cells in various types of artery differs. Some upper-body arterial smooth-muscle cells derive from the neural crest, whereas lower-body arteries generally recruit smooth-muscle cells from neighboring mesodermal structures during development. Derivatives of the proepicardial organ, which gives rise to the epicardial layer of the heart, contribute to the vascular smooth-muscle cells of the coronary arteries. Bone marrow–derived endothelial progenitors may aid repair of damaged or aging arteries. In addition, multipotent vascular stem cells resident in vessel walls may give rise to the smooth-muscle cells that accumulate in injured or atheromatous arteries (Chaps. 88, 89e, and 90e). VASCULAR CELL BIOLOGY Endothelial Cell The key cell of the vascular intima, the endothelial cell, has manifold functions in health and disease. The endothelium forms the interface between tissues and the blood compartment. It therefore must regulate the entry of molecules and cells into tissues in a selective manner. The ability of endothelial cells to serve as a selectively permeable barrier fails in many vascular disorders, including atherosclerosis, hypertension, and renal disease. This dysregulation of permeability also occurs in pulmonary edema and other situations of “capillary leak.” The endothelium also participates in the local regulation of blood flow and vascular caliber. Endogenous substances produced by endothelial cells such as prostacyclin, endothelium-derived hyperpolarizing factor, nitric oxide (NO), and hydrogen peroxide (H2O2) provide tonic vasodilatory stimuli under physiologic conditions in vivo (Table 265e-1). Impaired production or excess catabolism of NO C. Small muscular artery
Pericyte
Vascular smooth-muscle cell Endothelial cell
D. Large muscular artery
E. Large elastic artery
Internal elastic lamina
External elastic lamina
Adventitia
Figure 265e-1 Schematics of the structures of various types of blood vessels. A. Capillaries consist of an endothelial tube in contact with a discontinuous population of pericytes. B. Veins typically have thin medias and thicker adventitias. C. A small muscular artery features a prominent tunica media. D. Larger muscular arteries have a prominent media with smooth-muscle cells embedded in a complex extracellular matrix. E. Larger elastic arteries have cylindrical layers of elastic tissue alternating with concentric rings of smooth-muscle cells.
265e-1
CHAPTER 265e Basic Biology of the Cardiovascular System
VASCULAR ULTRASTRUCTURE Blood vessels participate in homeostasis on a moment-to-moment basis and contribute to the pathophysiology of diseases of virtually every organ system. Hence, an understanding of the fundamentals of vascular biology furnishes a foundation for understanding the normal function of all organ systems and many diseases. The smallest blood vessels—capillaries—consist of a monolayer of endothelial cells apposed to a basement membrane, adjacent to occasional smooth-muscle-like cells known as pericytes (Fig. 265e-1A). Unlike larger vessels, pericytes do not invest the entire microvessel to form a continuous sheath. Arteries typically have a trilaminar structure (Fig. 265e-1B–E). The intima consists of a monolayer of endothelial cells continuous with those of the capillaries. The middle layer, or tunica media, consists of layers of smooth-muscle cells; in veins, the media can contain just a few layers of smooth-muscle cells (Fig. 265e-1B). The outer layer, the adventitia, consists of looser extracellular matrix with occasional fibroblasts, mast cells, and nerve terminals. Larger arteries have their own vasculature, the vasa vasorum, which nourishes the outer aspects of the tunica media. The adventitia of many veins surpasses the intima in thickness. The tone of muscular arterioles regulates blood pressure and flow through various arterial beds. These smaller arteries have a relatively thick tunica media in relation to the adventitia (Fig. 265e-1C). Medium-size muscular arteries similarly contain a prominent tunica media (Fig. 265e-1D); atherosclerosis commonly affects this type of muscular artery. The larger elastic arteries have a much more structured tunica media consisting of concentric bands of smooth-muscle cells, interspersed with strata of elastin-rich extracellular matrix
sandwiched between layers of smooth-muscle cells (Fig. 265e-1E). Larger arteries have a clearly demarcated internal elastic lamina that forms the barrier between the intima and the media. An external elastic lamina demarcates the media of arteries from the surrounding adventitia.
265e-2
TABLE 265e-1 Endothelial Functions in Health and Disease Homeostatic Properties Optimize balance between vasodilation and vasoconstriction Antithrombotic, profibrinolytic Anti-inflammatory Antiproliferative Antioxidant Permselectivity
Dysfunctional Properties Impaired dilation, vasoconstriction Prothrombotic, antifibrinolytic Proinflammatory Proproliferative Prooxidant Impaired barrier function
PART 10 Disorders of the Cardiovascular System
impairs this endothelium-dependent vasodilator function and may contribute to excessive vasoconstriction in various pathologic situations. Measurement of flow-mediated dilatation can assess endothelial vasodilator function in humans (Fig. 265e-2). By contrast, endothelial cells also produce potent vasoconstrictor substances such as endothelin in a regulated fashion. Excessive production of reactive oxygen species, such as superoxide anion (O2−), by endothelial or smoothmuscle cells under pathologic conditions (e.g., excessive exposure to angiotensin II), can promote local oxidative stress and inactivate NO. The endothelial monolayer contributes critically to inflammatory processes involved in normal host defenses and pathologic states. The normal endothelium resists prolonged contact with blood leukocytes; however, when activated by bacterial products such as endotoxin or by proinflammatory cytokines released during infection or injury, endothelial cells express an array of leukocyte adhesion molecules that bind various classes of leukocytes. The endothelial cells appear to recruit selectively different classes of leukocytes in different pathologic conditions. The gamut of adhesion molecules and chemokines generated during acute bacterial infection tends to recruit granulocytes. In chronic inflammatory diseases such as tuberculosis and atherosclerosis, endothelial cells express adhesion molecules that favor the recruitment of mononuclear leukocytes that characteristically accumulate in these conditions. The endothelium also dynamically regulates thrombosis and hemostasis. NO, in addition to its vasodilatory properties, can limit platelet activation and aggregation. Like NO, prostacyclin produced by endothelial cells under normal conditions not only provides a vasodilatory stimulus but also antagonizes platelet activation and aggregation. Thrombomodulin expressed on the surface of endothelial cells binds thrombin at low concentrations and inhibits coagulation through activation of the protein C pathway, inactivating clotting factors Va and VIIIa and thus combating thrombus formation. The surface of endothelial cells contains heparan sulfate glycosaminoglycans that furnish an endogenous antithrombotic coating to the vasculature. Endothelial cells also participate actively in fibrinolysis and its regulation. They express receptors for plasminogen and plasminogen activators and produce tissue-type plasminogen activator. Through local generation of plasmin, the normal endothelial monolayer can promote the lysis of nascent thrombi. When activated by inflammatory cytokines, bacterial endotoxin, or angiotensin II, for example, endothelial cells can produce substantial quantities of the major inhibitor of fibrinolysis, plasminogen activator inhibitor 1 (PAI-1). Thus, in pathologic circumstances, the endothelial cell may promote local thrombus accumulation rather than combat it. Inflammatory stimuli also induce the expression of the potent procoagulant tissue factor, a contributor to disseminated intravascular coagulation in sepsis. Endothelial cells also participate in the pathophysiology of a number of immune-mediated diseases. Lysis of endothelial cells mediated by complement provides an example of immunologically mediated tissue injury. The presentation of foreign histocompatibility complex antigens by endothelial cells in solid-organ allografts can promote allograft arteriopathy. In addition, immune-mediated endothelial injury may contribute in some patients with thrombotic thrombocytopenic purpura and patients with hemolytic-uremic syndrome. Thus, in addition to the involvement of innate immune responses, endothelial cells participate actively in both humoral and cellular limbs of the immune response.
Figure 265e-2 Assessment of endothelial function in vivo using blood pressure cuff occlusion and release. Upon deflation of the cuff, an ultrasound probe monitors changes in diameter (A) and blood flow (B) of the brachial artery (C). (Reproduced with permission of J. Vita, MD.)
Endothelial cells regulate growth of subjacent smooth-muscle cells. Heparan sulfate glycosaminoglycans elaborated by endothelial cells can inhibit smooth-muscle proliferation. In contrast, when exposed to various injurious stimuli, endothelial cells can elaborate growth factors and chemoattractants, such as platelet-derived growth factor, that can promote the migration and proliferation of vascular smoothmuscle cells. Dysregulated elaboration of these growth-stimulatory molecules may promote smooth-muscle accumulation in atherosclerotic lesions.
Vascular Smooth-Muscle Cell Function Vascular smooth-muscle cells govern vessel tone. Those cells contract when stimulated by a rise in intracellular calcium concentration by calcium influx through the plasma membrane and by calcium release from intracellular stores (Fig. 265e-3). In vascular smooth-muscle cells, voltage-dependent L-type calcium channels open with membrane depolarization, which is regulated by energy-dependent ion pumps such as the Na+,K+-ATPase pump and ion channels such as the Ca2+-sensitive K+ channel. Local changes in intracellular calcium concentration, termed calcium sparks, result from the influx of calcium through the voltage-dependent calcium channel and are caused by the coordinated activation of a
NE, ET-1, Ang II
NO
VDCC PIP2
PLC
K+ Ch
Na-K ATPase
G
GTP
AC ATP
SR
RhoA IP3R RyrR
IP3
G
pGC sGC
DAG
BetaAgonist
ANP
Plb ATPase
cGMP
cAMP
PKG
PKA
Calcium
PKC Rho Kinase
MLCK
Caldesmon Calponin
MLCP
Figure 265e-3 Regulation of vascular smooth-muscle cell calcium concentration and actomyosin ATPase-dependent contraction. AC, adenylyl cyclase; Ang II, angiotensin II; ANP, atrial natriuretic peptide; DAG, diacylglycerol; ET-1, endothelin-1; G, G protein; IP3, inositol 1,4,5trisphosphate; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; NE, norepinephrine; NO, nitric oxide; pGC, particular guanylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum; VDCC, voltage-dependent calcium channel. (Modified from B Berk, in Vascular Medicine, 3rd ed. Philadelphia, Saunders, Elsevier, 2006, p. 23; with permission.)
265e-3
CHAPTER 265e Basic Biology of the Cardiovascular System
to maintain not only normal arterial structure, but also hemodynamic function. The ability of the larger arteries, such as the aorta, to store the kinetic energy of systole promotes tissue perfusion during diastole. Arterial stiffness associated with aging or disease, as manifested by a widening pulse pressure, increases left ventricular afterload and portends a poor outcome. Like endothelial cells, vascular smooth-muscle cells do not merely respond to vasomotor or inflammatory stimuli elaborated by other cell types but can themselves serve as a source of such stimuli. For example, when exposed to bacterial endotoxin or other proinflammatory stimuli, smooth-muscle cells can elaborate cytokines and other inflammatory mediators. Like endothelial cells, upon inflammatory activation, arterial smooth-muscle cells can produce prothrombotic mediators such as tissue factor, the antifibrinolytic protein PAI-1, and other molecules that modulate thrombosis and fibrinolysis. Smoothmuscle cells also elaborate autocrine growth factors that can amplify hyperplastic responses to arterial injury.
Vascular Smooth-Muscle Cell The vascular smooth-muscle cell, the major cell type of the media layer of blood vessels, also contributes actively to vascular pathobiology. Contraction and relaxation of smooth-muscle cells at the level of the muscular arteries controls blood pressure and, hence, regional blood flow and the afterload experienced by the left ventricle (see below). The vasomotor tone of veins, which is governed by smooth-muscle cell tone, regulates the capacitance of the venous tree and influences the preload experienced by both ventricles. Smooth-muscle cells in the adult vessel seldom replicate in the absence of arterial injury or inflammatory activation. Proliferation and migration of arterial smooth-muscle cells, associated with functional modulation characterized by lower content of contractile proteins and greater production of extracellular matrix macromolecules, can contribute to the development of arterial stenoses in atherosclerosis, arteriolar remodeling that can sustain and propagate hypertension, and the hyperplastic response of arteries injured by percutaneous intervention. In the pulmonary circulation, smooth-muscle migration and proliferation contribute decisively to the pulmonary vascular disease that gradually occurs in response to sustained high-flow states such as left-to-right shunts. Such pulmonary vascular disease provides a major obstacle to the management of many patients with adult congenital heart disease. Among other mediators, microRNAs have emerged as powerful regulators of this transition, offering new targets for intervention. Smooth-muscle cells secrete the bulk of vascular extracellular matrix. Excessive production of collagen and glycosaminoglycans contributes to the remodeling and altered functions and biomechanics of arteries affected by hypertension or atherosclerosis. In larger elastic arteries, the elastin synthesized by smooth-muscle cells serves
265e-4
PART 10 Disorders of the Cardiovascular System
cluster of ryanodine-sensitive calcium release channels in the sarcoplasmic reticulum (see below). Calcium sparks directly augment intracellular calcium concentration and indirectly increase intracellular calcium concentration by activating chloride channels. In addition, calcium sparks reduce smooth-muscle contractility by activating largeconductance calcium-sensitive K+ channels, hyperpolarizing the cell membrane and thereby limiting further voltage-dependent increases in intracellular calcium. Biochemical agonists also increase intracellular calcium concentration, in this case by receptor-dependent activation of phospholipase C with hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in the generation of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). These membrane lipid derivatives in turn activate protein kinase C and increase intracellular calcium concentration. In addition, IP3 binds to specific receptors on the sarcoplasmic reticulum membrane to increase calcium efflux from this calcium storage pool into the cytoplasm. Vascular smooth-muscle cell contraction depends principally on the phosphorylation of myosin light chain, which in the steady state, reflects the balance between the actions of myosin light chain kinase and myosin light chain phosphatase. Calcium activates myosin light chain kinase through the formation of a calciumcalmodulin complex. Phosphorylation of myosin light chain by this kinase augments myosin ATPase activity and enhances contraction. Myosin light chain phosphatase dephosphorylates myosin light chain, reducing myosin ATPase activity and contractile force. Phosphorylation of the myosin-binding subunit (thr695) of myosin light chain phosphatase by Rho kinase inhibits phosphatase activity and induces calcium sensitization of the contractile apparatus. Rho kinase is itself activated by the small GTPase RhoA, which is stimulated by guanosine exchange factors and inhibited by GTPase-activating proteins. Both cyclic AMP and cyclic GMP relax vascular smooth-muscle cells through complex mechanisms. β agonists, acting through their G-protein-coupled receptors activate adenylyl cyclase to convert ATP to cyclic AMP; NO and atrial natriuretic peptide acting directly and via a G-protein-coupled receptor, respectively, activate guanylyl cyclase to convert GTP to cyclic GMP. These agents in turn activate protein kinase A and protein kinase G, respectively, which inactivate myosin light chain kinase and decrease vascular smooth-muscle cell tone. In addition, protein kinase G can interact directly with the myosinbinding substrate subunit of myosin light chain phosphatase, increasing phosphatase activity and decreasing vascular tone. Finally, several mechanisms drive NO-dependent, protein kinase G–mediated reductions in vascular smooth-muscle cell calcium concentration, including phosphorylation-dependent inactivation of RhoA; decreased IP3 formation; phosphorylation of the IP3 receptor–associated cyclic GMP kinase substrate, with subsequent inhibition of IP3 receptor function; phosphorylation of phospholamban, which increases calcium ATPase activity and sequestration of calcium in the sarcoplasmic reticulum; and protein kinase G–dependent stimulation of plasma membrane calcium ATPase activity, perhaps by activation of the Na+,K+-ATPase pump or hyperpolarization of the cell membrane by activation of calcium-dependent K+ channels. Control of Vascular Smooth-Muscle Cell Tone The autonomic nervous system and endothelial cells modulate vascular smooth-muscle cells in a tightly regulated manner. Autonomic neurons enter the blood vessel medial layer from the adventitia and modulate vascular smoothmuscle cell tone in response to baroreceptors and chemoreceptors within the aortic arch and carotid bodies and in response to thermoreceptors in the skin. These regulatory components include rapidly acting reflex arcs modulated by central inputs that respond to sensory inputs (olfactory, visual, auditory, and tactile) as well as emotional stimuli. Three classes of nerves mediate autonomic regulation of vascular tone: sympathetic, whose principal neurotransmitters are epinephrine and norepinephrine; parasympathetic, whose principal neurotransmitter is acetylcholine; and nonadrenergic/noncholinergic, which include two subgroups—nitrergic, whose principal neurotransmitter
is NO, and peptidergic, whose principal neurotransmitters are substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, and ATP. Each of these neurotransmitters acts through specific receptors on the vascular smooth-muscle cell to modulate intracellular calcium and, consequently, contractile tone. Norepinephrine activates α receptors, and epinephrine activates α and β receptors (adrenergic receptors); in most blood vessels, norepinephrine activates postjunctional α1 receptors in large arteries and α2 receptors in small arteries and arterioles, leading to vasoconstriction. Most blood vessels express β2-adrenergic receptors on their vascular smooth-muscle cells and respond to β agonists by cyclic AMP–dependent relaxation. Acetylcholine released from parasympathetic neurons binds to muscarinic receptors (of which there are five subtypes, M1–5) on vascular smooth-muscle cells to yield vasorelaxation. In addition, NO stimulates presynaptic neurons to release acetylcholine, which can stimulate the release of NO from the endothelium. Nitrergic neurons release NO produced by neuronal NO synthase, which causes vascular smooth-muscle cell relaxation via the cyclic GMP–dependent and –independent mechanisms described above. The peptidergic neurotransmitters all potently vasodilate, acting either directly or through endothelium-dependent NO release to decrease vascular smooth-muscle cell tone. For the detailed molecular physiology of the autonomic nervous system, see Chap. 454. The endothelium modulates vascular smooth-muscle tone by the direct release of several effectors, including NO, prostacyclin, hydrogen sulfide, and endothelium-derived hyperpolarizing factor, all of which cause vasorelaxation, and endothelin, which causes vasoconstriction. The release of these endothelial effectors of vascular smooth-muscle cell tone is stimulated by mechanical (shear stress, cyclic strain, etc.) and biochemical mediators (purinergic agonists, muscarinic agonists, peptidergic agonists), with the biochemical mediators acting through endothelial receptors specific to each class. In addition to these local paracrine modulators of vascular smooth-muscle cell tone, circulating mediators can affect tone, including norepinephrine and epinephrine, vasopressin, angiotensin II, bradykinin, and the natriuretic peptides (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], C-type natriuretic peptide [CNP], and dendroaspis natriuretic peptide [DNP]), as discussed above. VASCULAR REGENERATION Growth of new blood vessels can occur in response to conditions such as chronic hypoxemia and tissue ischemia. Growth factors, including vascular endothelial growth factor (VEGF) and forms of fibroblast growth factor (FGF), activate a signaling cascade that stimulates endothelial proliferation and tube formation, defined as angiogenesis. Guidance molecules, including members of the semaphorin family of secreted peptides, direct blood vessel patterning by attracting or repelling nascent endothelial tubes. The development of collateral vascular networks in the ischemic myocardium, an example of angiogenesis, can result from selective activation of endothelial progenitor cells, which may reside in the blood vessel wall or home to the ischemic tissue from the bone marrow. True arteriogenesis, or the development of a new blood vessel that includes all three cell layers, normally does not occur in the cardiovascular system of adult mammals. The molecular mechanisms and progenitor cells that can recapitulate blood vessel development de novo are under rapidly advancing study (Chaps. 88, 89e, and 90e). VASCULAR PHARMACOGENOMICS The last decade has witnessed considerable progress in efforts to define the genetic differences underlying individual variations in vascular pharmacologic responses. Many investigators have focused on receptors and enzymes associated with neurohumoral modulation of vascular function as well as hepatic enzymes that metabolize drugs that affect vascular tone. The genetic polymorphisms thus far associated with differences in vascular response often (but not invariably) relate to functional differences in the activity or expression of the receptor or enzyme of interest. Some of these
polymorphisms appear to have different allele frequencies in specific ethnic groups.
Exchange
Pump
Ca2+ “trigger”
Myocy te
Myofibril
Ca2+ leaves Free Ca2+
Myofibril Mitochondrion
SR
Contract Relax
B
Systole Myofibril
Z C
Diastole
Actin
Head
Titin
Myosin M
43 nm
Z D
Figure 265e-4 A shows the branching myocytes making up the cardiac myofibers. B illustrates the critical role played by the changing [Ca2+] in the myocardial cytosol. Ca2+ ions are schematically shown as entering through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions “trigger” the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle. Eventually the small quantity of Ca2+ that has entered the cell leaves predominantly through an Na+/Ca2+ exchanger, with a lesser role for the sarcolemmal Ca2+ pump. The varying actin-myosin overlap is shown for (B) systole, when [Ca2+] is maximal, and (C) diastole, when [Ca2+] is minimal. D. The myosin heads, attached to the thick filaments, interact with the thin actin filaments. (From LH Opie: Heart Physiology: From Cell to Circulation, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2004. Reprinted with permission. Copyright LH Opie, 2004.)
THE CONTRACTILE PROCESS The sliding filament model for muscle contraction rests on the fundamental observation that both the thick and the thin filaments are constant in overall length during both contraction and relaxation. With activation, the actin filaments are propelled farther into the A band. In the process, the A band remains constant in length, whereas the I band shortens and the Z lines move toward one another. The myosin molecule is a complex, asymmetric fibrous protein with a molecular mass of about 500,000 Da; it has a rodlike portion that is about 150 nm (1500 Å) in length with a globular portion (head) at its end. These globular portions of myosin form the bridges between the myosin and actin molecules and are the site of ATPase activity. In forming the thick myofilament, which is composed of ~300 longitudinally stacked myosin molecules, the rodlike segments of the myosin molecules are laid down in an orderly, polarized manner, leaving the globular portions projecting outward so that they can interact with actin to generate force and shortening (Fig. 265e-4B). Actin has a molecular mass of about 47,000 Da. The thin filament consists of a double helix of two chains of actin molecules wound about each other on a larger molecule, tropomyosin. A group of regulatory proteins—troponins C, I, and T—are spaced at regular intervals on this filament (Fig. 265e-5). In contrast to myosin, actin lacks intrinsic enzymatic activity but does combine reversibly with myosin in the presence of ATP and Ca2+. The calcium ion activates the myosin ATPase, which in turn breaks down ATP, the energy source for contraction (Fig. 265e-5). The activity of myosin ATPase determines the rate of forming and breaking of the actomyosin cross-bridges and ultimately the velocity of muscle contraction. In relaxed muscle, tropomyosin inhibits this interaction. Titin (Fig. 265e-4D) is a large, flexible, myofibrillar protein that connects myosin to the Z line; its stretching contributes to the elasticity of the heart.
265e-5
CHAPTER 265e Basic Biology of the Cardiovascular System
centrally located nucleus, numerous mitochondria, and the intracellular membrane system, the sarcoplasmic reticulum. The sarcomere, the structural and functional unit of contraction, lies between adjacent Z lines, which are dark repeating bands that are CELLULAR BASIS OF CARDIAC CONTRACTION apparent on transmission electron microscopy. The distance between CARDIAC ULTRASTRUCTURE Z lines varies with the degree of contraction or stretch of the muscle About three-fourths of the ventricular mass is composed of cardiomy- and ranges between 1.6 and 2.2 μm. Within the confines of the sarocytes, normally 60–140 μm in length and 17–25 μm in diameter (Fig. comere are alternating light and dark bands, giving the myocardial 265e-4A). Each cell contains multiple, rodlike cross-banded strands fibers their striated appearance under the light microscope. At the (myofibrils) that run the length of the cell and are composed of seri- center of the sarcomere is a dark band of constant length (1.5 μm), the ally repeating structures, the sarcomeres. The cytoplasm between A band, which is flanked by two lighter bands, the I bands, which are the myofibrils contains other cell constituents, including the single of variable length. The sarcomere of heart muscle, like that of skeletal muscle, consists of two sets of interdigitating myofilaments. Thicker filaments, composed principally of the protein myosin, traverse the A band; they are about 10 nm (100 Å) in diameter, with tapered ends. Thinner filaments, composed primarily of actin, course from the Z lines through the I band into the A band; they are approximately 5 nm (50 Myofiber Å) in diameter and 1.0 μm in length. Thus, thick and thin filaments overlap only within the (dark) A A Myocyte 10 μm band, whereas the (light) I band contains only thin filaments. On electron-microscopic examination, Ca2+ bridges may be seen to extend between the thick enters and thin filaments within the A band; these are Na+ Ca2+ myosin heads (see below) bound to actin filaments. T tubule
265e-6 ADP
ATP
Pi
1. ATP hydrolysis
Relaxed 4. Dissociation of
Relaxed, energized Actin
Actin
actin and myosin
PART 10
ATP
2. Formation of active complex Pi
ADP
ADP
Disorders of the Cardiovascular System
3. Product dissociation Rigor complex
Active complex
Figure 265e-5 Four steps in cardiac muscle contraction and relaxation. In relaxed muscle (upper left), ATP bound to the myosin cross-bridge dissociates the thick and thin filaments. Step 1: Hydrolysis of myosin-bound ATP by the ATPase site on the myosin head transfers the chemical energy of the nucleotide to the activated cross-bridge (upper right). When cytosolic Ca2+ concentration is low, as in relaxed muscle, the reaction cannot proceed because tropomyosin and the troponin complex on the thin filament do not allow the active sites on actin to interact with the cross-bridges. Therefore, even though the crossbridges are energized, they cannot interact with actin. Step 2: When Ca2+ binding to troponin C has exposed active sites on the thin filament, actin interacts with the myosin crossbridges to form an active complex (lower right) in which the energy derived from ATP is retained in the actin-bound cross-bridge, whose orientation has not yet shifted. Step 3: The muscle contracts when ADP dissociates from the cross-bridge. This step leads to the formation of the low-energy rigor complex (lower left) in which the chemical energy derived from ATP hydrolysis has been expended to perform mechanical work (the “rowing” motion of the cross-bridge). Step 4: The muscle returns to its resting state, and the cycle ends when a new molecule of ATP binds to the rigor complex and dissociates the cross-bridge from the thin filament. This cycle continues until calcium is dissociated from troponin C in the thin filament, which causes the contractile proteins to return to the resting state with the cross-bridge in the energized state. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase. (From AM Katz: Heart failure: Cardiac function and dysfunction, in Atlas of Heart Diseases, 3rd ed, WS Colucci [ed]. Philadelphia, Current Medicine, 2002. Reprinted with permission.) Dystrophin is a long cytoskeletal protein that has an amino-terminal actin-binding domain and a carboxy-terminal domain that binds to the dystroglycan complex at adherens junctions on the cell membrane, thus tethering the sarcomere to the cell membrane at regions tightly coupled to adjacent contracting myocytes. Mutations in components of the dystrophin complex lead to muscular dystrophy and associated cardiomyopathy. During activation of the cardiac myocyte, Ca2+ becomes attached to one of three components of the heterotrimer troponin C, which results in a conformational change in the regulatory protein tropomyosin; the latter, in turn, exposes the actin cross-bridge interaction sites (Fig. 265e-5). Repetitive interaction between myosin heads and actin filaments is termed cross-bridge cycling, which results in sliding of the actin along the myosin filaments, ultimately causing muscle shortening and/or the development of tension. The splitting of ATP then dissociates the myosin cross-bridge from actin. In the presence of ATP (Fig. 265e-5), linkages between actin and myosin filaments are made and broken cyclically as long as sufficient Ca2+ is present; these linkages cease when [Ca2+] falls below a critical level, and the troponintropomyosin complex once more prevents interactions between the myosin cross-bridges and actin filaments (Fig. 265e-6). Intracytoplasmic Ca2+ is a principal determinant of the inotropic state of the heart. Most agents that stimulate myocardial contractility (positive inotropic stimuli), including the digitalis glycosides and
β-adrenergic agonists, increase the [Ca2+] in the vicinity of the myofilaments, which in turn triggers cross-bridge cycling. Increased impulse traffic in the cardiac adrenergic nerves stimulates myocardial contractility as a consequence of the release of norepinephrine from cardiac adrenergic nerve endings. Norepinephrine activates myocardial β receptors and, through the Gs-stimulated guanine nucleotide-binding protein, activates the enzyme adenylyl cyclase, which leads to the formation of the intracellular second messenger cyclic AMP from ATP (Fig. 265e-6). Cyclic AMP in turn activates protein kinase A (PKA), which phosphorylates the Ca2+ channel in the myocardial sarcolemma, thereby enhancing the influx of Ca2+ into the myocyte. Other functions of PKA are discussed below. The sarcoplasmic reticulum (SR) (Fig. 265e-7), a complex network of anastomosing intracellular channels, invests the myofibrils. Its longitudinally disposed tubules closely invest the surfaces of individual sarcomeres but have no direct continuity with the outside of the cell. However, closely related to the SR, both structurally and functionally, are the transverse tubules, or T system, formed by tubelike invaginations of the sarcolemma that extend into the myocardial fiber along the Z lines, i.e., the ends of the sarcomeres.
CARDIAC ACTIVATION In the inactive state, the cardiac cell is electrically polarized; i.e., the interior has a negative charge relative to the outside of the cell, with a transmembrane potential of –80 to –100 mV (Chap. 273e). The sarcolemma, which in the resting state is largely impermeable to Na+, has a Na+- and K+-stimulating pump energized by ATP that extrudes Na+ from the cell; this pump plays a critical role in establishing the resting potential. Thus, intracellular [K+] is relatively high and [Na+] is far lower; conversely, extracellular [Na+] is high and [K+] is low. At the same time, in the resting state, extracellular [Ca2+] greatly exceeds free intracellular [Ca2+]. The action potential has four phases (see Fig. 273e-1B). During the plateau of the action potential (phase 2), there is a slow inward current through L-type Ca2+ channels in the sarcolemma (Fig. 265e-7). The depolarizing current not only extends across the surface of the cell but penetrates deeply into the cell by way of the ramifying T tubular system. The absolute quantity of Ca2+ that crosses the sarcolemma and the T system is relatively small and by itself appears to be insufficient to bring about full activation of the contractile apparatus. However, this Ca2+ current triggers the release of much larger quantities of Ca2+ from the SR, a process termed Ca2+-induced Ca2+ release. The latter is a major determinant of intracytoplasmic [Ca2+] and therefore of myocardial contractility. Ca2+ is released from the SR through a Ca2+ release channel, a cardiac isoform of the ryanodine receptor (RyR2), which controls intracytoplasmic [Ca2+] and, as in vascular smooth-muscle cells, leads to the local changes in intracellular [Ca2+] called calcium sparks. A number of regulatory proteins, including calstabin 2, inhibit RyR2 and thereby the release of Ca2+ from the SR. PKA dissociates calstabin from the RyR2, enhancing Ca2+ release and thereby myocardial contractility. Excessive plasma catecholamine levels and cardiac sympathetic neuronal release of norepinephrine cause hyperphosphorylation of PKA, leading to calstabin 2–depleted RyR2. The latter depletes SR Ca2+ stores and thereby impairs cardiac contraction, leading to heart failure, and also triggers ventricular arrhythmias.
Ca2+
β - Adrenergic agonist
β αs
γ
Adenyl cyclase
P
SL
Ca2+ +
+
SR
cAMP
+
Via protein kinase A
CONTROL OF CARDIAC PERFORMANCE AND OUTPUT
P
Metabolic • glycolysis • lipolysis • citrate cycle
Ca2+ ADP + Pi + ATP
+
Troponin C + 2
Myosin ATPase +
ADP + Pi
cAMP via PL
1
Increased 1. rate of contraction 2. peak force 3. rate of relaxation
3
+ Control
Force
β
cAMP via Tnl
Time
Pattern of contraction
Figure 265e-6 Signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects of β-adrenergic stimulation. When the β-adrenergic agonist interacts with the β receptor, a series of G protein–mediated changes leads to activation of adenylyl cyclase and the formation of cyclic adenosine monophosphate (cAMP). The latter acts via protein kinase A to stimulate metabolism (left) and phosphorylate the Ca2+ channel protein (right). The result is an enhanced opening probability of the Ca2+ channel, thereby increasing the inward movement of Ca2+ ions through the sarcolemma (SL) of the T tubule. These Ca2+ ions release more calcium from the sarcoplasmic reticulum (SR) to increase cytosolic Ca2+ and activate troponin C. Ca2+ ions also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Enhanced myosin ATPase activity explains the increased rate of contraction, with increased activation of troponin C explaining increased peak force development. An increased rate of relaxation results from the ability of cAMP to activate as well the protein phospholamban, situated on the membrane of the SR, that controls the rate of uptake of calcium into the SR. The latter effect explains enhanced relaxation (lusitropic effect). P, phosphorylation; PL, phospholamban; TnI, troponin I. (Modified from LH Opie: Heart Physiology: From Cell to Circulation, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2004. Reprinted with permission. Copyright LH Opie, 2004.) The Ca2+ released from the SR then diffuses toward the myofibrils, where, as already described, it combines with troponin C (Fig. 265e-6). By repressing this inhibitor of contraction, Ca2+ activates the myofilaments to shorten. During repolarization, the activity of the Ca2+ pump in the SR, the SR Ca2+ ATPase (SERCA2A), reaccumulates Ca2+ against a concentration gradient, and the Ca2+ is stored in the SR by its attachment to a protein, calsequestrin. This reaccumulation of Ca2+ is an energy (ATP)-requiring process that lowers the cytoplasmic [Ca2+] to a level that inhibits the actomyosin interaction responsible for contraction, and in this manner leads to myocardial relaxation. Also,
The extent of shortening of heart muscle and, therefore, the stroke volume of the ventricle in the intact heart depend on three major influences: (1) the length of the muscle at the onset of contraction, i.e., the preload; (2) the tension that the muscle is called on to develop during contraction, i.e., the afterload; and (3) the contractility of the muscle, i.e., the extent and velocity of shortening at any given preload and afterload. The major determinants of preload, afterload, and contractility are shown in Table 265e-2. THE ROLE OF MUSCLE LENGTH (PRELOAD) The preload determines the length of the sarcomeres at the onset of contraction. The length of the sarcomeres associated with the most forceful contraction is ~2.2 μm. This length provides the optimum configuration for the interaction between the two sets of myofilaments. The length of the sarcomere also regulates the extent of activation of the contractile system, i.e., its sensitivity to Ca2+. According to this concept, termed length-dependent activation, myofilament sensitivity to Ca2+ is also maximal at the optimal sarcomere length. The relation between the initial length of the muscle fibers and the developed force has prime importance for the function of heart muscle. This relationship forms the basis of Starling’s law of the heart, which states that within limits, the force of ventricular contraction depends on the end-diastolic length of the cardiac muscle; in the intact heart, the latter relates closely to the ventricular end-diastolic volume.
CARDIAC PERFORMANCE The ventricular end-diastolic or “filling” pressure sometimes is used as a surrogate for the end-diastolic volume. In isolated heart and heart-lung preparations, the stroke volume varies directly with the end-diastolic fiber length (preload) and inversely with the arterial resistance (afterload), and as the heart fails—i.e., as its contractility declines—it delivers a progressively smaller stroke volume from a normal or even elevated end-diastolic volume. The relation between the ventricular end-diastolic pressure and the stroke work of the ventricle (the ventricular function curve) provides a useful definition of the level of contractility of the heart in the intact organism. An increase in contractility is accompanied by a shift of the ventricular function curve upward and to the left (greater stroke work at any level of ventricular end-diastolic pressure, or lower end-diastolic volume at any level of stroke work), whereas a shift downward and to the right characterizes depression of contractility (Fig. 265e-8).
265e-7
CHAPTER 265e Basic Biology of the Cardiovascular System
GTP
β Receptor
there is an exchange of Ca2+ for Na+ at the sarcolemma (Fig. 265e-7), reducing the cytoplasmic [Ca2+]. Cyclic AMP–dependent PKA phosphorylates the SR protein phospholamban; the latter, in turn, permits activation of the Ca2+ pump, thereby increasing the uptake of Ca2+ by the SR, accelerating the rate of relaxation, and providing larger quantities of Ca2+ in the SR for release by subsequent depolarization, thereby stimulating contraction. Thus, the combination of the cell membrane, transverse tubules, and SR, with their ability to transmit the action potential and release and then reaccumulate Ca2+, plays a fundamental role in the rhythmic contraction and relaxation of heart muscle. Genetic or pharmacologic alterations of any component, whatever its etiology, can disturb these functions.
265e-8
Na+ pump
Na+/Ca2+ exchanger B1
Plasma membrane Ca2+ pump B2 Extracellular
T tubule
Plasma membrane Ca2+ channel
Intracellular (cytosol)
Cisterna
Sarcoplasmic reticulum
Ca2+release channel ('foot' protein)
A
Plasma membrane
PART 10
Sarcotubular network A1
G Calsequestrin
Disorders of the Cardiovascular System
C
Sarcoplasmic reticulum Ca2+ pump
Mitochondria
D H
E
Z-line
Troponin C
F
Thin filament
Thick filament
Contractile proteins
Figure 265e-7 The Ca2+ fluxes and key structures involved in cardiac excitationcontraction coupling. The arrows denote the direction of Ca2+ fluxes. The thickness of each arrow indicates the magnitude of the calcium flux. Two Ca2+ cycles regulate excitation-contraction coupling and relaxation. The larger cycle is entirely intracellular and involves Ca2+ fluxes into and out of the sarcoplasmic reticulum, as well as Ca2+ binding to and release from troponin C. The smaller extracellular Ca2+ cycle occurs when this cation moves into and out of the cell. The action potential opens plasma membrane Ca2+ channels to allow passive entry of Ca2+ into the cell from the extracellular fluid (arrow A). Only a small portion of the Ca2+ that enters the cell directly activates the contractile proteins (arrow A1). The extracellular cycle is completed when Ca2+ is actively transported back out to the extracellular fluid by way of two plasma membrane fluxes mediated by the sodium-calcium exchanger (arrow B1) and the plasma membrane calcium pump (arrow B2). In the intracellular Ca2+ cycle, passive Ca2+ release occurs through channels in the cisternae (arrow C) and initiates contraction; active Ca2+ uptake by the Ca2+ pump of the sarcotubular network (arrow D) relaxes the heart. Diffusion of Ca2+ within the sarcoplasmic reticulum (arrow G) returns this activator cation to the cisternae, where it is stored in a complex with calsequestrin and other calcium-binding proteins. Ca2+ released from the sarcoplasmic reticulum initiates systole when it binds to troponin C (arrow E). Lowering of cytosolic [Ca2+] by the sarcoplasmic reticulum (SR) causes this ion to dissociate from troponin (arrow F) and relaxes the heart. Ca2+ also may move between mitochondria and cytoplasm (H). (Adapted from AM Katz: Physiology of the Heart, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2005, with permission.)
VENTRICULAR AFTERLOAD In the intact heart, as in isolated cardiac muscle, the extent and velocity of shortening of ventricular muscle fibers at any level of preload and of myocardial contractility relate inversely to the afterload, i.e., the load that opposes shortening. In the intact heart, the afterload may be defined as the tension developed in the ventricular wall during ejection. Afterload is determined by the aortic pressure as well as by the volume and thickness of the ventricular cavity. Laplace’s law states that the tension of the myocardial fiber is the product of the intracavitary ventricular pressure and ventricular radius divided by wall thickness. Therefore, at any particular level of aortic pressure, the afterload on a dilated left ventricle exceeds that on a normal-sized
ventricle. Conversely, at the same aortic pressure and ventricular diastolic volume, the afterload on a hypertrophied ventricle is lower than of a normal chamber. The aortic pressure in turn depends on the peripheral vascular resistance, the physical characteristics of the arterial tree, and the volume of blood it contains at the onset of ejection. Ventricular afterload critically regulates cardiovascular performance (Fig. 265e-9). As already noted, elevations in both preload and contractility increase myocardial fiber shortening, whereas increases in afterload reduce it. The extent of myocardial fiber shortening and left ventricular size determine stroke volume. An increase in arterial pressure induced by vasoconstriction, for example, augments afterload, which opposes myocardial fiber shortening, reducing stroke volume. When myocardial contractility becomes impaired and the ventricle dilates, afterload rises (Laplace’s law) and limits cardiac output. Increased afterload also may result from neural and humoral stimuli that occur in response to a fall in cardiac output. This increased afterload may reduce cardiac output further, thereby increasing ventricular volume and initiating a vicious circle, especially in patients with ischemic heart disease and limited myocardial O2 supply. Treatment with vasodilators has the opposite effect; when afterload is reduced, cardiac output rises (Chap. 279). Under normal circumstances, the various influences acting on cardiac performance enumerated above interact in a complex fashion to maintain cardiac output at a level appropriate to the requirements of the metabolizing tissues (Fig. 265e-9); interference with a single mechanism may not influence the cardiac output. For example, a moderate reduction of blood volume or the loss of the atrial contribution to ventricular contraction ordinarily can be sustained without a reduction in the cardiac output at rest. Under these circumstances, other factors, such as increases in the frequency of adrenergic nerve impulses to the heart, heart rate, and venous tone, will serve as compensatory mechanisms and sustain cardiac output in a normal individual.
EXERCISE The integrated response to exercise illustrates the interactions among the three determinants of stroke volume: preload, afterload, and contractility (Fig. 265e-8). Hyperventilation, the pumping action of the exercising muscles, and venoconstriction during exercise all augment venous return and hence ventricular filling and preload (Table 265e-2). Simultaneously, the increase in the adrenergic nerve impulse traffic to the myocardium, the increased concentration of circulating catecholamines, and the tachycardia that occur during exercise combine to augment the contractility of the myocardium (Fig. 265e-8, curves 1 and 2) and together elevate stroke volume and stroke work, without a change in or even a reduction of end-diastolic pressure and volume (Fig. 265e-8, points A and B). Vasodilation occurs in the exercising muscles, thus tending to limit the increase in arterial pressure that otherwise would occur as cardiac output rises to levels as high as five times greater than basal levels during maximal exercise. This vasodilation ultimately allows the achievement of a greatly elevated cardiac output during exercise at an arterial pressure only moderately higher than in the resting state.
TABLE 265e-2 Determinants of Stroke Volume
Arrows indicate directional effects of determinants of contractility. bContractility rises initially but later becomes depressed.
a
ASSESSMENT OF CARDIAC FUNCTION Several techniques can define impaired cardiac function in clinical practice. The cardiac output and stroke volume may be depressed in the presence of heart failure, but not uncommonly, these variables are within normal limits in this condition. A somewhat more sensitive index of cardiac function is the ejection fraction, i.e., the ratio of stroke volume to end-diastolic volume (normal value = 67 ± 8%), which is frequently depressed in systolic heart failure even when the stroke volume itself is normal. Alternatively, abnormally elevated ventricular end-diastolic volume (normal value = 75 ± 20 mL/m2) or end-systolic volume (normal value = 25 ± 7 mL/m2) signifies impairment of left ventricular systolic function. Noninvasive techniques, particularly echocardiography as well as radionuclide scintigraphy and cardiac magnetic resonance imaging (MRI) (Chap. 270e), have great value in the clinical assessment of myocardial function. They provide measurements of end-diastolic and end-systolic volumes, ejection fraction, and systolic shortening rate, and they allow assessment of ventricular filling (see below) as well as regional contraction and relaxation. The latter measurements are particularly important in ischemic heart disease, as myocardial infarction causes regional myocardial damage. A limitation of measurements of cardiac output, ejection fraction, and ventricular volumes in assessing cardiac function is that ventricular loading conditions strongly influence these variables. Thus, a depressed ejection fraction and lowered cardiac output may occur in patients with normal ventricular function but reduced preload, as occurs in hypovolemia, or with increased afterload, as occurs in acutely elevated arterial pressure.
2
1 Ventricular performance
Normal-exercise
C
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Normal-rest
Contractile state of myocardium Walking B
3 Exercise Heart failure
3′
D
Rest A
E
Dyspnea
4
Fatal myocardial depression
Pulmonary edema Ventricular EDV
Stretching of myocardium
Figure 265e-8 The interrelations among influences on ventricular end-diastolic volume (EDV) through stretching of the myocardium and the contractile state of the myocardium. Levels of ventricular EDV associated with filling pressures that result in dyspnea and pulmonary edema are shown on the abscissa. Levels of ventricular performance required when the subject is at rest, while walking, and during maximal activity are designated on the ordinate. The broken lines are the descending limbs of the ventricular-performance curves, which are rarely seen during life but show the level of ventricular performance if end-diastolic volume could be elevated to very high levels. For further explanation, see text. (Modified from WS Colucci and E Braunwald: Pathophysiology of heart failure, in Braunwald’s Heart Disease, 7th ed, DP Zipes et al [eds]. Philadelphia: Elsevier, 2005, pp 509–538.)
Venous return
Preload
Contractility
Stroke volume Cardiac output
Afterload
Heart rate Peripheral resistance
Medullary vasomotor and cardiac centers
Arterial pressure
Carotid and aortic baroreceptors
Higher nervous centers
Figure 265e-9 Interactions in the intact circulation of preload, contractility, and afterload in producing stroke volume. Stroke volume combined with heart rate determines cardiac output, which, when combined with peripheral vascular resistance, determines arterial pressure for tissue perfusion. The characteristics of the arterial system also contribute to afterload, an increase that reduces stroke volume. The interaction of these components with carotid and aortic arch baroreceptors provides a feedback mechanism to higher medullary and vasomotor cardiac centers and to higher levels in the central nervous system to effect a modulating influence on heart rate, peripheral vascular resistance, venous return, and contractility. (From MR Starling: Physiology of myocardial contraction, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 3rd ed, WS Colucci and E Braunwald [eds]. Philadelphia: Current Medicine, 2002, pp 19–35.)
CHAPTER 265e Basic Biology of the Cardiovascular System
I. Ventricular Preload A. Blood volume B. Distribution of blood volume 1. Body position 2. Intrathoracic pressure 3. Intrapericardial pressure 4. Venous tone 5. Pumping action of skeletal muscles C. Atrial contraction II. Ventricular Afterload A. Systemic vascular resistance B. Elasticity of arterial tree C. Arterial blood volume D. Ventricular wall tension 1. Ventricular radius 2. Ventricular wall thickness III. Myocardial Contractilitya A. Intramyocardial [Ca2+] ↑↓ b B. Cardiac adrenergic nerve activity ↑↓ b C. Circulating catecholamines ↑↓ b D. Cardiac rate ↑↓ E. Exogenous inotropic agents ↑ F. Myocardial ischemia ↓ G. Myocardial cell death (necrosis, apoptosis, autophagy) ↓ H. Alterations of sarcomeric and cytoskeletal proteins ↓ 1. Genetic 2. Hemodynamic overload I. Myocardial fibrosis ↓ J. Chronic overexpression of neurohormones ↓ K. Ventricular remodeling ↓ L. Chronic and/or excessive myocardial hypertrophy ↓
Maximal activity
as from the cell’s breakdown of its glycogen stores (glycogenolysis). These two principal sources of acetyl coenzyme A in cardiac muscle vary reciprocally. ESPVR Glucose is broken down in the cytoplasm into a threecarbon product, pyruvate, which passes into the mitoContractility afterload chondria, where it is metabolized to the two-carbon fragment, acetyl-CoA, and undergoes oxidation. FFAs preload are converted to acyl-CoA in the cytoplasm and acetylCoA in the mitochondria. Acetyl-CoA enters the citric acid (Krebs) cycle to produce ATP by oxidative phos2 2 phorylation within the mitochondria; ATP then enters 1 1 the cytoplasm from the mitochondrial compartment. 3 3 Intracellular ADP, resulting from the breakdown of ATP, enhances mitochondrial ATP production. In the fasted, resting state, circulating FFA concentrations and their myocardial uptake are high, and they furnish most of the heart’s acetyl-CoA LV volume LV volume (~70%). In the fed state, with elevations of blood Figure 265e-10 The responses of the left ventricle to increased afterload, glucose and insulin, glucose oxidation increases and increased preload, and increased and reduced contractility are shown in the FFA oxidation subsides. Increased cardiac work, the pressure-volume plane. Left. Effects of increases in preload and afterload on the administration of inotropic agents, hypoxia, and mild pressure-volume loop. Because there has been no change in contractility, the ischemia all enhance myocardial glucose uptake, gluend-systolic pressure-volume relationship (ESPVR) is unchanged. With an increase in cose production resulting from glycogenolysis, and afterload, stroke volume falls (1 → 2); with an increase in preload, stroke volume rises glucose metabolism to pyruvate (glycolysis). By con(1 → 3). Right. With increased myocardial contractility and constant left ventricular trast, β-adrenergic stimulation, as occurs during stress, end-diastolic volume, the ESPVR moves to the left of the normal line (lower endraises the circulating levels and metabolism of FFAs systolic volume at any end-systolic pressure) and stroke volume rises (1 → 3). With in favor of glucose. Severe ischemia inhibits the cytoreduced myocardial contractility, the ESPVR moves to the right; end-systolic volume is plasmic enzyme pyruvate dehydrogenase, and despite increased, and stroke volume falls (1 → 2). both glycogen and glucose breakdown, glucose is metabolized only to lactic acid (anaerobic glycolyThe end-systolic left ventricular pressure-volume relationship is a sis), which does not enter the citric acid cycle. Anaerobic glycolysis particularly useful index of ventricular performance because it does produces much less ATP than does aerobic glucose metabolism, in not depend on preload and afterload (Fig. 265e-10). At any level of which glucose is metabolized to pyruvate and subsequently oxidized to myocardial contractility, left ventricular end-systolic volume varies CO2. High concentrations of circulating FFAs, which can occur when inversely with end-systolic pressure; as contractility declines, end- adrenergic stimulation is superimposed on severe ischemia, reduce systolic volume (at any level of end-systolic pressure) rises. oxidative phosphorylation and also cause ATP wastage; the myocardial content of ATP declines and impairs myocardial contraction. In addition, products of FFA breakdown can exert toxic effects on cardiac cell DIASTOLIC FUNCTION membranes and may be arrhythmogenic. Ventricular filling is influenced by the extent and speed of myocardial 2+ relaxation, which in turn depends on the rate of uptake of Ca by the Abnormal relaxation Pericardial restraint SR; the latter may be enhanced by adrenergic activation and reduced 2+ by ischemia, which reduces the ATP available for pumping Ca into the SR (see above). The stiffness of the ventricular wall also may impede filling. Ventricular stiffness increases with hypertrophy and conditions that infiltrate the ventricle, such as amyloid, or is caused by an extrinsic constraint (e.g., pericardial compression) (Fig. 265e-11). Ventricular filling can be assessed by continuously measuring the velocity of flow across the mitral valve using Doppler ultrasound. Normally, the velocity of inflow is more rapid in early diastole than during atrial systole; with mild to moderately impaired relaxation, the rate of early diastolic filling declines, whereas the rate of presystolic Increased chamber Chamber stiffness dilation filling rises. With further impairment of filling, the pattern is “pseudonormalized,” and early ventricular filling becomes more rapid as left atrial pressure upstream to the stiff left ventricle rises.
PART 10 Disorders of the Cardiovascular System
Left ventricular pressure
LV pressure
Normal contractility Contractility
LV pressure
265e-10
CARDIAC METABOLISM The heart requires a continuous supply of energy (in the form of ATP) not only to perform its mechanical pumping functions, but also to regulate intracellular and transsarcolemmal ionic movements and concentration gradients. Among its pumping functions, the development of tension, the frequency of contraction, and the level of myocardial contractility are the principal determinants of the heart’s substantial energy needs, making its O2 requirements approximately 15% of that of the entire organism. Most ATP production depends on the oxidation of substrate (glucose and free fatty acids [FFAs]). Myocardial FFAs are derived from circulating FFAs, which result principally from lipolysis in adipose tissue, whereas the myocyte’s glucose derives from plasma as well
Left ventricular volume
Figure 265e-11 Mechanisms that cause diastolic dysfunction reflected in the pressure-volume relation. The bottom half of the pressure-volume loop is depicted. Solid lines represent normal subjects; broken lines represent patients with diastolic dysfunction. (From JD Carroll et al: The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation 74:815, 1986; with permission.)
development, such as NKX2-5 and GATA4. Mutations in these genes 265e-11 are responsible for some forms of inherited congenital heart disease. Cardiac precursors coalesce to form a midline heart tube composed of a single cell layer of endocardium surrounded by a single layer of myocardial precursors. The caudal, inflow region of the heart tube, which is destined to adopt a more rostral final position, represents the atrial anlagen, whereas the rostral, outflow portion of the tube forms the truncus arteriosus, which divides to produce the aorta and the proximal pulmonary artery. Between these extremes lie the structural precursors of the ventricles. The linear heart tube undergoes an asymmetric looping process (the Developmental Biology of the Cardiovascular System The heart is the first gross evidence of left-right asymmetry in the developing embryo), first organ to form during embryogenesis (Fig. 265e-12) and must which positions the portion of the heart tube destined to become the accomplish the simultaneous challenges of circulating blood, nutri- left ventricle to the left of the more rostral precursors of the right venents, and oxygen to the other forming organs while continuing to tricle and outflow tract. Looping is coordinated with chamber specifigrow and undergo complex morphogenetic changes. Early pro- cation and ballooning of various regions of the heart tube to produce genitors of the heart arise within very early crescent-shaped fields the presumptive atria and ventricles. of lateral splanchnic mesoderm under the influence of multiple Relatively recent work has demonstrated that significant portions of signals, including those derived from neural ectoderm long before the right ventricle are formed by cells that are added to the developing neural tube closure. Early cardiac precursors express genes encoding heart after looping has occurred. These cells, which are derived from regulatory transcription factors that play reiterated roles in cardiac what is called the second heart field, migrate to the heart from the ventral pharynx and express markers that allow for their identification, including Early heart-forming Neural folds Pericardial Foregut Forming heart Islet-1. Different embryologic origins of regions coelom cells within the right and left ventricles may help explain why some forms of congenital and adult heart diseases affect these regions of the heart to varying degrees. After looping and chamber formation, a series of septation events divide the left and right sides of the heart, separate A B the atria from the ventricles, and form the aorta and pulmonary artery from the truncus arteriosus. Cardiac valves First heart field Second heart field form between the atria and the ventricles and between the ventricles and the outflow vessels. Early in development, the single layer of myocardial cells secretes RA LA an extracellular matrix rich in hyaluronic acid. This extracellular matrix, termed “cardiac jelly,” accumulates within the endocardial cushions, precursors of the RV LV LV cardiac valves. Signals from overlying myocardial cells, including members of RV the transforming growth factor β family, C D E trigger migration, invasion, and phenotypic changes of underlying endocardial cells, which undergo an epithelial- mesenchymal transformation and invade the cardiac jelly to cellularize the endocardial cushions. Mesenchymal components proliferate and remodel to form the mature valve leaflets. The great vessels form as a series of bilaterally symmetric aortic arch arteries that undergo asymmetric remodeling events to form the mature vasculaF ture. The immigration of neural crest cells that arise in the dorsal neural tube Figure 265e-12 A. Schematic depiction of a transverse section through an early embryo depicts orchestrates this process. These cells are the bilateral regions where early heart tubes form. B. The bilateral heart tubes subsequently required for aortic arch remodeling and migrate to the midline and fuse to form the linear heart tube. C. At the early cardiac crescent stage of embryonic development, cardiac precursors include a primary heart field fated to form the linear septation of the truncus arteriosus. They develop into smooth-muscle cells within heart tube and a second heart field fated to add myocardium to the inflow and outflow poles of the tunica media of the aortic arch, the the heart. D. Second heart field cells populate the pharyngeal region before subsequently migratductus arteriosus, and the carotid artering to the maturing heart. E. Large portions of the right ventricle and outflow tract and some cells ies. Smooth-muscle cells within the within the atria derive from the second heart field. F. The aortic arch arteries form as symmetric descending aorta arise from a differsets of vessels that then remodel under the influence of the neural crest to form the asymmetric ent embryologic source, the lateral plate mature vasculature. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Myocardial energy is stored as creatine phosphate (CP), which is in equilibrium with ATP, the immediate source of energy. In states of reduced energy availability, the CP stores decline first. Cardiac hypertrophy, fibrosis, tachycardia, increased wall tension resulting from ventricular dilation, and increased intracytoplasmic [Ca2+] all contribute to increased myocardial energy needs. When coupled with reduced coronary flow reserve, as occurs with obstruction of coronary arteries or abnormalities of the coronary microcirculation, an imbalance in myocardial ATP production relative to demand may occur, and the resulting ischemia can worsen or cause heart failure.
CHAPTER 265e Basic Biology of the Cardiovascular System
265e-12 mesoderm, and smooth muscle of the proximal outflow tract arises
PART 10 Disorders of the Cardiovascular System
from the second heart field. Neural crest cells are sensitive to both vitamin A and folic acid, and congenital heart disease involving abnormal remodeling of the aortic arch arteries has been associated with maternal deficiencies of these vitamins. Congenital heart disease involving the outflow tract can be associated with other defects of neural crest, such as cleft palate or craniofacial abnormalities. Coronary artery formation requires yet another cell population that initiates extrinsic to the embryonic heart fields. Epicardial cells arise in the proepicardial organ, a derivative of the septum transversum, which also contributes to the fibrous portion of the diaphragm and to the liver. Proepicardial cells contribute to the smooth-muscle cells of the coronary arteries and are required for their proper patterning. Other cell types within the heart, including fibroblasts and potentially some myocardial and endocardial cells, also can arise from the proepicardium. The cardiac conduction system, which functions both to generate and to propagate electrical impulses, develops primarily from multipotential cardiac precursors, which also give rise to cardiac muscle. The conduction system is composed of slow-conducting (proximal) components, such as the sinoatrial (SA) and atrioventricular (AV) nodes, as well as fast-conducting (distal) components, including the His bundle, bundle branches, and Purkinje fibers. The AV node primarily serves to delay the electrical impulse between atria and ventricles (manifesting decremental conduction), whereas the distal conduction system rapidly delivers the impulse throughout the ventricles. Significant recent attention has been focused on the embryologic origins of various components of the specialized conduction
network. Precursors within the sinus venosus give rise to the SA node, whereas those within the AV canal mature into heterogeneous cell types that compose the AV node. Myocardial cells transdifferentiate into Purkinje fibers to form the distal conduction system. Fast and slow conducting cell types within the nodes and bundles are characterized by expression of distinct gap junction proteins, including connexins, and ion channels that characterize unique cell fates and electrical properties of the tissues. Developmental defects in conduction system morphogenesis and lineage determination can lead to various electrophysiologic disorders, including congenital heart block and preexcitation syndromes such as the Wolff-ParkinsonWhite syndrome (Chap. 276). Studies of cardiac stem and progenitor cells suggest that progressive lineage restriction results in the gradual and stepwise determination of mature cell fates within the heart, with early precursors capable of adopting endothelial, smooth-muscle, or cardiac phenotypes, and subsequent further specialization into atrial, ventricular, and specialized conduction cell types. REGENERATING CARDIAC TISSUE Until very recently, adult mammalian myocardial cells were viewed as fully differentiated and without regenerative potential. Evidence currently supports the existence of limited regenerative potential of the mature heart. Considerable current effort is being devoted to evaluating the utility of various putative stem cell populations and regenerative approaches to enhance cardiac repair after injury. The success of such approaches would offer the exciting possibility of reconstructing an infarcted or failing ventricle (Chaps. 88 and 90e).
266e
Epidemiology of Cardiovascular Disease Thomas A. Gaziano, J. Michael Gaziano
THE EPIDEMIOLOGIC TRANSITION The global rise in CVD is the result of an unprecedented transformation in the causes of morbidity and mortality during the twentieth century. Known as the epidemiologic transition, this shift is driven by industrialization, urbanization, and associated lifestyle changes and is taking place in every part of the world among all races, ethnic groups, and cultures. The transition is divided into four basic stages: pestilence and famine, receding pandemics, degenerative and man-made diseases, and delayed degenerative diseases. A fifth stage, characterized by an epidemic of inactivity and obesity, is emerging in some countries (Table 266e-1). The age of pestilence and famine is marked by malnutrition, infectious diseases, and high infant and child mortality that are offset by high fertility. Tuberculosis, dysentery, cholera, and influenza are often fatal, resulting in a mean life expectancy of about 30 years. CVD, which accounts for less than 10% of deaths, takes the form of rheumatic heart disease and cardiomyopathies due to infection and malnutrition. Approximately 10% of the world’s population remains in the age of pestilence and famine. Per capita income and life expectancy increase during the age of receding pandemics as the emergence of public health systems, cleaner water supplies, and improved nutrition combine to drive down deaths from infectious disease and malnutrition. Infant and childhood mortality also decline, but deaths due to CVD increase to between 10 and 35% of all deaths. Rheumatic valvular disease, hypertension, coronary heart disease (CHD), and stroke are the predominant forms of CVD. Almost 40% of the world’s population is currently in this stage.
PATTERNS IN THE EPIDEMIOLOGIC TRANSITION Unique regional features have modified aspects of the transition in various parts of the world. High-income countries experienced declines in CVD death rates by as much as 50–60% over the last 60 years, whereas CVD death rates increased by 15% over the past 20 years in the low- and middle-income range. However, given the large amount of available data, the United States serves as a useful reference point for comparisons. The age of pestilence and famine occurred before 1900, with a largely agrarian economy and population. Infectious diseases accounted for more deaths than any other cause. By the 1930s, the country proceeded through the age of receding pandemics. The establishment of public health infrastructures resulted in dramatic declines in infectious disease mortality rates. Lifestyle changes due to rapid urbanization resulted in a simultaneous increase in CVD mortality rates, reaching approximately 390 per 100,000. Between 1930 and 1965, the country entered the age of degenerative
Table 226e-1 Five Stages of the Epidemiologic Transition Stage Pestilence and famine
Receding pandemics
Degenerative and man-made diseases
Delayed degenerative diseases
Inactivity and obesity
Description Predominance of malnutrition and infectious diseases as causes of death; high rates of infant and child mortality; low mean life expectancy Improvements in nutrition and public health lead to decrease in rates of deaths related to malnutrition and infection; precipitous decline in infant and child mortality rates Increased fat and caloric intake and decrease in physical activity lead to emergence of hypertension and atherosclerosis; with increase in life expectancy, mortality from chronic, noncommunicable diseases exceeds mortality from malnutrition and infectious disease CVD and cancer are the major causes of morbidity and mortality; better treatment and prevention efforts help avoid deaths among those with disease and delay primary events; age-adjusted CVD morality declines; CVD affecting older and older individuals Overweight and obesity increase at alarming rate; diabetes and hypertension increase; decline in smoking rates levels off; a minority of the population meets physical activity recommendations
Deaths Related to CVD, % 115 mmHg systolic) blood pressure, which is believed to account for more than 7 million deaths annually. Remarkably, nearly half of this burden occurs among those with systolic blood pressure less than 140 mmHg, even as this level is used at the arbitrary threshold for defining hypertension in many national guidelines. Between 1980 and 2008, the agestandardized prevalence of uncontrolled prevalence has decreased even as the number of people with uncontrolled hypertension has increased. This trend results largely from population growth and aging. Rising mean population blood pressure also occurs as populations industrialize and move from rural to urban settings. For example, the prevalence of hypertension in urban India is 25%, but varies between 10% and 15% in rural communities. One major concern in LMICs is the high rate of undetected, and therefore untreated, hypertension. This may explain, at least in part, the higher stroke rates in these countries in relation to CHD rates during the early stages of the transition. The high rates of hypertension throughout Asia, especially undiagnosed hypertension, likely contribute to the high prevalence of hemorrhagic stroke in the region. Globally, however, mean systolic blood pressure has decreased among both genders (0.8 mmHg per decade among men; 1.0 mmHg per decade among women).
Diet Total caloric intake per capita increases as countries develop. With regard to CVD, a key element of dietary change is an increase in intake of saturated animal fats and hydrogenated vegetable fats, which contain atherogenic trans fatty acids, along with a decrease in intake of plant-based foods and an increase in simple carbohydrates. Fat contributes less than 20% of calories in rural China and India, less than 30% in Japan, and well above 30% in the United States. Caloric contributions from fat appear to be falling in the HICs. In the United States, between 1971 and 2010, the percentage of calories derived from saturated fat decreased from 13% to 11%. Physical inactivity The increased mechanization that accompanies the economic transition leads to a shift from physically demanding, agriculture-based work to largely sedentary industry- and office-based work. In the United States, approximately one-quarter of the population does not participate in any leisure-time physical activity, and only 51.6% of adults report engaging in physical activity three or more times a week. Physical inactivity is similarly high in other regions of the world and is increasing in countries that are rapidly urbanizing as part of their economic transition. In urban China, for example, the proportion of adults who participate in moderate- or high-level activity has decreased significantly, whereas those who participate in low-level activity has increased. Metabolic Risk Factors Examination of trends in metabolic risk factors provides insight into changes in the CVD burden globally. Here we describe four metabolic risk factors—lipid levels, hypertension, obesity, and diabetes mellitus—using data from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2010). The GBD project identified and compiled mortality and morbidity data from 187 countries from 1980 to 2010. Lipid Levels Worldwide, high cholesterol levels are estimated to play a role in 56% of ischemic heart disease events and 18% of strokes, amounting to 4.4 million deaths annually. Although mean population plasma cholesterol levels tend to rise as countries move through the epidemiologic transition, mean serum total cholesterol levels have decreased globally between 1980 and 2008 by 0.08 mmol/L per decade in men and 0.07 mmol/L per decade in women. In 2008, age-standardized mean total cholesterol was 4.64 mmol/L (179.4 mg/dL) in men and 4.76 mmol/L (184.2 mg/dL) in women. Large declines occurred in Australasia, North America, and Western Europe (0.19–0.21 mmol/L). Countries in the East Asia and Pacific region experienced increases of greater than 0.08 mmol/L in both men and women. Social and individual changes that accompany urbanization clearly play a role because plasma cholesterol levels tend to be higher among urban residents than among rural residents. This shift is largely driven by greater consumption of dietary fats—primarily from animal products and processed vegetable oils—and decreased physical activ-
Obesity Although clearly associated with increased risk of CHD, much of the risk posed by obesity may be mediated by other CVD risk factors, including hypertension, diabetes mellitus, and lipid profile imbalances. According to the latest GBD data, nearly 1.46 billion adults were overweight (body mass index ≥25 kg/m2) in 2008, and approximately 508 million were obese (BMI ≥30 kg/m2). Obesity is increasing throughout the world, particularly in developing countries, where the trajectories are steeper than those experienced by the developed countries. In many of the LMICs, obesity appears to coexist with undernutrition and malnutrition. Adolescents are at particular risk. Currently, 1 in 10 children are estimated to be overweight, a number that is increasing worldwide. Women are also more affected than men, with the number of overweight women generally exceeding underweight women based on data from 36 LMICs. Diabetes Mellitus As a consequence of, or in addition to, increasing body mass index and decreasing levels of physical activity, worldwide rates of diabetes—predominantly type 2 diabetes—are on the rise. According to the most recent data from the GBD project, mean fasting plasma glucose levels have increased globally between 1980 and 2008. An estimated 346 million people worldwide have diabetes. The International Diabetes Foundation predicts that this number will reach 522 million by 2030, a yearly rate of growth that is higher than that of the world’s adult population. Nearly 50% of people with diabetes are undiagnosed, and 80% live in LMICs. The highest regional prevalence for diabetes occurs in the Middle East and North Africa, where an estimated 12.5% of the adult population has diabetes. Future growth will also largely occur in this region, along with other LMICs in South Asia and sub-Saharan Africa. There appear to be clear genetic susceptibilities to diabetes mellitus of various racial and ethnic groups. For example, migration studies suggest that South Asians and Indians tend to be at higher risk than those of European extraction. SUMMARY Although CVD rates are declining in the HICs, they are increasing in virtually every other region of the world. The consequences of this preventable epidemic will be substantial on many levels, including individual mortality and morbidity, family suffering, and staggering economic costs. Three complementary strategies can be used to lessen the impact. First, the overall burden of CVD risk factors can be lowered through population-wide public health measures, such as national campaigns
against cigarette smoking, unhealthy diets, and physical inactivity. Second, it is important to identify higher risk subgroups of the population who stand to benefit the most from specific, low-cost prevention interventions, including screening for and treatment of hypertension and elevated cholesterol. Simple, low-cost interventions, such as the “polypill,” a regimen of aspirin, a statin, and an antihypertensive agent, also need to be explored. Third, resources should be allocated to acute as well as secondary prevention interventions. For countries with limited resources, a critical first step in developing a comprehensive plan
is better assessment of cause-specific mortality and morbidity, as well as the prevalence of the major preventable risk factors. In the meantime, the HICs must continue to bear the burden of research and development aimed at prevention and treatment, being mindful of the economic limitations of many countries. The concept of the epidemiologic transition provides insight into how to alter the course of the CVD epidemic. The efficient transfer of low-cost preventive and therapeutic strategies could alter the natural course of this epidemic and thereby reduce the excess global burden of preventable CVD.
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CHAPTER 266e Epidemiology of Cardiovascular Disease
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PART 10
Section 2 D iagnosis of Cardiovascular Disorders Disorders of the Cardiovascular System
267
Physical Examination of the Cardiovascular System Patrick T. O’Gara, Joseph Loscalzo
The approach to a patient with known or suspected cardiovascular disease begins with the time-honored traditions of a directed history and a targeted physical examination. The scope of these activities depends on the clinical context at the time of presentation, ranging from an elective ambulatory follow-up visit to a more focused emergency department encounter. There has been a gradual decline in physical examination skills over the last two decades at every level, from student to faculty specialist, a development of great concern to both clinicians and medical educators. Classic cardiac findings are recognized by only a minority of internal medicine and family practice residents. Despite popular perceptions, clinical performance does not improve predictably as a function of experience; instead, the acquisition of new examination skills may become more difficult for a busy individual practitioner. Less time is now devoted to mentored cardiovascular examinations during the training of students and residents. One widely recognized outcome of these trends is the progressive overutilization of noninvasive imaging studies to establish the presence and severity of cardiovascular disease even when the examination findings imply a low pretest probability of significant pathology. Educational techniques to improve bedside skills include repetition, patient-centered teaching conferences, and visual display feedback of auscultatory events with Doppler echocardiographic imaging. The evidence base that links the findings from the history and physical examination to the presence, severity, and prognosis of cardiovascular disease has been established most rigorously for coronary artery disease, heart failure, and valvular heart disease. For example, observations regarding heart rate, blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes. Observations from the physical examination in this setting can inform clinical decision making before the results of cardiac biomarkers testing are known. The prognosis of patients with systolic heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overestimated. THE GENERAL PHYSICAL EXAMINATION Any examination begins with an assessment of the general appearance of the patient, with notation of age, posture, demeanor, and
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overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body positions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be appreciated readily and provide additional clues. A chronically ill-appearing emaciated patient may suggest the presence of long-standing heart failure or another systemic disorder, such as a malignancy. Various genetic syndromes, often with cardiovascular involvement, can also be recognized easily, such as trisomy 21, Marfan’s syndrome, and Holt-Oram syndrome. Height and weight should be measured routinely, and both body mass index and body surface area should be calculated. Knowledge of the waist circumference and the waist-to-hip ratio can be used to predict long-term cardiovascular risk. Mental status, level of alertness, and mood should be assessed continuously during the interview and examination. Skin Central cyanosis occurs with significant right-to-left shunting at the level of the heart or lungs, allowing deoxygenated blood to reach the systemic circulation. Peripheral cyanosis or acrocyanosis, in contrast, is usually related to reduced extremity blood flow due to small vessel constriction, as seen in patients with severe heart failure, shock, or peripheral vascular disease; it can be aggravated by the use of β-adrenergic blockers with unopposed α-mediated constriction. Differential cyanosis refers to isolated cyanosis affecting the lower but not the upper extremities in a patient with a large patent ductus arteriosus (PDA) and secondary pulmonary hypertension with rightto-left to shunting at the great vessel level. Hereditary telangiectasias on the lips, tongue, and mucous membranes, as part of the OslerWeber-Rendu syndrome (hereditary hemorrhagic telangiectasia), resemble spider nevi and can be a source of right-to-left shunting when also present in the lung. Malar telangiectasias also are seen in patients with advanced mitral stenosis and scleroderma. An unusually tan or bronze discoloration of the skin may suggest hemochromatosis as the cause of the associated systolic heart failure. Jaundice, which may be visible first in the sclerae, has a broad differential diagnosis but, in the appropriate setting, can be consistent with advanced right heart failure and congestive hepatomegaly or late-term “cardiac cirrhosis.” Cutaneous ecchymoses are seen frequently among patients taking vitamin K antagonists or antiplatelet agents such as aspirin and thienopyridines. Various lipid disorders sometimes are associated with subcutaneous xanthomas, particularly along the tendon sheaths or over the extensor surfaces of the extremities. Severe hypertriglyceridemia can be associated with eruptive xanthomatosis and lipemia retinalis. Palmar crease xanthomas are specific for type III hyperlipoproteinemia. Pseudoxanthoma elasticum, a disease associated with premature atherosclerosis, is manifested by a leathery, cobblestoned appearance of the skin in the axilla and neck creases and by angioid streaks on
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funduscopic examination. Extensive lentiginoses have been described in a variety of development delay–cardiovascular syndromes, including Carney’s syndrome, which includes multiple atrial myxomas. Cutaneous manifestations of sarcoidosis such as lupus pernio and erythema nodosum may suggest this disease as a cause of an associated dilated cardiomyopathy, especially with heart block, intraventricular conduction delay, or ventricular tachycardia.
Abdomen In some patients with advanced obstructive lung disease, the point of maximal cardiac impulse may be in the epigastrium. The liver is frequently enlarged and tender in patients with chronic heart failure. Systolic pulsations over the liver signify severe tricuspid regurgitation (TR). Splenomegaly may be a feature of infective endocarditis, particularly when symptoms have persisted for weeks or months. Ascites is a nonspecific finding but may be present with advanced chronic right heart failure, constrictive pericarditis, hepatic cirrhosis, or an intraperitoneal malignancy. The finding of an elevated JVP implies a cardiovascular etiology. In nonobese patients, the aorta typically is palpated between the epigastrium and the umbilicus. The sensitivity of palpation for the detection of an abdominal aortic aneurysm (pulsatile and expansile mass) decreases as a function of body size. Because palpation alone is not sufficiently accurate to establish
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Physical Examination of the Cardiovascular System
Chest Midline sternotomy, left posterolateral thoracotomy, or infraclavicular scars at the site of pacemaker/defibrillator generator implantation should not be overlooked and may provide the first clue regarding an underlying cardiovascular disorder in patients unable to provide a relevant history. A prominent venous collateral pattern may suggest subclavian or vena caval obstruction. If the head and neck appear dusky and slightly cyanotic and the venous pressure is grossly elevated without visible pulsations, a diagnosis of superior vena cava syndrome should be entertained. Thoracic cage abnormalities have been well described among patients with connective tissue disease syndromes. They include pectus carinatum (“pigeon chest”) and pectus excavatum (“funnel chest”). Obstructive lung disease is suggested by a barrel chest deformity, especially with tachypnea, pursed-lip breathing, and use of accessory muscles. The characteristically severe kyphosis and compensatory lumbar, pelvic, and knee flexion of ankylosing spondylitis should prompt careful auscultation for a murmur of aortic regurgitation (AR). Straight back syndrome refers to the loss of the normal kyphosis of the thoracic spine and has been described in patients with mitral valve prolapse (MVP) and its variants. In some patients with cyanotic congenital heart disease, the chest wall appears to be asymmetric, with anterior displacement of the left hemithorax. The respiratory rate and pattern should be noted during spontaneous breathing, with additional attention to depth, audible wheezing, and stridor. Lung examination can reveal adventitious sounds indicative of pulmonary edema, pneumonia, or pleuritis.
Extremities The temperature and color of the extremities, the presence of clubbing, arachnodactyly, and pertinent nail findings can be surmised quickly during the examination. Clubbing implies the presence of central right-to-left shunting, although it has also been described in patients with endocarditis. Its appearance can range from cyanosis and softening of the root of the nail bed, to the classic loss of the normal angle between the base of the nail and the skin, to the skeletal and periosteal bony changes of hypertrophic osteoarthropathy, which is seen rarely in patients with advanced lung or liver disease. Patients with the Holt-Oram syndrome have an unopposable, “fingerized” thumb, whereas patients with Marfan’s syndrome may have arachnodactyly and a positive “wrist” (overlapping of the thumb and fifth finger around the wrist) or “thumb” (protrusion of the thumb beyond the ulnar aspect of the hand when the fingers are clenched over the thumb in a fist) sign. The Janeway lesions of endocarditis are nontender, slightly raised hemorrhages on the palms and soles, whereas Osler’s nodes are tender, raised nodules on the pads of the fingers or toes. Splinter hemorrhages are classically identified as linear petechiae in the midposition of the nail bed and should be distinguished from the more common traumatic petechiae, which are seen closer to the distal edge. Lower extremity or presacral edema in the setting of an elevated JVP defines volume overload and may be a feature of chronic heart failure or constrictive pericarditis. Lower extremity edema in the absence of jugular venous hypertension may be due to lymphatic or venous obstruction or, more commonly, to venous insufficiency, as further suggested by the appearance of varicosities, venous ulcers (typically medial in location), and brownish cutaneous discoloration from hemosiderin deposition (eburnation). Pitting edema can also be seen in patients who use dihydropyridine calcium channel blockers. A Homan’s sign (posterior calf pain on active dorsiflexion of the foot against resistance) is neither specific nor sensitive for deep venous thrombosis. Muscular atrophy or the absence of hair along an extremity is consistent with severe arterial insufficiency or a primary neuromuscular disorder.
CHAPTER 267
Head and Neck Dentition and oral hygiene should be assessed in every patient both as a source of potential infection and as an index of general health. A high-arched palate is a feature of Marfan’s syndrome and other connective tissue disease syndromes. Bifid uvula has been described in patients with Loeys-Dietz syndrome, and orange tonsils are characteristic of Tangier disease. The ocular manifestations of hyperthyroidism have been well described. Many patients with congenital heart disease have associated hypertelorism, low-set ears, or micrognathia. Blue sclerae are a feature of osteogenesis imperfecta. An arcus senilis pattern lacks specificity as an index of coronary heart disease risk. The funduscopic examination is an often underused method by which to assess the microvasculature, especially among patients with established atherosclerosis, hypertension, or diabetes mellitus. A mydriatic agent may be necessary for optimal visualization. A funduscopic examination should be performed routinely in the assessment of patients with suspected endocarditis and those with a history of acute visual change. Branch retinal artery occlusion or visualization of a Hollenhorst plaque can narrow the differential diagnosis rapidly in the appropriate setting. Relapsing polychondritis may manifest as an inflamed pinna or, in its later stages, as a saddle-nose deformity because of destruction of nasal cartilage; granulomatosis with polyangiitis (Wegener’s) can also lead to a saddle-nose deformity.
this diagnosis, a screening ultrasound examination is advised. The 1443 presence of an arterial bruit over the abdomen suggests high-grade atherosclerotic disease, although precise localization is difficult.
CARDIOVASCULAR EXAMINATION Jugular Venous Pressure and Waveform JVP is the single most important bedside measurement from which to estimate the volume status. The internal jugular vein is preferred because the external jugular vein is valved and not directly in line with the superior vena cava and right atrium. Nevertheless, the external jugular vein has been used to discriminate between high and low central venous pressure (CVP) when tested among medical students, residents, and attending physicians. Precise estimation of the central venous or right atrial pressure from bedside assessment of the jugular venous waveform has proved difficult. Venous pressure traditionally has been measured as the vertical distance between the top of the jugular venous pulsation and the sternal inflection point (angle of Louis). A distance >4.5 cm at 30° elevation is considered abnormal. However, the actual distance between the mid-right atrium and the angle of Louis varies considerably as a function of both body size and the patient angle at which the assessment is made (30°, 45°, or 60°). The use of the sternal angle as a reference point leads to systematic underestimation of CVP, and this method should be used less for semiquantification than to distinguish a normal from an abnormally elevated CVP. The use of the clavicle may provide an easier reference for standardization. Venous pulsations above this level in the sitting position are clearly abnormal, as the distance between the clavicle and the right atrium is at least 10 cm. The patient should always be placed in the sitting position, with the legs dangling below the bedside, when an elevated pressure is suspected in the semisupine position. It should also be noted that bedside estimates of CVP are made in centimeters of water but must be converted to millimeters of mercury to provide correlation with accepted hemodynamic norms (1.36 cmH2O = 1.0 mmHg).
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1444
PART 10 Disorders of the Cardiovascular System
The venous waveform sometimes can be difficult to distinguish from the carotid pulse, especially during casual inspection. Nevertheless, the venous waveform has several characteristic features, and its individual components can be appreciated in most patients (Fig. 267-1). The arterial pulsation is not easily obliterated with palpation; the venous waveform in patients with sinus rhythm is usually biphasic, while the carotid pulse is monophasic; and the jugular venous pulsation should change with changes in posture or inspiration (unless the venous pressure is quite elevated). The venous waveform is divided into several distinct peaks. The a wave reflects right atrial presystolic contraction and occurs just after the electrocardiographic P wave, preceding the first heart sound (S1). A prominent a wave is seen in patients with reduced right ventricular compliance; a cannon a wave occurs with atrioventricular (AV) dissociation and right atrial contraction against a closed tricuspid valve. In a patient with a wide complex tachycardia, the appreciation of cannon a waves in the jugular venous waveform identifies the rhythm as ventricular in origin. The a wave is not present with atrial fibrillation. The x descent defines the fall in right atrial pressure after inscription of the a wave. The c wave interrupts this x descent and is followed by a further descent. The v wave represents atrial filling (atrial diastole) and occurs during ventricular systole. The height of the v wave is determined by right atrial compliance as well as the volume of blood returning to the right atrium either antegrade from the cavae or retrograde through an incompetent tricuspid valve. In patients with TR, the v wave is accentuated and the subsequent fall in pressure (y descent) is rapid. With progressive degrees of TR, the v wave merges with the c wave, and the right atrial and jugular vein waveforms become “ventricularized.” The y descent, which follows the peak of the v wave, can become prolonged or blunted with obstruction to right ventricular inflow, as may occur with tricuspid stenosis or pericardial tamponade. Normally, the venous pressure should fall by at least 3 mmHg with inspiration. Kussmaul’s sign is defined by either a rise or a lack of fall of the JVP with inspiration and is classically associated with constrictive pericarditis, although it has been reported in patients with restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and advanced left ventricular systolic heart failure. It is also a common, isolated finding in patients after cardiac surgery without other hemodynamic abnormalities. Venous hypertension sometimes can be elicited by performance of the abdominojugular reflex or with passive leg elevation. When these signs are positive, a volume-overloaded state with limited compliance of an overly distended or constricted venous system is present. The abdominojugular reflex is elicited with firm and consistent pressure over the upper portion of the abdomen, preferably over the right upper quadrant, for at least 10 s. A positive response is defined by a sustained rise of more than 3 cm in JVP for at least 15 s after release of the hand. Patients must be coached to refrain from breath holding or a Valsalva-like maneuver during the procedure. The abdominojugular reflex is useful in predicting a pulmonary artery wedge pressure in excess of 15 mmHg in patients with heart failure. Although the JVP estimates right ventricular filling pressure, it has a predictable relationship with the pulmonary artery wedge pressure. In a large study of patients with advanced heart failure, the presence of a right atrial pressure >10 mmHg (as predicted on bedside examination) had a positive value of 88% for the prediction of a pulmonary artery wedge pressure of >22 mmHg. In addition, an elevated JVP has prognostic significance in patients with both symptomatic heart failure and asymptomatic left ventricular systolic dysfunction. The presence of an elevated JVP is associated with a higher risk of subsequent hospitalization for heart failure, death from heart failure, or both. Assessment of Blood Pressure Measurement of blood pressure usually is delegated to a medical assistant but should be repeated by the clinician. Accurate measurement depends on body position, arm size, time of measurement, place of measurement, device, device size, technique, and examiner. In general, physician-recorded blood pressures are higher than both nurse-recorded pressures and self-recorded pressures at home. Blood pressure is best measured in the seated position with
HPIM19_Part10_p1439-p1660.indd 1444
A V
C X A
IV I
Y II
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A Severe V
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A C Mild
X A C
V
Y
Normal Y
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II III
P
ECG
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V
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Figure 267-1 A. Jugular venous pulse wave tracing (top) with heart sounds (bottom). The A wave represents right atrial presystolic contraction and occurs just after the electrocardiographic P wave and just before the first heart sound (I). In this example, the A wave is accentuated and larger than normal due to decreased right ventricular compliance, as also suggested by the right-sided S4 (IV). The C wave may reflect the carotid pulsation in the neck and/or an early systolic increase in right atrial pressure as the right ventricle pushes the closed tricuspid valve into the right atrium. The x descent follows the A wave just as atrial pressure continues to fall. The V wave represents atrial filling during ventricular systole and peaks at the second heart sound (II). The y descent corresponds to the fall in right atrial pressure after tricuspid valve opening. B. Jugular venous wave forms in mild (middle) and severe (top) tricuspid regurgitation, compared with normal, with phonocardiographic representation of the corresponding heart sounds below. With increasing degrees of tricuspid regurgitation, the waveform becomes “ventricularized.” C. Electrocardiogram (ECG) (top), jugular venous waveform (JVP) (middle), and heart sounds (bottom) in pericardial constriction. Note the prominent and rapid y descent, corresponding in timing to the pericardial knock (K). (From J Abrams: Synopsis of Cardiac Physical Diagnosis, 2nd ed. Boston, Butterworth Heinemann, 2001, pp 25–35.)
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S4 S1
A
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Dicrotic notch
S4 S1
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S4 S1
P2 A2
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Dicrotic notch
S4 S1
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Dicrotic notch
S4 S1
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Physical Examination of the Cardiovascular System
Arterial Pulse The carotid artery pulse occurs just after the ascending aortic pulse. The aortic pulse is best appreciated in the epigastrium, just above the level of the umbilicus. Peripheral arterial pulses that should be assessed routinely include the subclavian, brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial. In patients in whom the diagnosis of either temporal arteritis or polymyalgia rheumatica is suspected, the temporal arteries also should be examined. Although one of the two pedal pulses may not be palpable in up to 10% of normal subjects, the pair should be symmetric. The integrity of the arcuate system of the hand is assessed by Allen’s test, which is performed routinely before instrumentation of the radial artery. The pulses should be examined for their symmetry, volume, timing, contour, amplitude, and duration. If necessary, simultaneous auscultation of the heart can help identify a delay in the arrival of an arterial pulse. Simultaneous palpation of the radial and femoral pulses may reveal a femoral delay in a patient with hypertension and suspected aortic coarctation. The carotid upstrokes should never be examined simultaneously or before listening for a bruit. Light pressure
should always be used to avoid precipitation of carotid hypersensitivity 1445 syndrome and syncope in a susceptible elderly individual. The arterial pulse usually becomes more rapid and spiking as a function of its distance from the heart, a phenomenon that reflects the muscular status of the more peripheral arteries and the summation of the incident and reflected waves. In general, the character and contour of the arterial pulse depend on the stroke volume, ejection velocity, vascular compliance, and systemic vascular resistance. The pulse examination can be misleading in patients with reduced cardiac output and in those with stiffened arteries from aging, chronic hypertension, or peripheral arterial disease. The character of the pulse is best appreciated at the carotid level (Fig. 267-2). A weak and delayed pulse (pulsus parvus et tardus) defines severe aortic stenosis (AS). Some patients with AS may also have a slow, notched, or interrupted upstroke (anacrotic pulse) with a thrill or shudder. With chronic severe AR, by contrast, the carotid upstroke has a sharp rise and rapid fall-off (Corrigan’s or water-hammer pulse). Some patients with advanced AR may have a bifid or bisferiens pulse, in which two systolic peaks can be appreciated. A bifid pulse is also described in patients with hypertrophic obstructive cardiomyopathy (HOCM), with inscription of percussion and tidal waves. A bifid pulse is easily appreciated in patients on intraaortic balloon counterpulsation (IABP), in whom the second pulse is diastolic in timing. Pulsus paradoxus refers to a fall in systolic pressure >10 mmHg with inspiration that is seen in patients with pericardial tamponade but also is described in those with massive pulmonary embolism, hemorrhagic shock, severe obstructive lung disease, and tension pneumothorax.
CHAPTER 267
the arm at the level of the heart, using an appropriately sized cuff, after 5–10 min of relaxation. When it is measured in the supine position, the arm should be raised to bring it to the level of the mid-right atrium. The length and width of the blood pressure cuff bladder should be 80% and 40% of the arm’s circumference, respectively. A common source of error in practice is to use an inappropriately small cuff, resulting in marked overestimation of true blood pressure, or an inappropriately large cuff, resulting in underestimation of true blood pressure. The cuff should be inflated to 30 mmHg above the expected systolic pressure and the pressure released at a rate of 2–3 mmHg/s. Systolic and diastolic pressures are defined by the first and fifth Korotkoff sounds, respectively. Very low (even 0 mmHg) diastolic blood pressures may be recorded in patients with chronic, severe AR or a large arteriovenous fistula because of enhanced diastolic “run-off.” In these instances, both the phase IV and phase V Korotkoff sounds should be recorded. Blood pressure is best assessed at the brachial artery level, though it can be measured at the radial, popliteal, or pedal pulse level. In general, systolic pressure increases and diastolic pressure decreases when measured in more distal arteries. Blood pressure should be measured in both arms, and the difference should be less than 10 mmHg. A blood pressure differential that exceeds this threshold may be associated with atherosclerotic or inflammatory subclavian artery disease, supravalvular aortic stenosis, aortic coarctation, or aortic dissection. Systolic leg pressures are usually as much as 20 mmHg higher than systolic arm pressures. Greater leg–arm pressure differences are seen in patients with chronic severe AR as well as patients with extensive and calcified lower extremity peripheral arterial disease. The ankle-brachial index (lower pressure in the dorsalis pedis or posterior tibial artery divided by the higher of the two brachial artery pressures) is a powerful predictor of long-term cardiovascular mortality. The blood pressure measured in an office or hospital setting may not accurately reflect the pressure in other venues. “White coat hypertension” is defined by at least three separate clinic-based measurements >140/90 mmHg and at least two non-clinic-based measurements 20 mmHg or in diastolic pressure >10 mmHg in response to assumption of the upright posture from a supine position within 3 min. There may also be a lack of a compensatory tachycardia, an abnormal response that suggests autonomic insufficiency, as may be seen in patients with diabetes or Parkinson’s disease. Orthostatic hypotension is a common cause of postural lightheadedness/syncope and should be assessed routinely in patients for whom this diagnosis might pertain. It can be exacerbated by advanced age, dehydration, certain medications, food, deconditioning, and ambient temperature.
P2 A2
Dicrotic notch
P2 A2
Dicrotic notch
Figure 267-2 Schematic diagrams of the configurational changes in carotid pulse and their differential diagnoses. Heart sounds are also illustrated. A. Normal. S4, fourth heart sound; S1, first heart sound; A2 aortic component of second heart sound; P2 pulmonic component of second heart sound. B. Aortic stenosis. Anacrotic pulse with slow upstroke to a reduced peak. C. Bisferiens pulse with two peaks in systole. This pulse is rarely appreciated in patients with severe aortic regurgitation. D. Bisferiens pulse in hypertrophic obstructive cardiomyopathy. There is a rapid upstroke to the first peak (percussion wave) and a slower rise to the second peak (tidal wave). E. Dicrotic pulse with peaks in systole and diastole. This waveform may be seen in patients with sepsis or during intraaortic balloon counterpulsation with inflation just after the dicrotic notch. (From K Chatterjee, W Parmley [eds]: Cardiology: An Illustrated Text/Reference. Philadelphia, Gower Medical Publishers, 1991.)
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1446 Pulsus paradoxus is measured by noting the difference between the
PART 10 Disorders of the Cardiovascular System
systolic pressure at which the Korotkoff sounds are first heard (during expiration) and the systolic pressure at which the Korotkoff sounds are heard with each heartbeat, independent of the respiratory phase. Between these two pressures, the Korotkoff sounds are heard only intermittently and during expiration. The cuff pressure must be decreased slowly to appreciate the finding. It can be difficult to measure pulsus paradoxus in patients with tachycardia, atrial fibrillation, or tachypnea. A pulsus paradoxus may be palpable at the brachial artery or femoral artery level when the pressure difference exceeds 15 mmHg. This inspiratory fall in systolic pressure is an exaggerated consequence of interventricular dependence. Pulsus alternans, in contrast, is defined by beat-to-beat variability of pulse amplitude. It is present only when every other phase I Korotkoff sound is audible as the cuff pressure is lowered slowly, typically in a patient with a regular heart rhythm and independent of the respiratory cycle. Pulsus alternans is seen in patients with severe left ventricular systolic dysfunction and is thought to be due to cyclic changes in intracellular calcium and action potential duration. When pulsus alternans is associated with electrocardiographic T-wave alternans, the risk for an arrhythmic event appears to be increased. Ascending aortic aneurysms can rarely be appreciated as a pulsatile mass in the right parasternal area. Appreciation of a prominent abdominal aortic pulse should prompt noninvasive imaging for better characterization. Femoral and/or popliteal artery aneurysms should be sought in patients with abdominal aortic aneurysm disease. The level of a claudication-producing arterial obstruction can often be identified on physical examination (Fig. 267-3). For example, in a
patient with calf claudication, a decrease in pulse amplitude between the common femoral and popliteal arteries will localize the obstruction to the level of the superficial femoral artery, although inflow obstruction above the level of the common femoral artery may coexist. Auscultation for carotid, subclavian, abdominal aortic, and femoral artery bruits should be routine. However, the correlation between the presence of a bruit and the degree of vascular obstruction is poor. A cervical bruit is a weak indicator of the degree of carotid artery stenosis; the absence of a bruit does not exclude the presence of significant luminal obstruction. If a bruit extends into diastole or if a thrill is present, the obstruction is usually severe. Another cause of an arterial bruit is an arteriovenous fistula with enhanced flow. The likelihood of significant lower extremity peripheral arterial disease increases with typical symptoms of claudication, cool skin, abnormalities on pulse examination, or the presence of a vascular bruit. Abnormal pulse oximetry (a >2% difference between finger and toe oxygen saturation) can be used to detect lower extremity peripheral arterial disease and is comparable in its performance characteristics to the ankle-brachial index. Inspection and Palpation of the Heart The left ventricular apex beat may be visible in the midclavicular line at the fifth intercostal space in thin-chested adults. Visible pulsations anywhere other than this expected location are abnormal. The left anterior chest wall may heave in patients with an enlarged or hyperdynamic left or right ventricle. As noted previously, a visible right upper parasternal pulsation may be suggestive of ascending aortic aneurysm disease. In thin, tall patients and patients with advanced obstructive lung disease and flattened
Posterior tibial artery pressure
Anterior superior iliac spine
Posterior tibial a.
Inguinal ligament External iliac a.
Symphysis pubis Doppler
Deep femoral a.
Palpatation of popliteal artery pulse
Blood pressure cuff
Femoral a. Dorsalis pedis artery pressure Popliteal a.
Anterior tibial a.
Popliteal a. Posterior tibial a.
Doppler
Femoral a. Anterior tibial a.
Extensor tendon
Dorsalis pedis a. Dorsalis pedis a.
A
Major arteries of the lower limb
B
Measurement of ankle systolic pressure
Figure 267-3 A. Anatomy of the major arteries of the leg. B. Measurement of the ankle systolic pressure. (From NA Khan et al: JAMA 295:536, 2006.)
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A2
A Normal
S1
B Atrial septal defect
E Close fixed splitting (pulmonary hypertension)
S1
S2
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A2 P 2
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C Expiratory splitting with inspiratory S1 increase (RBBB, idiopathic dilatation PA) D Reversed splitting (LBBB, aortic stenosis)
A2
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S1
1447
INSPIRATION
S2
A2 P2
S1
S2
Figure 267-4 Heart sounds. A. Normal. S1, first heart sound; S2, second heart sound; A2, aortic component of the second heart sound; P2, pulmonic component of the second heart sound. B. Atrial septal defect with fixed splitting of S2. C. Physiologic but wide splitting of S2 with right bundle branch block (RBBB). PA, pulmonary artery. D. Reversed or paradoxical splitting of S2 with left bundle branch block (LBBB). E. Narrow splitting of S2 with pulmonary hypertension. (From NO Fowler: Diagnosis of Heart Disease. New York, Springer-Verlag, 1991, p 31.)
Physical Examination of the Cardiovascular System
CARDIAC AUSCULTATION Heart Sounds Ventricular systole is defined by the interval between the first (S1) and second (S2) heart sounds (Fig. 267-4). The first heart sound (S1) includes mitral and tricuspid valve closure. Normal splitting can be appreciated in young patients and those with right bundle branch block, in whom tricuspid valve closure is relatively delayed. The intensity of S1 is determined by the distance over which the anterior leaflet of the mitral valve must travel to return to its annular plane, leaflet mobility, left ventricular contractility, and the PR interval. S1 is classically loud in the early phases of rheumatic mitral stenosis (MS) and in patients with hyperkinetic circulatory states or short PR intervals. S1 becomes softer in the later stages of MS when the leaflets are rigid and calcified, after exposure to β-adrenergic receptor blockers, with long PR intervals, and with left ventricular contractile dysfunction. The intensity of heart sounds, however, can be reduced by any process that increases the distance between the stethoscope and the responsible cardiac event, including mechanical ventilation, obstructive lung disease, obesity, pneumothorax, and a pericardial effusion. Aortic and pulmonic valve closure constitutes the second heart sound (S2). With normal or physiologic splitting, the A2–P2 interval increases with inspiration and narrows during expiration. This physiologic interval will widen with right bundle branch block because of the further delay in pulmonic valve closure and in patients with severe MR because of the premature closure of the aortic valve. An unusually narrowly split or even a singular S2 is a feature of pulmonary arterial hypertension. Fixed splitting of S2, in which the A2–P2 interval is wide and does not change during the respiratory cycle, occurs in patients with a secundum atrial septal defect. Reversed or paradoxical splitting refers to a pathologic delay in aortic valve closure, such as that which occurs in patients with left bundle branch block, right ventricular pacing, severe AS, HOCM, and acute myocardial ischemia. With reversed or paradoxical splitting, the individual components of S2 are audible at end expiration, and their interval narrows with inspiration, the opposite of what would be expected under normal physiologic conditions. P2 is considered loud when its intensity exceeds that of A2 at the base, when it can be palpated in the area of the proximal main pulmonary
EXPIRATION
CHAPTER 267
diaphragms, the cardiac impulse may be visible in the epigastrium and should be distinguished from a pulsatile liver edge. Palpation of the heart begins with the patient in the supine position at 30° and can be enhanced by placing the patient in the left lateral decubitus position. The normal left ventricular impulse is less than 2 cm in diameter and moves quickly away from the fingers; it is better appreciated at end expiration, with the heart closer to the anterior chest wall. Characteristics such as size, amplitude, and rate of force development should be noted. Enlargement of the left ventricular cavity is manifested by a leftward and downward displacement of an enlarged apex beat. A sustained apex beat is a sign of pressure overload, such as that which may be present in patients with AS or chronic hypertension. A palpable presystolic impulse corresponds to the fourth heart sound (S4) and is indicative of reduced left ventricular compliance and the forceful contribution of atrial contraction to ventricular filling. A palpable third sound (S3), which is indicative of a rapid early filling wave in patients with heart failure, may be present even when the gallop itself is not audible. A large left ventricular aneurysm may sometimes be palpable as an ectopic impulse, discrete from the apex beat. HOCM may very rarely cause a triple cadence beat at the apex with contributions from a palpable S4 and the two components of the bisferiens systolic pulse. Right ventricular pressure or volume overload may create a sternal lift. Signs of either TR (cv waves in the jugular venous pulse) and/or pulmonary arterial hypertension (a loud single or palpable P2) would be confirmatory. The right ventricle can enlarge to the extent that leftsided events cannot be appreciated. A zone of retraction between the right and left ventricular impulses sometimes can be appreciated in patients with right ventricle pressure or volume overload when they are placed in the left lateral decubitus position. Systolic and diastolic thrills signify turbulent and high-velocity blood flow. Their locations help identify the origin of heart murmurs.
artery (second left interspace), or when both components of S2 can be appreciated at the lower left sternal border or apex. The intensity of A2 and P2 decreases with aortic and pulmonic stenosis, respectively. In these conditions, a single S2 may result. Systolic Sounds An ejection sound is a high-pitched early systolic sound that corresponds in timing to the upstroke of the carotid pulse. It usually is associated with congenital bicuspid aortic or pulmonic valve disease; however, ejection sounds are also sometimes audible in patients with isolated aortic or pulmonary root dilation and normal semilunar valves. The ejection sound that accompanies bicuspid aortic valve disease becomes softer and then inaudible as the valve calcifies and becomes more rigid. The ejection sound that accompanies pulmonic stenosis (PS) moves closer to the first heart sound as the severity of the stenosis increases. In addition, the pulmonic ejection sound is the only right-sided acoustic event that decreases in intensity with inspiration. Ejection sounds are often heard more easily at the lower left sternal border than they are at the base. Nonejection sounds (clicks), which occur after the onset of the carotid upstroke, are related to MVP and may be single or multiple. The nonejection click may introduce a murmur. This click-murmur complex will move away from the first heart sound with maneuvers that increase ventricular preload, such as squatting. On standing, the click and murmur move closer to S1. Diastolic Sounds The high-pitched opening snap (OS) of MS occurs after a very short interval after the second heart sound. The A2–OS interval is inversely proportional to the height of the left atrial–left ventricular diastolic pressure gradient. The intensity of both S1 and the OS of MS decreases with progressive calcification and rigidity of the anterior mitral leaflets. The pericardial knock (PK) is also high-pitched
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1448 and occurs slightly later than the OS, corresponding in timing to the
PART 10 Disorders of the Cardiovascular System
abrupt cessation of ventricular expansion after tricuspid valve opening and to an exaggerated y descent seen in the jugular venous waveform in patients with constrictive pericarditis. A tumor plop is a lowerpitched sound that rarely can be heard in patients with atrial myxoma. It may be appreciated only in certain positions and arises from the diastolic prolapse of the tumor across the mitral valve. The third heart sound (S3) occurs during the rapid filling phase of ventricular diastole. It can be a normal finding in children, adolescents, and young adults; however, in older patients, it signifies heart failure. A left-sided S3 is a low-pitched sound best heard over the left ventricular (LV) apex. A right-sided S3 is usually better heard over the lower left sternal border and becomes louder with inspiration. A left-sided S3 in patients with chronic heart failure is predictive of cardiovascular morbidity and mortality. Interestingly, an S3 is equally prevalent among heart failure patients with and without LV systolic dysfunction. The fourth heart sound (S4) occurs during the atrial filling phase of ventricular diastole and indicates LV presystolic expansion. An S4 is more common among patients who derive significant benefit from the atrial contribution to ventricular filling, such as those with chronic LV hypertrophy or active myocardial ischemia. An S4 is not present with atrial fibrillation.
Cardiac Murmurs Heart murmurs result from audible vibrations that are caused by increased turbulence and are defined by their timing within the cardiac cycle. Not all murmurs are indicative of structural heart disease, and the accurate identification of a benign or functional systolic murmur often can obviate the need for additional testing in healthy subjects. The duration, frequency, configuration, and intensity of a heart murmur are dictated by the magnitude, variability, and duration of the responsible pressure difference between two cardiac chambers, the two ventricles, or the ventricles and their respective great arteries. The intensity of a heart murmur is graded on a scale of 1 to 6; a thrill is present with murmurs of grade 4 or greater intensity. Other attributes of the murmur that aid in its accurate identification include its location, radiation, and response to bedside maneuvers. Although clinicians can detect and correctly identify heart murmurs with only fair reliability, a careful and complete bedside examination usually can identify individuals with valvular heart disease for whom transthoracic echocardiography and clinical follow-up are indicated and exclude subjects for whom no further evaluation is necessary. Systolic murmurs can be early, mid, late, or holosystolic in timing (Fig. 267-5). Acute severe MR results in a decrescendo early systolic murmur, the characteristics of which are related to the progressive attenuation of the left ventricular to left atrial pressure gradient during systole because of the steep and rapid rise in left atrial pressure in this context. Severe MR associated with posterior leaflet prolapse or flail radiates anteriorly and to the base, where it can be confused with the murmur of AS. MR that is due to anterior leaflet involvement radiates posteriorly and to the axilla. With acute TR in patients with normal pulmonary artery pressures, an early systolic murmur that may increase in intensity with inspiration may be heard at the left lower sternal border, with regurgitant cv waves visible in the jugular venous pulse. A midsystolic murmur begins after S1 and ends before S2; it is typically crescendo-decrescendo in configuration. AS is the most common cause of a midsystolic murmur in an adult. It is often difficult to estimate the severity of the valve lesion on the basis of the physical examination findings, especially in older hypertensive patients with stiffened carotid arteries or patients with low cardiac output in whom the intensity of the systolic heart murmur is misleadingly soft. Examination findings consistent with severe AS would include parvus et tardus carotid upstrokes, a late-peaking grade 3 or greater midsystolic murmur, a soft A2, a sustained LV apical impulse, and an S4. It is sometimes difficult to distinguish aortic sclerosis from more advanced degrees of valve stenosis. The former is defined by focal thickening and calcification of the aortic valve leaflets that is not severe enough to result in obstruction. These valve changes are associated with a Doppler jet velocity across the aortic valve of 2.5 m/s or less. Patients
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A
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ECG
ECG LVP
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LAP HSM S1
EDM S1
S2
ECG
A2
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LVP AOP
LVP LAP
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PSM A2
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Figure 267-5 A. Top. Graphic representation of the systolic pressure difference (green shaded area) between left ventricle and left atrium with phonocardiographic recording of a holosystolic murmur (HSM) indicative of mitral regurgitation. ECG, electrocardiogram; LAP, left atrial pressure; LVP, left ventricular pressure; S1, first heart sound; S2 second heart sound. Bottom. Graphic representation of the systolic pressure gradient (green shaded area) between left ventricle and aorta in patient with aortic stenosis. A midsystolic murmur (MSM) with a crescendo-decrescendo configuration is recorded. AOP, aortic pressure. B. Top. Graphic representation of the diastolic pressure difference between the aorta and left ventricle (blue shaded area) in a patient with aortic regurgitation, resulting in a decrescendo, early diastolic murmur (EDM) beginning with A2. Bottom. Graphic representation of the diastolic left atrial–left ventricular gradient (blue areas) in a patient with mitral stenosis with a mid-diastolic murmur (MDM) and late presystolic murmurs (PSM).
with aortic sclerosis can have grade 2 or 3 midsystolic murmurs identical in their acoustic characteristics to the murmurs heard in patients with more advanced degrees of AS. Other causes of a midsystolic heart murmur include pulmonic valve stenosis (with or without an ejection sound), HOCM, increased pulmonary blood flow in patients with a large atrial septal defect and left-to-right shunting, and several states associated with accelerated blood flow in the absence of structural heart disease, such as fever, thyrotoxicosis, pregnancy, anemia, and normal childhood/adolescence. The murmur of HOCM has features of both obstruction to LV outflow and MR, as would be expected from knowledge of the pathophysiology of this condition. The systolic murmur of HOCM usually can be distinguished from other causes on the basis of its response to bedside maneuvers, including Valsalva, passive leg raising, and standing/ squatting. In general, maneuvers that decrease LV preload (or increase LV contractility) will cause the murmur to intensify, whereas maneuvers that increase LV preload or afterload will cause a decrease in the intensity of the murmur. Accordingly, the systolic murmur of HOCM becomes louder during the strain phase of the Valsalva maneuver and after standing quickly from a squatting position. The murmur becomes softer with passive leg raising and when squatting. The murmur of AS is typically loudest in the second right interspace with radiation into the carotids, whereas the murmur of HOCM is best heard between the lower left sternal border and the apex. The murmur of PS is best heard in the second left interspace. The midsystolic murmur associated with enhanced pulmonic blood flow in the setting of a large atrial septal defect (ASD) is usually loudest at the mid-left sternal border.
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CHAPTER 267
With chronic AR, the pulse pressure is wide 1449 and the arterial pulses are bounding in character. These signs of significant diastolic run-off Impedance are absent in the acute phase. The murmur of pulmonic regurgitation is also heard along the left sternal border. It is most commonly due to Ao pulmonary hypertension and enlargement of the annulus of the pulmonic valve. S2 is single LV and loud and may be palpable. There is a right Contractility ventricular/parasternal lift that is indicative of chronic right ventricular pressure overload. A less impressive murmur of PR is present after repair of tetralogy of Fallot or pulmonic valve atresia. In this postoperative setting, the murmur is softer and lower-pitched, and the Volume severity of the accompanying pulmonic regurgitation can be underestimated significantly. MS is the classic cause of a mid- to late diastolic murmur, which is best heard over the apex in the left lateral decubitus position, S2 S2 C C is low-pitched or rumbling, and is introduced M M S1 S1 by an OS in the early stages of the rheumatic disease process. Presystolic accentuation refers to an increase in the intensity of the murmur just before the first heart sound and occurs in patients with sinus rhythm. It is absent Figure 267-6 Behavior of the click (C) and murmur (M) of mitral valve prolapse with in patients with atrial fibrillation. The auschanges in loading (volume, impedance) and contractility. S1, first heart sound; S2, seccultatory findings in patients with rheumatic ond heart sound. With standing (left side of figure), volume and impedance decrease, as a tricuspid stenosis typically are obscured by result of which the click and murmur move closer to S1. With squatting (right), the click and left-sided events, although they are similar in murmur move away from S1 due to the increases in left ventricular volume and impedance nature to those described in patients with MS. (afterload). Ao, aorta; LV, left ventricle. (Adapted from RA O’Rourke, MH Crawford: Curr Prob “Functional” mitral or tricuspid stenosis refers Cardiol 1:9, 1976.) to the generation of mid-diastolic murmurs that are created by increased and accelerated transvalvular diastolic flow, even in the absence A late systolic murmur, heard best at the apex, indicates MVP. of valvular obstruction, in the setting of severe MR, severe TR, or As previously noted, the murmur may or may not be introduced by a large ASD with left-to-right shunting. The Austin Flint murmur a nonejection click. Differential radiation of the murmur, as previ- of chronic severe AR is a low-pitched mid- to late apical diastolic ously described, may help identify the specific leaflet involved by the murmur that sometimes can be confused with MS. The Austin Flint myxomatous process. The click-murmur complex behaves in a manner murmur typically decreases in intensity after exposure to vasodiladirectionally similar to that demonstrated by the murmur of HOCM tors, whereas the murmur of MS may be accompanied by an opening during the Valsalva and stand/squat maneuvers (Fig. 267-6). The mur- snap and also may increase in intensity after vasodilators because of mur of MVP can be identified by the accompanying nonejection click. the associated increase in cardiac output. Unusual causes of a midHolosystolic murmurs are plateau in configuration and reflect a diastolic murmur include atrial myxoma, complete heart block, and continuous and wide pressure gradient between the left ventricle and acute rheumatic mitral valvulitis. left atrium with chronic MR, the left ventricle and right ventricle with Continuous Murmur A continuous murmur is predicated on a pressure a ventricular septal defect (VSD), and the right ventricle and right gradient that persists between two cardiac chambers or blood vessels atrium with TR. In contrast to acute MR, in chronic MR the left atrium across systole and diastole. The murmurs typically begin in systole, is enlarged and its compliance is normal or increased to the extent envelop the second heart sound (S2), and continue through some porthat there is little if any further increase in left atrial pressure from tion of diastole. They can often be difficult to distinguish from indiany increase in regurgitant volume. The murmur of MR is best heard vidual systolic and diastolic murmurs in patients with mixed valvular over the cardiac apex. The intensity of the murmur increases with heart disease. The classic example of a continuous murmur is that maneuvers that increase LV afterload, such as sustained hand grip. associated with a PDA, which usually is heard in the second or third The murmur of a VSD (without significant pulmonary hypertension) interspace at a slight distance from the sternal border. Other causes of is holosystolic and loudest at the mid-left sternal border, where a thrill a continuous murmur include a ruptured sinus of Valsalva aneurysm is usually present. The murmur of TR is loudest at the lower left sternal with creation of an aortic–right atrial or right ventricular fistula, a corborder, increases in intensity with inspiration (Carvallo’s sign), and is onary or great vessel arteriovenous fistula, and an arteriovenous fistula accompanied by visible cv waves in the jugular venous wave form and, constructed to provide dialysis access. There are two types of benign on occasion, by pulsatile hepatomegaly. continuous murmurs. The cervical venous hum is heard in children or adolescents in the supraclavicular fossa. It can be obliterated with firm Diastolic Murmurs In contrast to some systolic murmurs, diastolic pressure applied to the diaphragm of the stethoscope, especially when heart murmurs always signify structural heart disease (Fig. 267-5). The the subject turns his or her head toward the examiner. The mammary murmur associated with acute, severe AR is relatively soft and of short soufflé of pregnancy relates to enhanced arterial blood flow through duration because of the rapid rise in LV diastolic pressure and the engorged breasts. The diastolic component of the murmur can be progressive diminution of the aortic-LV diastolic pressure gradient. obliterated with firm pressure over the stethoscope. In contrast, the murmur of chronic severe AR is classically heard as a decrescendo, blowing diastolic murmur along the left sternal border Dynamic Auscultation Diagnostic accuracy can be enhanced by the perin patients with primary valve pathology and sometimes along the formance of simple bedside maneuvers to identify heart murmurs and right sternal border in patients with primary aortic root pathology. characterize their significance (Table 267-1). Except for the pulmonic
Physical Examination of the Cardiovascular System
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1450 TABLE 267-1 Effects of Physiologic and Pharmacologic Interventions on the Intensity of Heart Murmurs and Sounds
PART 10 Disorders of the Cardiovascular System
Respiration Right-sided murmurs and sounds generally increase with inspiration, except for the PES. Left-sided murmurs and sounds are usually louder during expiration. Valsalva maneuver Most murmurs decrease in length and intensity. Two exceptions are the systolic murmur of HOCM, which usually becomes much louder, and that of MVP, which becomes longer and often louder. After release of the Valsalva maneuver, right-sided murmurs tend to return to control intensity earlier than do left-sided murmurs. After VPB or AF Murmurs originating at normal or stenotic semilunar valves increase in the cardiac cycle after a VPB or in the cycle after a long cycle length in AF. By contrast, systolic murmurs due to AV valve regurgitation do not change, diminish (papillary muscle dysfunction), or become shorter (MVP). Positional changes With standing, most murmurs diminish, with two exceptions being the murmur of HOCM, which becomes louder, and that of MVP, which lengthens and often is intensified. With squatting, most murmurs become louder, but those of HOCM and MVP usually soften and may disappear. Passive leg raising usually produces the same results. Exercise Murmurs due to blood flow across normal or obstructed valves (e.g., PS, MS) become louder with both isotonic and submaximal isometric (hand grip) exercise. Murmurs of MR, VSD, and AR also increase with hand grip exercise. However, the murmur of HOCM often decreases with nearly maximum hand grip exercise. Left-sided S4 and S3 sounds are often accentuated by exercise, particularly when due to ischemic heart disease. Abbreviations: AF, atrial fibrillation; AR, aortic regurgitation; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PES, pulmonic ejection sound; PR, pulmonic regurgitation; PS, pulmonic stenosis; TR, tricuspid regurgitation; TS, tricuspid stenosis; VPB, ventricular premature beat; VSD, ventricular septal defect.
ejection sound, right-sided events increase in intensity with inspiration and decrease with expiration; left-sided events behave oppositely (100% sensitivity, 88% specificity). As previously noted, the intensity of the murmurs associated with MR, VSD, and AR will increase in response to maneuvers that increase LV afterload, such as hand grip and vasopressors. The intensity of these murmurs will decrease after exposure to vasodilating agents. Squatting is associated with an abrupt increase in LV preload and afterload, whereas rapid standing results in a sudden decrease in preload. In patients with MVP, the click and murmur move away from the first heart sound with squatting because of the delay in onset of leaflet prolapse at higher ventricular volumes. With rapid standing, however, the click and murmur move closer to the first heart sound as prolapse occurs earlier in systole at a smaller chamber dimension. The murmur of HOCM behaves similarly, becoming softer and shorter with squatting (95% sensitivity, 85% specificity) and longer and louder on rapid standing (95% sensitivity, 84% specificity). A change in the intensity of a systolic murmur in the first beat after a premature beat or in the beat after a long cycle length in patients with atrial fibrillation suggests valvular AS rather than MR, particularly in an older patient in whom the murmur of the AS may be well transmitted to the apex (Gallavardin effect). Of note, however, the systolic murmur of HOCM also increases in intensity in the beat after a premature beat. This increase in intensity of any LV outflow murmur in the beat after a premature beat relates to the combined effects of enhanced LV filling (from the longer diastolic period) and postextrasystolic potentiation of LV contractile function. In either instance, forward flow will accelerate, causing an increase in the gradient across the LV outflow tract (dynamic or fixed) and a louder systolic murmur. In contrast, the intensity of the murmur of MR does not change in a postpremature beat, because there is relatively little change in the nearly constant LV to left atrial pressure gradient or further alteration in mitral valve flow. Bedside exercise can sometimes be performed to increase cardiac output and, secondarily, the intensity of both systolic and diastolic heart murmurs. Most left-sided heart murmurs decrease in intensity and duration during the strain phase of the Valsalva maneuver. The murmurs associated with MVP and HOCM are the two notable exceptions. The Valsalva maneuver also can be used to assess the integrity of the heart and vasculature in the setting of advanced heart failure.
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Prosthetic Heart Valves The first clue that prosthetic valve dysfunction may contribute to recurrent symptoms is frequently a change in the quality of the heart sounds or the appearance of a new murmur. The heart sounds with a bioprosthetic valve resemble those generated by native valves. A mitral bioprosthesis usually is associated with a grade 2 or 3 midsystolic murmur along the left sternal border (created by turbulence across the valve struts as they project into the LV outflow tract) as well as by a soft mid-diastolic murmur that occurs with normal LV filling. This diastolic murmur often can be heard only in the left lateral decubitus position and after exercise. A high pitched or holosystolic apical murmur is indicative of pathologic MR due to a paravalvular leak and/or intra-annular bioprosthetic regurgitation from leaflet degeneration, for which additional imaging is usually indicated. Clinical deterioration can occur rapidly after the first expression of mitral bioprosthetic failure. A tissue valve in the aortic position is always associated with a grade 2 to 3 midsystolic murmur at the base or just below the suprasternal notch. A diastolic murmur of AR is abnormal in any circumstance. Mechanical valve dysfunction may first be suggested by a decrease in the intensity of either the opening or the closing sound. A high-pitched apical systolic murmur in patients with a mechanical mitral prosthesis and a diastolic decrescendo murmur in patients with a mechanical aortic prosthesis indicate paravalvular regurgitation. Patients with prosthetic valve thrombosis may present clinically with signs of shock, muffled heart sounds, and soft murmurs. Pericardial Disease A pericardial friction rub is nearly 100% specific for the diagnosis of acute pericarditis, although the sensitivity of this finding is not nearly as high, because the rub may come and go over the course of an acute illness or be very difficult to elicit. The rub is heard as a leathery or scratchy three-component or two-component sound, although it may be monophasic. Classically, the three components are ventricular systole, rapid early diastolic filling, and late presystolic filling after atrial contraction in patients in sinus rhythm. It is necessary to listen to the heart in several positions. Additional clues may be present from the history and 12-lead electrocardiogram. The rub typically disappears as the volume of any pericardial effusion increases. Pericardial tamponade can be diagnosed with a sensitivity of 98%, a specificity of 83%, and a positive likelihood ratio of 5.9 (95% confidence interval 2.4–14) by a pulsus paradoxus that exceeds 12 mmHg in a patient with a large pericardial effusion. The findings on physical examination are integrated with the symptoms previously elicited with a careful history to construct an appropriate differential diagnosis and proceed with indicated imaging and laboratory assessment. The physical examination is an irreplaceable component of the diagnostic algorithm and in selected patients can inform prognosis. Educational efforts to improve clinician competence eventually may result in cost saving, particularly if the indications for imaging can be influenced by the examination findings.
268
Electrocardiography Ary L. Goldberger
An electrocardiogram (ECG or EKG) is a graphic recording of electric potentials generated by the heart. The signals are detected by means of metal electrodes attached to the extremities and chest wall and then are amplified and recorded by the electrocardiograph. ECG leads actually display the instantaneous differences in potential between the electrodes. The clinical utility of the ECG derives from its immediate availability as a noninvasive, inexpensive, and highly versatile test. In addition to its use in detecting arrhythmias, conduction disturbances, and myocardial ischemia, electrocardiography may reveal findings related to life-threatening metabolic disturbances (e.g., hyperkalemia) or increased susceptibility to sudden cardiac death (e.g., QT prolongation syndromes).
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Sinoatrial (SA) node AV junction AV node
LA Ventricular myocardium
RA
His bundle
LV Purkinje fibers
RV
Left bundle branch Right bundle branch Ventricular septum
Figure 268-1 Schematic of the cardiac conduction system.
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T
P
U
ST J PR interval QRS interval QT interval
Figure 268-2 Basic ECG waveforms and intervals. Not shown is the RR interval, the time between consecutive QRS complexes.
fibers (Chap. 274). The rapid upstroke (phase 0) of the action potential corresponds to the onset of QRS. The plateau (phase 2) corresponds to the isoelectric ST segment, and active repolarization (phase 3) corresponds to the inscription of the T wave. Factors that decrease the slope of phase 0 by impairing the influx of Na+ (e.g., hyperkalemia and drugs such as flecainide) tend to increase QRS duration. Conditions that prolong phase 2 (amiodarone, hypocalcemia) increase the QT interval. In contrast, shortening of ventricular repolarization (phase 2), such as by digitalis administration or hypercalcemia, abbreviates the ST segment. The ECG ordinarily is recorded on special graph paper that is divided into 1-mm2 gridlike boxes. Since the usual ECG paper speed is 25 mm/s, the smallest (1 mm) horizontal divisions correspond to 0.04 (40 ms), with heavier lines at intervals of 0.20 s (200 ms). Vertically, the ECG graph measures the amplitude of a specific wave or deflection (1 mV = 10 mm with standard calibration; the voltage criteria for hypertrophy mentioned below are given in millimeters). There are four major ECG intervals: RR, PR, QRS, and QT (Fig. 268-2). The heart rate (beats per minute) can be computed readily from the interbeat (RR) interval by dividing the number of large (0.20 s) time units between consecutive R waves into 300 or the number of small (0.04 s) units into 1500. The PR interval measures the time (normally 120–200 ms) between atrial and ventricular depolarization, which includes the physiologic delay imposed by stimulation of cells in the AV junction area. The QRS interval (normally 100–110 ms or less) reflects the duration of ventricular depolarization. The QT interval includes both ventricular depolarization and repolarization times and varies inversely with the heart rate. A rate-related (“corrected”) QT interval, QTc, can be calculated as QT/√RR and normally is ≤0.44 s. (Some references give QTc upper normal limits as 0.43 s in men and 0.45 s in women. Also, a number of different formulas have been proposed, without consensus, for calculating the QTc.) The QRS complex is subdivided into specific deflections or waves. If the initial QRS deflection in a particular lead is negative, it is termed a Q wave; the first positive deflection is termed an R wave. A negative deflection after an R wave is an S wave. Subsequent positive or negative waves are labeled R′ and S′, respectively. Lowercase letters (qrs) are used for waves of relatively small amplitude. An entirely negative QRS complex is termed a QS wave.
Electrocardiography
ECG WAVEFORMS AND INTERVALS The ECG waveforms are labeled alphabetically, beginning with the P wave, which represents atrial depolarization (Fig. 268-2). The QRS complex represents ventricular depolarization, and the ST-T-U complex (ST segment, T wave, and U wave) represents ventricular repolarization. The J point is the junction between the end of the QRS complex and the beginning of the ST segment. Atrial repolarization (STa and Ta) is usually too low in amplitude to be detected, but it may become apparent in conditions such as acute pericarditis and atrial infarction. The QRS-T waveforms of the surface ECG correspond in a general way with the different phases of simultaneously obtained ventricular action potentials, the intracellular recordings from single myocardial
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CHAPTER 268
ELECTROPHYSIOLOGY (See also Chaps. 274 and 276) Depolarization of the heart is the initiating event for cardiac contraction. The electric currents that spread through the heart are produced by three components: cardiac pacemaker cells, specialized conduction tissue, and the heart muscle itself. The ECG, however, records only the depolarization (stimulation) and repolarization (recovery) potentials generated by the “working” atrial and ventricular myocardium. The depolarization stimulus for the normal heartbeat originates in the sinoatrial (SA) node (Fig. 268-1), or sinus node, a collection of pacemaker cells. These cells fire spontaneously; that is, they exhibit automaticity. The first phase of cardiac electrical activation is the spread of the depolarization wave through the right and left atria, followed by atrial contraction. Next, the impulse stimulates pacemaker and specialized conduction tissues in the atrioventricular (AV) nodal and His-bundle areas; together, these two regions constitute the AV junction. The bundle of His bifurcates into two main branches, the right and left bundles, which rapidly transmit depolarization wavefronts to the right and left ventricular myocardium by way of Purkinje fibers. The main left bundle bifurcates into two primary subdivisions: a left anterior fascicle and a left posterior fascicle. The depolarization wavefronts then spread through the ventricular wall, from endocardium to epicardium, triggering ventricular contraction. Since the cardiac depolarization and repolarization waves have direction and magnitude, they can be represented by vectors. Vector analysis illustrates a central concept of electrocardiography: The ECG records the complex spatial and temporal summation of electrical potentials from multiple myocardial fibers conducted to the surface of the body. This principle accounts for inherent limitations in both ECG sensitivity (activity from certain cardiac regions may be canceled out or may be too weak to be recorded) and specificity (the same vectorial sum can result from either a selective gain or a loss of forces in opposite directions).
ECG LEADS The 12 conventional ECG leads record the difference in potential between electrodes placed on the surface of the body. These leads are divided into two groups: six limb (extremity) leads and six chest (precordial) leads. The limb leads record potentials transmitted onto the frontal plane (Fig. 268-3A), and the chest leads record potentials transmitted onto the horizontal plane (Fig. 268-3B).
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–
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PART 10
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Anterior
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ambulatory ECG (Holter) recordings usually employ only one or two modified leads. Intracardiac electrocardiography and electrophysiologic testing are discussed in Chaps. 274 and 276. The ECG leads are configured so that a positive (upright) deflection is recorded in a lead if a wave of depolarization spreads toward the positive pole of that lead, and a negative deflection is recorded if the wave spreads toward the negative pole. If the mean orientation of the depolarization vector is at right angles to a particular lead axis, a biphasic (equally positive and negative) deflection will be recorded.
The spatial orientation and polarity of the six frontal plane leads is represented on the hexaxial diagram (Fig. 268-4). The six chest leads (Fig. 268-5) are unipolar recordings obtained by electrodes in the following positions: lead V1, fourth intercostal space, just to the right of the sternum; lead V2, fourth intercostal space, just to the left of the sternum; lead V3, midway between V2 and V4; lead V4, midclavicular line, fifth intercostal space; lead V5, anterior axillary line, same level as V4; and lead V6, midaxillary line, same level as V4 and V5. Additional posterior leads are sometimes placed on the same horizontal plane as V4 to facilitate detection of acute posterolateral infarction (V7, midaxillary line; V8 posterior axillary line; and V9, posterior scapular line). Together, the frontal and horizontal plane electrodes provide a threedimensional representation of cardiac electrical activity. Each lead can be likened to a different video camera angle “looking” at the same events—atrial and ventricular depolarization and repolarization— from different spatial orientations. The conventional 12-lead ECG can be supplemented with additional leads in special circumstances. For example, right precordial leads V3R, V4R, etc., are useful in detecting evidence of acute right ventricular ischemia. Bedside monitors and
Ex tre me
is
tion via e d –120° – II
– 90° –aVF
Left axi sd ev ia ti – 60° –III
–150° + aVR
on
ax
Disorders of the Cardiovascular System
P WAVE The normal atrial depolarization vector is oriented downward and toward the subject’s left, reflecting the spread of depolarization from the sinus node to the right and then the left atrial myocardium. Since this vector points toward the positive pole of lead II and toward the negative pole of lead aVR, the normal P wave will be positive in lead II and negative in lead aVR. By contrast, activation of the atria from an ectopic pacemaker in the lower part of either atrium or in the AV junction region may produce retrograde P waves (negative in lead II, positive in lead aVR). The normal P wave in lead V1 may be biphasic with a positive component reflecting right atrial depolarization, followed by a small (35 mm). Repolarization abnormalities (ST depression with T-wave inversions, formerly called the left ventricular “strain” pattern) also may appear in leads with prominent R waves. However, prominent precordial voltages may occur as a normal variant, especially in athletic or young individuals. Left ventricular hypertrophy may increase limb lead voltage with or without increased precordial voltage (e.g., RaVL + SV3 >20 mm in women and >28 mm in men). The presence of left atrial abnormality increases the likelihood of underlying left ventricular hypertrophy in cases with borderline voltage criteria. Left ventricular hypertrophy often progresses to incomplete or complete left bundle branch block. The sensitivity of conventional voltage criteria for left ventricular hypertrophy is decreased in obese persons and smokers. ECG evidence for left ventricular hypertrophy is a major noninvasive marker of increased risk of cardiovascular morbidity and mortality rates, including sudden cardiac death. However, because of false-positive and false-negative diagnoses, the ECG is of limited utility in diagnosing atrial or ventricular enlargement. More definitive information is provided by echocardiography (Chap. 270e). BUNDLE BRANCH BLOCKS AND RELATED PATTERNS Intrinsic impairment of conduction in either the right or the left bundle system (intraventricular conduction disturbances) leads to prolongation of the QRS interval. With complete bundle branch blocks, the QRS interval is ≥120 ms in duration; with incomplete blocks, the QRS interval is between 100 and 120 ms. The QRS vector usually is oriented in the direction of the myocardial region where depolarization is delayed (Fig. 268-10). Thus, with right bundle branch block, the terminal QRS vector is oriented to the right and anteriorly (rSR′ in V1 and qRS in V6, typically). Left bundle branch block alters both early and later phases of ventricular depolarization. The major QRS vector is directed to the left and posteriorly. In addition, the normal early left-to-right pattern of septal activation is disrupted such that septal depolarization proceeds from right to left as well. As a result, left bundle branch block generates wide, predominantly negative (QS) complexes in lead V1 and entirely positive (R) complexes in lead V6. A pattern identical to that of left bundle branch block, preceded by a sharp spike, is seen in most cases of electronic right ventricular pacing because of the relative delay in left ventricular activation. Bundle branch block may occur in a variety of conditions. In subjects without structural heart disease, right bundle branch block is seen more commonly than left bundle branch block. Right bundle branch block also occurs with heart disease, both congenital (e.g., atrial septal defect) and acquired (e.g., valvular, ischemic). Left bundle branch block is often a marker of one of four underlying conditions associated with increased risk of cardiovascular morbidity and mortality rates: coronary heart disease (frequently with impaired left ventricular
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V6
V1 Normal
R
R′ r RBBB
CHAPTER 268
T S
rightward than +110–120°) is extremely rare as an isolated finding 1455 and requires exclusion of other factors causing right axis deviation mentioned earlier. More complex combinations of fascicular and bundle branch blocks may occur that involve the left and right bundle system. Examples of bifascicular block include right bundle branch block and left posterior fascicular block, right bundle branch block with left anterior fascicular block, and complete left bundle branch block. Chronic bifascicular block in an asymptomatic individual is associated with a relatively low risk of progression to high-degree AV heart block. In contrast, new bifascicular block with acute anterior myocardial infarction carries a much greater risk of complete heart block. Alternation of right and left bundle branch block is a sign of trifascicular disease. However, the presence of a prolonged PR interval and bifascicular block does not necessarily indicate trifascicular involvement, since this combination may arise with AV node disease and bifascicular block. Intraventricular conduction delays also can be caused by extrinsic (toxic) factors that slow ventricular conduction, particularly hyperkalemia or drugs (e.g., class 1 antiarrhythmic agents, tricyclic antidepressants, phenothiazines). Prolongation of QRS duration does not necessarily indicate a conduction delay but may be due to preexcitation of the ventricles via a bypass tract, as in Wolff-Parkinson-White (WPW) patterns (Chap. 276) and related variants. The diagnostic triad of WPW consists of a wide QRS complex associated with a relatively short PR interval and slurring of the initial part of the QRS (delta wave), with the latter effect being due to aberrant activation of ventricular myocardium. The presence of a bypass tract predisposes to reentrant supraventricular tachyarrhythmias.
q S
LBBB
Figure 268-10 Comparison of typical QRS-T patterns in right bundle branch block (RBBB) and left bundle branch block (LBBB) with the normal pattern in leads V1 and V6. Note the secondary T-wave inversions (arrows) in leads with an rSR′ complex with RBBB and in leads with a wide R wave with LBBB.
Electrocardiography
T
MYOCARDIAL ISCHEMIA AND INFARCTION (See also Chap. 295) The ECG is a cornerstone in the diagnosis of acute and chronic ischemic heart disease. The findings depend on several key factors: the nature of the process (reversible [i.e., ischemia] versus irreversible [i.e., infarction]), the duration (acute versus chronic), the extent (transmural versus subendocardial), and localization (anterior versus inferoposterior), as well as the presence of other underlying abnormalities (ventricular hypertrophy, conduction defects). Ischemia exerts complex time-dependent effects on the electrical properties of myocardial cells. Severe, acute ischemia lowers the resting membrane potential and shortens the duration of the action potential. Such changes cause a voltage gradient between normal and ischemic zones. As a consequence, current flows between those regions. These currents of injury are represented on the surface ECG by deviation of the ST segment (Fig. 268-11). When the acute ischemia is transmural, the ST vector usually is shifted in the direction of the outer (epicardial) layers, producing ST elevations and sometimes, in the earliest stages of ischemia, tall, positive so-called hyperacute T waves over the ischemic zone. With ischemia confined primarily to the subendocardium, the ST vector typically shifts toward the subendocardium and ventricular cavity, so that overlying (e.g., anterior precordial) leads show ST-segment depression (with ST elevation in lead aVR). Multiple factors affect the amplitude of acute ischemic ST deviations. Profound ST elevation or depression in multiple leads usually indicates very severe ischemia.
function), hypertensive heart disease, aortic valve disease, and cardiomyopathy. Bundle branch blocks may be chronic or intermittent. A bundle branch block may be rate-related; for example, it often occurs when the heart rate exceeds some critical value. Bundle branch blocks and depolarization abnormalities secondary to artificial pacemakers not only affect ventricular depolarization (QRS) but also are characteristically associated with secondary repolarization (ST-T) abnormalities. With bundle branch blocks, the T wave is typically opposite in polarity to the last deflection of the QRS (Fig. 268-10). This discordance of the QRS–T-wave vectors is caused by the altered sequence of repolarization that occurs secondary to altered depolarization. In contrast, primary repolarization abnormalities are independent of QRS changes and are related instead to actual alterations in the electrical properties of the myocardial fibers themselves (e.g., in the resting membrane potential or action potential duration), not just to changes in the sequence of repolarization. Ischemia, electrolyte imbalance, and drugs such as digitalis all cause such primary ST–T-wave changes. Primary and secondary T-wave changes may coexist. For example, T-wave inversions in the right precordial leads with left bundle branch block or in the left precordial leads with right bundle branch block may be important markers of underlying ischemia or other abnormalities. A distinctive abnormality simulating right bundle branch block with ST-segment elevaA B tions in the right chest leads is seen with the ST Brugada pattern (Chap. 276). ST Partial blocks (fascicular or “hemiblocks”) V5 in the left bundle system (left anterior or V5 posterior fascicular blocks) generally do not ST prolong the QRS duration substantially but instead are associated with shifts in the fronST tal plane QRS axis (leftward or rightward, respectively). Left anterior fascicular block Figure 268-11 Acute ischemia causes a current of injury. With predominant subendocar(QRS axis more negative than –45°) is prob- dial ischemia (A), the resultant ST vector will be directed toward the inner layer of the affected ably the most common cause of marked ventricle and the ventricular cavity. Overlying leads therefore will record ST depression. With left axis deviation in adults. In contrast, left ischemia involving the outer ventricular layer (B) (transmural or epicardial injury), the ST vector posterior fascicular block (QRS axis more will be directed outward. Overlying leads will record ST elevation.
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1456 From a clinical viewpoint, the division of
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PART 10 Disorders of the Cardiovascular System
acute myocardial infarction into ST-segment elevation and non-ST elevation types is useful since the efficacy of acute reperfusion therapy is limited to the former group. The ECG leads are usually more helpful in localizing regions of ST elevation than nonST elevation ischemia. For example, acute transmural anterior (including apical and Figure 268-12 Severe anterior wall ischemia (with or without infarction) may cause promilateral) wall ischemia is reflected by ST eleva- nent T-wave inversions in the precordial leads. This pattern (sometimes referred to as Wellens tions or increased T-wave positivity in one T waves) is usually associated with a high-grade stenosis of the left anterior descending or more of the precordial leads (V1–V6) and coronary artery. leads I and aVL. Inferior wall ischemia produces changes in leads II, III, and aVF. “Posterior” wall ischemia (usu- tissue may lead to decreased R-wave amplitude or abnormal Q waves ally associated with lateral or inferior involvement) may be indirectly (even in the absence of transmurality) in the anterior or inferior leads recognized by reciprocal ST depressions in leads V1 to V3 (thus consti- (Fig. 268-13). Previously, abnormal Q waves were considered marktuting an ST elevation “equivalent” acute coronary syndrome). Right ers of transmural myocardial infarction, whereas subendocardial ventricular ischemia usually produces ST elevations in right-sided infarcts were thought not to produce Q waves. However, careful ECGchest leads (Fig. 268-5). When ischemic ST elevations occur as the ear- pathology correlative studies have indicated that transmural infarcts liest sign of acute infarction, they typically are followed within a period may occur without Q waves and that subendocardial (nontransmural) ranging from hours to days by evolving T-wave inversions and often infarcts sometimes may be associated with Q waves. Therefore, infarcts by Q waves occurring in the same lead distribution. Reversible trans- are more appropriately classified as “Q-wave” or “non-Q-wave.” The mural ischemia, for example, due to coronary vasospasm (Prinzmetal’s major acute ECG changes in syndromes of ischemic heart disease variant angina and possibly the Tako-tsubo “stress” cardiomyopathy are summarized schematically in Fig. 268-14. Loss of depolarizasyndrome), may cause transient ST-segment elevations without devel- tion forces due to posterior or lateral infarction may cause reciprocal opment of Q waves, as may very early reperfusion in acute coronary increases in R-wave amplitude in leads V1 and V2 without diagnostic Q syndromes. Depending on the severity and duration of ischemia, the waves in any of the conventional leads. Atrial infarction may be assoST elevations may resolve completely in minutes or be followed by ciated with PR-segment deviations due to an atrial current of injury, T-wave inversions that persist for hours or even days. Patients with changes in P-wave morphology, or atrial arrhythmias. In the weeks ischemic chest pain who present with deep T-wave inversions in mul- and months after infarction, these ECG changes may persist or begin tiple precordial leads (e.g., V1–V4,, I, and aVL) with or without cardiac to resolve. Complete normalization of the ECG after Q-wave infarcenzyme elevations typically have severe obstruction in the left anterior tion is uncommon but may occur, particularly with smaller infarcts. In descending coronary artery system (Fig. 268-12). In contrast, patients contrast, ST-segment elevations that persist for several weeks or more whose baseline ECG already shows abnormal T-wave inversions may after a Q-wave infarct usually correlate with a severe underlying wall develop T-wave normalization (pseudonormalization) during episodes motion disorder (akinetic or dyskinetic zone), although not necessarily a frank ventricular aneurysm. ECG changes due to ischemia may of acute transmural ischemia. With infarction, depolarization (QRS) changes often accompany occur spontaneously or may be provoked by various exercise protocols repolarization (ST-T) abnormalities. Necrosis of sufficient myocardial (stress electrocardiography; Chap. 293). ECG sequence with anterior Q-wave infarction
A
I
II
III
aVR
aVL
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V4
V6
aVL
aVF
V2
V4
V6
Early
Evolving
ECG sequence with inferior Q-wave infarction
B
I
II
III
aVR
Early
Evolving
Figure 268-13 Sequence of depolarization and repolarization changes with (A) acute anterior and (B) acute inferior wall Q-wave infarctions. With anterior infarcts, ST elevation in leads I and aVL and the precordial leads may be accompanied by reciprocal ST depressions in leads II, III, and aVF. Conversely, acute inferior (or posterolateral) infarcts may be associated with reciprocal ST depressions in leads V1 to V3. (After AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.)
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Non-Q wave (Non-ST elevation) infarction ST depressions or T wave inversions without Q waves
Noninfarction subendocardial ischemia (classic angina) Transient ST depressions
MYOCARDIAL ISCHEMIA
ST elevation/ Q wave infarction New Q waves preceded by hyperacute T waves/ST elevations and followed by T wave inversions
Electrocardiography
Figure 268-14 Variability of ECG patterns with acute myocardial ischemia. The ECG also may be normal or nonspecifically abnormal. Furthermore, these categorizations are not mutually exclusive. (After AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.)
Ischemia/myocardial infarction Noninfarction, transmural ischemia (Prinzmetal’s angina, and probably Tako-tsubo syndrome, which may also exactly simulate classical acute infarction) Acute myocardial infarction Postmyocardial infarction (ventricular aneurysm pattern) Acute pericarditis Normal variants (including benign “early repolarization” patterns) Left ventricular hypertrophy/left bundle branch blocka Other (rarer) Acute pulmonary embolisma Brugada patterns (right bundle branch block–like pattern with ST elevations in right precordial leads)a Class 1C antiarrhythmic drugsa DC cardioversion Hypercalcemiaa Hyperkalemiaa Hypothermia (J [Osborn] waves) Nonischemic myocardial injury Myocarditis Tumor invading left ventricle Trauma to ventricles
CHAPTER 268
Noninfarction transmural ischemia Transient ST elevations or paradoxical T wave normalization, sometimes followed by T wave inversions
1457
TABLE 268-1 Differential Diagnosis of ST-Segment Elevations
Usually localized to V1–V2 or V3.
a
The ECG has important limitations in both sensitivity and specificity in the diagnosis of ischemic heart disease. Although a single normal ECG does not exclude ischemia or even acute infarction, a normal ECG throughout the course of an acute infarct is distinctly uncommon. Prolonged chest pain without diagnostic ECG changes therefore should always prompt a careful search for other noncoronary causes of chest pain (Chap. 19). Furthermore, the diagnostic changes of acute or evolving ischemia are often masked by the presence of left bundle branch block, electronic ventricular pacemaker patterns, and WolffParkinson-White preexcitation. However, clinicians continue to overdiagnose ischemia or infarction based on the presence of ST-segment elevations or depressions; T-wave inversions; tall, positive T waves; or Q waves not related to ischemic heart disease (pseudoinfarct patterns). For example, ST-segment elevations simulating ischemia may occur with acute pericarditis or myocarditis, as a normal variant (including the typical “early repolarization” pattern), or in a variety of other conditions (Table 268-1). Similarly, tall, positive T waves do not invariably represent hyperacute ischemic changes but may also be caused by normal variants, hyperkalemia, cerebrovascular injury, and left ventricular volume overload due to mitral or aortic regurgitation, among other causes. ST-segment elevations and tall, positive T waves are common findings in leads V1 and V2 in left bundle branch block or left ventricular hypertrophy in the absence of ischemia. The differential diagnosis of Q waves includes physiologic or positional variants, ventricular hypertrophy, acute or chronic noncoronary myocardial injury, hypertrophic cardiomyopathy, and ventricular conduction disorders. Digoxin, ventricular hypertrophy, hypokalemia, and a variety of other factors may cause ST-segment depression mimicking subendocardial ischemia. Prominent T-wave inversion may occur with ventricular hypertrophy, cardiomyopathies, myocarditis, and cerebrovascular injury (particularly intracranial bleeds), among many other conditions. METABOLIC FACTORS AND DRUG EFFECTS A variety of metabolic and pharmacologic agents alter the ECG and, in particular, cause changes in repolarization (ST-T-U) and sometimes QRS prolongation. Certain life-threatening electrolyte disturbances may be diagnosed initially and monitored from the ECG. Hyperkalemia produces a sequence of changes (Fig. 268-15), usually beginning with narrowing and peaking (tenting) of the T waves. Further elevation of extracellular K+ leads to AV conduction disturbances, diminution in P-wave amplitude, and widening of the QRS interval. Severe hyperkalemia
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Source: Modified from AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.
eventually causes cardiac arrest with a slow s inusoidal type of mechanism (“sine-wave” pattern) followed by asystole. Hypokalemia (Fig. 268-16) prolongs ventricular repolarization, often with prominent U waves. Prolongation of the QT interval is also seen with drugs that increase the duration of the ventricular action potential: class 1A antiarrhythmic agents and related drugs (e.g., quinidine, disopyramide, procainamide, tricyclic antidepressants, phenothiazines) and class III agents (e.g., amiodarone [Fig. 268-16], dofetilide, dronedarone, sotalol, ibutilide). Marked QT prolongation, sometimes with deep, wide T-wave inversions, may occur with intracranial bleeds, particularly subarachnoid hemorrhage (“CVA T-wave” pattern) (Fig. 268-16). Systemic hypothermia also prolongs repolarization, usually with a distinctive convex elevation of the J point (Osborn wave). Hypocalcemia typically prolongs the QT interval (ST portion), whereas hypercalcemia shortens it (Fig. 268-17). Digitalis glycosides also shorten the QT interval, often with a characteristic “scooping” of the ST–T-wave complex (digitalis effect). Many other factors are associated with ECG changes, particularly alterations in ventricular repolarization. T-wave flattening, minimal T-wave inversions, or slight ST-segment depression (“nonspecific ST–T-wave changes”) may occur with a variety of electrolyte and acidbase disturbances, a number of infectious processes, central nervous system disorders, endocrine abnormalities, many drugs, ischemia, hypoxia, and virtually any type of cardiopulmonary abnormality. Although subtle ST–T-wave changes may be markers of ischemia, transient nonspecific repolarization changes may also occur after a meal or with postural (orthostatic) change, hyperventilation, or exercise in healthy individuals. LOW QRS VOLTAGE Low QRS voltage is arbitrarily defined as peak-to-trough QRS amplitudes of ≤5 mm in the six limb leads and/or ≤10 mm in the chest leads. Multiple factors may be responsible. Among the most serious include pericardial (Fig. 268-18) or pleural effusions, chronic obstructive pulmonary disease, infiltrative cardiomyopathies, and anasarca. ELECTRICAL ALTERNANS Electrical alternans—a beat-to-beat alternation in one or more components of the ECG signal—is a common type of nonlinear cardiovascular response to a variety of hemodynamic and electrophysiologic
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1458
Hyperkalemia Mild-Moderate
Moderate-Severe
V1
Very Severe Lead I
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P 1mV
Disorders of the Cardiovascular System
1s
Figure 268-15 The earliest ECG change with hyperkalemia is usually peaking (“tenting”) of the T waves. With further increases in the serum potassium concentration, the QRS complexes widen, the P waves decrease in amplitude and may disappear, and finally a sine-wave pattern leads to asystole unless emergency therapy is given. (After AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.) perturbations. Total electrical alternans (P-QRS-T) with sinus tachycardia is a relatively specific sign of pericardial effusion, usually with cardiac tamponade (Fig. 268-18). The mechanism relates to a periodic swinging motion of the heart in the effusion at a frequency exactly onehalf the heart rate. In contrast, pure repolarization (ST-T or U wave) alternans is a sign of electrical instability and may precede ventricular tachyarrhythmias. CLINICAL INTERPRETATION OF THE ECG Accurate analysis of ECGs requires thoroughness and care. The patient’s age, gender, and clinical status should always be taken into account. Many mistakes in ECG interpretation are errors of omission. Therefore, a systematic approach is essential. The following 14 points should be analyzed carefully in every ECG: (1) standardization (calibration) and technical features (including lead placement and artifacts), (2) rhythm, (3) heart rate, (4) PR interval/AV conduction, (5) QRS interval, (6) QT/QTc intervals, (7) mean QRS electrical axis, (8) P waves, (9) QRS voltages, (10) precordial R-wave progression,
Hypokalemia II
Hypocalcemia
I
II
II
II
QT 0.36 s QTc 0.41
QT 0.26 s QTc 0.36
Figure 268-17 Prolongation of the Q-T interval (ST-segment ortion) is typical of hypocalcemia. Hypercalcemia may cause abbrep viation of the ST segment and shortening of the QT interval.
V5
Amiodarone V4
Tricyclic overdose V2
I
QT 0.48 s QTc 0.52
U
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I
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Subarachnoid hemorrhage III
V3
Figure 268-16 A variety of metabolic derangements, drug effects, and other factors may prolong ventricular repolarization with QT prolongation or prominent U waves. Prominent repolarization prolongation, particularly if due to hypokalemia, inherited “channelopathies,” or certain pharmacologic agents, indicates increased susceptibility to torsades des pointes–type ventricular tachycardia (Chap. 277). Marked systemic hypothermia is associated with a distinctive convex “hump” at the J point (Osborn wave, arrow) due to altered ventricular action potential characteristics. Note QRS and QT prolongation along with sinus tachycardia in the case of tricyclic antidepressant overdose.
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1459
CHAPTER 268 Electrocardiography
Figure 268-18 Classic triad of findings for pericardial effusion with cardiac tamponade: (1) sinus tachycardia; (2) low QRS voltages; and (3) electrical alternans (best seen in leads V3 and V4 in this case; arrows). This triad is highly specific for pericardial effusion, usually with tamponade physiology, but of limited sensitivity. (Adapted from LA Nathanson et al: ECG Wave-Maven. http://ecg.bidmc.harvard.edu.)
(11) abnormal Q waves, (12) ST segments, (13) T waves, and (14) U waves. Comparison with any previous ECGs is invaluable. The diagnosis and management of specific cardiac arrhythmias and conduction disturbances are discussed in chaps. 274 and 276. CoMPUTERIZEd ELECTRoCARdIogRAPHY Computerized ECG systems are widely used for immediate retrieval of thousands of ECG records. Computer interpretation of ECGs still has major limitations. Incomplete or inaccurate readings are most likely with arrhythmias and complex abnormalities. Therefore, computerized interpretation (including measurements of basic ECG intervals) should not be accepted without careful clinician review.
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269e
269e-1
Atlas of Electrocardiography Ary L. Goldberger
MYOCARDIAL ISCHEMIA AND INFARCTION I
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Figure 269e-1 Anterior wall ischemia (deep T-wave inversions and ST-segment depressions in I, aVL, V3–V6) in a patient with LVH (increased voltage in V2–V5).
CHAPTER 269e Atlas of Electrocardiography
The electrocardiograms (ECGs) in this atlas supplement those illustrated in Chap. 268. The interpretations emphasize findings of specific teaching value. All of the figures are from ECG Wave-Maven, Copyright 2003, Beth Israel Deaconess Medical Center, http://ecg.bidmc.harvard.edu. The abbreviations used in this chapter are as follows: AF—atrial fibrillation HCM—hypertrophic cardiomyopathy LBBB—left bundle branch block LVH—left ventricular hypertrophy MI—myocardial infarction RBBB—right bundle branch block RV—right ventricular RVH—right ventricular hypertrophy SR—sinus rhythm
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Disorders of the Cardiovascular System
Figure 269e-2 Acute anterolateral wall ischemia with ST elevations in V4–V6. Probable prior inferior MI with Q waves in leads II, III, and aVF.
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Figure 269e-3 Acute lateral ischemia with ST elevations in I and aVL with probable reciprocal ST depressions inferiorly (II, III, and aVF). Ischemic ST depressions also in V3 and V4. Left atrial abnormality.
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F gu 269e-4 Sinus tachycardia. Marked ischemic ST-segment elevations in inferior limb leads (II, III, aVF) and laterally (V6) suggestive of acute inferolateral MI, and prominent ST-segment depressions with upright T waves in V1–V4 are consistent with associated acute posterior MI.
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F gu 269e-5 Acute, extensive anterior MI with marked ST elevations in I, aVL, V1–V6 and low amplitude pathologic Q waves in V3–V6. Marked reciprocal ST-segment depressions in III and aVF.
269e-3
CHAPTER 269e Atlas of Electrocardiography
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Acute anterior wall MI with ST elevations and Q waves in V1–V4 and aVL and reciprocal inferior ST depressions.
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Disorders of the Cardiovascular System
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SR with premature atrial complexes. RBBB; pathologic Q waves and ST elevation due to acute anterior/septal MI in V1–V3.
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Acute anteroseptal MI (Q waves and ST elevations in V1–V4) with RBBB (note terminal R waves in V1).
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F gu 269e-9 Extensive prior MI involving inferior-posterior-lateral wall (Q waves in leads II, III, aVF, tall R waves in V1, V2, and Q waves in V5, V6). T-wave abnormalities in leads I and aVL, V5, and V6.
269e-5
CHAPTER 269e Atlas of Electrocardiography
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F gu 269e-11 Prior inferior-posterior MI. Wide (0.04 s) Q waves in the inferior leads (II, III, aVF); broad R wave in V1 (a Q wave “equivalent” here). Absence of right-axis deviation and the presence of upright T waves in V1–V2 are also against RVH. i
Disorders of the Cardiovascular System
F gu 269e-10 SR with PR prolongation (“first-degree AV block”), left atrial abnormality, LVH, and RBBB. Pathologic Q waves in V1–V5 and aVL with ST elevations (a chronic finding in this patient). Findings compatible with prior anterolateral MI and left ventricular aneurysm.
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F gu 269e-12 SR with RBBB (broad terminal R wave in V1) and left anterior fascicular block (hemiblock) and pathologic anterior Q waves in V1–V3. Patient had severe multivessel coronary artery disease, with echocardiogram showing septal dyskinesis and apical akinesis.
PERICARDITIS I
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F gu 269e-13 Acute pericarditis with diffuse ST elevations in I, II, III, aVF, V3–V6, without T-wave inversions. Also note concomitant PR-segment elevation in aVR and PR depression in the inferolateral leads.
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CHAPTER 269e Atlas of Electrocardiography
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VALV LAR HEART DISEASE AND HYPERTROPHIC CARDIOMYOPATHY I
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F gu 269e-15 SR, prominent left atrial abnormality (see I, II, V1), right-axis deviation, and RVH (tall, relatively narrow R wave in V1) in a patient with mitral stenosis. i
Disorders of the Cardiovascular System
F gu 269e-14 SR; diffuse ST elevations (I, II, aVL, aVF, V2–V6) with associated PR deviations (elevated PR in aVR; depressed in V4–V6); borderline low voltage. Q-wave and T-wave inversions in II, III, and aVF. Diagnosis: acute pericarditis with inferior Q-wave MI.
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F gu 269e-16 SR, left atrial abnormality, and LVH by voltage criteria with borderline right-axis deviation in a patient with mixed mitral stenosis (left atrial abnormality and right-axis deviation) and mitral regurgitation (LVH). Prominent precordial T-wave inversions and QT prolongation also present.
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F gu 269e-17 Coarse AF, tall R in V2 with vertical QRS axis (positive R in aVF) indicating RVH. Tall R in V4 may be due to concomitant LVH. Patient had severe mitral stenosis with moderate mitral regurgitation.
269e-9
CHAPTER 269e Atlas of Electrocardiography
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F gu 269e-19 LVH with deep T-wave inversions in limb leads and precordial leads. Striking T-wave inversions in mid-precordial leads suggest apical HCM (Yamaguchi’s syndrome). i
Disorders of the Cardiovascular System
F gu 269e-18 SR; first-degree AV “block” (PR prolongation); LVH (tall R in aVL); RBBB (wide multiphasic R wave in V1) and left anterior fascicular block in a patient with HCM. Deep Q waves in I and aVL are consistent with septal hypertrophy.
269e-11
U
U
P LMONARY EMBOLISM AND CHRONIC P LMONARY HYPERTENSION aVR
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F gu 269e-20 Sinus tachycardia with S1Q3T3 pattern (T-wave inversion in III), incomplete RBBB, and right precordial T-wave inversions consistent with acute RV overload in a patient with pulmonary emboli.
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F gu 269e-21 Sinus tachycardia, right-axis deviation, RVH with tall R in V1 and deep S in V6, and inverted T waves in II, III, aVF, and V1–V5 in a patient with atrial septal defect and severe pulmonary hypertension.
CHAPTER 269e Atlas of Electrocardiography
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F gu 269e-23 (1) Low voltage; (2) incomplete RBBB (rsr′ in V1–V3); (3) borderline peaked P waves in lead II with vertical P-wave axis (probable right atrial overload); (4) slow R-wave progression in V1–V3; (5) prominent S waves in V6; and (6) atrial premature beats. This combination is seen typically in severe chronic obstructive lung disease. i
Disorders of the Cardiovascular System
F gu 269e-22 Signs of right atrial/RV overload in a patient with chronic obstructive lung disease: (1) peaked P waves in II; (2) QR in V1 with narrow QRS; (3) delayed precordial transition, with terminal S waves in V5/V6; (4) superior axis deviation with an S1-S2-S3 pattern.
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F gu 269e-24 Prominent U waves (II, III, and V4–V6) with ventricular repolarization prolongation in a patient with severe hypokalemia.
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F gu 269e-25 Abbreviated ST segment such that the T wave looks like it takes off directly from QRS in some leads (I, V4, aVL, and V5) in a patient with severe hypercalcemia. Note also high takeoff of ST segment in V2/V3 simulating acute ischemia.
CHAPTER 269e Atlas of Electrocardiography
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F gu 269e-27 Normal ECG in an 11-year-old male. T-wave inversions in V1–V2. Vertical QRS axis (+90°) and early precordial transition between V2 and V3 are normal findings in children. i
Disorders of the Cardiovascular System
F gu 269e-26 SR with LVH, left atrial abnormality, and tall peaked T waves in the precordial leads with inferolateral ST depressions (II, III, aVF, and V6); left anterior fascicular block and borderline prolonged QT interval in a patient with renal failure, hypertension, and hyperkalemia; prolonged QT is secondary to associated hypocalcemia.
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Figure 269e-28 Left atrial abnormality and LVH in a patient with long-standing hypertension.
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Figure 269e-29 Normal variant ST-segment elevations in a healthy 21-year-old male (commonly referred to as benign early repolarization pattern). ST elevations exhibit upward concavity and are most apparent in V3 and V4, and less than 1 mm in the limb leads. Precordial QRS voltages are prominent, but within normal limits for a young adult. No evidence of left atrial abnormality or ST depression/T-wave inversions to go along with LVH.
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CHAPTER 269e Atlas of Electrocardiography
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Disorders of the Cardiovascular System
Figure 269e-30 SR with first-degree AV “block” (PR interval = 0.24 s) and complete LBBB.
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Figure 269e-31 Dextrocardia with: (1) inverted P waves in I and aVL; (2) negative QRS complex and T wave in I; and (3) progressively decreasing voltage across the precordium.
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Figure 269e-32 Sinus tachycardia; intraventricular conduction delay (IVCD) with a rightward QRS axis. QT interval is prolonged for the rate. The triad of sinus tachycardia, a wide QRS complex, and a long QT in appropriate clinical context suggests tricyclic antidepressant overdose. Terminal S wave (rS) in I and terminal R wave (qR) in aVR are also noted as part of this IVCD variant.
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ECG Wave-Maven
http://ecg.bidmc.harvard.edu
Copyright, 2007 Beth Israel Deaconess Med Ctr
Figure 269e-33 Borderline sinus bradycardia (59 beats/min), prolonged PR interval (250 ms), and RBBB are present with marked right-axis deviation (RAD), the latter consistent with left posterior fascicular block (LPFB). LPFB is a diagnosis of exclusion, which requires ruling out lead reversal, normal variant, RV overload syndromes, or lateral MI, in particular, as causes of the RAD. This ECG also shows nondiagnostic Q waves in the inferior leads. In concert with RBBB, the LPFB indicates bifascicular block. (From LA Nathanson et al: ECG Wave-Maven. http://ecg.bidmc.harvard.edu.)
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CHAPTER 269e Atlas of Electrocardiography
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270e
Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
The ability to image the heart and blood vessels noninvasively has been one of the greatest advances in cardiovascular medicine since the development of the electrocardiogram. Cardiac imaging complements history taking and physical examination, blood and laboratory testing, and exercise testing in the diagnosis and management of most diseases of the cardiovascular system. Modern cardiovascular imaging consists of echocardiography (cardiac ultrasound), nuclear scintigraphy including positron emission tomography (PET) imaging, magnetic resonance imaging (MRI), and computed tomography (CT). These studies, often used in conjunction with exercise testing, can be used independently or in concert depending on the specific diagnostic needs. In this chapter, we review the principles of each of these modalities and the utility and relative benefits of each for the most common cardiovascular diseases.
PRINCIPLES OF MULTIMODALITY CARDIAC IMAGING ECHOCARDIOGRAPHY Echocardiography uses high-frequency sound waves (ultrasound) to penetrate the body, reflect from relevant structures, and generate an image. The basic physical principles of echocardiography are identical to other types of ultrasound imaging, although the hardware and software are optimized for evaluation of cardiac structure and function. Early echocardiography machines displayed “M-mode” echocardiograms in which a single ultrasound beam was displayed over time on a moving sheet of paper (Fig. 270e-1, left panel). Modern
Image Generation in M-Mode and 2D Echocardiography Phased array transducer
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Figure 270e-1 Principle of image generation in two-dimensional (2D) echocardiography. An electronically steerable phased-array transducer emits ultrasound from piezoelectric elements, and returning echoes are used to generate a 2D image (right) using a scan converter. Early echocardiography machines used a single ultrasound beam to generate an “M-mode” echocardiogram (see text), although modern equipment generates M-mode echocardiograms digitally from the 2D data. LV, left ventricle.
270e-1
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
Marcelo F. Di Carli, Raymond Y. Kwong, Scott D. Solomon
echocardiographic machinery uses phased array transducers that contain up to 512 elements and emit ultrasound in sequence. The reflected ultrasound is then sensed by the receiving elements. A “scan converter” uses information about the timing and magnitude of the reflected ultrasound to generate an image (Fig. 270e-1, right panel). This sequence happens repeatedly in “real time” to generate moving images with frame rates that are typically greater than 30 frames per second, but can exceed 100 frames per second. The gray scale of the image features indicates the intensity of the reflected ultrasound; fluid or blood appears black, and highly reflective structures, such as calcifications on cardiac valves or the pericardium, appear white. Tissues such as myocardium appear more gray, and tissues such as muscle display a unique speckle pattern. Although M-mode echocardiography has largely been supplanted by two-dimensional echocardiography, it is still used because of its high temporal resolution and accuracy for making linear measurements. The spatial resolution of ultrasound is dependent on the wavelength: the smaller the wavelength and the higher the frequency of the ultrasound beam, the greater are the spatial resolution and ability to discern small structures. Increasing the frequency of ultrasound will increase resolution but at the expense of reduced penetration. Higher frequencies can be used in pediatric imaging or transesophageal echocardiography where the transducer can be much closer to the structures being interrogated, and this is a rationale for using transesophageal echocardiography to obtain higher quality images. Three-dimensional ultrasound transducers use a waffle-like matrix array transducer and receive a pyramidal data sector. Three-dimensional echocardiography is being increasingly used for assessment of congenital heart disease and valves, although current image quality lags behind two-dimensional ultrasound (Fig. 270e-2). In addition to the generation of two-dimensional images that provide information about cardiac structure and function, echocardiography can be used to interrogate blood flow within the heart and blood vessels by using the Doppler principle to ascertain the velocity of blood flow. When ultrasound emitted from a transducer reflects off red blood cells that are moving toward the transducer, the reflected ultrasound will return at a slightly higher frequency than emitted; the opposite is true when flow is away from the transducer. That frequency difference, termed the Doppler shift, is directly related to the velocity
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Disorders of the Cardiovascular System
Figure 270e-2 Three-dimensional (3D) probe and 3D image. of the flow of the red blood cells. The velocity of blood flow between two chambers will be directly related to the pressure gradient between those chambers. A modified form of the Bernoulli equation, p = 4v2 where p = the pressure gradient and v = the velocity of blood flow in meters per second, can be used to calculate this pressure gradient in the majority of clinical circumstances. This principle can be used to determine the pressure gradient between chambers and across valves and has become central to the quantitative assessment of valvular heart disease. There are three types of Doppler ultrasound that are typically used in standard echocardiographic examinations: spectral Doppler, which consists of both pulsed wave Doppler and continuous wave Doppler, and color flow Doppler. Both types of spectral Doppler will display a waveform representing the velocity of blood flow, with time on the horizontal axis and velocity on the vertical axis. Pulsed wave Doppler is used to interrogate relatively low velocity flow and has the ability to determine blood flow velocity at a particular location within the heart. Continuous wave Doppler is used to assess high-velocity flow but can only identify the highest velocity in a particular direction and cannot interrogate the velocity at a specific depth location. Both of these techniques can only accurately assess velocities that are in the direction of the ultrasound scan lines, and velocities that are at an angle to the direction of the ultrasound beam will be underestimated. Color flow Doppler is a form of pulsed wave Doppler in which the velocity of blood flow is color encoded according to a scale and superimposed on a two-dimensional grayscale image in real time, giving the appearance of real-time flow within the heart. The Doppler principle
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can also be used to assess the velocity of myocardial motion, which is a sensitive way to assess myocardial function (Fig. 270e-3). A standard full transthoracic echocardiographic examination consists of a series of two-dimensional views made up of different imaging planes from various scanning locations and spectral and color flow Doppler assessment. Transesophageal echocardiography is a form of echocardiography in which the transducer is located on the tip of an endoscope that can be inserted into the esophagus. This procedure allows closer, less obstructed views of cardiac structures, without having to penetrate through chest wall, muscle, and ribs. Because less penetration is needed, a higher frequency probe can be used, and image quality and spatial resolution are generally higher than with standard transthoracic imaging, particularly for structures that are more posterior. Transesophageal echocardiography has become the test of choice for assessment of small lesions in the heart such as valvular vegetations, especially in the setting of a prosthetic valve disease, and intracardiac thrombi, including assessment of the left atrial appendage, which is difficult to visualize with standard transthoracic imaging, and for assessment of congenital abnormalities. Transesophageal echocardiography requires both topical and systemic anesthesia, generally conscious sedation, and carries additional risks such as potential damage to the esophagus, including the rare possibility of perforation, aspiration, and anesthesia-related complications. Patients generally need to give consent for transesophageal echocardiography and be monitored during and subsequent to the procedure. Transesophageal echocardiography can be carried out in intubated patients and is routinely used for intraoperative monitoring during cardiac surgery. Stress echocardiography is routinely used to assess cardiac function during exercise and can be used to identify myocardial ischemia or to assess valvular function under exercise conditions. Stress echocardiography is typically performed in conjunction with treadmill or bicycle exercise testing, but can also be performed using pharmacologic stress most typically with an intravenous infusion of dobutamine (see section on stress imaging below). Whereas typical echocardiographic equipment is large, bulky, and expensive, small hand-held ultrasound equipment developed over the last decade now offers diagnostic quality imaging in a package small enough to be carried on rounds (Fig. 270e-4). These relatively inexpensive point-of-care devices currently lack full diagnostic capabilities but represent an excellent screening tool if used by an experienced operator. As these units become even smaller and less expensive, they are being increasingly used not just by cardiologists, but also by emergency medicine physicians, intensivists, anesthesiologists, and internists. RADIONUCLIDE IMAGING Radionuclide imaging techniques are commonly used for the evaluation of patients with known or suspected coronary artery disease (CAD),
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Figure 270e-3 Three types of Doppler ultrasound. A and B. Pulsed and continuous wave Doppler waveforms with time on horizontal axis and velocity of blood flow on vertical axis. C. Color flow Doppler, where velocities are encoded by colors according to scale on right side of screen and superimposed on a two-dimensional grayscale image.
commonly used as a pharmacologic alternative to stress testing in stress echocardiography.
TABLE 270e-1 Radiopharmaceuticals for Clinical Nuclear Cardiology Radiopharmaceutical Technetium-99m sestamibi Technetium-99m tetrofosmin Thalium-201 Iodine-123 metaiodobenzylguanidine (MIBG) Rubidium-82 13 N-ammonia 18 F-fluorodeoxyglucose
Imaging Technique SPECT SPECT SPECT SPECT PET PET PET
Physical Half-Life 6h 6h 72 h 13 h 76 s 10 min 110 min
Abbreviations: PET, positron emission tomography; SPECT, single-photon emission computed tomography.
Application Myocardial perfusion imaging Myocardial perfusion imaging Myocardial perfusion imaging Cardiac sympathetic innervation Myocardial perfusion imaging Myocardial perfusion imaging Myocardial viability and inflammation imaging
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
Myocardial Perfusion and Viability Imaging Protocols Imaging protocols are tailored to the individual patient based on the clinical question, patient’s risk, ability to exercise, body mass index, and other factors. For SPECT imaging, technetium-99m (99mTc)-labeled tracers are the most commonly used imaging agents because they are associated with the best image quality and the lowest radiation dose to the patient (Fig. 270e-5). Selection of the protocol (stress-only, single-day, or 2-day) depends on the patient and clinical question. After intravenous injection, myocardial uptake of 99mTc-labeled tracers is rapid (1–2 min). After uptake, these tracers become trapped intracellularly in mitochondria and show minimal change over time. This is why 99mTc tracers can Figure 270e-4 Two examples of hand-held ultrasound equipment: V-Scan be helpful in patients with chest pain of unclear etiology (General Electric, left) and Sonosite (right). occurring at rest, because patients can be injected while having chest pain and imaged some time later after symptoms subside. Because the radiotracer is trapped at the including for initial diagnosis and risk stratification as well as the assess- time of injection, the images provide a snapshot of myocardial perfument of myocardial viability. These techniques use small amounts of sion at the time of injection, even if the acquisition is delayed. Indeed, radiopharmaceuticals (Table 270e-1), which are injected intrave- a normal myocardial perfusion study following a rest injection in a nously and trapped in the heart and/or vascular cells. Radioactivity patient with active chest pain effectively excludes myocardial ischemia within the heart and vasculature decays by emitting gamma rays. The as the cause of chest pain (high negative predictive value). While used interaction between these gamma rays and the detectors in specialized commonly in the past for perfusion imaging, thallium-201 protocols scanners (single-photon emission computed tomography [SPECT] are now rarely used because they are typically associated with a higher and PET) creates a scintillation event or light output, which can be radiation dose to the patient. PET myocardial perfusion imaging is an alternative to SPECT and captured by digital recording equipment to form an image of the heart and vasculature. Like CT and MRI, radionuclide images also generate is associated with improved diagnostic accuracy and lower radiation dose to patients due to the fact that radiotracers are typically short tomographic (three-dimensional) views of the heart and vasculature. lived (Table 270e-1). The ultra-short half-life of some PET radiopharRadiopharmaceuticals Used in Clinical Imaging Table 270e-1 summarizes maceuticals in clinical use (e.g., rubidium-82) is the primary reason the most commonly used radiopharmaceuticals in clinical SPECT and why imaging is generally combined with pharmacologic stress, as PET imaging. opposed to exercise, because this allows for faster imaging of these Protocols for Stress Myocardial Perfusion Imaging Both exercise and rapidly decaying radiopharmaceuticals. However, exercise is possible pharmacologic stress can be used for myocardial perfusion imaging. for relatively longer lived radiotracers (e.g., 13N-ammonia). PET imagExercise stress is generally preferred because it is physiologic and ing protocols are typically faster than SPECT, but more expensive. For provides additional clinically important information (i.e., clinical and myocardial perfusion imaging, rubidium-82 does not require an onhemodynamic responses, ST-segment changes, exercise duration, site medical cyclotron (it is available from a strontium-82/rubidium-82 and functional status). However, submaximal effort will lower the generator) and, thus, is the most commonly used radiopharmaceutisensitivity of the test and should be avoided, especially if the test is cal. 13N-ammonia has better flow characteristics (higher myocardial requested for initial diagnosis of CAD. In patients who are unable to extraction) and imaging properties than rubidium-82, but it does exercise or who exercise submaximally, pharmacologic stress offers an require an on-site medical cyclotron. In comparison to SPECT, PET adequate alternative to exercise stress testing. Pharmacologic stress can has improved spatial and contrast resolution and provides absolute be accomplished either with coronary vasodilators, such as adenos- measures of myocardial perfusion (in mL/min per gram of tissue), ine, dipyridamole, or regadenoson, or β1-receptor agonists, such as thereby providing the patients’ regional and global coronary flow dobutamine. For patients unable to exercise, vasodilators are the most reserve. The latter helps improve diagnostic accuracy and risk stratificommonly used stressors in combination with myocardial perfusion cation, especially in obese patients, women, and higher risk individuals imaging. Dobutamine is a potent β1-receptor agonist that increases (e.g., diabetes mellitus) (Fig. 270e-6). Contemporary PET and SPECT myocardial oxygen demand by augmenting contractility, heart rate, scanners are combined with a CT scanner (so-called hybrid PET/CT and blood pressure similar to exercise. It is generally used as an alter- and SPECT/CT). CT is used primarily to guide patient positioning native to vasodilator stress in patients with chronic pulmonary disease, in the field of view and for correcting inhomogeneities in radiotracer in whom vasodilators may be contraindicated. Dobutamine is also distribution due to attenuation by soft tissues (so-called attenuation
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Figure 270e-5 Tomographic stress (top of each pair) and rest myocardial perfusion images with technetium-99m sestamibi singlephoton emission computed tomography imaging demonstrating a large perfusion defect throughout the anterior and anteroseptal walls. The right panel demonstrates the quantitative extent of the perfusion abnormality at stress (top bull’s-eye), at rest (middle bull’s-eye), and the extent of defect reversibility (lower bull’s-eye). The lower left panel demonstrates electrocardiogram-gated myocardial perfusion images from which one can determine the presence of regional wall motion abnormalities and calculate left ventricular volumes and ejection fraction.
correction). However, it can also be used to obtain diagnostic data including coronary artery calcium score and/or CT coronary angiography (discussed below). For the evaluation of myocardial viability in patients with ischemic cardiomyopathy, myocardial perfusion imaging (with SPECT or PET) is usually combined with metabolic imaging (i.e., fluorodeoxyglucose [FDG] PET). In hospital settings lacking access to PET scanning, thallium-201 SPECT imaging is an excellent alternative. CARDIAC COMPUTED TOMOGRAPHY CT acquires images by passing a thin x-ray beam through the body at many angles to generate cross-sectional images. The x-ray transmission measurements are collected by a detector array and digitized into pixels that form an image. The grayscale information in individual pixels is determined by the attenuation of the x-ray beam along its path by tissues of different densities, referenced to the value for water in units known as Hounsfield units. In the resulting CT images, bone appears bright white, air is black, and blood and muscle show varying shades of gray. However, due to the limited contrast between cardiac chambers and vascular structures, iodinated contrast agents are necessary for most cardiovascular indications. Cardiac CT produces tomographic images of the heart and surrounding structures. With modern CT scanners, a three-dimensional dataset of the heart can be acquired in 5–15 s with submillimeter spatial resolution. CT Calcium Scoring CT calcium scoring is the simplest application of cardiac CT and does not require administration of iodinated contrast. The presence of coronary artery calcification has been associated with increased burden of atherosclerosis and cardiovascular mortality. Coronary calcium is then quantified (e.g., Agatston score) and categorized as minimal (0–10), mild (10–100), moderate (100–400), or severe (>400) (Fig. 270e-7). Coronary artery calcium (CAC) scores are then normalized by age and gender and reported as percentile scores. Population-based studies in asymptomatic cohorts have reported high cardiac prognostic
value of CT calcium score. With appropriate techniques, the radiation dose associated with CAC scanning is very low (~1–2 mSv). CT Coronary Angiography Coronary CT angiography (CTA) is emerging as a viable alternative to coronary angiography in selected patients. Imaging of the coronary arteries by CT is challenging because of their small luminal size and because of cardiac and respiratory motion. Respiratory motion can be reduced by breath-holding, and cardiac motion is best reduced by slowing the patient’s heart rate, ideally to under 60 beats/min, using intravenous or oral beta blockade or other rate-lowering drugs. When performing a coronary CTA, image quality is further enhanced using sublingual nitroglycerin to enlarge the coronary lumen just prior to contrast injection. Imaging the whole-heart volume is synchronized to the administration of weight-based and appropriately timed intravenous iodinated contrast. Image acquisition is linked to the timing of the cardiac cycle through electrocardiogram (ECG) triggering. Prospective ECG triggering, whereby the x-ray beam is turned on during a specific part of the cardiac cycle (e.g., end systole, combined end-systolic and end-diastolic timing, or mid-diastole), is generally used to limit the radiation exposure to the patient by acquiring data only through that portion of the cardiac cycle with least motion. Dose modulation is another method that should be routinely used to reduce radiation when performing CTA. It delivers a maximal amount of x-ray during the portion of the cardiac cycle of interest, but reduces x-ray delivery throughout the remaining portion of the cardiac cycle. The resulting images are then postprocessed using a three-dimensional workstation, which facilitates interpretation of the coronary anatomy and estimation of the severity of atherosclerosis (Fig. 270e-7). CARDIAC MAGNETIC RESONANCE Cardiac magnetic resonance (CMR) imaging is based on imaging of protons in hydrogen. Hydrogen is abundant because 80% of the human body consists of water. When put inside the MRI scanner,
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Figure 270e-6 Multidimensional cardiac imaging protocol with positron emission tomography. The left upper panel demonstrates stress and rest short-axis images of the left and right ventricles demonstrating normal regional myocardial perfusion. The middle panel demonstrates the quantitative bull’s-eye display to evaluate the extent and severity of perfusion defects. The lower right panel illustrates the time-activity curves for quantification of myocardial blood flow. The right upper panel demonstrates electrocardiogram-gated myocardial perfusion images from which one can determine the presence of regional wall motion abnormalities and calculate left ventricular volumes and ejection fraction. LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; TOT, total left ventricle.
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Figure 270e-7 Examples of non-contrast- and contrast-enhanced coronary imaging with computed tomography (CT). A. Calcified coronary plaques in the distal left main and proximal left anterior descending coronary artery (LAD) in a noncontrast cardiac CT scan. Calcium deposits are dense and present as bright white structures on CT, even without contrast enhancement. B, C, and D. Different types of atherosclerotic plaques on contrast-enhanced CT scans. Importantly, noncalcified plaques are evident only on contrast-enhanced CT scans. AO, aorta; PA, pulmonary artery; RCA, right coronary artery.
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
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TABLE 270e-2 Clinical Cardiac Magnetic Resonance Pulse Sequences and Their Application
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Pulse Sequence Cardiac Morphology Still frame imaging (black or bright blood) Cardiac Function Cine imaging Cine myocardial tagging Blood Flow Imaging Velocity-encoded phase contrast Stress Testing Myocardial perfusion imaging Cine imaging Myocardial Tissue Characterization Late gadolinium enhancement
Disorders of the Cardiovascular System
T2-weighted imaging Iron content imaging Magnetic Resonance Angiography Aorta, peripheral and coronary arteries
Key Imaging Interests Cardiac structures
Left ventricular volume and function Left ventricular deformation (strain) Cardiac and great vessel flow Regional myocardial blood flow Regional wall motion Myocardial infarction and infiltrative disease Myocardial edema Myocardial iron infiltration Luminal stenosis and vessel wall remodeling
the magnetic field causes the protons (spins) to spin around their axis (a process known as precession) at specific frequencies. Spins within water have a different frequency than spins within more complex macromolecules such as fat or protein. Inside the MRI, a set of gradient coils slightly modifies the magnetic field in each of the three orthogonal directions. As a result, this additional process alters the frequencies of spins, and now the spins can be spatially located inside the MRI bore. This system allows the MRI to selectively deposit radiofrequency energy (in the form or radiofrequency pulse) into specific locations of the body for the purpose of imaging those locations. Once the radiofrequency pulses stop, the energy absorbed by the body will quickly be released back. Using the proper arrangement of surface phased-array coils, this released energy can be read, and important information such as spin locations and frequencies can be digitally recorded in a data matrix known as the K-space, before reconstructed into a magnetic resonance image. Radiofrequency energy deposition into the patient’s body can be arranged in many complex ways, known as pulse sequences, that allow extraction of different types of information from the body regions of interests. In CMR, these types of information in general are categorized under T1, T2, or T2∗ weighting, each of them containing a different combination of diagnostic information regarding cardiac structure, tissue characteristics, blood flow, or other physiologic properties of the heart. In clinical CMR, most pulse sequences are T1-weighted sequences, which characterize cardiac structure and function, blood flow, and myocardial perfusion, whereas T2-weighted and T2∗-weighted pulse sequences characterize myocardial edema and myocardial iron infiltration, respectively. A combination of more than one weighting is possible in some pulse sequences. ECG-triggered cine CMR is the modality that serves as a reference standard for quantifying ventricular volumes and function. Respiratory motion during CMR imaging is suppressed most commonly using repetitive patient breath-holding, but more advanced algorithms such as motion averaging or gating diaphragmatic motion (known as navigator guidance) are also used in clinical CMR. A list of common pulse sequence used in CMR is shown in Table 270e-2.
ASSESSMENT OF CARDIAC STRUCTURE AND FUNCTION Echocardiography, CMR, and cardiac CT are all capable of assessing cardiac structure and function, although echocardiography is generally considered the primary imaging method for these assessments. Radionuclide imaging can also be used to assess left ventricular
regional and global systolic function. Echocardiography is most often used to assess the size of all four chambers and thickness of ventricular walls, which are affected by both cardiac and systemic diseases. The structure of the left ventricle is generally assessed by determining its volume and mass. Left ventricular volumes can be easily estimated from two-dimensional echocardiography by using one of several validated methods. The accuracy of these methods by echocardiography is limited by the fact that, as a nontomographic technique, foreshortening of the imaging plane can lead to underestimation of volumes. Moreover, virtually all of these methods require accurate identification of the endocardial border, which is dependent on image quality. In this regard, high-resolution tomographic techniques such as CMR or cardiac CT are considered generally more accurate for volumetric assessment. Three-dimensional echocardiography has several advantages over two-dimensional echocardiography by not requiring any geometric assumptions about the left ventricle for quantification of volumes and ejection fraction. However, acquisition of threedimensional echocardiographic images requires substantial expertise, and these techniques are not widely used in practice. Left ventricular dilatation is common to a number of cardiac diseases. For example, regional dysfunction secondary to myocardial infarction can ultimately lead to progressive ventricular dilatation or remodeling. Although dilatation often begins in the region affected by the infarction, subsequent compensatory dilatation can occur in remote myocardial regions as well. The presence of regional wall motion abnormalities associated with ventricular thinning (reflecting scar) in a coronary distribution is strongly suggestive of an ischemic etiology. Direct assessment of infarcted myocardium is possible with both CMR (evident as areas of late gadolinium enhancement [LGE]) and radionuclide imaging (as assessed by regional perfusion or metabolic defects at rest). CMR can be particularly useful in determining etiology of ventricular dilatation and dysfunction, with LGE in coronary distributions being nearly pathognomonic for infarction (Video 270e-1). More global ventricular dilatation is seen in cardiomyopathy and dilatation due to valvular heart disease. Idiopathic, nonischemic cardiomyopathies will typically result in global ventricular dilatation and dysfunction, with thinning of the walls. Patients with substantial ventricular dyssynchrony due to conduction abnormalities will have a typical pattern of contraction (e.g., delay of contraction of the lateral wall with left bundle branch block). Although various methods for determining ventricular dyssynchrony have been proposed as ways to identify patients who would benefit from cardiac resynchronization therapy, it is not yet clear that they are superior to ECG assessment of QRS duration and morphology. As discussed later in this chapter, regurgitant lesions of either the mitral or aortic valves can lead to substantial ventricular dilatation, and assessment of ventricular size is integral in the evaluation and timing of surgical correction. Because changes in ventricular size are used clinically to determine which patients should undergo valve surgery, accurate assessment of changes in ventricular size is essential. Although serial echocardiography can provide these data, serial assessment by CMR may be more accurate when appreciation of subtle changes over time is important. Left ventricular wall thickness and mass are also important measures of cardiac and systemic disease. The left ventricle will hypertrophy under any condition in which its afterload is increased, including conditions that obstruct outflow, such as aortic stenosis, hypertrophic cardiomyopathy, and subaortic membranes; in postcardiac aortic obstruction seen in coarctation; or in systemic conditions characterized by increased afterload, such as hypertension. The pattern of ventricular hypertrophy can change depending on the etiology. Aortic stenosis and hypertension are typically characterized by concentric hypertrophy, in which the ventricular walls thicken “concentrically” and cavity size is usually small. In volume overload conditions such as mitral or aortic regurgitation, there may be minimal increase in ventricular wall thickness, but substantial ventricular dilatation leads to marked increases in left ventricular mass. Ventricular wall thickness can be measured and ventricular mass can be calculated by either echocardiography or CMR. Although radionuclide imaging and cardiac CT can also provide measures of
left ventricular mass, they are not generally used for this purpose. Although measurement of wall thickness with echocardiography is relatively straightforward and accurate, determining left ventricular mass by echocardiography requires using one of several formulas that takes into account both wall thickness and ventricular cavity dimensions. Assessment of left ventricular mass by CMR has the advantage of not requiring geometric assumptions and is thus more accurate than echocardiography.
ASSESSMENT OF LEFT VENTRICULAR DIASTOLIC FUNCTION Echocardiography remains the primary method for clinical assessment of diastolic function. Recent advances in Doppler tissue imaging allow for accurate assessment of the velocity of myocardial wall motion by assessing the excursion of the mitral annulus in diastole. Mitral annular relaxation velocity, or E′, is inversely related to the time constant of relaxation, tau, and has been shown to have prognostic significance. Dividing the standard mitral inflow maximal velocity, E, by the mitral annular relaxation velocity yields E/E′, which has been shown to correlate with left ventricular filling pressures. The utility of standard E and A wave ratios for assessment of diastolic function has been questioned. Mitral deceleration time can be a useful measure if very short (60 mL/min) is low. In most patients, CIN is self-limited, and renal function usually returns to baseline within 7–10 days, without progressing to chronic renal failure. However, this risk increases in patients with GFR 0.1 mmol/ kg) GBCA use in presence of severe renal dysfunction (estimated GFR [eGFR] 400), however, specificity is reduced because the blooming artifact of calcium does not allow one to evaluate the vessel lumen accurately. Given the high negative predictive value of CTA, a normal scan result effectively excludes obstructive CAD and abolishes the need for further investigation. As discussed below, this may be quite useful in patients with low-intermediate clinical risk presenting to the emergency room for chest pain. However, the limited capability of this technique to determine the severity of stenosis and to predict which obstructions are flow limiting can make abnormal scan results more difficult to interpret, especially in terms of the possible need of coronary revascularization. There are emerging data suggesting that by adding a stress myocardial perfusion CT evaluation (similar to stress perfusion CMR) (Fig. 270e-13, top panel) or an estimated fractional flow reserve (so-called FFRCT) (Fig. 270e-13, lower panel), one can define the hemodynamic significance of anatomic stenosis. However, these are not in routine clinical use and remain emerging technologies. As with invasive coronary angiography, assessments of the extent of CAD by CTA can also provide useful prognostic information. A low 1-year cardiac event rate has been reported for patients without obstructive CAD on CTA. For patients with obstructive CAD, the risk of adverse cardiac events increases proportionally with the extent of angiographically obstructive CAD.
Although CTA can be helpful in assessing patency of bypass grafts, the assessment of stents is somewhat more challenging because the limited spatial resolution of CT and stent diameter (2 mm ST-segment depression in multiple leads, ST elevation during exercise, drop in blood pressure, or sustained ventricular arrhtyhmias) be referred for coronary angiography. The use of exercise testing in women presents difficulties that are not seen in men, reflecting the differences in the lower prevalence of obstructive CAD in women and the different accuracy of exercise testing in men and women. Compared with men, the lower pretest probability of disease in women means that more test results are false positive. In some of these patients, a positive ETT may reflect true myocardial ischemia caused my microvascular coronary artery dysfunction (so-called microvascular disease). In addition, the inability of many women to exercise to maximum aerobic capacity, the greater prevalence of mitral valve prolapse and microvascular disease in women, and possibly other reasons may contribute to the differences with men as well. The difficulties of using exercise testing for diagnosing obstructive CAD in women have led to speculation that stress imaging may be preferred over standard stress testing. However, recent data from the WOMEN study suggests that in symptomatic, low-risk women who are able to exercise, standard ETT is a very effective initial diagnostic strategy as compared to stress radionuclide imaging. Women included in the study were randomized to standard ETT or exercise radionuclide perfusion imaging. The primary endpoint was the 2-year incidence of major adverse cardiac
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
FFRCT
environment of the magnetic resonance 270e-13 scanner. It occurs rarely (~5%), and most cases can be prevented with proper monitoring of vital signs and regional cine function. The advantage of stress perfusion CMR over SPECT is its clearly higher spatial resolution, allowing detection of subendocardial defects that may be missed by SPECT. The addition of the information from LGE imaging allows differentiation of hypoperfused (potentially ischemic) from infarcted myocardium and characterizes the extent of myocardial ischemia. As with other imaging modalities, there is evidence that ischemia measurements derived from stress CMR studies also have prognostic value. In line with the nuclear and echocardiography literature, a normal CMR study is associated with a good prognosis. Conversely, the presence of new wall motion abnormalities, regional perfusion defects, the combination of wall motion abnormalities and perfusion defects, and the presence of LGE are all predictors of adverse events.
Event rate (%/year)
270e-14
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PART 10
Figure 270e-15 Incremental risk stratification of stress imaging over Duke treadmill score in patients with suspected coronary artery disease. Stress imaging is most valuable in the intermediate-risk group. SPECT, single-photon emission computed tomography; VD, vessel disease. (Reproduced with permission from R Hachamovitch et al: Circulation 93:905, 1996; and TH Marwick et al: Circulation 103:2566, 2001.)
Disorders of the Cardiovascular System
events, defined as CAD death or hospitalization for an acute coronary avoidance of excess catheterizations with their associated cost and risk syndrome or heart failure. At 2 years, there was no difference in major and the potential for intervening unnecessarily. The acceptable diagadverse cardiac events. As expected, ETT resulted in 48% lower costs nostic accuracy of stress imaging approaches, along with their robust compared to exercise radionuclide imaging. risk stratification, and the ability of ischemia information to identify Patients with intermediate-high risk after ETT (e.g., low exercise patients who would benefit from revascularization suggest a potential duration, chest pain, and/or ST-segment depression without high- role as a first imaging strategy in patients with intermediate-high likelirisk features) will often require additional testing, either stress imag- hood of CAD. Although the available data suggest similar diagnostic ing or noninvasive CT coronary angiography, to more accurately accuracy for SPECT, PET, echocardiography, and CMR, the choice of characterize clinical risk. Most common stress imaging strategies in strategy depends on availability and local expertise. intermediate-risk patients include stress echocardiography and radionuclide imaging. In such patients, stress imaging with either SPECT or Selecting a Testing Strategy in Patients with Known CAD Use and selection echocardiography has been shown to accurately reclassify patients who of testing strategies in symptomatic patients with established CAD (i.e., are initially classified as intermediate risk by ETT as low or high risk prior angiography, prior myocardial infarction, prior revascularization) (Fig. 270e-15). Following this staged strategy of applying the low-cost differ from those in patients without prior CAD. Although standard ETT first and reserving more expensive imaging to refine risk stratification to patients initially classified as intermediate risk by ETT is more cost effective than applying stress or anatomic imaging as the initial test routinely. A stress imaging strategy is the recommended first step for patients who are unable to exercise to an adequate workload and/or those with abnormal resting ECGs (e.g., left ventricular hypertrophy with strain, left bundle branch block). Importantly, the most recent documents regarding appropriate use of radionuclide and echocardiography imaging also considered that an imaging strategy may be an appropriate first step in patients with intermediate-high likelihood of CAD (e.g., diabetics, Stress renal impairment) due to increased overall sensitivity for diagnosis of CAD and improved risk stratification. In considering the potential clinical application of imaging modalities, the evidence supporting the role of Rest assessment of ischemia versus anatomy must be considered. From the discussion above, a normal CTA is helpful because it effectively excludes the presence of obstrucStress tive CAD and the need for further testing, defines a low clinical risk, and makes management decisions regarding referral to coronary angiography straightforward. Because of its limited accuracy to define stenosis severity Rest and predict ischemia, however, abnormal CTA results are more problematic to interpret and to use as the basis for defining the potential need of invasive coronary angiogStress raphy and revascularization. In such patients, a follow-up stress test is usually required to determine the possible need of revascularization (Fig. 270e-16). Rest The justification of stress imaging in testing strategies has hinged on the identification of which patients may benefit from a revascularization strategy by means of Figure 270e-16 Selected views from coronary computed tomography angiononinvasive estimates of jeopardized myocardium rather graphic (CTA) images (top panel) and stress and rest rubidium-82 myocardial than angiography-derived anatomic stenoses. Indeed, perfusion positron emission tomography images (lower panel) obtained on there is evidence that only the presence of moder- a 64-year-old male patient with atypical angina. The CTA images demonstrate ate-severe ischemia identifies patients with apparent dense focal calcifications in the left main (LM) and left anterior descending (LAD) improved survival with revascularization. Patients with coronary arteries and a significant noncalcified plaque in the mid right coronary mild or no ischemia are better candidates for optimal artery (RCA; arrow). The myocardial perfusion images demonstrated no evidence of medical therapy. The advantages of this approach include flow-limiting stenosis. LCx, left circumflex artery; OM, obtuse marginal branch.
Testing Strategy Considerations in Patients Presenting with Chest Pain to the Emergency Department Although acute chest pain is a frequent reason for patient visits to the emergency department (ED), only a small minority of those presentations represent an acute coronary syndrome (ACS). Strategies used in the evaluation of these patients include novel cardiac biomarkers (e.g., serum troponins), conventional stress testing (ETT), and noninvasive cardiac imaging. It is generally accepted that the primary goal of this evaluation is exclusion of ACS and other serious conditions rather than detection of CAD. The routine evaluation of acute chest pain in most centers in the United States includes admission to a chest pain unit to rule out ACS with the use of serial ECGs and cardiac biomarkers. In selected patients, stress testing with or without imaging may be used for further risk stratification. Stress echocardiography and radionuclide imaging are among the most frequently used imaging approaches in these patients. The relative strengths and weaknesses of these testing options have been discussed above. Both approaches have been shown to be effective for identifying low-risk patients who can be safely discharged from the ED. Multiparametric CMR imaging has also been used successfully in patients with acute chest pain. In addition to the combined assessment of regional and global left ventricular function, myocardial perfusion, and tissue viability, it is also possible to evaluate the presence of myocardial edema to characterize the myocardium at risk secondary to reduced coronary flow (Video 270e-5). Due to its ability to probe multiple aspects of myocardial physiology, cardiac anatomy, and tissue characterization with LGE imaging, CMR is also useful in diagnosing conditions that mimic ACS (e.g., acute myocarditis, takotsubo cardiomyopathy, pericarditis) (Fig. 270e-17). Thus, CMR imaging offers unique information of myocardial pathophysiology in the spectrum of ACS and is, perhaps, the most versatile of all noninvasive imaging techniques. Unfortunately, it is not widely available even at specialized centers and is not a first-line testing strategy. The main disadvantages of the “functional” testing strategy are that it is time consuming and is generally associated with a prolonged length of stay and, thus, is more costly.
270e-15
Figure 270e-17 A four-chamber long-axis late gadolinium enhancement (LGE) image of a patient with acute myocarditis. Note that the LGE primarily involved the epicardial aspect of the myocardium (arrows), sparing the endocardium, which is a feature that distinguishes myocarditis from myocardial infarction, which affects the endocardium. Also note the multiple foci of LGE in this case affecting the lateral wall of the left ventricle. Viral myocarditis often presents with this pattern. As discussed above, coronary CTA is a rapid and accurate imaging technique to exclude the presence of CAD and is well suited for the evaluation of patients with acute chest pain (Fig. 270e-18). Several singlecenter and, more recently, multicenter studies have demonstrated the feasibility, safety, and accuracy of coronary CTA in the ED. There have been four randomized controlled trials evaluating the efficacy of coronary CTA as the initial testing strategy as compared to usual care (which typically includes stress imaging). Patients in these trials had a very low clinical risk. Overall, there were no deaths and very few myocardial infarctions without differences between the groups. Likewise, there were no differences in postdischarge ED visits or rehospitalizations. These studies showed decreased length of stay with coronary CTA, and most but not all reported cost savings. An observation from a recent meta-analysis was that, compared to usual care, more patients assigned to coronary CTA underwent cardiac catheterization (6.3% vs 8.4%, respectively) and revascularization (2.6% vs 4.6%, respectively). The relative increased frequency in the referral to cardiac catheterization and revascularization after coronary CTA compared to stress imaging testing strategies has also been observed in patients with stable chest pain syndromes. Taken together, the available data clearly suggest that not all patients presenting with acute chest pain require specialized imaging testing. Patients with very low clinical risk and negative biomarkers (especially high-sensitivity troponin assays) can be safely triaged. The use of imaging tests in patients with low-intermediate risk should be carefully considered, especially given the trade-offs discussed above. VALVULAR HEART DISEASE Abnormalities of any of the four valvular structures in the heart can lead to significant cardiac dysfunction, heart failure, or even death. Echocardiography, CMR, and cardiac CT can be used for the evaluation of valvular heart disease, although echocardiography has generally been considered the first imaging test of choice for the assessment of valvular heart disease. In addition, echocardiography is the most costeffective screening method for valvular heart disease. In some cases,
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
ETT may help distinguish cardiac from noncardiac chest pain, exercise ECG has a number of limitations following myocardial infarction and revascularization (especially coronary artery bypass grafting). These patients frequently have rest ECG abnormalities. In addition, there is a clinical need to document both the magnitude and localization of ischemia to be able to direct therapy, especially the potential need for targeted revascularization. Consequently, imaging tests are preferred for evaluating patients with known CAD. There are also important differences in the effectiveness of imaging tests in these patients. As discussed above, coronary CTA is limited in patients with prior revascularization. Patients with prior coronary artery bypass grafting are a particularly heterogeneous group with respect to the anatomic basis of ischemia and its implications for subsequent morbidity and mortality. In addition to graft attrition, progression of disease in the native coronary arteries is not uncommon in symptomatic patients. While CTA provides excellent visualization of the bypass grafts, the native circulation tends to get heavily calcified and is generally not a good target for imaging with CTA. Likewise, blooming artifacts from metallic stents also limit the application of coronary CTA in patients with prior percutaneous coronary intervention. Although newer stent material may change the potential role of CTA in the future, it is probably not the first line of testing in these patients. If an anatomic strategy is indicated, direct referral to invasive angiography is preferred. Stress imaging approaches are especially useful and preferred in symptomatic patients with established CAD. As in patients without prior CAD, normal imaging studies in symptomatic patients with established CAD also identify a low-risk cohort. In those with abnormal stress imaging studies, the degree of abnormality relates to posttest risk. In addition, stress imaging approaches can localize and quantify the magnitude of ischemia (especially with perfusion imaging), thereby assisting in planning targeted revascularization procedures. As in patients without prior CAD, the choice of stress imaging strategy depends on availability and local expertise.
270e-16 A
B
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RCA
PART 10
Figure 270e-18 Representative coronary computed tomography angiographic (CTA) images of two patients presenting to the emergency department with chest pain and negative biomarkers. The patient in A had angiographically normal coronary arteries; the panel shows a representative view of the right coronary artery (RCA). B and C show a corresponding significant stenosis in the mid portion of the RCA on both the CTA (B) and invasive angiographic view (C). (Images courtesy of Dr. Quynh Truong, Massachusetts General Hospital, Boston, MA.)
Disorders of the Cardiovascular System
CMR can complement echocardiography when echocardiographic acoustic window is inadequate, quantifying blood flow data more precisely, or providing complimentary assessment of adjacent vascular structures relevant to the valvular condition. Echocardiography can be used to assess both regurgitant and stenotic lesions of any of the cardiac valves. Typical indications for echocardiography to assess valvular heart disease include cardiac murmurs identified on physical examination, symptoms of breathlessness that may represent valvular heart disease, syncope or presyncope, and preoperative exams in patients undergoing bypass surgery. A standard echocardiographic examination should include qualitative and quantitative assessment of all valves regardless of indication and should serve as an adequate screening test for significant valvular disease. General Principles of Valvular Assessment • Direct visualization of valvular structures Direct visualization of valve structures by twodimensional echocardiography represents the first step in valvular evaluation. The morphology of valvular structures provides useful information regarding the etiology and severity of valvular disease. For example, two-dimensional imaging assessment of the aortic valve can identify the number of leaflets, determine whether the valve is bicuspid or tricuspid, and determine the severity of calcification and degree of leaflet excursion. Similarly, the classic appearance of a rheumatic mitral valve is extremely useful in determining the etiology of mitral stenosis, and mitral valve prolapse can be instantly identified without even the need for Doppler-based quantification. Evaluation of stenotic valves As described earlier in the chapter, evaluation of stenotic valves generally includes estimation of the pressure gradient across the stenosis and determination of the valve area. Both of these measures have diagnostic and prognostic value. For example, when Doppler echocardiography is used to assess the maximal velocity across a stenotic aortic valve, this calculation will provide an accurate measure of the instantaneous gradient across the valve. This gradient will be higher than the mean gradient, as well as higher than that peakto-peak gradient obtained at cardiac catheterization. This gradient is dependent on both the degree of stenosis and the contractile function of the left ventricle. Patients with significant left ventricular dysfunction may have severe aortic stenosis but will be unable to generate a high gradient across the valve because generated pressure within the left ventricle will be diminished. Assessment of stenotic valves generally requires estimation of both the pressure gradient across the valve and the valve area. Pressure gradient is estimated through direct application of the Bernoulli principle, and the formula p = 4v2 is usually sufficient to estimate the gradient across the valve. Several methods can be used to estimate valve areas, including the continuity principle based on the principle of conservation of mass. By this method, flow is estimated in two places. For example, for assessment of the aortic valve area, we measure the flow in the region of the left ventricular outflow tract and the cross-sectional area in this region, the product of which should be equal to the flow
across the stenotic aortic valve and its cross-sectional area. Estimation of the mitral valve area in patients with suspected mitral stenosis can also be performed in a number of ways, including planimetry of the valve directly, estimation with continuity methods, or the most commonly used pressure half-time method, in which the stenosis severity is estimated by the time it takes for the pressure—estimated from velocity by the Bernoulli equation—to reach half of its original value during mitral inflow. Evaluation of regurgitant lesions Regurgitant lesions are generally assessed by both visual assessment of the valve morphology and a variety of Doppler-based methods to assess the severity of regurgitation. The etiology of regurgitation can often be inferred from visual inspection. For example, prolapse of the mitral valve leaflets—and to a lesser extent, the aortic valve leaflets—can be easily visualized with two-dimensional echocardiography. In general, valvular regurgitation can be caused by abnormalities of the valve leaflets themselves or abnormalities of the annulus and supporting structures, and these can usually be distinguished visually on transthoracic echocardiography (see discussion below). Quantification of valvular regurgitation is more difficult with echocardiography than quantification of valvular stenoses. Doppler-based methods are best suited to assess blood velocities rather than volumetric flow. The most widely used technique for assessing the severity of valvular regurgitation is color flow Doppler estimation, which is qualitative. More quantitative methods such as the proximal isovelocity surface area (PISA) method (see below) allow for more accurate assessment of regurgitation and provide estimation of the regurgitant fraction and effective regurgitant orifice area but are less widely used. Assessment of regurgitant lesions with CMR also has a number of advantages (see below). Assessment of Aortic Stenosis Aortic stenosis, one of the most common forms of valvular heart disease, most often occurs because of gradual progression of valvular calcification in both normal and congenitally abnormal valves. Assessment of aortic stenosis is most commonly performed with echocardiography, although techniques for quantitative assessment of aortic stenosis with CMR have been developed and increasingly used over the past decade. Echocardiographic assessment generally begins with visual inspection of the valve, usually in the parasternal long-axis and short-axis views. This allows for assessment of valvular morphology, whether it is tricuspid, bicuspid, or some variant; degree of leaflet calcification; and leaflet excursion. The normal aortic valve consists of three leaflets or cusps: the right coronary, the left coronary, and the noncoronary cusps. Abnormalities of cusp development are some of the most common congenital heart anomalies, the most common of which is bicuspid aortic valve, with two opening leaflets rather than three (Fig. 270e-19). The aortic valve can be visualized on echocardiography, although sometimes it can be difficult to distinguish true bicuspid aortic valve from variants, including the presence of a vestigial commissure (raphe). Bicuspid aortic
A
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valve, one of the most common congenital anomalies, predisposes to aortic insufficiency, paravalvular leak resulting from patient–prosthesis mismatch). Echocardiography is the imaging modality of choice both aortic stenosis and aortic insufficiency. As discussed above, the degree of aortic stenosis is assessed by for long-term surveillance. estimating both the pressure gradient across the valve and the valve area. Patients with moderate aortic stenosis or higher generally have Assessment of Aortic Regurgitation Assessment of aortic regurgitation peak instantaneous velocities of 3.0 m/s and higher, and often higher requires qualitative assessment of the aortic valve structure. Aortic than 4.0 m/s, corresponding to pressure gradients of 36 and 64 mmHg, regurgitation is common with congenital abnormalities of the aortic respectively. Because pressure gradients across the aortic valve can valve, the most common of which is bicuspid aortic valve. Aortic be underestimated in patients with severe left ventricular dysfunc- regurgitation often coexists with aortic stenosis, and it is not uncomtion, estimation of valve area by the continuity principle is the most mon for patients to have both severe aortic stenosis and regurgitation. accurate technique for assessing the severity of the stenosis. However, Congenital abnormalities of the aortic leaflets, such as bicuspid aortic evaluation of the patient with so-called low-flow or low-gradient aortic valve, are common causes of aortic insufficiency. Dilatation of the aorstenosis can be challenging and can sometimes require provocative tic root, as occurs in patients with hypertension and other disorders in testing such as dobutamine echocardiography. In these cases, it is which aortic dilatation can occur, can also lead to aortic regurgitation important to distinguish whether the valve is indeed capable of open- even when the valve leaflets are intrinsically normal due to malcoaptaing further or simply behaving like a stenotic valve because of the tion of the leaflets. Aortic root dilatation is common in patients with low-pressure gradient. aortic regurgitation, both as a cause or coexisting lesion, and the aortic Aortic valve areas less than 1.0 cm2 are generally considered severe, root and ascending aorta should be measured and followed in these and valve areas less than 0.6 cm2 are considered critical. Because patients (Fig. 270e-20). patients with good left ventricular function can often tolerate severe Because aortic regurgitation can result in dilatation of the left venaortic stenosis for a considerable period of time, valve areas or gra- tricle over time with ultimate reduction in ventricular function, caring dients alone should not be used to determine whether an individual for the patient with aortic regurgitation requires serial assessment of patient should undergo aortic valve surgery, as this remains a clinical ventricular size and function. Patients whose ventricles dilate beyond decision. an end-systolic diameter of 5.5 cm or whose LVEF declines below Some patients with apparent aortic stenosis actually have subvalvu- normal are at significantly higher risk of death or heart failure, and lar or even supravalvular obstruction. Hypertrophic cardiomyopathy these measures are often used to decide the need for valve surgery. represents the classic form of subvalvular aortic stenosis, but this is Quantitation of regurgitation itself can be performed using a number usually easily distinguished from aortic stenosis on echocardiography of methods. Semiquantitative visual assessment of aortic regurgitant as the valve leaflets can be seen opening during systole. Subaortic jet width and depth by color flow Doppler remains the most used. The membranes can behave very similarly to leaflet aortic stenosis, and jet diameter as a ratio of the left ventricular outflow tract diameter the membranes themselves can be very thin and difficult to visualize, proximal to the valve represents one of the most reliable indices of although the presence of a murmur, a gradient across the valve with severity and correlates well with angiographic assessment. Similarly, aortic leaflets that appear to open normally, is highly suggestive of a the vena contracta, which represents the smallest diameter of the membrane. Supravalvular aortic stenosis, although exceedingly rare, regurgitant flow at the level of the valve, can be used to assess the also occurs. severity of aortic regurgitation. Other Doppler-based methods include The emergence of transcatheter aortic valve intervention as a assessing the pressure half-time, or rate of decline of the pressure therapeutic option for patients with severe aortic stenosis who are gradient between the aorta and left ventricle, a measure of acuity of not optimal candidates for surgical replacement has resulted in a aortic regurgitation, and assessing aortic flow reversal in the descendvery important clinical role for multimodality imaging. Imaging ing aorta. The regurgitant volume can be calculated by comparing the plays a critical role in preprocedural planning, intraprocedural implantation optimization, and follow-up of these patients. CT plays an A B important role in defining the eligibility of the proposed access site (CTA of the aorta and iliac arteries) and in defining the anatomic relationships between the aortic valve and aortic root, left ventricle, and coronary ostia. Cardiac CT and transesophageal echocardiography are also used to define the device size. Transesophageal echocardiography is used during the device implantation to ensure the best prosthesis–patient match, to assess prosthesis position and function after deployment, Figure 270e-20 Aortic regurgitation visualized by color flow Doppler in the parasternal and to identify immediate complications (e.g., long-axis view (A) and the parasternal short-axis view (B).
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
Figure 270e-19 Normal aortic valve in the parasternal long-axis view (A) and short-axis view (B), and bicuspid aortic valve showing typical 10 o’clock to 4 o’clock leaflet orientation (C).
270e-17
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of the aortic size that in some cases can be helpful in determining the etiology of the aortic regurgitation or in monitoring the patient (Fig. 270e-21 and Video 270e-6).
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Disorders of the Cardiovascular System
Figure 270e-21 The resultant flow curve generated from phase contrast imaging demonstrates a forward flow of 123 mL and a regurgitant volume of 67 mL, yielding a regurgitant fraction of 54% indicating severe aortic regurgitation. flow across the aortic and pulmonic valves, assuming the pulmonic valve is competent. CMR offers a number of advantages over echocardiography in the assessment of aortic regurgitation. CMR can be more accurate than echocardiography for assessing small changes in cardiac size or function that can occur over time in patients with aortic insufficiency. In addition, CMR techniques can very accurately quantify regurgitant volume in patients with aortic insufficiency, a known limitation of echocardiography. CMR can also capture three-dimensional imaging
Assessment of Mitral Regurgitation The normal mitral valve consists of an anterior and posterior leaflet in a saddle shape configuration (Fig. 270e-22). The leaflets are attached to the papillary muscles via chordae tendineae that insert on the ventricular side of the leaflets. Mitral regurgitation can occur due to abnormalities of the leaflets, the chordal structures, or the ventricle, or any combination of these (Fig. 270e-23). Mitral valve prolapse, in which one leaflet moves behind the plane of the other leaflet, can be due to myxomatous degeneration of the valves and leaflet redundancy, disruption of chordal structures secondary to degenerative disease, or papillary muscle rupture or dysfunction following myocardial infarction. Regurgitant jets can be visualized using color flow Doppler. The velocity of regurgitant jets is driven by the pressure gradient between the two chambers. This velocity tends to be quite high for left-sided regurgitant lesions, including mitral regurgitation and aortic regurgitation, resulting in turbulent jets on color flow Doppler (Fig. 270e-23). Visual estimation of color flow Doppler is generally sufficient for qualitative assessment of regurgitant severity but can dramatically under- or overestimate regurgitation severity, particularly when regurgitant jets are quite eccentric. For this reason, quantitative assessment is generally recommended, especially when making clinical decisions about surgical intervention. The PISA method is generally used for quantitative assessment of severity of mitral regurgitation. This method relies on estimation of the velocity of flow acceleration at a specific distance proximal to the valve with the assumption that the flow accelerates in concentric hemispheres.
Figure 270e-22 Normal mitral valve in two-dimensional views (left) and with three-dimensional imaging (right).
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As with aortic insufficiency, assessment of ventricular structure and function is also integral in the evaluation of mitral regurgitation. Although some patients have mitral regurgitation due to intrinsic abnormalities of the valve itself, in others, the valve can be relatively normal but the mitral regurgitation can be secondary to dilatation and remodeling of the left ventricle. So-called functional mitral regurgitation is generally secondary to apical displacement of the papillary muscles in a dilated ventricle, resulting in the leaflets of the mitral valve being pulled toward the apex of the heart, resulting in poor coaptation during systole and resultant relatively central mitral regurgitation. This type of mitral regurgitation can generally be distinguished from intrinsic mitral valve disease, and the surgical or procedural treatment of these conditions can be different. Knowledge of the etiology of mitral regurgitation can be important for a surgeon planning mitral valve surgery. Moreover, new procedural approaches to mitral valve disease may be different depending on the etiology. Ventricular dilatation is an important predictor of outcome in patients with mitral regurgitation of any cause. It is important to realize that in a patient with significant mitral regurgitation, a large portion of the blood being ejected from the left ventricle with every beat is regurgitant, thus artificially increasing the ejection fraction. Thus, an ejection fraction of 55% in a patient with severe mitral regurgitation may actually represent substantial reduction in myocardial systolic function. CMR can be helpful in evaluating mitral regurgitation in a subset of patients when echocardiographic assessment is inadequate. CMR can directly quantify regurgitant volume of the mitral regurgitant jet or indirectly quantify regurgitant volume by measuring the difference of left ventricular stroke volume and aortic forward flow.
MYOCARDIAL INFARCTION AND HEART FAILURE Role of Imaging after Myocardial Infarction Imaging can be particularly useful in the immediate and long-term follow-up of patients with myocardial infarction. As discussed earlier in the chapter, CMR is the best technique for direct assessment of infarcted myocardium. LGE imaging by CMR provides accurate delineation of infarct size and morphology. In a recent multicenter study, LGE imaging by CMR identified infarct location accurately and detected acute and chronic infarcts with a sensitivity of 99% and 94%, respectively. With an in-plane spatial resolution of 1.5–2 mm and a high contrast-to-noise ratio, LGE by CMR has excellent sensitivity in detecting small areas of myocardial scar. In addition, regions of microvascular obstruction (no-reflow) can be seen as dense hypoenhanced areas within the core of a bright region of infarction. Both the presence of LGE and microvascular obstruction are markers of increased clinical risk. While echocardiography is often used to assess myocardial function immediately after myocardial infarction, myocardial stunning is common in the early post–myocardial infarction period, especially in patients who undergo reperfusion therapy. In these patients, either partial or complete recovery of ventricular function is common within several days, so that early estimation of ejection fraction may be misleading. In patients with uncomplicated myocardial infarction, imaging can generally be deferred for several days so that a more accurate assessment of cardiac function, including regional wall motion, can be assessed (Fig. 270e-25). Echocardiography is the best method for assessment of patients with suspected mechanical complications after myocardial infarction. These include mitral regurgitation secondary to either papillary muscle dysfunction or rupture of papillary muscle head, ventricular septal defect, or even cardiac rupture. A new severe systolic murmur should raise suspicions for either severe mitral regurgitation or ventricular septal defect. While cardiac rupture is often catastrophic, contained ruptures, also known as pseudoaneurysms, can occur, and early diagnosis and surgical treatment are the best way to maximize survival. The presence of thrombus within the pericardial space following myocardial infarction should immediately raise suspicion of myocardial rupture and represents a surgical emergency.
Assessment of Mitral Stenosis Rheumatic mitral disease remains the most common cause of mitral stenosis, although mitral stenosis can also result from severe calcification of the mitral leaflets. Rheumatic mitral stenosis has a distinct appearance characterized by tethering at the leaflet tips and relative pliability of the leaflets themselves, resulting in a hockey stick–type deformation particularly of the anterior leaflet (Fig. 270e-24). Narrowing of the mitral orifice impedes flow from the left atrium to the left ventricle, resulting in A B increased pressures in the left atrium, which are then transmitted backward into the pulmonary vasculature and the right side of the heart. When mitral stenosis is suspected, echocardiography can be useful for determining etiology (specifically whether it is rheumatic or not), estimating the valve areas and gradients across the valve, assessing the left atrium, and assessing right ventricular size and function. Assessment of left atrial size and right ventricular size and function is Figure 270e-24 A. Rheumatic mitral stenosis showing pliable leaflets tethered at the tips (arrow). particularly useful in helping determine Note the characteristically enlarged left atrium. B. Mitral stenosis visualized from a three-dimensional echocardiogram. the severity of the mitral stenosis.
CHAPTER 270e Noninvasive Cardiac Imaging: Echocardiography, Nuclear Cardiology, and Magnetic Resonance/Computed Tomography Imaging
Figure 270e-23 A. Mitral valve prolapse with posterior leaflet visualized prolapsing behind the plane of the anterior leaflet (arrow). B. Color flow Doppler showing mitral regurgitation in a patient with mitral valve prolapse. C. Severe functional mitral regurgitation in a patient with a dilated left ventricle.
clinical question, especially among those with recurrent symptoms after myocardial infarction (Fig. 270e-26). All cardiac imaging techniques can provide information regarding myocardial viability and ischemia. In the absence of definitive trials offering head-to-head comparisons between techniques in large series of patients, uncertainty persists concerning the relative accuracies of each method for predicting functional and prognostic benefit after revascularization. Thus, one should exercise caution in the interpretation of the relative diagnostic accuracy of each imaging technology. Nevertheless, the available data suggest that radionuclide imaging, especially PET, is highly sensitive, with higher negative predictive value than dobutamine echocardiography. In contrast, dobutamine echocardiography tends to be associated with higher specificity and positive predictive accuracy than the radionuclide imaging methods. The experience with CMR suggests that it offers similar predictive accuracies as those seen with dobutamine echocardiography.
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PART 10 Figure 270e-25 Acute left anterior descending artery distribution myocardial infarction at end systole showing akinetic region (arrows).
Disorders of the Cardiovascular System
Some patients demonstrate progressive left ventricular dilatation and dysfunction, known as cardiac remodeling, after myocardial infarction. Assessment of cardiac function and regional wall motion is useful in the follow-up period, generally between 1 and 6 months following infarction. The persistence of left ventricular systolic dysfunction following infarction is used to determine the type of therapy (e.g., angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are typically used in patients with systolic dysfunction following myocardial infarction). In patients with acute or subacute myocardial infarction, investigation of residual ischemia and/or viability is occasionally an important
Role of Imaging in New-Onset Heart Failure Echocardiography is usually a first-line test in patients presenting with new-onset heart failure. As discussed above, this test provides a direct assessment of ventricular function and can help distinguish patients with reduced ejection fraction from those with preserved ejection fraction. In addition, it provides additional structural information including an assessment of valves, myocardium, and pericardium. Although coronary angiography is commonly performed in patients with reduced ejection fraction, the determination of heart failure etiology in an individual patient may be difficult even if angiographically obstructive CAD is present. Indeed, patients with heart failure and no angiographic CAD may have typical angina or regional wall motion abnormalities on noninvasive imaging, whereas patients with angiographically obstructive CAD may have no symptoms of angina
Contrast-enhanced MRI
Positron emission tomography Perfusion
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Figure 270e-26 Examples of myocardial viability patterns obtained with cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) in three different patients with coronary artery disease. The top panel demonstrates extensive late gadolinium enhancement (bright white areas) involving the anterior, anteroseptal, and apical left ventricular walls (arrows), consistent with myocardial scar and nonviable myocardium. The lower left panel demonstrates rubidium-82 myocardial perfusion and 18F-fluorodeoxyglucose (FDG) images showing a large and severe perfusion defect in the anterior, anterolateral, and apical walls, indicating preserved glucose metabolism (so-called perfusion-metabolic mismatch) consistent with viable myocardium. The right lower panel shows similar PET images demonstrating concordant reduction in perfusion and metabolism (so called perfusion-metabolic match) in the lateral wall, consistent with nonviable myocardium.
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Figure 270e-27 A case of cardiac amyloidosis. Note on this late gadolinium enhancement image that there were multiple foci of gadolinium accumulation in the left ventricle (LV) myocardium (red arrows), as well as the left atrial (LA) walls (blue arrows). The LV walls were markedly increased in thickness, and both atria were dilated, consistent with a restrictive cardiac morphology. The blood pool signal was diminished after contrast injection, which was consistent with high burden of amyloid disease in other organs that causes gadolinium concentration in the blood to rapidly go down. RA, right atrium; RV, right ventricle.
ASSESSING CARDIAC FUNCTION IN PATIENTS UNDERGOING CANCER TREATMENT Therapies used to treat cancer can adversely affect the cardiovascular system. As the efficacy of cancer treatment and survival improve, many patients are presenting with late adverse consequences from chemotherapy and/or radiation therapy on cardiovascular function. Thus, the morbidity and mortality from late cardiovascular complications threaten to offset the early gains in cancer survival, especially among children and young adults. Early recognition and treatment of cardiomyocyte injury are critical for successful application of preventative therapies, but difficult because the adverse effects on cardiac function are a relatively late manifestation after exposure to anticancer therapy. The accepted standard for clinical diagnosis of cardiotoxicity is defined as a >5% reduction in LVEF to 10% drop in LVEF to 200 ms) is a slowing of conduction through the AV junction (Fig. 275-1). The site of delay is typically in the AV node but may be in the atria, bundle of His, or His-Purkinje system. A wide QRS is suggestive of delay in the distal conduction system, whereas a narrow QRS suggests delay in the AV node proper or, less commonly, in the bundle of His. In second-degree AV block there is an intermittent failure of electrical impulse conduction from atrium to ventricle. Second-degree AV block is subclassified as Mobitz type I (Wenckebach) or Mobitz type II. The periodic failure of conduction in Mobitz type I block is characterized by a progressively lengthening PR interval, shortening of the RR interval, and a pause that is less than two times the immediately preceding RR interval on the electrocardiogram (ECG). The ECG complex after the pause exhibits a shorter PR interval than that immediately preceding the pause (Fig. 275-2). This ECG pattern most often arises because of decremental conduction of electrical impulses in the AV node.
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Figure 275-2 Mobitz type I second-degree AV block. The PR interval prolongs before the pause, as shown in the ladder diagram. The ECG pattern results from slowing of conduction in the AV node.
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It is important to distinguish type I from type II second-degree AV nodal block because the latter has more serious prognostic implications. Type II second-degree AV block is characterized by intermittent failure of conduction of the P wave without changes in the preceding PR or RR intervals. When AV block is 2:1, it may be difficult to distinguish type I from type II block. Type II second-degree AV block typically occurs in the distal or infra-His conduction system, is often associated with intraventricular conduction delays (e.g., bundle branch block), and is more likely to proceed to higher grades of AV block than is type I second-degree AV block. Second-degree AV block (particularly type II) may be associated with a series of nonconducted P waves, referred to as paroxysmal AV block (Fig. 275-3), and implies significant conduction system disease and is an indication for permanent pacing. Complete failure of conduction from atrium to ventricle is referred to as complete or third-degree AV block. AV block that is intermediate between second degree and third degree is referred to as high-grade AV block and, as with CHB, implies advanced AV conduction system disease. In both cases, the block is most often distal to the AV node, and the duration of the QRS complex can be helpful in determining the level of the block. In the absence of a preexisting bundle branch block, a wide QRS escape rhythm (Fig. 275-4B) implies a block in the distal His or bundle branches; in contrast, a narrow QRS rhythm implies a block in the AV node or proximal His and an escape rhythm originating in the AV junction (Fig. 275-4A). Narrow QRS escape rhythms are typically faster and more stable than wide QRS escape rhythms and originate more proximally in the AV conduction system.
patients, since the prognosis and therapy depend on whether the block is in or below the AV node. Vagal maneuvers, carotid sinus massage, exercise, and administration of drugs such as atropine and isoproterenol may be diagnostically informative. Owing to the differences in the innervation of the AV node and infranodal conduction system, vagal stimulation and carotid sinus massage slow conduction in the AV node but have less of an effect on infranodal tissue and may even improve conduction due to a reduced rate of activation of distal tissues. Conversely, atropine, isoproterenol, and exercise improve conduction through the AV node and impair infranodal conduction. In patients with congenital CHB and a narrow QRS complex, exercise typically increases heart rate; by contrast, those with acquired CHB, particularly with wide QRS, do not respond to exercise with an increase in heart rate. Additional diagnostic evaluation, including electrophysiologic testing, may be indicated in patients with syncope and suspected highgrade AV block. This is particularly relevant if noninvasive testing does not reveal the cause of syncope or if the patient has structural heart disease with ventricular tachyarrhythmias as a cause of symptoms. Electrophysiologic testing provides more precise information regarding the location of AV conduction block and permits studies of AV conduction under conditions of pharmacologic stress and exercise. Recording of the His bundle electrogram by a catheter positioned at the superior margin of the tricuspid valve annulus provides information about conduction at all levels of the AV conduction axis. A properly recorded His bundle electrogram reveals local atrial activity, the His electrogram, and local ventricular activation; when it is monitored simultaneously with recorded body surface electrocardiographic traces, intraatrial, AV nodal, and infranodal conduction times can be assessed (Fig. 275-1). The time from the most rapid deflection of the
DIAGNOSTIC TESTING Diagnostic testing in the evaluation of AV block is aimed at determining the level of conduction block, particularly in asymptomatic
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The Bradyarrhythmias: Disorders of the Atrioventricular Node
Figure 275-3 Paroxysmal AV block. Multiple nonconducted P waves after a period of sinus bradycardia with a normal PR interval. This implies significant conduction system disease, requiring permanent pacemaker implantation.
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Figure 275-4 High-grade AV block. A. Multiple nonconducted P waves with a regular narrow complex QRS escape rhythm probably emanating from the AV junction. B. A wide complex QRS escape and a single premature ventricular contraction. In both cases, there is no consistent temporal relationship between the P waves and QRS complexes.
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Figure 275-5 High-grade AV block below the His. The AH interval is normal and is not changing before the block. Atrial and His bundle electrograms are recorded consistent with block below the distal AV junction. I, II, III, and V1 are surface ECG leads. HISp, HISd, and RVA are the proximal HIS, distal HIS, and right ventricular apical electrical recordings, respectively. A, H, and V represent the atrial, His, and ventricular electrograms on the His bundle recording, respectively. (Tracing courtesy of Dr. Joseph Marine; with permission.)
atrial electrogram in the His bundle recording to the His electrogram (AH interval) represents conduction through the AV node and is normally 500 ms (100 ms, the annual incidence of complete AV block approaches 10%, indicating a need for pacing. In patients with acquired CHB, even if intermittent, there is little role for electrophysiologic testing, and pacemaker implantation is almost always indicated. TREATMENT
Management of AV Conduction Block
Temporary or permanent artificial pacing is the most reliable treatment for patients with symptomatic AV conduction system disease. However, exclusion of reversible causes of AV block and the need for temporary heart rate support based on the hemodynamic condition of the patient are essential considerations in each patient. Correction of electrolyte derangements and ischemia, inhibition of excessive vagal tone, and withholding of drugs with AV nodal blocking properties may increase the heart rate. Adjunctive pharmacologic treatment with atropine or isoproterenol may be useful if the block is in the AV node. Since most pharmacologic treatment may take some time to initiate and become effective, temporary pacing may be necessary. The most expeditious technique is the use of transcutaneous pacing, where pacing patches are placed anteriorly over the cardiac apex (cathode) and posteriorly between the spine and the scapula or above the right nipple (anode). Acutely, transcutaneous pacing is highly effective, but its duration is limited by patient discomfort and longer-term failure to capture the ventricle owing to changes in lead impedance. If a patient requires more
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TABLE 275-2 Guideline Summary for Pacemaker Implantation in Acquired AV Block
than a few minutes of pacemaker support, transvenous temporary pacing should be instituted. Temporary pacing leads can be placed from the jugular or subclavian venous system and advanced to the right ventricle, permitting stable temporary pacing for many days, if necessary. In most circumstances, in the absence of prompt resolution, conduction block distal to the AV node requires permanent pacemaking. Pacemakers in AV Conduction Disease There are no randomized trials that evaluate the efficacy of pacing in patients with AV block, as there are no reliable therapeutic alternatives for AV block and untreated high-grade AV block is potentially lethal. The consensus guidelines for pacing in acquired AV conduction block in adults provide a general outline for situations in which pacing is indicated (Table 275-2). Pacemaker implantation should be performed in any patient with symptomatic bradycardia and irreversible second-or third-degree AV block, regardless of the cause or level of block in the conducting system. Symptoms may include those directly related to bradycardia and low cardiac output or to worsening heart failure, angina, or intolerance to an essential medication. Pacing in patients with asymptomatic AV block should be individualized; situations in which pacing should be considered are patients with acquired CHB, particularly in the setting of cardiac enlargement; left ventricular dysfunction; and waking heart rates ≤40 beats/min. Patients who have asymptomatic second-degree AV block of either type should be considered for pacing if the block is demonstrated to be intra- or infra-His or is associated with a wide QRS complex. Pacing may be indicated in asymptomatic patients in special circumstances, in patients with profound first-degree AV block and left ventricular dysfunction in whom a shorter AV interval produces hemodynamic improvement, and in the setting of milder forms of AV conduction delay (first-degree AV block, intraventricular conduction delay) in patients with neuromuscular diseases that have
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a predilection for the conduction system, such as myotonic dystrophy and other muscular dystrophies, and Kearns-Sayre syndrome. Pacemaker Therapy in Myocardial Infarction AV block in acute MI is often transient, particularly in inferior infarction. The circumstances in which pacing is indicated in acute MI are persistent second-or third-degree AV block, particularly if symptomatic, and transient second-or third-degree AV block associated with bundle branch block (Table 275-3). Pacing is generally not indicated in the setting of transient AV block in the absence of intraventricular conduction delays or in the presence of fascicular block
The Bradyarrhythmias: Disorders of the Atrioventricular Node
Source: Modified from AE Epstein et al: J Am Coll Cardiol 51:e1, 2008.
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Class I 1. Third-degree or high-grade AV block at any anatomic level associated with: a. Symptomatic bradycardia b. Essential drug therapy that produces symptomatic bradycardia c. Periods of asystole >3 s or any escape rate 5 s Class IIa 1. Asymptomatic third-degree AV block regardless of level 2. Asymptomatic type II second-degree AV block with a narrow QRS complex 3. Asymptomatic type II second-degree AV block with block within or below the His at electrophysiologic study 4. First- or second-degree AV block with symptoms similar to pacemaker syndrome Class IIb 1. AV block in the setting of drug use/toxicity, when the block is expected to recur even with drug discontinuation 2. Neuromuscular diseases such as myotonic dystrophy, Kearns-Sayre syndrome, Erb dystrophy, and peroneal muscular atrophy with any degree of AV block regardless of the presence of symptoms Class III 1. Asymptomatic first-degree AV block 2. Asymptomatic type I second-degree AV block at the AV node level 3. AV block that is expected to resolve or is unlikely to recur (Lyme disease, drug toxicity)
TABLE 275-3 Guideline Summary for Pacemaker Implantation in AV Conduction Block in Acute Myocardial Infarction (AMI) Class I 1. Persistent second-degree AV block in the His-Purkinje system with bilateral bundle branch block or third-degree block within or below the His after AMI 2. Transient advanced (second-or third-degree) infranodal AV block and associated bundle branch block. If the site of block is uncertain, an electrophysiologic study may be necessary 3. Persistent and symptomatic second-or third-degree AV block Class IIb 1. Persistent second- or third-degree AV block at the AV node level Class III 1. Transient AV block in the absence of intraventricular conduction defects 2. Transient AV block in the presence of isolated left anterior fascicular block 3. Acquired left anterior fascicular block in the absence of AV block 4. Persistent first-degree AV block in the presence of bundle branch block that is old or age-indeterminate Source: Modified from AE Epstein et al: J Am Coll Cardiol 51:e1, 2008.
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PART 10 Disorders of the Cardiovascular System
Class I 1. Intermittent third-degree AV block 2. Type II second-degree AV block 3. Alternating bundle branch block Class IIa 1. Syncope not demonstrated to be due to AV block when other likely causes (e.g., ventricular tachycardia) have been excluded 2. Incidental finding at electrophysiologic study of a markedly prolonged HV interval (>100 ms) in asymptomatic patients 3. Incidental finding at electrophysiologic study of pacing-induced infra-His block that is not physiologic Class IIb 1. Neuromuscular diseases such as myotonic dystrophy, Kearns-Sayre syndrome, Erb dystrophy, and peroneal muscular atrophy with any degree of fascicular block regardless of the presence of symptoms, because there may be unpredictable progression of AV conduction disease Class III 1. Fascicular block without AV block or symptoms 2. Fascicular block with first-degree AV block without symptoms Source: Modified from AE Epstein et al: J Am Coll Cardiol 51:e1, 2008.
or first-degree AV block that develops in the setting of preexisting bundle branch block. Fascicular blocks that develop in acute MI in the absence of other forms of AV block also do not require pacing (Table 275-3 and Table 275-4). Pacemaker Therapy in Bifascicular and Trifascicular Block Distal forms of AV conduction block may require pacemaker implantation in certain clinical settings. Patients with bifascicular or trifascicular block and symptoms, particularly syncope that is not attributable to other causes, should undergo pacemaker implantation. Pacemaking is indicated in asymptomatic patients with bifascicular or trifascicular block who experience intermittent thirddegree, type II second-degree AV block or alternating bundle branch block. In patients with fascicular block who are undergoing electrophysiologic study, a markedly prolonged HV interval or block below the His at long cycle lengths also may constitute an indication for permanent pacing. Patients with fascicular block and the neuromuscular diseases previously described should also undergo pacemaker implantation (Table 275-4). Selection of Pacing Mode In general, a pacing mode that maintains AV synchrony reduces complications of pacing such as pacemaker syndrome and pacemaker-mediated tachycardia. This is particularly true in younger patients; the importance of dual-chamber pacing in the elderly, however, is not well established. Several studies have failed to demonstrate a difference in mortality rate in older patients with AV block treated with a single-(VVI) compared with a dual-(DDD) chamber pacing mode. In some of the studies that randomized pacing mode, the risk of chronic atrial fibrillation and stroke risk decreased with physiologic pacing. In patients with sinus rhythm and AV block, the very modest increase in risk with dual-chamber pacemaker implantation appears to be justified to avoid the possible complications of single-chamber pacing.
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Supraventricular Tachyarrhythmias Gregory F. Michaud, William G. Stevenson
Supraventricular tachyarrhythmias originate from or are dependent on conduction through the atrium or atrioventricular (AV) node to the ventricles. Most produce narrow QRS-complex tachycardia (QRS duration 100 beats/min) typically occurs in response to sympathetic stimulation and vagal withdrawal, whereby the rate of spontaneous depolarization of the sinus node increases and the focus of earliest activation within the node typically shifts more leftward and closer to the superior septal aspect of the crista terminalis, thus producing taller p waves in the inferior limb leads when compared to normal sinus rhythm. Sinus tachycardia is considered physiologic when it is an appropriate response to exercise, stress, or illness. Sinus tachycardia can be difficult to distinguish from focal atrial tachycardia (see below) that originates from a focus near the sinus node. A causative factor (such as exertion) and a gradual increase and decrease in rate favors sinus tachycardia, whereas an abrupt onset and offset favor atrial tachycardia. The distinction can be difficult and occasionally requires extended ECG monitoring or even invasive electrophysiology study. Treatment for physiologic sinus tachycardia is aimed at the underlying condition (Table 276-2). Nonphysiologic Sinus Tachycardia Inappropriate sinus tachycardia is an uncommon condition in which the sinus rate increases spontaneously at rest or out of proportion to physiologic stress or exertion.
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TABLE 276-1 Supraventricular Tachycardia
Affected individuals are often women in the third or fourth decade of life. Fatigue, dizziness, and even syncope may accompany palpitations, which can be disabling. Additional symptoms of chest pain, headaches, and gastrointestinal upset are common. It must be distinguished from appropriate sinus tachycardia and from focal atrial tachycardia, as discussed above. Misdiagnosis of physiologic sinus tachycardia with an anxiety disorder is common. Therapy is often ineffective or poorly tolerated. Careful titration of beta blockers and/
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Abbreviations: AV, atrioventricular; VT, ventricular tachycardia.
Focal Atrial Tachycardia Focal atrial tachycardia (AT) can be due to abnormal automaticity, triggered automaticity, or a small reentry circuit confined to the atrium or atrial tissue extending into a pulmonary vein, the coronary sinus, or vena cava. It can be sustained, nonsustained, paroxysmal, or incessant. Focal AT accounts for approximately 10% of PSVT referred for catheter ablation. Nonsustained AT is commonly observed on 24-h ambulatory ECG recordings, and the prevalence increases with age. Tachycardia can occur in the absence of structural heart disease or can be associated with any form of heart disease that affects the atrium. Sympathetic stimulation is a promoting factor such that AT can be a sign of underlying illness. AT with AV block can occur in digitalis toxicity. Symptoms are similar to other supraventricular tachycardias (SVTs). Incessant AT can cause tachycardia-induced cardiomyopathy. AT typically presents as an SVT either with 1:1 AV conduction or with AV block that can be Wenckebach type conduction or fixed (e.g., 2:1 or 3:1) block. Because it is not dependent on AV nodal conduction, AT will not terminate with AV block, and the atrial rate will not be affected, which distinguishes AT from most AV nodal–dependent SVTs, such as AV nodal reentry and AV reentry using an accessory pathway (see below). An accelerated warm-up phase after initiation or cool-down phase prior to termination also favors AT rather than AV nodal–dependent SVT. P waves are often discrete, with an intervening isoelectric segment, in contrast to atrial flutter and macroreentrant AT (see below). When 1:1 conduction to the ventricles is present, the arrhythmia can resemble sinus tachycardia typically with a P-R interval shorter than the R-P interval (Fig. 276-2). It can be distinguished from sinus tachycardia by the p-wave morphology, which usually differs from sinus p waves depending on the location of the focus. Focal AT tends to originate in areas of complex atrial anatomy, such as the crista terminalis, valve annuli, atrial septum, and atrial muscle extending along cardiac thoracic veins (superior vena cava, coronary sinus, and pulmonary veins) (Fig. 276-3), and the location can often be estimated by the P-wave morphology. AT from the right atrium has a positive P-wave morphology in lead I and biphasic P-wave morphology in lead V1. AT from the atrial septum will frequently have a narrower P-wave duration than sinus rhythm. AT from the left atrium will usually have a monophasic, positive P wave in lead V1. AT that originates from superior atrial locations, such as the superior vena cava or superior pulmonary veins, will be positive in the inferior limb leads II, III, and aVF, whereas AT from a more inferior location, such as the ostium of the coronary sinus, will inscribe negative P waves in these same leads. When the focus is in the superior aspect of the crista terminalis, close to the sinus node, however, the p wave will resemble that of sinus tachycardia. Abrupt onset and offset then favor AT rather than sinus tachycardia. Depending on the atrial rate, the P wave may fall on top of the t wave or, during 2:1 conduction, may fall coincident with the QRS. Maneuvers that increase AV block, such as carotid sinus massage, Valsalva maneuver, or administration of AV nodal–blocking agents, such as adenosine, are useful to create AV block that will expose the p wave (Fig. 276-4).
CHAPTER 276
I. Physiologic sinus tachycardia Defining feature: normal sinus mechanism precipitated by exertion, stress, concurrent illness (Table 276-2) II. Pathologic supraventricular tachycardia A. Tachycardia originating from the atrium Defining feature: tachycardia may continue despite beats that fail to conduct to the ventricles, indicating that the AV node is not participating in the tachycardia circuit 1. Inappropriate sinus tachycardia Defining feature: tachycardia from the normal sinus node area that occurs without an identifiable precipitating factor as a result of dysfunctional autonomic regulation 2. Focal atrial tachycardia Defining feature: Regular atrial tachycardia with defined p wave; may be sustained, nonsustained, paroxysmal, or incessant. Frequent sites of origin occur along the valve annuli of left or right atrium, pulmonary veins, coronary sinus musculature, superior vena cava 3. Atrial flutter – macroreentrant atrial tachycardia Defining feature: organized reentry creates organized atrial activity, commonly seen as sawtooth flutter waves at rates typically faster than 200 beats/min a. Common atrial flutter i. Right atrial reentry parallel to the tricuspid annulus and dependent on conduction through the isthmus between the inferior vena cava and tricuspid annulus 1. Counterclockwise (as viewed from the ventricular aspect) 2. Clockwise b. Atypical atrial flutter i. Usually due to reentry in left or right atrium associated with scars usually from prior surgery or catheter ablation for atrial fibrillation, but may be idiopathic 4. Atrial fibrillation Defining feature: chaotic rapid atrial electrical activity with variable ventricular rate; the most common sustained cardiac arrhythmia in older adults 5. Multifocal atrial tachycardia Defining feature: multiple discrete p waves often seen in patients with pulmonary disease during acute exacerbations of pulmonary insufficiency B. AV nodal reentry tachycardia Defining feature: paroxsymal regular tachycardia with P waves visible at the end of the QRS complex or not visible at all; the most common paroxysmal sustained tachycardia in healthy young adults; more common in women C. Tachycardias associated with accessory atrioventricular pathways a. Orthodromic AV reentry tachycardia Defining feature: paroxysmal sustained tachycardia similar to AV nodal reentry; during sinus rhythm, evidence of ventricular preexcitation may be present (Wolff-Parkinson-White syndrome) or absent (concealed accessory pathway) b. Preexcited tachycardia Defining feature: wide QRS tachycardia with QRS morphology similar to VT 1. Antidromic AV reentry – regular paroxysmal tachycardia 2. Atrial fibrillation with preexcitation – irregular wide complex, or intermittently wide complex tachycardia, some with dangerously rapid rates faster than 250/min 3. Atrial tachycardia or flutter with preexcitation
or calcium channel blockers may reduce symptoms. Clonidine and 1477 serotonin reuptake inhibitors have also been used. Ivabradine, a drug that blocks the If current causing sinus node depolarization, is promising but is not approved for use in the United States. Catheter ablation of the sinus node has been used, but long-term control of symptoms is usually poor, and it often leaves young individuals with a permanent pacemaker. When symptomatic sinus tachycardia occurs with postural hypotension, the syndrome is called postural orthostatic tachycardia syndrome (POTS). Symptoms are often similar to those in patients with inappropriate sinus tachycardia. POTS is sometimes due to autonomic dysfunction following a viral illness and may resolve spontaneously over 3–12 months. Volume expansion with salt supplementation, oral fludrocortisone, compression stockings, and the α-agonist midodrine, often in combination, can be helpful. Exercise training has also been purported to improve symptoms.
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1478
A
B
Crista terminalis
II, III, aVF SVC Pectinate muscles
Sinus node V1
TVA
Compact AVN
PART 10
FO CS Os aVR
Eustachian ridge
Triangle of Koch
Figure 276-1 Right atrial anatomy pertinent to normal sinus rhythm and supraventricular tachycardia. A. Typical P-wave morphology during normal sinus rhythm based on standard 12-lead electrocardiogram. There is a positive P wave in leads II, III, and aVF; biphasic, initially positive P wave in V1; and negative P wave in aVR. B. Right atrial anatomy seen from a right lateral perspective with the lateral wall opened to view the septum. AVN, atrioventricular node; CS Os, coronary sinus ostium; FO, fossa ovalis; IVC, inferior vena cava; SVC, superior vena cava; TVA, tricuspid valve annulus. V1
AA
L
RS
TABLE 276-2 Common Causes of Physiologic Sinus Tachycardia
V
Left atrium
LIV
Right atrium
V
LS
A
1. Exercise 2. Acute illness with fever, infection, pain 3. Hypovolemia, anemia 4. Hyperthyroidism 5. Pulmonary insufficiency 6. Drugs that have sympathomimetic, vagolytic, or vasodilator properties, e.g., albuterol, theophylline, tricyclic antidepressants, nifedipine, hydralazine 7. Pheochromocytoma
aVL
SVC
RA
Disorders of the Cardiovascular System
IVC
Lateral left atrium
II, III, aVF
RIV
IVC
Posterior septum narrow P-wave
Figure 276-3 Location of focal atrial tachycardia focus estimated by P-wave morphology. LAA, left atrial appendage; LIV, left inferior pulmonary vein; LSV, left superior pulmonary vein; RAA, right atrial appendage; RIV, right inferior pulmonary vein; RSV, right superior pulmonary vein; SVC, superior vena cava.
A
B No P-wave visible
AVNRT
• AV node reentry
AT
RP < PR AVRT
RP< PR
• AV node reentry • AV reentry using an accessory pathway • Focal atrial tachycardia • AV reentry using an accessory pathway • AV node reentry uncommon form
Figure 276-2 Common mechanisms underlying paroxysmal supraventricular tachycardia along with typical R-P relationships. A. Schematic showing a four-chamber view of the heart with atrioventricular node in green and an accessory pathway between the left atrium and left ventricle in yellow. Atrial tachycardia (AT; red circuit) is confined completely to atrial tissue. Atrioventricular nodal reentry tachycardia (AVNRT; blue circuit) uses atrioventricular (AV) nodal and perinodal atrial tissue. Atrioventricular reentry tachycardia (AVRT; black circuit) uses atrial and ventricular tissue, accessory pathway, AV node, and specialized conduction fibers (His-Purkinje) as part of the reentry circuit. B. Typical relation of the p wave to QRS, commonly described as the R-P to P-R relationships for the different tachycardia mechanisms.
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focus is effective in more than 80% of patients and is recommended for 1479 recurrent symptomatic AT when drugs fail or are not desired or for incessant AT causing tachycardia-induced cardiomyopathy. VI A
B
Acute management of sudden-onset, sustained AT is the same as for PSVT (see below), but the response to pharmacologic therapy is variable, likely depending on the mechanism. For AT due to reentry, administration of adenosine or vagal maneuvers may transiently increase AV block without terminating tachycardia. Some ATs terminate with a sufficient dose of adenosine, consistent with triggered activity as the mechanism. Cardioversion can be effective in some, but fails in others, suggesting automaticity as the mechanism. Beta blockers and calcium channel blockers may slow the ventricular rate by increasing AV block, which can improve tolerance of the arrhythmias. Potential precipitating factors and intercurrent illness should be sought and corrected. Underlying heart disease should be considered and excluded. For patients with recurrent episodes, beta blockers, the calcium channel blockers diltiazem or verapamil, and the antiarrhythmic drugs flecainide, propafenone, disopyramide, sotalol, and amiodarone can be effective, but potential toxicities and adverse effects often warrant avoiding these agents (Tables 276-3, 276-4, and 276-5). Catheter ablation targeting the AT
Supraventricular Tachyarrhythmias
Figure 276-4 Atrial tachycardia (AT) with 1:1 and 2:1 atrioventricular (AV) conduction. Arrows indicate p waves. A. AT with 1:1 AV relationship and R-P > P-R. B. Same AT with 2:1 AV relationship after AV nodal–blocking agent administered. (Adapted from F Marchlinski: The tachyarrhythmias. In Longo DL et al [eds]: Harrison’s Principles of Internal Medicine, 18th ed. New York, McGraw-Hill, 2012, pp 1878–1900.)
CHAPTER 276
VI
Atrioventricular Nodal Reentry Tachycardia AV nodal reentry tachycardia (AVNRT) is the most common form of PSVT, representing approximately 60% of cases referred for catheter ablation. It most commonly manifests in the second to fourth decades of life, often in women. It is often well tolerated, but rapid tachycardia, particularly in the elderly, may cause angina, pulmonary edema, hypotension, or syncope. It is not usually associated with structural heart disease. The mechanism is reentry involving the AV node and likely the perinodal atrium, made possible by the existence of multiple pathways for conduction from the atrium into the AV node (Fig. 276-5). In the most common form, a slowly conducting AV nodal pathway extends from the compact AV node near the bundle of His, inferiorly along the tricuspid annulus, adjacent to the coronary sinus os. The reentry wavefront propagates up this slow pathway to the compact AV node and then exits from the fast pathway at the top of the AV node. The path back to the slow pathway to complete the circuit is not defined. The conduction time from the compact AV node region to the atrium is similar to that from the compact node to the His bundle and ventricles, such that atrial activation occurs at about the same time as ventricular activation. The p wave is therefore inscribed during, slightly before, or slightly after the QRS and can be difficult to discern. Often the P wave is seen at the end of the QRS complex as a pseudo-r′ in lead V1 and pseudo-S waves in leads II, III, and aVF (Fig. 276-5A). The rate can vary with sympathetic tone. Simultaneous atrial and ventricular contraction results in atrial contraction against a closed tricuspid valve that produces cannon a waves visible in the jugular venous pulse and that the patient often perceives as a fluttering sensation in the neck. Elevated venous pressures may also lead to release of natriuretic peptides that cause posttachycardia diuresis. Less frequently, the AV nodal reentry circuit revolves in the opposite direction and gives rise to a tachycardia with an R-P interval longer than the P-R interval, similar to AT. The p wave will have the morphology noted above, and in contrast to ATs, maneuvers or medications that produce AV block terminate the arrhythmia. Acute treatment is the same as for PSVT (discussed below). Whether ongoing therapy is warranted depends on the severity of symptoms and frequency of episodes. Reassurance and instruction as to performance of the Valsalva maneuver to terminate episodes are sufficient for many patients. Administration of an oral beta blocker, verapamil, or diltiazem at the onset of an episode has been used to
TABLE 276-3 Commonly Used Antiarrhythmic Agents—Intravenous Dose Range/Primary Indication Drug Adenosine
Loading 6–18 mg (rapid bolus)
Maintenance N/A
Amiodarone
15 mg/min for 10 min, 1 mg/ min for 6 h 0.25 mg q2h until 1 mg total 0.25 mg/kg over 3–5 min (max 20 mg) 500 μg/kg over 1 min 1 mg over 10 min if over 60 kg 1–3 mg/kg at 20–50 mg/min 5 mg over 3–5 min × 3 doses
Digoxin Diltiazem Esmolol Ibutilide Lidocaine Metoprolol Procainamide Quinidine Verapamil
15 mg/kg over 60 min 6–10 mg/kg at 0.3–0.5 mg/kg per min 5–10 mg over 3–5 min
Classa —
0.5–1 mg/min
Primary Indication Terminate reentrant SVT involving AV node AF, AFL, SVT, VT/VF
0.125–0.25 mg/d 5–15 mg/h
AF/AFL rate control SVT, AF/AFL rate control
— IV
50 μg/kg per min N/A 1–4 mg/min 1.25–5 mg q6h
II III IB II
1–4 mg/min N/A
AF/AFL rate control Terminate AF/AFL VT SVT, AF rate control; exerciseinduced VT; long QT Convert/prevent AF/VT Convert/prevent AF/VT
2.5–10 mg/h
SVT, AF rate control
IV
III
IA IA
Classification of antiarrhythmic drugs: class I—agents that primarily block inward sodium current; class IA agents also prolong action potential duration; class II—antisympathetic agents; class III—agents that primarily prolong action potential duration; class IV—calcium channel–blocking agents.
a
Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; SVT, supraventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia.
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1480 TABLE 276-4 Commonly Used Antiarrhythmic Agents: Chronic Oral Dosing/Primary Indications
PART 10 Disorders of the Cardiovascular System
Drug Acebutolol
Dosing Oral, mg, Maintenance 200–400 q12h
Half-Life, h 6–7
Primary Route(s) of Metabolism/ Elimination Renal/hepatic
Amiodarone Atenolol
100–400 qd 25–100 per d
40–55 d 6–9
Hepatic Renal
Digoxin Diltiazem Disopyramide Dofetilide Dronedarone Flecainide Metoprolol
0.125–0.25 qd 30–60 q6h 100–300 q6–8h 0.125–0.5 q12h 400 q12h 50–200 q12h 25–100 q6h
38–48 3–4.5 4–10 10 13–19 7–22 3–8
Renal Hepatic Renal 50%/hepatic Renal Hepatic Hepatic 75%/renal Hepatic
Mexiletine Nadolol Propafenone Quinidine Sotalol Verapamil
150–300 q8–12h 40–240 per d 150–300 q8h 300–600 q6h 80–160 q12h 80–120 q6–8h
10–14 10–24 2–8 6–8 12 4.5–12
Hepatic Renal Hepatic Hepatic 75%/renal Renal Hepatic/renal
Most Common Indication AF rate control/SVT Long QT/RVOT VT AF/VT prevention AF rate control/SVT Long QT/RVOT VT AF rate control AF rate control/SVT AF/SVT prevention AF prevention AF prevention AF/SVT/VT prevention AF rate control/SVT Long QT/RVOT VT VT prevention Same as metoprolol AF/SVT/VT prevention AF/SVT/VT prevention AF/VT prevention AF rate control/RVOT VT Idiopathic LV VT
Classa II IIIb II — IV Ia III IIIb Ic II Ib II Ic Ia III IV
Classification of antiarrhythmic drugs: class I—agents that primarily block inward sodium current; class II—antisympathetic agents; class III—agents that primarily prolong action potential duration; class IV—calcium channel-blocking agents. bAmiodarone and dronedarone both are grouped in class III, but both also have class I, II, and IV properties.
a
Abbreviations: AF, atrial fibrillation; LV, left ventricular; RVOT, right ventricular outflow tract; SVT, supraventricular tachycardia; VT, ventricular tachycardia.
facilitate termination. Chronic therapy with these medications or flecainide is an option if prophylactic therapy is needed. Catheter ablation of the slow AV nodal pathway is recommended for patients with recurrent or severe episodes or when drug therapy is ineffective, not tolerated, or not desired by the patient. Catheter ablation is curative in over 95% of patients. The major risk is heart block requiring permanent pacemaker implantation, which occurs in less than 1% of patients. Junctional Tachycardia Junctional ectopic tachycardia (JET) is due to automaticity within the AV node. It is rare in adults and more
frequently encountered as an incessant tachycardia in children, often in the perioperative period of surgery for congenital heart disease. It presents as a narrow QRS tachycardia, often with ventriculoatrial (VA) block, such that AV dissociation is present. JET can occur as a manifestation of increased adrenergic tone and may be seen after administration of isoproterenol. It may also occur for a short period of time after ablation for AVNRT. Accelerated junctional rhythm is a junctional automatic rhythm between 50 and 100 beats/min. Initiation may occur with gradual acceleration in rate, suggesting an automatic focus, or after a premature
TABLE 276-5 Common and Proarrhythmic Toxicities of Antiarrhythmic Agents Drug Amiodarone Adenosine Digoxin Disopyramide Dofetilide Dronedarone Flecainide Ibutilide Lidocaine Mexiletine Procainamide Propafenone Quinidine Sotalol
Potential Proarrhythmic Toxicities Sinus bradycardia, AV block, increase in defibrillation threshold. Rare: long QT and torsades des pointes, incessant slow VT in heart disease Transient profound pauses, atrial fibrillation AV block, fascicular tachycardia, accelerated junctional rhythm, atrial tachycardia with AV block Long QT and torsades des pointes, 1:1 ventricular response to atrial flutter Long QT and torsades des pointes Bradyarrhythmias and AV block, long QT and torsades des pointes (rare) 1:1 Ventricular response to atrial flutter; increased risk of ventricular tachycardias in patients with structural heart disease; sinus bradycardia Long QT and torsades des pointes Slow VT in some patients with structural heart disease Slow VT in patients with structural heart disease Long QT and torsades des pointes, accelerated ventricular rate in AF or flutter 1:1 Ventricular response to atrial flutter; increased risk ventricular tachycardias in patients with structural heart disease; sinus bradycardia Long QT and torsades des pointes, accelerated ventricular rate in AF or flutter Long QT and torsades des pointes
Common Toxicities Tremor, peripheral neuropathy, pulmonary fibrosis or inflammation, hypo- and hyperthyroidism, hepatitis, photosensitivity Cough, flushing, chest pain, anxiety Anorexia, nausea, vomiting, visual changes Anticholinergic effects, acute urinary retention (males), negative inotropy Nausea Gastrointestinal intolerance, exacerbation of heart failure Dizziness, nausea, headache, decreased myocardial contractility Nausea Dizziness, confusion, delirium, seizures, coma Ataxia, tremor, gait disturbances, rash, nausea Lupus erythematosus–like syndrome (more common in slow acetylators), anorexia, nausea, neutropenia Taste disturbance, dyspepsia, nausea, vomiting Diarrhea, nausea, vomiting, cinchonism, thrombocytopenia Hypotension, bronchospasm from β-blocking effect
Abbreviations: AF, atrial fibrillation; AV, atrioventricular; VT, ventricular tachycardia.
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A
1481
B II
Inferior AV node extension: Slow pathway
P-waves V1
Tricuspid valve
Figure 276-5 Atrioventricular (AV) node reentry. A. Leads II and V1 are shown. P waves are visible at the end of the QRS complex and are negative in lead II, and may give the impression of S waves in the inferior limb leads II, III, and aVF and an R’ in lead V1. B. Stylized version of the AV nodal reentry circuit within the triangle of Koch (Fig. 276-1) that involves AV node and its extensions along with perinodal atrial tissue.
ventricular contraction, suggesting a focus of triggered automaticity. VA conduction is usually present, with p-wave morphology and timing such that it resembles slow AVNRT. ACCESSORY PATHWAYS AND THE WOLFF-PARKINSON-WHITE SYNDROME Accessory pathways (APs) occur in 1 in 1500–2000 people and are associated with a variety of arrhythmias including narrow-complex PSVT, wide-complex tachycardias, and, rarely, sudden death. Most patients have structurally normal hearts, but APs are associated with Ebstein’s anomaly of the tricuspid valve and forms of hypertrophic cardiomyopathy including PRKAG2 mutations, Danon’s disease, and Fabry’s disease. APs are abnormal connections that allow conduction between the atrium and ventricles across the AV ring (Fig. 276-6). They are present from birth and are due to failure of complete partitioning of atrium and ventricle by the fibrous AV rings. They occur across either an AV valve annulus or the septum, most frequently between the left atrium and free wall of the left ventricle, followed by posteroseptal, right free wall, and anteroseptal locations. If the AP conducts from atrium to ventricle (antegrade) with a shorter conduction time than the AV node and His bundle, then the ventricles are preexcited during sinus rhythm, and the ECG shows a short P-R interval (1000 IU/L—occur almost exclusively in disorders associated with extensive hepatocellular injury such as (1) viral hepatitis, (2) ischemic liver injury (prolonged hypotension or acute heart failure), or (3) toxin- or drug-induced liver injury. The pattern of the aminotransferase elevation can be helpful diagnostically. In most acute hepatocellular disorders, the ALT is higher than or equal to the AST. Whereas the AST:ALT ratio is typically 1. An AST:ALT ratio >2:1 is suggestive, whereas a ratio >3:1 is highly suggestive, of alcoholic liver disease. The AST in alcoholic liver disease is rarely >300 IU/L, and the ALT is often normal. A low level of ALT in the serum is due to an alcohol-induced deficiency of pyridoxal phosphate. The aminotransferases are usually not greatly elevated in obstructive jaundice. One notable exception occurs during the acute phase of biliary obstruction caused by the passage of a gallstone into the common bile duct. In this setting, the aminotransferases can briefly be in the 1000– 2000 IU/L range. However, aminotransferase levels decrease quickly, and the liver function tests rapidly evolve into those typical of cholestasis.
5ʹ-nucleotidase are found in or near the bile canalicular membrane of 1997 hepatocytes, whereas GGT is located in the endoplasmic reticulum and in bile duct epithelial cells. Reflecting its more diffuse localization in the liver, GGT elevation in serum is less specific for cholestasis than are elevations of alkaline phosphatase or 5ʹ-nucleotidase. Some have advocated the use of GGT to identify patients with occult alcohol use. Its lack of specificity makes its use in this setting questionable. The normal serum alkaline phosphatase consists of many distinct isoenzymes found in the liver; bone; placenta; and, less commonly, small intestine. Patients over age 60 can have a mildly elevated alkaline phosphatase (1–1.5 times normal), whereas individuals with blood types O and B can have an elevation of the serum alkaline phosphatase after eating a fatty meal due to the influx of intestinal alkaline phosphatase into the blood. It is also nonpathologically elevated in children and adolescents undergoing rapid bone growth because of bone alkaline phosphatase, and late in normal pregnancies due to the influx of placental alkaline phosphatase. Elevation of liver-derived alkaline phosphatase is not totally specific for cholestasis, and a less than threefold elevation can be seen in almost any type of liver disease. Alkaline phosphatase elevations greater than four times normal occur primarily in patients with cholestatic liver disorders, infiltrative liver diseases such as cancer and amyloidosis, and bone conditions characterized by rapid bone turnover (e.g., Paget’s disease). In bone diseases, the elevation is due to increased amounts of the bone isoenzymes. In liver diseases, the elevation is almost always due to increased amounts of the liver isoenzyme. If an elevated serum alkaline phosphatase is the only abnormal finding in an apparently healthy person, or if the degree of elevation is higher than expected in the clinical setting, identification of the source of elevated isoenzymes is helpful (Fig. 358-1). This problem can be approached in two ways. First, and most precise, is the fractionation of the alkaline phosphatase by electrophoresis. The second, best substantiated, and most available approach involves the measurement of serum 5′-nucleotidase or GGT. These enzymes are rarely elevated in conditions other than liver disease. In the absence of jaundice or elevated aminotransferases, an elevated alkaline phosphatase of liver origin often, but not always, suggests early cholestasis and, less often, hepatic infiltration by tumor or granulomata. Other conditions that cause isolated elevations of the alkaline phosphatase include Hodgkin’s disease, diabetes, hyperthyroidism, congestive heart failure, amyloidosis, and inflammatory bowel disease. The level of serum alkaline phosphatase elevation is not helpful in distinguishing between intrahepatic and extrahepatic cholestasis. There is essentially no difference among the values found in obstructive jaundice due to cancer, common duct stone, sclerosing cholangitis, or bile duct stricture. Values are similarly increased in patients with intrahepatic cholestasis due to drug-induced hepatitis; primary biliary cirrhosis; rejection of transplanted livers; and, rarely, alcohol-induced steatohepatitis. Values are also greatly elevated in hepatobiliary disorders seen in patients with AIDS (e.g., AIDS cholangiopathy due to cytomegalovirus or cryptosporidial infection and tuberculosis with hepatic involvement).
CHAPTER 358
Serum Enzymes The liver contains thousands of enzymes, some of which are also present in the serum in very low concentrations. These enzymes have no known function in the serum and behave like other serum proteins. They are distributed in the plasma and in interstitial fluid and have characteristic half-lives, which are usually measured in days. Very little is known about the catabolism of serum enzymes, although they are probably cleared by cells in the reticuloendothelial system. The elevation of a given enzyme activity in the serum is thought to primarily reflect its increased rate of entrance into serum from damaged liver cells. Serum enzyme tests can be grouped into three categories: (1) enzymes whose elevation in serum reflects damage to hepatocytes, (2) enzymes whose elevation in serum reflects cholestasis, and (3) enzyme tests that do not fit precisely into either pattern.
TESTS THAT MEASURE BIOSYNTHETIC FUNCTION OF THE LIVER Serum Albumin Serum albumin is synthesized exclusively by hepatocytes. Serum albumin has a long half-life: 18–20 days, with ~4% degraded per day. Because of this slow turnover, the serum albumin is not a good indicator of acute or mild hepatic dysfunction; only minimal changes in the serum albumin are seen in acute liver conditions such as viral hepatitis, drug-related hepatotoxicity, and obstructive jaundice. In hepatitis, albumin levels 100% should alert the clinician to this possibility. Increases in the IgM levels are common in primary biliary cirrhosis, whereas increases in the IgA levels occur in alcoholic liver disease. COAGULATION FACTORS With the exception of factor VIII, which is produced by vascular endothelial cells, the blood clotting factors are made exclusively in hepatocytes. Their serum half-lives are much shorter than albumin, ranging from 6 h for factor VII to 5 days for fibrinogen. Because of their rapid turnover, measurement of the clotting factors is the single best acute measure of hepatic synthetic function and helpful in both diagnosis and assessing the prognosis of acute parenchymal liver disease. Useful for this purpose is the serum prothrombin time, which collectively measures factors II, V, VII, and X. Biosynthesis of factors II, VII, IX, and X depends on vitamin K. The international normalized ratio (INR) is used to express the degree of anticoagulation on warfarin therapy. The INR standardizes prothrombin time measurement according to the
characteristics of the thromboplastin reagent used in a particular lab, which is expressed as an International Sensitivity Index (ISI); the ISI is then used in calculating the INR. The prothrombin time may be elevated in hepatitis and cirrhosis as well as in disorders that lead to vitamin K deficiency such as obstructive jaundice or fat malabsorption of any kind. Marked prolongation of the prothrombin time, >5 s above control and not corrected by parenteral vitamin K administration, is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases. The INR, along with the total serum bilirubin and creatinine, are components of the MELD score, which is used as a measure of hepatic decompensation and to allocate organs for liver transplantation. OTHER DIAGNOSTIC TESTS Although tests may direct the physician to a category of liver disease, additional radiologic testing and procedures are often necessary to make the proper diagnosis, as shown in Fig. 358-1. The most commonly used ancillary tests are reviewed here, as are the noninvasive tests available for assessing hepatic fibrosis. Percutaneous Liver Biopsy Percutaneous biopsy of the liver is a safe procedure that can be easily performed at the bedside with local anesthesia and ultrasound guidance. Liver biopsy is of proven value in the following situations: (1) hepatocellular disease of uncertain cause, (2) prolonged hepatitis with the possibility of autoimmune hepatitis, (3) unexplained hepatomegaly, (4) unexplained splenomegaly, (5) hepatic filling defects by radiologic imaging, (6) fever of unknown origin, (7) and staging of malignant lymphoma. Liver biopsy is most accurate in disorders causing diffuse changes throughout the liver and is subject to sampling error in focal infiltrative disorders such as hepatic metastases. Liver biopsy should not be the initial procedure in the diagnosis of cholestasis. The biliary tree should first be assessed for signs of obstruction. Contraindications to performing a percutaneous liver biopsy include significant ascites and prolonged INR. Under these circumstances, the biopsy can be performed via the transjugular approach.
Table 358-1 Liver Test Patterns in Hepatobiliary Disorders Type of Disorder Hemolysis/Gilbert’s syndrome
Acute hepatocellular necrosis (viral and drug hepatitis, hepatotoxins, acute heart failure) Chronic hepatocellular disorders Alcoholic hepatitis, cirrhosis Intra- and extrahepatic cholestasis (Obstructive jaundice) Infiltrative diseases (tumor, granulomata); partial bile duct obstruction
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Bilirubin Normal to 86 μmol/L (5 mg/dL) 85% due to indirect fractions No bilirubinuria Both fractions may be elevated Peak usually follows aminotransferases Bilirubinuria Both fractions may be elevated Bilirubinuria Both fractions may be elevated Bilirubinuria Both fractions may be elevated
Aminotransferases Normal
Alkaline Phosphatase Normal
Albumin Normal
Prothrombin Time Normal
Elevated, often >500 IU, ALT > AST
Normal to 5× above control and not corrected by parenteral vitamin K, suggests poor prognosis
Elevated, but usually 500 IU Normal to slight elevation
Often prolonged Fails to correct with parenteral vitamin K Often prolonged Fails to correct with parenteral vitamin K Normal If prolonged, will correct with parenteral vitamin K Normal
Normal Elevated, often >4× normal elevation Fractionate, or confirm liver origin with 5’nucleotidase or γ glutamyl transpeptidase
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Ultrasonography Ultrasonography is the first diagnostic test to use in patients whose liver tests suggest cholestasis, to look for the presence of a dilated intrahepatic or extrahepatic biliary tree or to identify gallstones. In addition, it shows space-occupying lesions within the liver, enables the clinician to distinguish between cystic and solid masses, and helps direct percutaneous biopsies. Ultrasound with Doppler imaging can detect the patency of the portal vein, hepatic artery, and hepatic veins and determine the direction of blood flow. This is the first test ordered in patients suspected of having Budd-Chiari syndrome. USE OF LIVER TESTS As previously noted, the best way to increase the sensitivity and specificity of laboratory tests in the detection of liver disease is to employ a battery of tests that includes the aminotransferases, alkaline phosphatase, bilirubin, albumin, and prothrombin time along with the judicious use of the other tests described in this chapter. Table 358-1 shows how patterns of liver tests can lead the clinician to a category of disease that will direct further evaluation. However, it is important to remember that no single set of liver tests will necessarily provide a diagnosis. It is often necessary to repeat these tests on several occasions over days to weeks for a diagnostic pattern to emerge. Figure 358-1 is an algorithm for the evaluation of chronically abnormal liver tests. GLOBAL CONSIDERATIONS The tests and principles presented in this chapter are applicable worldwide. The causes of liver test abnormalities vary according to region. In developing nations, infectious diseases are more commonly the etiology of abnormal serum liver tests than in developed nations. Acknowledgment This chapter represents a revised version of a chapter in previous editions of Harrison’s in which Marshall M. Kaplan was a co-author.
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359
1999
The Hyperbilirubinemias Allan W. Wolkoff
BILIRUBIN METABOLISM The details of bilirubin metabolism are presented in Chap. 58. However, the hyperbilirubinemias are best understood in terms of perturbations of specific aspects of bilirubin metabolism and transport, and these will be briefly reviewed here as depicted in Fig. 359-1. Bilirubin is the end product of heme degradation. Some 70–90% of bilirubin is derived from degradation of the hemoglobin of senescent red blood cells. Bilirubin produced in the periphery is transported to the liver within the plasma, where, due to its insolubility in aqueous solutions, it is tightly bound to albumin. Under normal circumstances, bilirubin is removed from the circulation rapidly and efficiently by hepatocytes. Transfer of bilirubin from blood to bile involves four distinct but interrelated steps (Fig. 359-1). 1. Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has carrier-mediated kinetics. Although a number of candidate bilirubin transporters have been proposed, the actual transporter remains elusive. 2. Intracellular binding: Within the hepatocyte, bilirubin is kept in solution by binding as a nonsubstrate ligand to several of the glutathione-S-transferases, formerly called ligandins. 3. Conjugation: Bilirubin is conjugated with one or two glucuronic acid moieties by a specific UDP-glucuronosyltransferase to form bilirubin mono- and diglucuronide, respectively. Conjugation disrupts the internal hydrogen bonding that limits aqueous solubility of bilirubin, and the resulting glucuronide conjugates are highly soluble in water. Conjugation is obligatory for excretion of bilirubin across the bile canalicular membrane into bile. The UDP-glucuronosyltransferases have been classified into gene families based on the degree of homology among the mRNAs for the various isoforms. Those that conjugate bilirubin and certain
OATP1B1 OATP1B3
ALB
BMG BDG MRP3
UCB
UGT1A1 BMG
GST:UCB
UGT1A1 MRP2
BT ALB:UCB
Sinusoid
UCB
UCB + GST
CHAPTER 358 359 The Hyperbilirubinemias
Noninvasive Tests to Detect Hepatic Fibrosis Although liver biopsy is the standard for the assessment of hepatic fibrosis, noninvasive measures of hepatic fibrosis have been developed and show promise. These measures include multiparameter tests aimed at detecting and staging the degree of hepatic fibrosis and imaging techniques. FibroTest (marketed as FibroSure in the United States) is the best evaluated of the multiparameter blood tests. The test incorporates haptoglobin, bilirubin, GGT, apolipoprotein A-I, and α2-macroglobulin and has been found to have high positive and negative predictive values for diagnosing advanced fibrosis in patients with chronic hepatitis C, chronic hepatitis B, and alcoholic liver disease and patients taking methotrexate for psoriasis. Transient elastography (TE), marketed as FibroScan, and magnetic resonance elastography (MRE) both have gained U.S. Food and Drug Administration approval for use in the management of patients with liver disease. TE uses ultrasound waves to measure hepatic stiffness noninvasively. TE has been shown to be accurate for identifying advanced fibrosis in patients with chronic hepatitis C, primary biliary cirrhosis, hemochromatosis, nonalcoholic fatty liver disease, and recurrent chronic hepatitis after liver transplantation. MRE has been found to be superior to TE for staging liver fibrosis in patients with a variety of chronic liver diseases, but requires access to a magnetic resonance imaging scanner.
BMG BDG
BDG
Space of Disse
Figure 359-1 Hepatocellular bilirubin transport. Albumin-bound bilirubin in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both facilitated and simple diffusional processes. Within the cell, it is bound to glutathione-S-transferases and conjugated by bilirubin-UDP-glucuronosyltransferase (UGT1A1) to mono- and diglucuronides, which are actively transported across the canalicular membrane into the bile. In addition to this direct excretion of bilirubin glucuronides, a portion are transported into the portal circulation by MRP3 and subjected to reuptake into the hepatocyte by OATP1B1 and OATP1B3. ALB, albumin; BDG, bilirubin diglucuronide; BMG, bilirubin monoglucuronide; BT, proposed bilirubin transporter; GST, glutathione-S-transferase; MRP2 and MRP3, multidrug resistance–associated proteins 2 and 3; OATP1B1 and OATP1B3, organic anion transport proteins 1B1 and 1B3; UCB, unconjugated bilirubin; UGT1A1, bilirubin-UDP-glucuronosyltransferase.
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2000
5′
500 kb
3′ Common Exons
Variable (Substrate Specific) First Exons
2 3
A13 A12 A11 A10
A9
A8
A7
A6
A5
A4
A3
A2
4
5
A1
~286 AA
~245 AA
A(TA)6TAA TATA Box
PART 14 Disorders of the Gastrointestinal System
Figure 359-2 Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 contains at least 13 substrate-specific first exons (A1, A2, etc.). Since four of these are pseudogenes, nine UGT1 isoforms with differing substrate specificities are expressed. Each exon 1 has its own promoter and encodes the amino-terminal substrate-specific ∼286 amino acids of the various UGT1-encoded isoforms, and common exons 2–5 that encode the 245 carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms are assembled by splicing a particular first exon such as the bilirubin-specific exon A1 to exons 2 to 5. The resulting message encodes a complete enzyme, in this particular case bilirubin-UDP-glucuronosyltransferase (UGT1A1). Mutations in a first exon affect only a single isoform. Those in exons 2–5 affect all enzymes encoded by the UGT1 complex.
other substrates have been designated the UGT1 family. These are expressed from a single gene complex by alternative promoter usage. This gene complex contains multiple substrate-specific first exons, designated A1, A2, etc. (Fig. 359-2), each with its own promoter and each encoding the amino-terminal half of a specific isoform. In addition, there are four common exons (exons 2–5) that encode the shared carboxyl-terminal half of all of the UGT1 isoforms. The various first exons encode the specific aglycone substrate binding sites for each isoform, while the shared exons encode the binding site for the sugar donor, UDP-glucuronic acid, and the transmembrane domain. Exon A1 and the four common exons, collectively designated the UGT1A1 gene (Fig. 359-2), encode the physiologically critical enzyme bilirubin-UDPglucuronosyltransferase (UGT1A1). A functional corollary of the organization of the UGT1 gene is that a mutation in one of the first exons will affect only a single enzyme isoform. By contrast, a mutation in exons 2–5 will alter all isoforms encoded by the UGT1 gene complex. 4. Biliary excretion: It has been thought until recently that bilirubin mono- and diglucuronides are excreted directly across the canalicular plasma membrane into the bile canaliculus by an ATPdependent transport process mediated by a canalicular membrane protein called multidrug resistance–associated protein 2 (MRP2). Mutations of MRP2 result in the Dubin-Johnson syndrome (see below). However, studies in patients with Rotor syndrome (see below) indicate that after formation, a portion of the glucuronides are transported into the portal circulation by a sinusoidal membrane protein called multidrug resistance–associated protein 3 (MRP3) and subjected to reuptake into the hepatocyte by the sinusoidal membrane uptake transporters organic anion transport protein 1B1 (OATP1B1) and OATP1B3. EXTRAHEPATIC ASPECTS OF BILIRUBIN DISPOSITION Bilirubin in the Gut Following secretion into bile, conjugated bilirubin reaches the duodenum and passes down the gastrointestinal tract without reabsorption by the intestinal mucosa. An appreciable fraction is converted by bacterial metabolism in the gut to the water-soluble colorless compound urobilinogen. Urobilinogen undergoes enterohepatic cycling. Urobilinogen not taken up by the liver reaches the systemic circulation, from which some is cleared by the kidneys. Unconjugated bilirubin ordinarily does not reach the gut except in neonates or, by illdefined alternative pathways, in the presence of severe unconjugated
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hyperbilirubinemia (e.g., Crigler-Najjar syndrome, type I [CN-I]). Unconjugated bilirubin that reaches the gut is partly reabsorbed, amplifying any underlying hyperbilirubinemia. Recent reports suggest that oral administration of calcium phosphate with or without the lipase inhibitor orlistat may be an efficient means to interrupt bilirubin enterohepatic cycling to reduce serum bilirubin levels in this situation. Although orlistat administration for 4–6 weeks to 16 patients with Crigler-Najjar syndrome was associated with a 10–20% decrease in serum bilirubin in 7 patients, the cost and side effects (i.e., diarrhea) may obviate the small benefit achievable with this treatment.
Renal Excretion of Bilirubin Conjugates Unconjugated bilirubin is not excreted in urine, as it is too tightly bound to albumin for effective glomerular filtration and there is no tubular mechanism for its renal secretion. In contrast, the bilirubin conjugates are readily filtered at the glomerulus and can appear in urine in disorders characterized by increased bilirubin conjugates in the circulation.
DISORDERS OF BILIRUBIN METABOLISM LEADING TO UNCONJUGATED HYPERBILIRUBINEMIA INCREASED BILIRUBIN PRODUCTION Hemolysis Increased destruction of erythrocytes leads to increased bilirubin turnover and unconjugated hyperbilirubinemia; the hyperbilirubinemia is usually modest in the presence of normal liver function. In particular, the bone marrow is only capable of a sustained eightfold increase in erythrocyte production in response to a hemolytic stress. Therefore, hemolysis alone cannot result in a sustained hyperbilirubinemia of more than ∼68 μmol/L (4 mg/dL). Higher values imply concomitant hepatic dysfunction. When hemolysis is the only abnormality in an otherwise healthy individual, the result is a purely unconjugated hyperbilirubinemia, with the direct-reacting fraction as measured in a typical clinical laboratory being ≤15% of the total serum bilirubin. In the presence of systemic disease, which may include a degree of hepatic dysfunction, hemolysis may produce a component of conjugated hyperbilirubinemia in addition to an elevated unconjugated bilirubin concentration. Prolonged hemolysis may lead to the precipitation of bilirubin salts within the gallbladder or biliary tree, resulting in the formation of gallstones in which bilirubin, rather than cholesterol, is the major component. Such pigment stones may lead to acute or chronic cholecystitis, biliary obstruction, or any other biliary tract consequence of calculous disease. Ineffective Erythropoiesis During erythroid maturation, small amounts of hemoglobin may be lost at the time of nuclear extrusion, and a fraction of developing erythroid cells is destroyed within the marrow. These processes normally account for a small proportion of bilirubin that is produced. In various disorders, including thalassemia major, megaloblastic anemias due to folate or vitamin B12 deficiency, congenital erythropoietic porphyria, lead poisoning, and various congenital and acquired dyserythropoietic anemias, the fraction of total bilirubin production derived from ineffective erythropoiesis is increased, reaching as much as 70% of the total. This may be sufficient to produce modest degrees of unconjugated hyperbilirubinemia. Miscellaneous Degradation of the hemoglobin of extravascular collections of erythrocytes, such as those seen in massive tissue infarctions or large hematomas, may lead transiently to unconjugated hyperbilirubinemia.
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(breast milk jaundice). Alternatively, there may be increased entero- 2001 hepatic circulation of bilirubin in these infants. A recent study has correlated epidermal growth factor (EGF) content of breast milk with elevated bilirubin levels in these infants; however, a cause-and-effect relationship remains to be established. The pathogenesis of breast milk jaundice appears to differ from that of transient familial neonatal hyperbilirubinemia (Lucey-Driscoll syndrome), in which there is a UGT1A1 inhibitor in maternal serum.
Impaired Conjugation • Physiologic neonatal jaundice Bilirubin produced by the fetus is cleared by the placenta and eliminated by the maternal liver. Immediately after birth, the neonatal liver must assume responsibility for bilirubin clearance and excretion. However, many hepatic physiologic processes are incompletely developed at birth. Levels of UGT1A1 are low, and alternative excretory pathways allow passage of unconjugated bilirubin into the gut. Since the intestinal flora that convert bilirubin to urobilinogen are also undeveloped, an enterohepatic circulation of unconjugated bilirubin ensues. As a consequence, most neonates develop mild unconjugated hyperbilirubinemia between days 2 and 5 after birth. Peak levels are typically 340 μmol/L (20 mg/dL), puts the infant at risk for bilirubin encephalopathy, or kernicterus. Under these circumstances, bilirubin crosses an immature blood-brain barrier and precipitates in the basal ganglia and other areas of the brain. The consequences range from appreciable neurologic deficits to death. Treatment options include phototherapy, which converts bilirubin into water-soluble photoisomers that are excreted directly into bile, and exchange transfusion. The canalicular mechanisms responsible for bilirubin excretion are also immature at birth, and their maturation may lag behind that of UGT1A1; this can lead to transient conjugated neonatal hyperbilirubinemia, especially in infants with hemolysis.
HEREDITARY DEFECTS IN BILIRUBIN CONJUGATION Three familial disorders characterized by differing degrees of unconjugated hyperbilirubinemia have long been recognized. The defining clinical features of each are described below (Table 359-1). While these disorders have been recognized for decades to reflect differing degrees of deficiency in the ability to conjugate bilirubin, recent advances in the molecular biology of the UGT1 gene complex have elucidated their interrelationships and clarified previously puzzling features.
The Hyperbilirubinemias
Acquired conjugation defects A modest reduction in bilirubin conjugating capacity may be observed in advanced hepatitis or cirrhosis. However, in this setting, conjugation is better preserved than other aspects of bilirubin disposition, such as canalicular excretion. Various drugs, including pregnanediol, novobiocin, chloramphenicol, and gentamicin, may produce unconjugated hyperbilirubinemia by inhibiting UGT1A1 activity. Bilirubin conjugation may be inhibited by certain fatty acids that are present in breast milk but not serum of mothers whose infants have excessive neonatal hyperbilirubinemia
Crigler-Najjar Syndrome, Type I CN-I is characterized by striking unconjugated hyperbilirubinemia of about 340–765 μmol/L (20–45 mg/dL) that appears in the neonatal period and persists for life. Other conventional hepatic biochemical tests such as serum aminotransferases and alkaline phosphatase are normal, and there is no evidence of hemolysis. Hepatic histology is also essentially normal except for the occasional presence of bile plugs within canaliculi. Bilirubin glucuronides are virtually absent from the bile, and there is no detectable constitutive expression of UGT1A1 activity in hepatic tissue. Neither UGT1A1 activity nor the serum bilirubin concentration responds to administration of phenobarbital or other enzyme inducers. In the absence of conjugation, unconjugated bilirubin accumulates in plasma, from which it is eliminated very slowly by alternative pathways that include direct passage into the bile and small intestine. These account for the small amounts of urobilinogen found in feces. No bilirubin is found in the urine. First described in 1952, the disorder is rare (estimated prevalence, 0.6–1.0 per million). Many patients are from geographically or socially isolated communities in which consanguinity is common, and pedigree analyses show an autosomal recessive pattern of inheritance. The majority of patients (type IA) exhibit defects in the glucuronide conjugation of a spectrum of substrates in addition to bilirubin, including various drugs and other xenobiotics. These individuals have mutations in one of the common exons (2–5) of the UGT1 gene (Fig. 359-2). In a smaller subset (type IB), the defect is limited largely to bilirubin conjugation, and the causative mutation is in the bilirubin-specific exon A1. Estrogen glucuronidation is mediated by UGT1A1 and is defective in all CN-I patients. More than 30 different genetic lesions of UGT1A1 responsible for CN-I have been identified,
CHAPTER 359
DECREASED HEPATIC BILIRUBIN CLEARANCE Decreased Hepatic Uptake Decreased hepatic bilirubin uptake is believed to contribute to the unconjugated hyperbilirubinemia of Gilbert syndrome (GS), although the molecular basis for this finding remains unclear (see below). Several drugs, including flavaspidic acid, novobiocin, and rifampin, as well as various cholecystographic contrast agents, have been reported to inhibit bilirubin uptake. The resulting unconjugated hyperbilirubinemia resolves with cessation of the medication.
Table 359-1 Principal Differential Characteristics of Gilbert and Crigler-Najjar Syndromes Crigler-Najjar Syndrome Feature Total serum bilirubin, μmol/L (mg/dL) Routine liver tests Response to phenobarbital Kernicterus Hepatic histology
Type I 310–755 (usually >345) (18–45 [usually >20]) Normal None Usual Normal
Type II 100–430 (usually ≤345) (6–25 [usually ≤20]) Normal Decreases bilirubin by >25% Rare Normal
Gilbert Syndrome Typically ≤70 μmol/L (≤4 mg/dL) in absence of fasting or hemolysis Normal Decreases bilirubin to normal No Usually normal; increased lipofuscin pigment in some
Bile characteristics Color Bilirubin fractions
Pale or colorless >90% unconjugated
Bilirubin UDP-glucuronosyltransferase activity Inheritance (all autosomal)
Typically absent; traces in some patients Recessive
Pigmented Largest fraction (mean: 57%) monoconjugates Markedly reduced: 0–10% of normal
Normal dark color Mainly diconjugates but monoconjugates increased (mean: 23%) Reduced: typically 10–33% of normal
Predominantly recessive
Promoter mutation: recessive Missense mutations: 7 of 8 dominant; 1 reportedly recessive
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2002 including deletions, insertions, alterations in intron splice donor and
PART 14
acceptor sites, exon skipping, and point mutations that introduce premature stop codons or alter critical amino acids. Their common feature is that they all encode proteins with absent or, at most, traces of bilirubin-UDP-glucuronosyltransferase enzymatic activity. Prior to the availability of phototherapy, most patients with CN-I died of bilirubin encephalopathy (kernicterus) in infancy or early childhood. A few lived as long as early adult life without overt neurologic damage, although more subtle testing usually indicated mild but progressive brain damage. In the absence of liver transplantation, death eventually supervened from late-onset bilirubin encephalopathy, which often followed a nonspecific febrile illness. Although isolated hepatocyte transplantation has been used in a small number of cases of CN-I, early liver transplantation (Chap. 368) remains the best hope to prevent brain injury and death.
Disorders of the Gastrointestinal System
Crigler-Najjar Syndrome, Type II (CN-II) This condition was recognized as a distinct entity in 1962 and is characterized by marked unconjugated hyperbilirubinemia in the absence of abnormalities of other conventional hepatic biochemical tests, hepatic histology, or hemolysis. It differs from CN-I in several specific ways (Table 359-1): (1) Although there is considerable overlap, average bilirubin concentrations are lower in CN-II; (2) accordingly, CN-II is only infrequently associated with kernicterus; (3) bile is deeply colored, and bilirubin glucuronides are present, with a striking, characteristic increase in the proportion of monoglucuronides; (4) UGT1A1 in liver is usually present at reduced levels (typically ≤10% of normal) but may be undetectable by older, less sensitive assays; and (5) while typically detected in infancy, hyperbilirubinemia was not recognized in some cases until later in life and, in one instance, at age 34. As with CN-I, most CN-II cases exhibit abnormalities in the conjugation of other compounds, such as salicylamide and menthol, but in some instances, the defect appears limited to bilirubin. Reduction of serum bilirubin concentrations by >25% in response to enzyme inducers such as phenobarbital distinguishes CN-II from CN-I, although this response may not be elicited in early infancy and often is not accompanied by measurable UGT1A1 induction. Bilirubin concentrations during phenobarbital administration do not return to normal but are typically in the range of 51–86 μmol/L (3–5 mg/dL). Although the incidence of kernicterus in CN-II is low, instances have occurred, not only in infants but also in adolescents and adults, often in the setting of an intercurrent illness, fasting, or another factor that temporarily raises the serum bilirubin concentration above baseline and reduces serum albumin levels. For this reason, phenobarbital therapy is widely recommended, a single bedtime dose often sufficing to maintain clinically safe serum bilirubin concentrations. Over 77 different mutations in the UGT1 gene have been identified as causing CN-I or CN-II. It was found that missense mutations are more common in CN-II patients, as would be expected in this less severe phenotype. Their common feature is that they encode for a bilirubin-UDP-glucuronosyltransferase with markedly reduced, but detectable, enzymatic activity. The spectrum of residual enzyme activity explains the spectrum of phenotypic severity of the resulting hyperbilirubinemia. Molecular analysis has established that a large majority of CN-II patients are either homozygotes or compound heterozygotes for CN-II mutations and that individuals carrying one mutated and one entirely normal allele have normal bilirubin concentrations. Gilbert Syndrome (GS) This syndrome is characterized by mild unconjugated hyperbilirubinemia, normal values for standard hepatic biochemical tests, and normal hepatic histology other than a modest increase of lipofuscin pigment in some patients. Serum bilirubin concentrations are most often 80% is isomer I. Heterozygotes for the syndrome show an intermediate pattern. The molecular basis for this phenomenon remains unclear.
PART 14 Disorders of the Gastrointestinal System
Rotor Syndrome This benign, autosomal recessive disorder is clinically similar to DJS (Table 359-2), although it is seen even less frequently. A major phenotypic difference is that the liver in patients with Rotor syndrome has no increased pigmentation and appears totally normal. The only abnormality in routine laboratory tests is an elevation of total serum bilirubin, due to a predominant rise in conjugated bilirubin. This is accompanied by bilirubinuria. Several additional features differentiate Rotor syndrome from DJS. In Rotor syndrome, the gallbladder is usually visualized on oral cholecystography, in contrast to the nonvisualization that is typical of DJS. The pattern of urinary coproporphyrin excretion also differs. The pattern in Rotor syndrome resembles that of many acquired disorders of hepatobiliary function, in which coproporphyrin I, the major coproporphyrin isomer in bile, refluxes from the hepatocyte back into the circulation and is excreted in urine. Thus, total urinary coproporphyrin excretion is substantially increased in Rotor syndrome, in contrast to the normal levels seen in DJS. Although the fraction of coproporphyrin I in urine is elevated, it is usually 95% of patients with acute hepatitis B; found in serum, body fluids, hepatocyte cytoplasm; anti-HBs appears following infection—protective antibody Bloodborne agent, formerly labeled non-A, non-B hepatitis Acute diagnosis: anti-HCV (C33c, C22-3, NS5), HCV RNA Chronic diagnosis: anti-HCV (C100-3, C33c, C223, NS5) and HCV RNA; cytoplasmic location in hepatocytes Defective RNA virus, requires helper function of HBV (hepadnaviruses); HDV antigen (HDAg) present in hepatocyte nucleus Diagnosis: anti-HDV, HDV RNA; HBV/HDV co-infection—IgM anti-HBc and anti-HDV; HDV superinfection—IgG anti-HBc and anti-HDV Agent of enterically transmitted hepatitis; rare in United States; occurs in Asia, Mediterranean countries, Central America Diagnosis: IgM/IgG anti-HEV (assays not routinely available); virus in stool, bile, hepatocyte cytoplasm
ss, single-strand; ss/ds, partially single-strand, partially double-strand; −, minus-strand; +, plus-strand.
a
Note: See text for abbreviations.
genotypes (A–J). Geographic distribution of genotypes and subtypes varies; genotypes A (corresponding to subtype adw) and D (ayw) predominate in the United States and Europe, whereas genotypes B (adw) and C (adr) predominate in Asia. Clinical course and outcome are independent of subtype, but genotype B appears to be associated with less rapidly progressive liver disease and cirrhosis and a lower likelihood, or delayed appearance, of hepatocellular carcinoma than genotype C or D. Patients with genotype A are more likely to clear circulating viremia and to achieve HBeAg and HBsAg seroconversion, both spontaneously and in response to antiviral therapy. In addition, “precore” mutations are favored by certain genotypes (see below). Upstream of the S gene are the pre-S genes (Fig. 360-3), which code for pre-S gene products, including receptors on the HBV surface for polymerized human serum albumin and for hepatocyte membrane proteins. The pre-S region actually consists of both pre-S1 and pre-S2. Depending on where translation is initiated, three potential HBsAg gene products are synthesized. The protein product of the S gene is HBsAg (major protein), the product of the S region plus the adjacent pre-S2 region is the middle protein, and the product of the pre-S1 plus pre-S2 plus S regions is the large protein. Compared with the smaller spherical and tubular particles of HBV, complete 42-nm virions are enriched in the large protein. Both pre-S proteins and their respective antibodies can be detected during HBV infection, and the period of pre-S antigenemia appears to coincide with other markers of virus replication, as detailed below; however, pre-S proteins have little clinical relevance and are not included in routine serologic testing repertoires. The intact 42-nm virion contains a 27-nm nucleocapsid core particle. Nucleocapsid proteins are coded for by the C gene. The
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antigen expressed on the surface of the nucleocapsid core is hepatitis B core antigen (HBcAg), and its corresponding antibody is anti-HBc. A third HBV antigen is hepatitis B e antigen (HBeAg), a soluble, nonparticulate, nucleocapsid protein that is immunologically distinct from intact HBcAg but is a product of the same C gene. The C gene has two initiation codons, a precore and a core region (Fig. 360-3). If translation is initiated at the precore region, the protein product is HBeAg, which has a signal peptide that binds it to the smooth endoplasmic reticulum, the secretory apparatus of the cell, leading to its secretion into the circulation. If translation begins at the core region, HBcAg is the protein product; it has no signal peptide, it is not secreted, but it assembles into nucleocapsid particles, which bind to and incorporate RNA, and which, ultimately, contain HBV DNA. Also packaged within the nucleocapsid core is a DNA polymerase, which directs replication and repair of HBV DNA. When packaging within viral proteins is complete, synthesis of the incomplete plus strand stops; this accounts for the single-strand gap and for differences in the size of the gap. HBcAg particles remain in the hepatocyte, where they are readily detectable by immunohistochemical staining and are exported after encapsidation by an envelope of HBsAg. Therefore, naked core particles do not circulate in the serum. The secreted nucleocapsid protein, HBeAg, provides a convenient, readily detectable, qualitative marker of HBV replication and relative infectivity. HBsAg-positive serum containing HBeAg is more likely to be highly infectious and to be associated with the presence of hepatitis B virions (and detectable HBV DNA, see below) than HBeAg-negative or anti-HBe-positive serum. For example, HBsAg-positive mothers who are HBeAg-positive almost invariably (>90%) transmit hepatitis
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Jaundice ALT HBeAg
Anti-HBe IgG Anti-HBc
HBsAg
Anti-HBs IgM Anti-HBc
0
4
8
12
16
20 24 28 32 36 Weeks after exposure
52
100
Figure 360-4 Scheme of typical clinical and laboratory features of acute hepatitis B. ALT, alanine aminotransferase.
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Acute Viral Hepatitis
Serologic and virologic markers After a person is infected with HBV, the first virologic marker detectable in serum within 1–12 weeks, usually between 8 and 12 weeks, is HBsAg (Fig. 360-4). Circulating HBsAg precedes elevations of serum aminotransferase activity and clinical symptoms by 2–6 weeks and remains detectable during the entire icteric or symptomatic phase of acute hepatitis B and beyond. In typical cases, HBsAg becomes undetectable 1–2 months after the onset of jaundice and rarely persists beyond 6 months. After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter. Because HBcAg is intracellular and, when in the serum, sequestered within an HBsAg coat, naked core particles do not circulate in serum, and therefore, HBcAg is not detectable routinely in the serum of patients with HBV infection. By contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1–2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months.
Because variability exists in the time of appearance of anti-HBs after 2007 HBV infection, occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs. During this “gap” or “window” period, anti-HBc may represent the only serologic evidence of current or recent HBV infection, and blood containing anti-HBc in the absence of HBsAg and anti-HBs has been implicated in transfusion-associated hepatitis B. In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased, however, this window period is rarely encountered. In some persons, years after HBV infection, anti-HBc may persist in the circulation longer than anti-HBs. Therefore, isolated anti-HBc does not necessarily indicate active virus replication; most instances of isolated anti-HBc represent hepatitis B infection in the remote past. Rarely, however, isolated anti-HBc represents low-level hepatitis B viremia, with HBsAg below the detection threshold, and, occasionally, isolated anti-HBc represents a cross-reacting or false-positive immunologic specificity. Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc. Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months. Therefore, patients with current or recent acute hepatitis B, including those in the anti-HBc window, have IgM anti-HBc in their serum. In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, anti-HBc is predominantly of the IgG class. Infrequently, in ≤1–5% of patients with acute HBV infection, levels of HBsAg are too low to be detected; in such cases, the presence of IgM anti-HBc establishes the diagnosis of acute hepatitis B. When isolated anti-HBc occurs in the rare patient with chronic hepatitis B whose HBsAg level is below the sensitivity threshold of contemporary immunoassays (a low-level carrier), anti-HBc is of the IgG class. Generally, in persons who have recovered from hepatitis B, anti-HBs and anti-HBc persist indefinitely. The temporal association between the appearance of anti-HBs and resolution of HBV infection as well as the observation that persons with anti-HBs in serum are protected against reinfection with HBV suggests that anti-HBs is the protective antibody. Therefore, strategies for prevention of HBV infection are based on providing susceptible persons with circulating anti-HBs (see below). Occasionally, in ~10% of patients with chronic hepatitis B, low-level, low-affinity anti-HBs can be detected. This antibody is directed against a subtype determinant different from that represented by the patient’s HBsAg; its presence is thought to reflect the stimulation of a related clone of antibody-forming cells, but it has no clinical relevance and does not signal imminent clearance of hepatitis B. These patients with HBsAg and such nonneutralizing anti-HBs should be categorized as having chronic HBV infection. The other readily detectable serologic marker of HBV infection, HBeAg, appears concurrently with or shortly after HBsAg. Its appearance coincides temporally with high levels of virus replication and reflects the presence of circulating intact virions and detectable HBV DNA (with the notable exception of patients with precore mutations who cannot synthesize HBeAg—see “Molecular Variants”). Pre-S1 and pre-S2 proteins are also expressed during periods of peak replication, but assays for these gene products are not routinely available. In selflimited HBV infections, HBeAg becomes undetectable shortly after peak elevations in aminotransferase activity, before the disappearance of HBsAg, and anti-HBe then becomes detectable, coinciding with a period of relatively lower infectivity (Fig. 360-4). Because markers of HBV replication appear transiently during acute infection, testing for such markers is of little clinical utility in typical cases of acute HBV infection. In contrast, markers of HBV replication provide valuable information in patients with protracted infections. Departing from the pattern typical of acute HBV infections, in chronic HBV infection, HBsAg remains detectable beyond 6 months, anti-HBc is primarily of the IgG class, and anti-HBs is either undetectable or detectable at low levels (see “Laboratory Features”) (Fig. 360-5). During early chronic HBV infection, HBV DNA can be detected both in serum and in hepatocyte nuclei, where it is present in free or episomal form. This relatively highly replicative stage of HBV infection is
CHAPTER 360
B infection to their offspring, whereas HBsAg-positive mothers with anti-HBe rarely (10–15%) infect their offspring. Early during the course of acute hepatitis B, HBeAg appears transiently; its disappearance may be a harbinger of clinical improvement and resolution of infection. Persistence of HBeAg in serum beyond the first 3 months of acute infection may be predictive of the development of chronic infection, and the presence of HBeAg during chronic hepatitis B tends to be associated with ongoing viral replication, infectivity, and inflammatory liver injury (except during the early decades after perinatally acquired HBV infection; see below). The third and largest of the HBV genes, the P gene (Fig. 360-3), codes for HBV DNA polymerase; as noted above, this enzyme has both DNA-dependent DNA polymerase and RNA-dependent reverse transcriptase activities. The fourth gene, X, codes for a small, nonparticulate protein, hepatitis B x antigen (HBxAg), that is capable of transactivating the transcription of both viral and cellular genes (Fig. 360-3). In the cytoplasm, HBxAg effects calcium release (possibly from mitochondria), which activates signal-transduction pathways that lead to stimulation of HBV reverse transcription and HBV DNA replication. Such transactivation may enhance the replication of HBV, leading to the clinical association observed between the expression of HBxAg and antibodies to it in patients with severe chronic hepatitis and hepatocellular carcinoma. The transactivating activity can enhance the transcription and replication of other viruses besides HBV, such as HIV. Cellular processes transactivated by X include the human interferon γ gene and class I major histocompatibility genes; potentially, these effects could contribute to enhanced susceptibility of HBV-infected hepatocytes to cytolytic T cells. The expression of X can also induce programmed cell death (apoptosis). The clinical relevance of HBxAg is limited, however, and testing for it is not part of routine clinical practice.
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Figure 360-5 Scheme of typical laboratory features of wildtype chronic hepatitis B. HBeAg and hepatitis B virus (HBV) DNA can be detected in serum during the relatively replicative phase of chronic infection, which is associated with infectivity and liver injury. Seroconversion from the replicative phase to the relatively nonreplicative phase occurs at a rate of ~10% per year and is heralded by an acute hepatitis–like elevation of alanine aminotransferase (ALT) activity; during the nonreplicative phase, infectivity and liver injury are limited. In HBeAg-negative chronic hepatitis B associated with mutations in the precore region of the HBV genome, replicative chronic hepatitis B occurs in the absence of HBeAg. the time of maximal infectivity and liver injury; HBeAg is a qualitative marker and HBV DNA a quantitative marker of this replicative phase, during which all three forms of HBV circulate, including intact virions. Over time, the relatively replicative phase of chronic HBV infection gives way to a relatively nonreplicative phase. This occurs at a rate of ~10% per year and is accompanied by seroconversion from HBeAg to anti-HBe. In many cases, this seroconversion coincides with a transient, usually mild, acute hepatitis-like elevation in aminotransferase activity, believed to reflect cell-mediated immune clearance of virus-infected hepatocytes. In the nonreplicative phase of chronic infection, when HBV DNA is demonstrable in hepatocyte nuclei, it tends to be integrated into the host genome. In this phase, only spherical and tubular forms of HBV, not intact virions, circulate, and liver injury tends to subside. Most such patients would be characterized as inactive HBV carriers. In reality, the designations replicative and nonreplicative are only relative; even in the so-called nonreplicative phase, HBV replication can be detected at levels of approximately ≤103 virions with highly sensitive amplification probes such as the polymerase chain reaction (PCR); below this replication threshold, liver injury and infectivity of HBV are limited to negligible. Still, the distinctions are pathophysiologically and clinically meaningful. Occasionally, nonreplicative HBV infection converts back to replicative infection. Such spontaneous reactivations are accompanied by reexpression of HBeAg and HBV DNA, and sometimes of IgM anti-HBc, as well as by exacerbations of liver injury. Because high-titer IgM anti-HBc can reappear during acute exacerbations of chronic hepatitis B, relying on IgM anti-HBc versus IgG anti-HBc to distinguish between acute and chronic hepatitis B infection, respectively, may not always be reliable; in such cases, patient history is invaluable in helping to distinguish de novo acute hepatitis B infection from acute exacerbation of chronic hepatitis B infection. Molecular variants Variation occurs throughout the HBV genome, and clinical isolates of HBV that do not express typical viral proteins have been attributed to mutations in individual or even multiple gene locations. For example, variants have been described that lack nucleocapsid proteins (commonly), envelope proteins (very rarely), or both. Two categories of naturally occurring HBV variants have attracted the most attention. One of these was identified initially in Mediterranean countries among patients with severe chronic HBV infection and
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detectable HBV DNA but with anti-HBe instead of HBeAg. These patients were found to be infected with an HBV mutant that contained an alteration in the precore region rendering the virus incapable of encoding HBeAg. Although several potential mutation sites exist in the pre-C region, the region of the C gene necessary for the expression of HBeAg (see “Virology and Etiology”), the most commonly encountered in such patients is a single base substitution, from G to A in the second to last codon of the pre-C gene at nucleotide 1896. This substitution results in the replacement of the TGG tryptophan codon by a stop codon (TAG), which prevents the translation of HBeAg. Another mutation, in the core-promoter region, prevents transcription of the coding region for HBeAg and yields an HBeAgnegative phenotype. Patients with such mutations in the precore region and who are unable to secrete HBeAg may have severe liver disease that progresses more rapidly to cirrhosis, or alternatively, they are identified clinically later in the course of the natural history of chronic hepatitis B, when the disease is more advanced. Both “wild-type” HBV and precore-mutant HBV can coexist in the same patient, or mutant HBV may arise late during wild-type HBV infection. In addition, clusters of fulminant hepatitis B in Israel and Japan were attributed to common-source infection with a precore mutant. Fulminant hepatitis B in North America and western Europe, however, occurs in patients infected with wild-type HBV, in the absence of precore mutants, and both precore mutants and other mutations throughout the HBV genome occur commonly, even in patients with typical, self-limited, milder forms of HBV infection. HBeAg-negative chronic hepatitis with mutations in the precore region is now the most frequently encountered form of hepatitis B in Mediterranean countries and in Europe. In the United States, where HBV genotype A (less prone to G1896A mutation) is prevalent, precore-mutant HBV is much less common; however, as a result of immigration from Asia and Europe, the proportion of HBeAg-negative hepatitis B–infected individuals has increased in the United States, and they now represent approximately 30–40% of patients with chronic hepatitis B. Characteristic of such HBeAg-negative chronic hepatitis B are lower levels of HBV DNA (usually ≤105 IU/mL) and one of several patterns of aminotransferase activity—persistent elevations, periodic fluctuations above the normal range, and periodic fluctuations between the normal and elevated range. The second important category of HBV mutants consists of escape mutants, in which a single amino acid substitution, from glycine to arginine, occurs at position 145 of the immunodominant a determinant common to all HBsAg subtypes. This HBsAg alteration leads to a critical conformational change that results in a loss of neutralizing activity by anti-HBs. This specific HBV/a mutant has been observed in two situations, active and passive immunization, in which humoral immunologic pressure may favor evolutionary change (“escape”) in the virus— in a small number of hepatitis B vaccine recipients who acquired HBV infection despite the prior appearance of neutralizing anti-HBs and in HBV-infected liver transplant recipients treated with a high-potency human monoclonal anti-HBs preparation. Although such mutants have not been recognized frequently, their existence raises a concern that may complicate vaccination strategies and serologic diagnosis. Different types of mutations emerge during antiviral therapy of chronic hepatitis B with nucleoside analogues; such “YMDD” and similar mutations in the polymerase motif of HBV are described in Chap. 362. Extrahepatic sites Hepatitis B antigens and HBV DNA have been identified in extrahepatic sites, including lymph nodes, bone marrow, circulating lymphocytes, spleen, and pancreas. Although the virus does not appear to be associated with tissue injury in any of these extrahepatic sites, its presence in these “remote” reservoirs has been invoked (but is not necessary) to explain the recurrence of HBV infection after orthotopic liver transplantation. The clinical relevance of such extrahepatic HBV is limited. Hepatitis D The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a defective RNA virus that co-infects with and requires the helper function of HBV (or other hepadnaviruses)
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CHAPTER 360
for its replication and expression. Slightly smaller than HBV, HDV virus polyprotein of ~3000 amino acids, which is cleaved after transla- 2009 is a formalin-sensitive, 35- to 37-nm virus with a hybrid structure. tion to yield 10 viral proteins. The 5′ end of the genome consists of an Its nucleocapsid expresses HDV antigen (HDAg), which bears no untranslated region (containing an internal ribosomal entry site, IRES) antigenic homology with any of the HBV antigens, and contains the adjacent to the genes for three structural proteins, the nucleocapsid virus genome. The HDV core is “encapsidated” by an outer envelope core protein, C, and two structural envelope glycoproteins, E1 and E2. of HBsAg, indistinguishable from that of HBV except in its relative The 5′ untranslated region and core gene are highly conserved among compositions of major, middle, and large HBsAg component proteins. genotypes, but the envelope proteins are coded for by the hypervariThe genome is a small, 1700-nucleotide, circular, single-strand RNA able region, which varies from isolate to isolate and may allow the of negative polarity that is nonhomologous with HBV DNA (except virus to evade host immunologic containment directed at accessible for a small area of the polymerase gene) but that has features and virus-envelope proteins. The 3′ end of the genome also includes an the rolling circle model of replication common to genomes of plant untranslated region and contains the genes for seven nonstructural satellite viruses or viroids. HDV RNA contains many areas of internal (NS) proteins, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. p7 is a complementarity; therefore, it can fold on itself by internal base pair- membrane ion channel protein necessary for efficient assembly and ing to form an unusual, very stable, rodlike structure that contains release of HCV. The NS2 cysteine protease cleaves NS3 from NS2, and a very stable, self-cleaving and self-ligating ribozyme. HDV RNA the NS3-4A serine protease cleaves all the downstream proteins from requires host RNA polymerase II for its replication in the hepatocyte the polyprotein. Important NS proteins involved in virus replication nucleus via RNA-directed RNA synthesis by transcription of genomic include the NS3 helicase; NS3-4A serine protease; the multifunctional RNA to a complementary antigenomic (plus strand) RNA; the anti- membrane-associated phosphoprotein NS5A, an essential component genomic RNA, in turn, serves as a template for subsequent genomic of the viral replication membranous web (along with NS4B); and the RNA synthesis effected by host RNA polymerase I. HDV RNA has NS5B RNA-dependent RNA polymerase (Fig. 360-6). Because HCV only one open reading frame, and HDAg, a product of the antigenomic does not replicate via a DNA intermediate, it does not integrate into strand, is the only known HDV protein; HDAg exists in two forms: a the host genome. Because HCV tends to circulate in relatively low titer, small, 195-amino-acid species, which plays a role in facilitating HDV 103−107 virions/mL, visualization of the 50- to 80-nm virus particles RNA replication, and a large, 214-amino-acid species, which appears remains difficult. Still, the replication rate of HCV is very high, 1012 to suppress replication but is required for assembly of the antigen virions per day; its half-life is 2.7 h. The chimpanzee is a helpful but into virions. HDV antigens have been shown to bind directly to RNA cumbersome animal model. Although a robust, reproducible, small polymerase II, resulting in stimulation of transcription. Although animal model is lacking, HCV replication has been documented in an complete hepatitis D virions and liver injury require the cooperative immunodeficient mouse model containing explants of human liver helper function of HBV, intracellular replication of HDV RNA can and in transgenic mouse and rat models. Although in vitro replication occur without HBV. Genomic heterogeneity among HDV isolates has is difficult, replicons in hepatocellular carcinoma–derived cell lines been described; however, pathophysiologic and clinical consequences support replication of genetically manipulated, truncated, or fullof this genetic diversity have not been recognized. The clinical spec- length HCV RNA (but not intact virions); infectious pseudotyped rettrum of hepatitis D is common to all eight genotypes identified, the roviral HCV particles have been shown to yield functioning envelope proteins. In 2005, complete replication of HCV and intact 55-nm viripredominant of which is genotype 1. HDV can either infect a person simultaneously with HBV (co- ons were described in cell culture systems. HCV entry into the hepainfection) or superinfect a person already infected with HBV (super- tocyte occurs via the nonliver-specific CD81 receptor and the liverinfection); when HDV infection is transmitted from a donor with specific tight junction protein claudin-1. A growing list of additional one HBsAg subtype to an HBsAg-positive recipient with a different host receptors to which HCV binds on cell entry includes occludin, subtype, HDV assumes the HBsAg subtype of the recipient, rather than low-density lipoprotein receptors, glycosaminoglycans, scavenger the donor. Because HDV relies absolutely on HBV, the duration of receptor B1, and epidermal growth factor receptor, among others. HDV infection is determined by the duration of (and cannot outlast) Relying on the same assembly and secretion pathway as low-density HBV infection. HDV replication tends to suppress HBV replication; and very-low-density lipoproteins, HCV is a lipoviroparticle and therefore, patients with hepatitis D tend to have lower levels of HBV masquerades as a lipoprotein, which may limit its visibility to the replication. HDV antigen is expressed primarily in hepatocyte nuclei adaptive immune system and which may explain its ability to evade and is occasionally detectable in serum. During acute HDV infection, immune containment and clearance. After viral entry and uncoatanti-HDV of the IgM class predominates, and 30–40 days may elapse ing, translation is initiated by the IRES on the endoplasmic reticulum after symptoms appear before anti-HDV 500 1000 1500 2000 2500 3000 can be detected. In self-limited infecAA tion, anti-HDV is low-titer and transient, Helicase rarely remaining detectable beyond the Envelope Serine RNA-dependent clearance of HBsAg and HDV antigen. Core glycoproteins protease RNA polymerase In chronic HDV infection, anti-HDV circulates in high titer, and both IgM and 5' 3' C E1 E2 NS2 NS3 NS4B NS5A NS5B IgG anti-HDV can be detected. HDV antigen in the liver and HDV RNA in p7 NS4A serum and liver can be detected during Conserved Hypervariable HDV replication.
Acute Viral Hepatitis
region
Hepatitis C Hepatitis C virus, which, before its identification was labeled “non-A, non-B hepatitis,” is a linear, single-strand, positive-sense, 9600-nucleotide RNA virus, the genome of which is similar in organization to that of flaviviruses and pestiviruses; HCV is the only member of the genus Hepacivirus in the family Flaviviridae. The HCV genome contains a single, large open reading frame (gene) that codes for a
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region
Figure 360-6 Organization of the hepatitis C virus genome and its associated, 3000-aminoacid (AA) proteins. The three structural genes at the 5’ end are the core region, C, which codes for the nucleocapsid, and the envelope regions, E1 and E2, which code for envelope glycoproteins. The 5’ untranslated region and the C region are highly conserved among isolates, whereas the envelope domain E2 contains the hypervariable region. At the 3’ end are seven nonstructural (NS) regions—p7, a membrane protein adjacent to the structural proteins that appears to function as an ion channel; NS2, which codes for a cysteine protease; NS3, which codes for a serine protease and an RNA helicase; NS4 and NS4B; NS5A, a multifunctional membrane-associated phosphoprotein, an essential component of the viral replication membranous web; and NS5B, which codes for an RNA-dependent RNA polymerase. After translation of the entire polyprotein, individual proteins are cleaved by both host and viral proteases.
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2010 membrane, and the HCV polyprotein is cleaved during translation and
PART 14 Disorders of the Gastrointestinal System
posttranslationally by host cellular proteases as well as HCV NS2-3 and NS3-4A proteases. Host cofactors involved in HCV replication include cyclophilin A, which binds to NS5A and yields conformational changes required for viral replication, and liver-specific host microRNA miR-122. At least six distinct major genotypes (and a minor genotype 7), as well as >50 subtypes within genotypes, of HCV have been identified by nucleotide sequencing. Genotypes differ from one another in sequence homology by ≥30%, and subtypes differ by approximately 20%. Because divergence of HCV isolates within a genotype or subtype and within the same host may vary insufficiently to define a distinct genotype, these intragenotypic differences are referred to as quasispecies and differ in sequence homology by only a few percent. The genotypic and quasispecies diversity of HCV, resulting from its high mutation rate, interferes with effective humoral immunity. Neutralizing antibodies to HCV have been demonstrated, but they tend to be short lived, and HCV infection does not induce lasting immunity against reinfection with different virus isolates or even the same virus isolate. Thus, neither heterologous nor homologous immunity appears to develop commonly after acute HCV infection. Some HCV genotypes are distributed worldwide, whereas others are more geographically confined (see “Epidemiology and Global Features”). In addition, differences exist among genotypes in responsiveness to antiviral therapy but not in pathogenicity or clinical progression (except for genotype 3, in which hepatic steatosis and clinical progression are more likely). Currently available, third-generation immunoassays, which incorporate proteins from the core, NS3, and NS5 regions, detect anti-HCV antibodies during acute infection. The most sensitive indicator of HCV infection is the presence of HCV RNA, which requires molecular amplification by PCR or transcription-mediated amplification (TMA) (Fig. 360-7). To allow standardization of the quantification of HCV RNA among laboratories and commercial assays, HCV RNA is reported as international units (IUs) per milliliter; quantitative assays with a broad dynamic range are available that allow detection of HCV RNA with a sensitivity as low as 5 IU/mL. HCV RNA can be detected within a few days of exposure to HCV—well before the appearance of anti-HCV—and tends to persist for the duration of HCV infection. Application of sensitive molecular probes for HCV RNA has revealed the presence of replicative HCV in peripheral blood lymphocytes of infected persons; however, as is the case for HBV in lymphocytes, the clinical relevance of HCV lymphocyte infection is not known. Hepatitis E Previously labeled epidemic or enterically transmitted non-A, non-B hepatitis, HEV is an enterically transmitted virus that causes clinically apparent hepatitis primarily in India, Asia, Africa, and Central America; in those geographic areas, HEV is the most common cause of acute hepatitis; one-third of the global population appears to have been infected. This agent, with epidemiologic features resembling those of hepatitis A, is a 27- to 34-nm, nonenveloped, HAV-like virus with a 7200-nucleotide, single-strand, positive-sense RNA genome. HEV has three open reading frames (ORF) (genes), the largest of Anti-HCV HCV RNA ALT
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12
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Figure 360-7 Scheme of typical laboratory features during acute hepatitis C progressing to chronicity. Hepatitis C virus (HCV) RNA is the first detectable event, preceding alanine aminotransferase (ALT) elevation and the appearance of anti-HCV.
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which, ORF1, encodes nonstructural proteins involved in virus replication. A middle-sized gene, ORF2, encodes the nucleocapsid protein, the major nonstructural protein, and the smallest, ORF3, encodes a structural protein whose function remains undetermined. All HEV isolates appear to belong to a single serotype, despite genomic heterogeneity of up to 25% and the existence of five genotypes, only four of which have been detected in humans; genotypes 1 and 2 appear to be more virulent, whereas genotypes 3 and 4 are more attenuated and account for subclinical infections. Contributing to the perpetuation of this virus are animal reservoirs, most notably in swine. No genomic or antigenic homology, however, exists between HEV and HAV or other picornaviruses; and HEV, although resembling caliciviruses, is sufficiently distinct from any known agent to merit its own classification as a unique genus, Hepevirus, within the family Hepeviridae. The virus has been detected in stool, bile, and liver and is excreted in the stool during the late incubation period. Both IgM anti-HEV during early acute infection and IgG anti-HEV predominating after the first 3 months can be detected. Currently, availability and reliability of serologic/virologic testing for HEV infection is limited but can be done in specialized laboratories (e.g., the Centers for Disease Control and Prevention). PATHOGENESIS Under ordinary circumstances, none of the hepatitis viruses is known to be directly cytopathic to hepatocytes. Evidence suggests that the clinical manifestations and outcomes after acute liver injury associated with viral hepatitis are determined by the immunologic responses of the host. Among the viral hepatitides, the immunopathogenesis of hepatitis B and C has been studied most extensively. Hepatitis B For HBV, the existence of inactive hepatitis B carriers with normal liver histology and function suggests that the virus is not directly cytopathic. The fact that patients with defects in cellular immune competence are more likely to remain chronically infected rather than to clear HBV supports the role of cellular immune responses in the pathogenesis of hepatitis B–related liver injury. The model that has the most experimental support involves cytolytic T cells sensitized specifically to recognize host and hepatitis B viral antigens on the liver cell surface. Nucleocapsid proteins (HBcAg and possibly HBeAg), present on the cell membrane in minute quantities, are the viral target antigens that, with host antigens, invite cytolytic T cells to destroy HBV-infected hepatocytes. Differences in the robustness and broad polyclonality of CD8+ cytolytic T cell responsiveness; in the level of HBV-specific helper CD4+ T cells; in attenuation, depletion, and exhaustion of virus-specific T cells; in viral T cell epitope escape mutations that allow the virus to evade T cell containment; and in the elaboration of antiviral cytokines by T cells have been invoked to explain differences in outcomes between those who recover after acute hepatitis and those who progress to chronic hepatitis, or between those with mild and those with severe (fulminant) acute HBV infection. Although a robust cytolytic T cell response occurs and eliminates virus-infected liver cells during acute hepatitis B, >90% of HBV DNA has been found in experimentally infected chimpanzees to disappear from the liver and blood before maximal T cell infiltration of the liver and before most of the biochemical and histologic evidence of liver injury. This observation suggests that components of the innate immune system and inflammatory cytokines, independent of cytopathic antiviral mechanisms, participate in the early immune response to HBV infection; this effect has been shown to represent elimination of HBV replicative intermediates from the cytoplasm and covalently closed circular viral DNA from the nucleus of infected hepatocytes. In turn, the innate immune response to HBV infection is mediated largely by natural killer (NK) cell cytotoxicity, activated by immunosuppressive cytokines (e.g., interleukin [IL] 10 and transforming growth factor [TGF] β), reduced signals from inhibitory receptor expression (e.g., major histocompatibility complex), or increased signals from activating receptor expression on infected hepatocytes. In addition, NK cells reduce helper CD4+ cells, which results in reduced CD8+ cells and exhaustion of the virus-specific T cell response to HBV infection. Ultimately, HBV-HLA-specific cytolytic T cell responses of the adaptive immune system are felt to be responsible for recovery from HBV infection.
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Acute Viral Hepatitis
Hepatitis C Cell-mediated immune responses and elaboration by T cells of antiviral cytokines contribute to the multicellular innate and adaptive immune responses involved in the containment of infection and pathogenesis of liver injury associated with hepatitis C. The fact that HCV is so efficient in evading these immune mechanisms is a testament to its highly evolved ability to disrupt host immune responses
at multiple levels. After exposure to HCV, the host cell identifies viral 2011 product motifs (pattern recognition receptors) that distinguish the virus from “self,” resulting in the elaboration of interferons and other cytokines that result in activation of innate and adaptive immune responses. Intrahepatic HLA class I restricted cytolytic T cells directed at nucleocapsid, envelope, and nonstructural viral protein antigens have been demonstrated in patients with chronic hepatitis C; however, such virus-specific cytolytic T cell responses do not correlate adequately with the degree of liver injury or with recovery. Yet, a consensus has emerged supporting a role in the pathogenesis of HCV-associated liver injury of virus-activated CD4+ helper T cells that stimulate, via the cytokines they elaborate, HCV-specific CD8+ cytotoxic T cells. These responses appear to be more robust (higher in number, more diverse in viral antigen specificity, more functionally effective, and more long lasting) in those who recover from HCV than in those who have chronic infection. Contributing to chronic infection are a CD4+ proliferative defect that results in rapid contraction of CD4+ responses, mutations in CD8+ T cell–targeted viral epitopes that allow HCV to escape immune-mediated clearance, and upregulation of inhibitory receptors on functionally impaired, exhausted T cells. Although attention has focused on adaptive immunity, HCV proteins have been shown to interfere with innate immunity by resulting in blocking of type 1 interferon responses and inhibition of interferon signaling and effector molecules in the interferon signaling cascade. Several HLA alleles have been linked with self-limited hepatitis C, the most convincing of which is the CC haplotype of the IL28B gene, which codes for interferon λ3, a component of innate immune antiviral defense. The IL28B association is even stronger when combined with HLA class II DQB1*03:01. The link between non-CC IL28B polymorphisms and failure to clear HCV infection has been explained by a chromosome 19q13.13 frameshift variant upstream of IL28B, the ΔG polymorphism of which creates an ORF in a novel interferon gene (IFN-λ4) associated with impaired HCV clearance. Also shown to contribute to limiting HCV infection are NK cells of the innate immune system that function when HLA class I molecules required for successful adaptive immunity are underexpressed. Both peripheral and intrahepatic NK cell cytotoxicity are dysfunctional in persistent HCV infection. Adding to the complexity of the immune response, HCV core, NS4B, and NS5B have been shown to suppress the immunoregulatory nuclear factor (NF)-κB pathway, resulting in reduced antiapoptotic proteins and a resultant increased vulnerability to tumor necrosis factor (TNF) α–mediated cell death. Patients with hepatitis C and unfavorable (non-CC, associated with reduced HCV clearance) IL28B alleles have been shown to have depressed NK cell/innate immune function. Of note, the emergence of substantial viral quasispecies diversity and HCV sequence variation allow the virus to evade attempts by the host to contain HCV infection by both humoral and cellular immunity. Finally, cross-reactivity between viral antigens (HCV NS3 and NS5A) and host autoantigens (cytochrome P450 2D6) has been invoked to explain the association between hepatitis C and a subset of patients with autoimmune hepatitis and antibodies to liver-kidney microsomal (LKM) antigen (anti-LKM) (Chap. 362).
CHAPTER 360
Debate continues over the relative importance of viral and host factors in the pathogenesis of HBV-associated liver injury and its outcome. As noted above, precore genetic mutants of HBV have been associated with the more severe outcomes of HBV infection (severe chronic and fulminant hepatitis), suggesting that, under certain circumstances, relative pathogenicity is a property of the virus, not the host. The fact that concomitant HDV and HBV infections are associated with more severe liver injury than HBV infection alone and the fact that cells transfected in vitro with the gene for HDV antigen express HDV antigen and then become necrotic in the absence of any immunologic influences are also consistent with a viral effect on pathogenicity. Similarly, in patients who undergo liver transplantation for end-stage chronic hepatitis B, occasionally, rapidly progressive liver injury appears in the new liver. This clinical pattern is associated with an unusual histologic pattern in the new liver, fibrosing cholestatic hepatitis, which, ultrastructurally, appears to represent a choking of the cell with overwhelming quantities of HBsAg. This observation suggests that, under the influence of the potent immunosuppressive agents required to prevent allograft rejection, HBV may have a direct cytopathic effect on liver cells, independent of the immune system. Although the precise mechanism of liver injury in HBV infection remains elusive, studies of nucleocapsid proteins have shed light on the profound immunologic tolerance to HBV of babies born to mothers with highly replicative (HBeAg-positive), chronic HBV infection. In HBeAg-expressing transgenic mice, in utero exposure to HBeAg, which is sufficiently small to traverse the placenta, induces T cell tolerance to both nucleocapsid proteins. This, in turn, may explain why, when infection occurs so early in life, immunologic clearance does not occur, and protracted, lifelong infection ensues. An important distinction should be drawn between HBV infection acquired at birth, common in endemic areas, such as East Asia, and infection acquired in adulthood, common in the West. Infection in the neonatal period is associated with the acquisition of high-level immunologic tolerance to HBV and absence of an acute hepatitis illness, but the almost invariable establishment of chronic, often lifelong infection. Neonatally acquired HBV infection can culminate decades later in cirrhosis and hepatocellular carcinoma (see “Complications and Sequelae”). In contrast, when HBV infection is acquired during adolescence or early adulthood, the host immune response to HBVinfected hepatocytes tends to be robust, an acute hepatitis-like illness is the rule, and failure to recover is the exception. After adulthoodacquired infection, chronicity is uncommon, and the risk of hepatocellular carcinoma is very low. Based on these observations, some authorities categorize HBV infection into an “immunotolerant” phase, an “immunoreactive” phase, and an “inactive” phase. This somewhat simplistic formulation does not apply at all to the typical adult in the West with self-limited acute hepatitis B, in whom no period of immunologic tolerance occurs. Even among those with neonatally acquired HBV infection, in whom immunologic tolerance is established definitively, intermittent bursts of hepatic necroinflammatory activity punctuate the early decades of life during which liver injury appears to be quiescent (labeled by some as the “immunotolerant” phase). In addition, even when clinically apparent liver injury and progressive fibrosis emerge during later decades (the so-called immunoreactive, or immunointolerant, phase), the level of immunologic tolerance to HBV remains substantial. More accurately, in patients with neonatally acquired HBV infection, a dynamic equilibrium exists between tolerance and intolerance, the outcome of which determines the clinical expression of chronic infection. Persons infected as neonates tend to have a relatively higher level of immunologic tolerance during the early decades of life and a relatively lower level (but only rarely a loss) of tolerance in the later decades of life.
EXTRAHEPATIC MANIFESTATIONS Immune complex–mediated tissue damage appears to play a pathogenetic role in the extrahepatic manifestations of acute hepatitis B. The occasional prodromal serum sickness–like syndrome observed in acute hepatitis B appears to be related to the deposition in tissue blood vessel walls of HBsAg-anti-HBs circulating immune complexes, leading to activation of the complement system and depressed serum complement levels. In patients with chronic hepatitis B, other types of immune-complex disease may be seen. Glomerulonephritis with the nephrotic syndrome is observed occasionally; HBsAg, immunoglobulin, and C3 deposition has been found in the glomerular basement membrane. Whereas generalized vasculitis (polyarteritis nodosa) develops in considerably fewer than 1% of patients with chronic HBV infection, 20–30% of patients with polyarteritis nodosa have HBsAg in serum (Chap. 385). In these patients, the affected small- and medium-size arterioles contain
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2012 HBsAg, immunoglobulins, and complement components. Another
extrahepatic manifestation of viral hepatitis, essential mixed cryoglobulinemia (EMC), was reported initially to be associated with hepatitis B. The disorder is characterized clinically by arthritis, cutaneous vasculitis (palpable purpura), and occasionally, glomerulonephritis and serologically by the presence of circulating cryoprecipitable immune complexes of more than one immunoglobulin class (Chaps. 338 and 385). Many patients with this syndrome have chronic liver disease, but the association with HBV infection is limited; instead, a substantial proportion has chronic HCV infection, with circulating immune complexes containing HCV RNA. Immune-complex glomerulonephritis is another recognized extrahepatic manifestation of chronic hepatitis C.
PART 14 Disorders of the Gastrointestinal System
PATHOLOGY The typical morphologic lesions of all types of viral hepatitis are similar and consist of panlobular infiltration with mononuclear cells, hepatic cell necrosis, hyperplasia of Kupffer cells, and variable degrees of cholestasis. Hepatic cell regeneration is present, as evidenced by numerous mitotic figures, multinucleated cells, and “rosette” or “pseudoacinar” formation. The mononuclear infiltration consists primarily of small lymphocytes, although plasma cells and eosinophils occasionally are present. Liver cell damage consists of hepatic cell degeneration and necrosis, cell dropout, ballooning of cells, and acidophilic degeneration of hepatocytes (forming so-called Councilman or apoptotic bodies). Large hepatocytes with a ground-glass appearance of the cytoplasm may be seen in chronic but not in acute HBV infection; these cells contain HBsAg and can be identified histochemically with orcein or aldehyde fuchsin. In uncomplicated viral hepatitis, the reticulin framework is preserved. In hepatitis C, the histologic lesion is often remarkable for a relative paucity of inflammation, a marked increase in activation of sinusoidal lining cells, lymphoid aggregates, the presence of fat (more frequent in genotype 3 and linked to increased fibrosis), and, occasionally, bile duct lesions in which biliary epithelial cells appear to be piled up without interruption of the basement membrane. Occasionally, microvesicular steatosis occurs in hepatitis D. In hepatitis E, a common histologic feature is marked cholestasis. A cholestatic variant of slowly resolving acute hepatitis A also has been described. A more severe histologic lesion, bridging hepatic necrosis, also termed subacute or confluent necrosis or interface hepatitis, is observed occasionally in acute hepatitis. “Bridging” between lobules results from large areas of hepatic cell dropout, with collapse of the reticulin framework. Characteristically, the bridge consists of condensed reticulum, inflammatory debris, and degenerating liver cells that span adjacent portal areas, portal to central veins, or central vein to central vein. This lesion had been thought to have prognostic significance; in many of the originally described patients with this lesion, a subacute course terminated in death within several weeks to months, or severe chronic hepatitis and cirrhosis developed; however, the association between bridging necrosis and a poor prognosis in patients with acute hepatitis has not been upheld. Therefore, although demonstration of this lesion in patients with chronic hepatitis has prognostic significance (Chap. 362), its demonstration during acute hepatitis is less meaningful, and liver biopsies to identify this lesion are no longer undertaken routinely in patients with acute hepatitis. In massive hepatic necrosis (fulminant hepatitis, “acute yellow atrophy”), the striking feature at postmortem examination is the finding of a small, shrunken, soft liver. Histologic examination reveals massive necrosis and dropout of liver cells of most lobules with extensive collapse and condensation of the reticulin framework. When histologic documentation is required in the management of fulminant or very severe hepatitis, a biopsy can be done by the angiographically guided transjugular route, which permits the performance of this invasive procedure in the presence of severe coagulopathy. Immunohistochemical and electron-microscopic studies have localized HBsAg to the cytoplasm and plasma membrane of infected liver cells. In contrast, HBcAg predominates in the nucleus, but, occasionally, scant amounts are also seen in the cytoplasm and on the cell membrane. HDV antigen is localized to the hepatocyte nucleus, whereas HAV, HCV, and HEV antigens are localized to the cytoplasm.
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EPIDEMIOLOGY AND GLOBAL FEATURES Before the availability of serologic tests for hepatitis viruses, all viral hepatitis cases were labeled either as “infectious” or “serum” hepatitis. Modes of transmission overlap, however, and a clear distinction among the different types of viral hepatitis cannot be made solely on the basis of clinical or epidemiologic features (Table 360-2). The most accurate means to distinguish the various types of viral hepatitis involves specific serologic testing. Hepatitis A This agent is transmitted almost exclusively by the fecaloral route. Person-to-person spread of HAV is enhanced by poor personal hygiene and overcrowding; large outbreaks as well as sporadic cases have been traced to contaminated food, water, milk, frozen raspberries and strawberries, green onions imported from Mexico, and shellfish. Intrafamily and intrainstitutional spread are also common. Early epidemiologic observations supported a predilection for hepatitis A to occur in late fall and early winter. In temperate zones, epidemic waves have been recorded every 5–20 years as new segments of nonimmune population appeared; however, in developed countries, the incidence of hepatitis A has been declining, presumably as a function of improved sanitation, and these cyclic patterns are no longer observed. No HAV carrier state has been identified after acute hepatitis A; perpetuation of the virus in nature depends presumably on nonepidemic, inapparent subclinical infection, ingestion of contaminated food or water in, or imported from, endemic areas, and/or contamination linked to environmental reservoirs. In the general population, anti-HAV, a marker for previous HAV infection, increases in prevalence as a function of increasing age and of decreasing socioeconomic status. In the 1970s, serologic evidence of prior hepatitis A infection occurred in ~40% of urban populations in the United States, most of whose members never recalled having had a symptomatic case of hepatitis. In subsequent decades, however, the prevalence of anti-HAV has been declining in the United States. In developing countries, exposure, infection, and subsequent immunity are almost universal in childhood. As the frequency of subclinical childhood infections declines in developed countries, a susceptible cohort of adults emerges. Hepatitis A tends to be more symptomatic in adults; therefore, paradoxically, as the frequency of HAV infection declines, the likelihood of clinically apparent, even severe, HAV illnesses increases in the susceptible adult population. Travel to endemic areas is a common source of infection for adults from nonendemic areas. More recently recognized epidemiologic foci of HAV infection include child care centers, neonatal intensive care units, promiscuous men who have sex with men, injection drug users, and unvaccinated close contacts of newly arrived international adopted children, most of whom emanate from countries with intermediate-to-high hepatitis A endemicity. Although hepatitis A is rarely bloodborne, several outbreaks have been recognized in recipients of clotting-factor concentrates. In the United States, the introduction of hepatitis A vaccination programs among children from high-incidence states has resulted in a >70% reduction in the annual incidence of new HAV infections and has shifted the burden of new infections from children to young adults. In the most recent, 1999–2006 U.S. Public Health Service National Health and Nutrition Examination Survey (NHANES), the prevalence of anti-HAV in the U.S. population was 35%, representing (compared to the 1988–1994 survey) a stable frequency of infection and natural immunity in adults >19 years old but an increase in vaccine-induced immunity for children age 6–19 years. Hepatitis B Percutaneous inoculation has long been recognized as a major route of hepatitis B transmission, but the outmoded designation “serum hepatitis” is an inaccurate label for the epidemiologic spectrum of HBV infection. As detailed below, most of the hepatitis transmitted by blood transfusion is not caused by HBV; moreover, in approximately two-thirds of patients with acute type B hepatitis, no history of an identifiable percutaneous exposure can be elicited. We now recognize that many cases of hepatitis B result from less obvious modes of nonpercutaneous or covert percutaneous transmission. HBsAg has been identified in almost every body fluid from
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2013
Table 360-2 Clinical and Epidemiologic Features of Viral Hepatitis Feature Incubation (days) Onset Age preference
Therapy
HCV 15–160, mean 50 Insidious Any age, but more common in adults
HDV 30–180, mean 60–90 Insidious or acute Any age (similar to HBV)
HEV 14–60, mean 40 Acute Epidemic cases: young adults (20–40 years); sporadic cases: older adults (>60)
+++ Unusual − ±
− +++ +++ ++
− +++ ±a ±a
− +++ + ++
+++ − − −
Mild 0.1% None
Occasionally severe 0.1–1% Occasional (1–10%) (90% of neonates) 0.1–30%c + (neonatal infection) Worse with age, debility
Moderate 0.1% Common (85%)
Occasionally severe 5–20%b Commond
Mild 1–2%e Nonef
1.5–3.2% + Moderate
None None Good
HBIG, recombinant vaccine Interferon Lamivudine Adefovir Pegylated interferon Entecavir Telbivudine Tenofovir
None
Variableg ± Acute, good Chronic, poor HBV vaccine (none for HBV carriers) Pegylated interferon ±
None None Excellent Ig, inactivated vaccine None
Pegylated interferon plus ribavirin, telaprevir, boceprevir
Acute Viral Hepatitis
Prophylaxis
HBV 30–180, mean 60–90 Insidious or acute Young adults (sexual and percutaneous), babies, toddlers
CHAPTER 360
Transmission Fecal-oral Percutaneous Perinatal Sexual Clinical Severity Fulminant Progression to chronicity Carrier Cancer Prognosis
HAV 15–45, mean 30 Acute Children, young adults
Vaccine Noneh
Primarily with HIV co-infection and high-level viremia in index case; risk ~5%. bUp to 5% in acute HBV/HDV co-infection; up to 20% in HDV superinfection of chronic HBV infection. Varies considerably throughout the world and in subpopulations within countries; see text. dIn acute HBV/HDV co-infection, the frequency of chronicity is the same as that for HBV; in HDV superinfection, chronicity is invariable. e10–20% in pregnant women. f Except as observed in immunosuppressed liver allograft recipients or other immunosuppressed hosts. gCommon in Mediterranean countries; rare in North America and western Europe. hAnecdotal reports and retrospective studies suggest that pegylated interferon and/or ribavirin are effective in treating chronic hepatitis E, observed in immunocompromised persons. a c
Abbreviation: HBIG, hepatitis B immunoglobulin. See text for other abbreviations.
infected persons, and at least some of these body fluids—most notably semen and saliva—are infectious, albeit less so than serum, when administered percutaneously or nonpercutaneously to experimental animals. Among the nonpercutaneous modes of HBV transmission, oral ingestion has been documented as a potential but inefficient route of exposure. By contrast, the two nonpercutaneous routes considered to have the greatest impact are intimate (especially sexual) contact and perinatal transmission. In sub-Saharan Africa, intimate contact among toddlers is considered instrumental in contributing to the maintenance of the high frequency of hepatitis B in the population. Perinatal transmission occurs primarily in infants born to mothers with chronic hepatitis B or (rarely) mothers with acute hepatitis B during the third trimester of pregnancy or during the early postpartum period. Perinatal transmission is uncommon in North America and western Europe but occurs with great frequency and is the most important mode of HBV perpetuation in East Asia and developing countries. Although the precise mode of perinatal transmission is unknown, and although ~10% of infections may be acquired in utero, epidemiologic evidence suggests that most infections occur approximately at the time of delivery and are not related to breast-feeding. The likelihood of perinatal transmission of HBV correlates with the presence of HBeAg and high-level viral replication; 90% of HBeAg-positive mothers but only 10–15% of anti-HBe-positive mothers transmit HBV infection to their offspring. In most cases, acute infection in the neonate is clinically asymptomatic, but the child is very likely to remain chronically infected. The >350–400 million HBsAg carriers in the world constitute the main reservoir of hepatitis B in human beings. Whereas serum HBsAg is infrequent (0.1–0.5%) in normal populations in the United States and western Europe, a prevalence of up to 5–20% has been found in East Asia and in some tropical countries; in persons with Down’s
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syndrome, lepromatous leprosy, leukemia, Hodgkin’s disease, or polyarteritis nodosa; in patients with chronic renal disease on hemodialysis; and in injection drug users. Other groups with high rates of HBV infection include spouses of acutely infected persons; sexually promiscuous persons (especially promiscuous men who have sex with men); health care workers exposed to blood; persons who require repeated transfusions especially with pooled blood-product concentrates (e.g., hemophiliacs); residents and staff of custodial institutions for the developmentally handicapped; prisoners; and, to a lesser extent, family members of chronically infected patients. In volunteer blood donors, the prevalence of anti-HBs, a reflection of previous HBV infection, ranges from 5–10%, but the prevalence is higher in lower socioeconomic strata, older age groups, and persons—including those mentioned above—exposed to blood products. Because of highly sensitive virologic screening of donor blood, the risk of acquiring HBV infection from a blood transfusion is 1 in 230,000. Prevalence of infection, modes of transmission, and human behavior conspire to mold geographically different epidemiologic patterns of HBV infection. In East Asia and Africa, hepatitis B, a disease of the newborn and young children, is perpetuated by a cycle of maternalneonatal spread. In North America and western Europe, hepatitis B is primarily a disease of adolescence and early adulthood, the time of life when intimate sexual contact and recreational and occupational percutaneous exposures tend to occur. To some degree, however, this dichotomy between high-prevalence and low-prevalence geographic regions has been minimized by immigration from high-prevalence to low-prevalence areas. The introduction of hepatitis B vaccine in the early 1980s and adoption of universal childhood vaccination policies in many countries resulted in a dramatic, ~90% decline in the incidence of new HBV infections in those countries as well as in the dire
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2014 Table 360-3 High-Risk Populations for Whom HBV Infection Screening Is Recommended
PART 14 Disorders of the Gastrointestinal System
Persons born in countries/regions with a high (≥8%) and intermediate (≥2%) prevalence of HBV infection including immigrants and adopted children and including persons born in the United States who were not vaccinated as infants and whose parents emigrated from areas of high HBV endemicity Household and sexual contacts of persons with hepatitis B Babies born to HBsAg-positive mothers Persons who have used injection drugs Persons with multiple sexual contacts or a history of sexually transmitted disease Men who have sex with men Inmates of correctional facilities Persons with elevated alanine or aspartate aminotransferase levels Blood/plasma/organ/tissue/semen donors Persons with HCV or HIV infection Hemodialysis patients Pregnant women Persons who are the source of blood or body fluids that would be an indication for postexposure prophylaxis (e.g., needlestick, mucosal exposure, sexual assault) Persons who require immunosuppressive or cytotoxic therapy (including anti–tumor necrosis factor α therapy for rheumatologic or inflammatory bowel disorders)
consequences of chronic infection, including hepatocellular carcinoma. Populations and groups for whom HBV infection screening is recommended are listed in Table 360-3. Hepatitis D Infection with HDV has a worldwide distribution, but two epidemiologic patterns exist. In Mediterranean countries (northern Africa, southern Europe, the Middle East), HDV infection is endemic among those with hepatitis B, and the disease is transmitted predominantly by nonpercutaneous means, especially close personal contact. In nonendemic areas, such as the United States and northern Europe, HDV infection is confined to persons exposed frequently to blood and blood products, primarily injection drug users and hemophiliacs. HDV infection can be introduced into a population through drug users or by migration of persons from endemic to nonendemic areas. Thus, patterns of population migration and human behavior facilitating percutaneous contact play important roles in the introduction and amplification of HDV infection. Occasionally, the migrating epidemiology of hepatitis D is expressed in explosive outbreaks of severe hepatitis, such as those that have occurred in remote South American villages as well as in urban centers in the United States. Ultimately, such outbreaks of hepatitis D—either of co-infections with acute hepatitis B or of superinfections in those already infected with HBV—may blur the distinctions between endemic and nonendemic areas. On a global scale, HDV infection declined at the end of the 1990s. Even in Italy, an HDV-endemic area, public health measures introduced to control HBV infection resulted during the 1990s in a 1.5%/year reduction in the prevalence of HDV infection. Still, the frequency of HDV infection during the first decade of the twenty-first century has not fallen below levels reached during the 1990s; the reservoir has been sustained by survivors infected during 1970–1980 and recent immigrants from stillendemic to less-endemic countries. Hepatitis C Routine screening of blood donors for HBsAg and the elimination of commercial blood sources in the early 1970s reduced the frequency of, but did not eliminate, transfusion-associated hepatitis. During the 1970s, the likelihood of acquiring hepatitis after transfusion of voluntarily donated, HBsAg-screened blood was ~10% per patient (up to 0.9% per unit transfused); 90–95% of these cases were classified, based on serologic exclusion of hepatitis A and B, as “non-A, non-B” hepatitis. For patients requiring transfusion of pooled products, such as clotting factor concentrates, the risk was even higher, up to 20–30%. During the 1980s, voluntary self-exclusion of blood donors with risk factors for AIDS and then the introduction of donor screening
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for anti-HIV reduced further the likelihood of transfusion-associated hepatitis to 20% of the population (as high as 50% in persons born prior to 1960) in some cities is infected. The high frequency in Egypt is attributable to contaminated equipment used for medical procedures and unsafe injection practices in the 1950s to 1980s (during a campaign to eradicate schistosomiasis with intravenous tartar emetic). In the United States, African Americans and Mexican Americans have higher frequencies of HCV infection than whites. Between 1988 and 1994, 30- to 40-year-old adult males had the highest prevalence of HCV infection; however, in a survey conducted between 1999 and 2002, the peak age decile had shifted to those age 40–49 years; an increase in hepatitis C–related mortality has paralleled this secular trend, increasing since 1995 predominantly in the 45- to 65-year age group. Thus, despite an 80% reduction in new HCV infections during the 1990s, the prevalence of HCV infection in the population was sustained by an aging cohort that had acquired their infections three to four decades earlier, during the 1960s and 1970s, as a result predominantly of self-inoculation with recreational drugs. As death resulting from HIV infection fell after 1999, age-adjusted mortality associated with HCV infection surpassed that of HIV infection in 2007; >70% of HCV-associated deaths occurred in the “baby boomer” cohort born between 1945 and 1965. Compared to the 1.6%
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Persons born between 1945 and 1965 Persons who have ever used injection drugs Persons with HIV infection Hemophiliacs treated with clotting factor concentrates prior to 1987 Persons who have ever undergone long-term hemodialysis Persons with unexplained elevations of aminotransferase levels Transfusion or transplantation recipients prior to July 1992 Recipients of blood or organs from a donor found to be positive for hepatitis C Children born to women with hepatitis C Health care, public safety, and emergency medical personnel following needle injury or mucosal exposure to HCV-contaminated blood Sexual partners of persons with hepatitis C infection
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Hepatitis E This type of hepatitis, identified in India, Asia, Africa, the Middle East, and Central America, resembles hepatitis A in its primarily enteric mode of spread. The commonly recognized cases occur after contamination of water supplies such as after monsoon flooding, but sporadic, isolated cases occur. An epidemiologic feature that distinguishes HEV from other enteric agents is the rarity of secondary person-to-person spread from infected persons to their close contacts. Large waterborne outbreaks in endemic areas are linked to genotypes 1 and 2, arise in populations that are immune to HAV, favor young adults, and account for antibody prevalences of 30–80%. In nonendemic areas of the world, such as the United States, clinically apparent acute hepatitis E is extremely rare; however, during the 1988–1994 NHANES survey conducted by the U.S. Public Health Service, the prevalence of anti-HEV was 21%, reflecting subclinical infections, infection with genotypes 3 and 4, predominantly in older males (>60 years). In nonendemic areas, HEV accounts hardly at all for cases of sporadic hepatitis; however, cases imported from endemic areas have been found in the United States. Evidence supports a zoonotic reservoir for HEV primarily in swine, which may account for the mostly subclinical infections in nonendemic areas. CLINICAL AND LABORATORY FEATURES Symptoms and Signs Acute viral hepatitis occurs after an incubation period that varies according to the responsible agent. Generally, incubation periods for hepatitis A range from 15–45 days (mean, 4 weeks), for hepatitis B and D from 30–180 days (mean, 8–12 weeks), for hepatitis C from 15–160 days (mean, 7 weeks), and for hepatitis E from 14–60 days (mean, 5–6 weeks). The prodromal symptoms of acute viral hepatitis are systemic and quite variable. Constitutional symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza may precede the onset of jaundice by 1–2 weeks. The nausea, vomiting, and anorexia are frequently associated with alterations in olfaction and taste. A low-grade fever between 38° and 39°C (100°–102°F) is more often present in hepatitis A and E than in hepatitis B or C, except when hepatitis B is heralded by a serum sickness–like syndrome; rarely, a fever of 39.5°–40°C (103°–104°F) may accompany the constitutional symptoms. Dark urine and clay-colored stools may be noticed by the patient from 1–5 days before the onset of clinical jaundice. With the onset of clinical jaundice, the constitutional prodromal symptoms usually diminish, but in some patients, mild weight loss (2.5–5 kg) is common and may continue during the entire icteric phase. The liver becomes enlarged and tender and may be associated with right upper quadrant pain and discomfort. Infrequently, patients present with a cholestatic picture, suggesting extrahepatic biliary obstruction. Splenomegaly and cervical adenopathy are present in 10–20% of patients with acute hepatitis. Rarely, a few spider angiomas appear during the icteric phase and disappear during convalescence. During the recovery phase, constitutional symptoms disappear, but usually some liver enlargement and abnormalities in liver biochemical tests are still evident. The duration of the posticteric phase is variable, ranging from 2–12 weeks, and is usually more prolonged in acute hepatitis B and C. Complete clinical and biochemical recovery is to be expected 1–2 months after all cases of hepatitis A and E and 3–4 months after the onset of jaundice in three-quarters of uncomplicated, self-limited cases of hepatitis B and C (among healthy adults, acute hepatitis B is self-limited in 95–99%, whereas hepatitis C is selflimited in only ~15%). In the remainder, biochemical recovery may be delayed. A substantial proportion of patients with viral hepatitis never become icteric. Infection with HDV can occur in the presence of acute or chronic HBV infection; the duration of HBV infection determines the duration of HDV infection. When acute HDV and HBV infection occur simultaneously, clinical and biochemical features may be indistinguishable from those of HBV infection alone, although occasionally they are
Acute Viral Hepatitis
Table 360-4 High-Risk Populations for Whom HCV-Infection Screening Is Recommended
of young injection drug users, age 15–24 years (accounting for more 2015 than two-thirds of all acute cases), who, unlike older cohorts, had not learned to take precautions to prevent bloodborne infections.
CHAPTER 360
prevalence of HCV infection in the population at large, the prevalence in the 1945–1965 birth cohort was 3.2%, representing three-quarters of all infected persons. Therefore, in 2012, the Centers for Disease Control and Prevention recommended that all persons born between 1945 and 1965 be screened for hepatitis C, without ascertainment of risk, a recommendation shown to be cost-effective and predicted to identify 800,000 infected persons. Because of the availability of highly effective antiviral therapy, such screening would have the potential to avert 200,000 cases of cirrhosis and 47,000 cases of hepatocellular carcinoma and to prevent 120,000 hepatitis-related deaths. Hepatitis C accounts for 40% of chronic liver disease, is the most frequent indication for liver transplantation, and is estimated to account for 8000–10,000 deaths per year in the United States. The distribution of HCV genotypes varies in different parts of the world. Worldwide, genotype 1 is the most common. In the United States, genotype 1 accounts for 70% of HCV infections, whereas genotypes 2 and 3 account for the remaining 30%; among African Americans, the frequency of genotype 1 is even higher (i.e., 90%). Genotype 4 predominates in Egypt; genotype 5 is localized to South Africa, genotype 6 to Hong Kong, and genotype 7 to Central Africa. Most asymptomatic blood donors found to have anti-HCV and ~20–30% of persons with reported cases of acute hepatitis C do not fall into a recognized risk group; however, many such blood donors do recall risk-associated behaviors when questioned carefully. As a bloodborne infection, HCV potentially can be transmitted sexually and perinatally; however, both of these modes of transmission are inefficient for hepatitis C. Although 10–15% of patients with acute hepatitis C report having potential sexual sources of infection, most studies have failed to identify sexual transmission of this agent. The chances of sexual and perinatal transmission have been estimated to be ~5% but shown in a prospective study to be only 1% between monogamous sexual partners, well below comparable rates for HIV and HBV infections. Moreover, sexual transmission appears to be confined to such subgroups as persons with multiple sexual partners and sexually transmitted diseases. Breast-feeding does not increase the risk of HCV infection between an infected mother and her infant. Infection of health workers is not dramatically higher than among the general population; however, health workers are more likely to acquire HCV infection through accidental needle punctures, the efficiency of which is ~3%. Infection of household contacts is rare as well. Besides persons born between 1945 and 1965, other groups with an increased frequency of HCV infection are listed in Table 360-4. In immunosuppressed individuals, levels of anti-HCV may be undetectable, and a diagnosis may require testing for HCV RNA. Although new acute cases of hepatitis C are rare, newly diagnosed cases are common among otherwise healthy persons who experimented briefly with injection drugs, as noted above, three or four decades earlier. Such instances usually remain unrecognized for years, until unearthed by laboratory screening for routine medical examinations, insurance applications, and attempted blood donation. Although, overall, the annual incidence of new HCV infections has continued to fall, the rate of new infections has been increasing since 2002 in a new cohort
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2016 more severe. As opposed to patients with acute HBV infection, patients
PART 14 Disorders of the Gastrointestinal System
with chronic HBV infection can support HDV replication indefinitely, as when acute HDV infection occurs in the presence of a nonresolving acute HBV infection or, more commonly, when acute hepatitis D is superimposed on underlying chronic hepatitis B. In such cases, the HDV superinfection appears as a clinical exacerbation or an episode resembling acute viral hepatitis in someone already chronically infected with HBV. Superinfection with HDV in a patient with chronic hepatitis B often leads to clinical deterioration (see below). In addition to superinfections with other hepatitis agents, acute hepatitis-like clinical events in persons with chronic hepatitis B may accompany spontaneous HBeAg to anti-HBe seroconversion or spontaneous reactivation (i.e., reversion from relatively nonreplicative to replicative infection). Such reactivations can occur as well in therapeutically immunosuppressed patients with chronic HBV infection when cytotoxic/immunosuppressive drugs are withdrawn; in these cases, restoration of immune competence is thought to allow resumption of previously checked cell-mediated immune cytolysis of HBV-infected hepatocytes. Occasionally, acute clinical exacerbations of chronic hepatitis B may represent the emergence of a precore mutant (see “Virology and Etiology”), and the subsequent course in such patients may be characterized by periodic exacerbations. Cytotoxic chemotherapy can lead to reactivation of chronic hepatitis C as well, and anti-TNF-α therapy can lead to reactivation of both hepatitis B and C. Laboratory Features The serum aminotransferases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (previously designated SGOT and SGPT) increase to a variable degree during the prodromal phase of acute viral hepatitis and precede the rise in bilirubin level (Figs. 360-2 and 360-4). The level of these enzymes, however, does not correlate well with the degree of liver cell damage. Peak levels vary from 400–4000 IU or more; these levels are usually reached at the time the patient is clinically icteric and diminish progressively during the recovery phase of acute hepatitis. The diagnosis of anicteric hepatitis is based on clinical features and on aminotransferase elevations. Jaundice is usually visible in the sclera or skin when the serum bilirubin value is >43 μmol/L (2.5 mg/dL). When jaundice appears, the serum bilirubin typically rises to levels ranging from 85–340 μmol/L (5–20 mg/dL). The serum bilirubin may continue to rise despite falling serum aminotransferase levels. In most instances, the total bilirubin is equally divided between the conjugated and unconjugated fractions. Bilirubin levels >340 μmol/L (20 mg/dL) extending and persisting late into the course of viral hepatitis are more likely to be associated with severe disease. In certain patients with underlying hemolytic anemia, however, such as glucose-6-phosphate dehydrogenase deficiency and sickle cell anemia, a high serum bilirubin level is common, resulting from superimposed hemolysis. In such patients, bilirubin levels >513 μmol/L (30 mg/dL) have been observed and are not necessarily associated with a poor prognosis. Neutropenia and lymphopenia are transient and are followed by a relative lymphocytosis. Atypical lymphocytes (varying between 2 and 20%) are common during the acute phase. Measurement of the prothrombin time (PT) is important in patients with acute viral hepatitis, because a prolonged value may reflect a severe hepatic synthetic defect, signify extensive hepatocellular necrosis, and indicate a worse prognosis. Occasionally, a prolonged PT may occur with only mild increases in the serum bilirubin and aminotransferase levels. Prolonged nausea and vomiting, inadequate carbohydrate intake, and poor hepatic glycogen reserves may contribute to hypoglycemia noted occasionally in patients with severe viral hepatitis. Serum alkaline phosphatase may be normal or only mildly elevated, whereas a fall in serum albumin is uncommon in uncomplicated acute viral hepatitis. In some patients, mild and transient steatorrhea has been noted, as well as slight microscopic hematuria and minimal proteinuria. A diffuse but mild elevation of the γ globulin fraction is common during acute viral hepatitis. Serum IgG and IgM levels are elevated in about one-third of patients during the acute phase of viral hepatitis, but the serum IgM level is elevated more characteristically during acute hepatitis A. During the acute phase of viral hepatitis, antibodies
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to smooth muscle and other cell constituents may be present, and low titers of rheumatoid factor, nuclear antibody, and heterophile antibody can also be found occasionally. In hepatitis C and D, antibodies to LKM may occur; however, the species of LKM antibodies in the two types of hepatitis are different from each other as well as from the LKM antibody species characteristic of autoimmune hepatitis type 2 (Chap. 362). The autoantibodies in viral hepatitis are nonspecific and can also be associated with other viral and systemic diseases. In contrast, virus-specific antibodies, which appear during and after hepatitis virus infection, are serologic markers of diagnostic importance. As described above, serologic tests are available routinely with which to establish a diagnosis of hepatitis A, B, D, and C. Tests for fecal or serum HAV are not routinely available. Therefore, a diagnosis of hepatitis A is based on detection of IgM anti-HAV during acute illness (Fig. 360-2). Rheumatoid factor can give rise to false-positive results in this test. A diagnosis of HBV infection can usually be made by detection of HBsAg in serum. Infrequently, levels of HBsAg are too low to be detected during acute HBV infection, even with contemporary, highly sensitive immunoassays. In such cases, the diagnosis can be established by the presence of IgM anti-HBc. The titer of HBsAg bears little relation to the severity of clinical disease. Indeed, an inverse correlation exists between the serum concentration of HBsAg and the degree of liver cell damage. For example, titers are highest in immunosuppressed patients, lower in patients with chronic liver disease (but higher in mild chronic than in severe chronic hepatitis), and very low in patients with acute fulminant hepatitis. These observations suggest that, in hepatitis B, the degree of liver cell damage and the clinical course are related to variations in the patient’s immune response to HBV rather than to the amount of circulating HBsAg. In immunocompetent persons, however, a correlation exists between markers of HBV replication and liver injury (see below). Another important serologic marker in patients with hepatitis B is HBeAg. Its principal clinical usefulness is as an indicator of relative infectivity. Because HBeAg is invariably present during early acute hepatitis B, HBeAg testing is indicated primarily in chronic infection. In patients with hepatitis B surface antigenemia of unknown duration (e.g., blood donors found to be HBsAg-positive) testing for IgM anti-HBc may be useful to distinguish between acute or recent infection (IgM anti-HBc-positive) and chronic HBV infection (IgM antiHBc-negative, IgG anti-HBc-positive). A false-positive test for IgM anti-HBc may be encountered in patients with high-titer rheumatoid factor. Also, IgM anti-HBc may be reexpressed during acute reactivation of chronic hepatitis B. Anti-HBs is rarely detectable in the presence of HBsAg in patients with acute hepatitis B, but 10–20% of persons with chronic HBV infection may harbor low-level anti-HBs. This antibody is directed not against the common group determinant, a, but against the heterotypic subtype determinant (e.g., HBsAg of subtype ad with anti-HBs of subtype y). In most cases, this serologic pattern cannot be attributed to infection with two different HBV subtypes, and the presence of this antibody is not a harbinger of imminent HBsAg clearance. When such antibody is detected, its presence is of no recognized clinical significance (see “Virology and Etiology”). After immunization with hepatitis B vaccine, which consists of HBsAg alone, anti-HBs is the only serologic marker to appear. The commonly encountered serologic patterns of hepatitis B and their interpretations are summarized in Table 360-5. Tests for the detection of HBV DNA in liver and serum are now available. Like HBeAg, serum HBV DNA is an indicator of HBV replication, but tests for HBV DNA are more sensitive and quantitative. First-generation hybridization assays for HBV DNA had a sensitivity of 105−106 virions/mL, a relative threshold below which infectivity and liver injury are limited and HBeAg is usually undetectable. Currently, testing for HBV DNA has shifted from insensitive hybridization assays to amplification assays (e.g., the PCR-based assay, which can detect as few as 10 or 100 virions/mL); among the commercially available PCR assays, the most useful are those with the highest sensitivity (5–10 IU/mL) and the largest dynamic range (100–109 IU/mL). With increased sensitivity,
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detectable enzyme bound to a com- 2017 plementary DNA probe) is ampliHBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe Interpretation fied. The other involves target ampli+ − IgM + − Acute hepatitis B, high infectivitya fication (i.e., synthesis of multiple + − IgG + − Chronic hepatitis B, high infectivity copies of the viral genome) by PCR + − IgG − + 1. Late acute or chronic hepatitis B, low infectivity or TMA, in which the viral RNA is reverse transcribed to complemen2. HBeAg-negative (“precore-mutant”) hepatitis B (chronic or, rarely, acute) tary DNA and then amplified by repeated cycles of DNA synthesis. + + + +/− +/− 1. HBsAg of one subtype and heterotypic anti-HBs (common) Both can be used as quantitative assays and a measurement of relative 2. Process of seroconversion from HBsAg to antiHBs (rare) “viral load”; PCR and TMA, with a sensitivity of 10–102 IU/mL, are − − IgM +/− +/− 1. Acute hepatitis Ba more sensitive than bDNA, with a 2. Anti-HBc “window” sensitivity of 103 IU/mL; assays are − − IgG − +/− 1. Low-level hepatitis B carrier available with a wide dynamic range 2. Hepatitis B in remote past (10–107 IU/mL). Determination of − + IgG − +/− Recovery from hepatitis B HCV RNA level is not a reliable − + − − − 1. Immunization with HBsAg (after vaccination) marker of disease severity or progno2. Hepatitis B in the remote past (?) sis but is helpful in predicting relative responsiveness to antiviral therapy. 3. False-positive The same is true for determinations a IgM anti-HBc may reappear during acute reactivation of chronic hepatitis B. of HCV genotype (Chap. 362). Note: See text for abbreviations. A proportion of patients with hepatitis C have isolated anti-HBc amplification assays remain reactive well below the current 103–104 IU/ in their blood, a reflection of a common risk in certain populations mL threshold for infectivity and liver injury. These markers are useful of exposure to multiple bloodborne hepatitis agents. The anti-HBc in in following the course of HBV replication in patients with chronic such cases is almost invariably of the IgG class and usually represents hepatitis B receiving antiviral chemotherapy (Chap. 362). Except HBV infection in the remote past (HBV DNA undetectable); it rarely for the early decades of life after perinatally acquired HBV infection represents current HBV infection with low-level virus carriage. The presence of HDV infection can be identified by demonstrat(see above), in immunocompetent adults with chronic hepatitis B, a general correlation exists between the level of HBV replication, as ing intrahepatic HDV antigen or, more practically, an anti-HDV reflected by the level of serum HBV DNA, and the degree of liver seroconversion (a rise in titer of anti-HDV or de novo appearance of injury. High-serum HBV DNA levels, increased expression of viral anti-HDV). Circulating HDV antigen, also diagnostic of acute infecantigens, and necroinflammatory activity in the liver go hand in hand tion, is detectable only briefly, if at all. Because anti-HDV is often unless immunosuppression interferes with cytolytic T cell responses to undetectable once HBsAg disappears, retrospective serodiagnosis of virus-infected cells; reduction of HBV replication with antiviral drugs acute self-limited, simultaneous HBV and HDV infection is difficult. tends to be accompanied by an improvement in liver histology. Among Early diagnosis of acute infection may be hampered by a delay of up to patients with chronic hepatitis B, high levels of HBV DNA increase 30–40 days in the appearance of anti-HDV. When a patient presents with acute hepatitis and has HBsAg and the risk of cirrhosis, hepatic decompensation, and hepatocellular caranti-HDV in serum, determination of the class of anti-HBc is helpful cinoma (see “Complications and Sequelae”). In patients with hepatitis C, an episodic pattern of aminotransfer- in establishing the relationship between infection with HBV and HDV. ase elevation is common. A specific serologic diagnosis of hepatitis Although IgM anti-HBc does not distinguish absolutely between acute C can be made by demonstrating the presence in serum of anti- and chronic HBV infection, its presence is a reliable indicator of recent HCV. When contemporary immunoassays are used, anti-HCV can infection and its absence a reliable indicator of infection in the remote be detected in acute hepatitis C during the initial phase of elevated past. In simultaneous acute HBV and HDV infections, IgM anti-HBc aminotransferase activity and remains detectable after recovery (rare) will be detectable, whereas in acute HDV infection superimposed on and during chronic infection (common). Nonspecificity can confound chronic HBV infection, anti-HBc will be of the IgG class. Tests for immunoassays for anti-HCV, especially in persons with a low prior the presence of HDV RNA are useful for determining the presence of probability of infection, such as volunteer blood donors, or in persons ongoing HDV replication and relative infectivity. The serologic/virologic course of events during acute hepatitis E is with circulating rheumatoid factor, which can bind nonspecifically to assay reagents; testing for HCV RNA can be used in such settings to entirely analogous to that of acute hepatitis A, with brief fecal sheddistinguish between true-positive and false-positive anti-HCV deter- ding of virus and viremia and an early IgM anti-HEV response that minations. Assays for HCV RNA are the most sensitive tests for HCV predominates during approximately the first 3 months but is eclipsed infection and represent the “gold standard” in establishing a diagnosis thereafter by long-lasting IgG anti-HEV. Diagnostic tests of varying of hepatitis C. HCV RNA can be detected even before acute elevation reliability for hepatitis E are commercially available but used routinely of aminotransferase activity and before the appearance of anti-HCV primarily outside the United States; in the United States, diagnostic in patients with acute hepatitis C. In addition, HCV RNA remains serologic/virologic assays can be performed at the Centers for Disease detectable indefinitely, continuously in most but intermittently in Control and Prevention or other specialized reference laboratories. Liver biopsy is rarely necessary or indicated in acute viral hepatitis, some, in patients with chronic hepatitis C (detectable as well in some persons with normal liver tests, i.e., inactive carriers). In the very small except when the diagnosis is questionable or when clinical evidence minority of patients with hepatitis C who lack anti-HCV, a diagnosis suggests a diagnosis of chronic hepatitis. A diagnostic algorithm can be applied in the evaluation of cases of can be supported by detection of HCV RNA. If all these tests are negative and the patient has a well-characterized case of hepatitis after acute viral hepatitis. A patient with acute hepatitis should undergo four percutaneous exposure to blood or blood products, a diagnosis of serologic tests, HBsAg, IgM anti-HAV, IgM anti-HBc, and anti-HCV (Table 360-6). The presence of HBsAg, with or without IgM anti-HBc, hepatitis caused by an unidentified agent can be entertained. Amplification techniques are required to detect HCV RNA, and represents HBV infection. If IgM anti-HBc is present, the HBV infectwo types are available. One is a branched-chain complementary tion is considered acute; if IgM anti-HBc is absent, the HBV infection DNA (bDNA) assay, in which the detection signal (a colorimetrically is considered chronic. A diagnosis of acute hepatitis B can be made in Table 360-5 Commonly Encountered Serologic Patterns of Hepatitis B Infection
CHAPTER 360 Acute Viral Hepatitis
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2018 Table 360-6 Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis
Serologic Tests of Patient’s Serum
PART 14
HBsAg + + +
IgM Anti-HAV − − +
IgM Anti-HBc + − −
AntiHCV − − −
+ − −
+ + +
+ − +
− − −
−
−
+
−
−
−
−
+
Diagnostic Interpretation Acute hepatitis B Chronic hepatitis B Acute hepatitis A superimposed on chronic hepatitis B Acute hepatitis A and B Acute hepatitis A Acute hepatitis A and B (HBsAg below detection threshold) Acute hepatitis B (HBsAg below detection threshold) Acute hepatitis C
Note: See text for abbreviations.
Disorders of the Gastrointestinal System
the absence of HBsAg when IgM anti-HBc is detectable. A diagnosis of acute hepatitis A is based on the presence of IgM anti-HAV. If IgM anti-HAV coexists with HBsAg, a diagnosis of simultaneous HAV and HBV infections can be made; if IgM anti-HBc (with or without HBsAg) is detectable, the patient has simultaneous acute hepatitis A and B, and if IgM anti-HBc is undetectable, the patient has acute hepatitis A superimposed on chronic HBV infection. The presence of anti-HCV supports a diagnosis of acute hepatitis C. Occasionally, testing for HCV RNA or repeat anti-HCV testing later during the illness is necessary to establish the diagnosis. Absence of all serologic markers is consistent with a diagnosis of “non-A, non-B, non-C” hepatitis, if the epidemiologic setting is appropriate. In patients with chronic hepatitis, initial testing should consist of HBsAg and anti-HCV. Anti-HCV supports and HCV RNA testing establishes the diagnosis of chronic hepatitis C. If a serologic diagnosis of chronic hepatitis B is made, testing for HBeAg and anti-HBe is indicated to evaluate relative infectivity. Testing for HBV DNA in such patients provides a more quantitative and sensitive measure of the level of virus replication and, therefore, is very helpful during antiviral therapy (Chap. 362). In patients with chronic hepatitis B and normal aminotransferase activity in the absence of HBeAg, serial testing over time is often required to distinguish between inactive carriage and HBeAg-negative chronic hepatitis B with fluctuating virologic and necroinflammatory activity. In persons with hepatitis B, testing for anti-HDV is useful in those with severe and fulminant disease, with severe chronic disease, with chronic hepatitis B and acute hepatitis-like exacerbations, with frequent percutaneous exposures, and from areas where HDV infection is endemic. PROGNOSIS Virtually all previously healthy patients with hepatitis A recover completely with no clinical sequelae. Similarly, in acute hepatitis B, 95–99% of previously healthy adults have a favorable course and recover completely. Certain clinical and laboratory features, however, suggest a more complicated and protracted course. Patients of advanced age and with serious underlying medical disorders may have a prolonged course and are more likely to experience severe hepatitis. Initial presenting features such as ascites, peripheral edema, and symptoms of hepatic encephalopathy suggest a poorer prognosis. In addition, a prolonged PT, low serum albumin level, hypoglycemia, and very high serum bilirubin values suggest severe hepatocellular disease. Patients with these clinical and laboratory features deserve prompt hospital admission. The case fatality rate in hepatitis A and B is very low (~0.1%) but is increased by advanced age and underlying debilitating disorders. Among patients ill enough to be hospitalized for acute hepatitis B, the fatality rate is 1%. Hepatitis C is less severe during the acute phase than hepatitis B and is more likely to be anicteric; fatalities are rare, but the precise case fatality rate is not known. In outbreaks of waterborne hepatitis E in India and Asia, the case fatality rate is 1–2%
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and up to 10–20% in pregnant women. Contributing to fulminant hepatitis E in endemic countries are instances of acute hepatitis E superimposed on underlying chronic liver disease (“acute-on-chronic” liver disease). Patients with simultaneous acute hepatitis B and hepatitis D do not necessarily experience a higher mortality rate than do patients with acute hepatitis B alone; however, in several outbreaks of acute simultaneous HBV and HDV infection among injection drug users, the case fatality rate was ~5%. When HDV superinfection occurs in a person with chronic hepatitis B, the likelihood of fulminant hepatitis and death is increased substantially. Although the case fatality rate for hepatitis D is not known definitively, in outbreaks of severe HDV superinfection in isolated populations with a high hepatitis B carrier rate, a mortality rate >20% has been recorded. COMPLICATIONS AND SEQUELAE A small proportion of patients with hepatitis A experience relapsing hepatitis weeks to months after apparent recovery from acute hepatitis. Relapses are characterized by recurrence of symptoms, aminotransferase elevations, occasionally jaundice, and fecal excretion of HAV. Another unusual variant of acute hepatitis A is cholestatic hepatitis, characterized by protracted cholestatic jaundice and pruritus. Rarely, liver test abnormalities persist for many months, even up to a year. Even when these complications occur, hepatitis A remains self-limited and does not progress to chronic liver disease. During the prodromal phase of acute hepatitis B, a serum sickness–like syndrome characterized by arthralgia or arthritis, rash, angioedema, and rarely, hematuria and proteinuria may develop in 5–10% of patients. This syndrome occurs before the onset of clinical jaundice, and these patients are often diagnosed erroneously as having rheumatologic diseases. The diagnosis can be established by measuring serum aminotransferase levels, which are almost invariably elevated, and serum HBsAg. As noted above, EMC is an immune-complex disease that can complicate chronic hepatitis C and is part of a spectrum of B cell lymphoproliferative disorders, which, in rare instances, can evolve to B cell lymphoma (Chap. 134). Attention has been drawn as well to associations between hepatitis C and such cutaneous disorders as porphyria cutanea tarda and lichen planus. A mechanism for these associations is unknown. Finally, related to the reliance of HCV on lipoprotein secretion and assembly pathways and on interactions of HCV with glucose metabolism, HCV infection may be complicated by hepatic steatosis, hypercholesterolemia, insulin resistance (and other manifestations of the metabolic syndrome), and type 2 diabetes mellitus; both hepatic steatosis and insulin resistance appear to accelerate hepatic fibrosis and blunt responsiveness to antiviral therapy (Chap. 362). The most feared complication of viral hepatitis is fulminant hepatitis (massive hepatic necrosis); fortunately, this is a rare event. Fulminant hepatitis is seen primarily in hepatitis B, D, and E, but rare fulminant cases of hepatitis A occur primarily in older adults and in persons with underlying chronic liver disease, including, according to some reports, chronic hepatitis B and C. Hepatitis B accounts for >50% of fulminant cases of viral hepatitis, a sizable proportion of which are associated with HDV infection and another proportion with underlying chronic hepatitis C. Fulminant hepatitis is hardly ever seen in hepatitis C, but hepatitis E, as noted above, can be complicated by fatal fulminant hepatitis in 1–2% of all cases and in up to 20% of cases in pregnant women. Patients usually present with signs and symptoms of encephalopathy that may evolve to deep coma. The liver is usually small and the PT excessively prolonged. The combination of rapidly shrinking liver size, rapidly rising bilirubin level, and marked prolongation of the PT, even as aminotransferase levels fall, together with clinical signs of confusion, disorientation, somnolence, ascites, and edema, indicates that the patient has hepatic failure with encephalopathy. Cerebral edema is common; brainstem compression, gastrointestinal bleeding, sepsis, respiratory failure, cardiovascular collapse, and renal failure are terminal events. The mortality rate is exceedingly high (>80% in patients with deep coma), but patients who survive may have a complete biochemical and histologic recovery. If a donor liver can be located in time, liver transplantation may be life-saving in patients with fulminant hepatitis (Chap. 368).
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DIFFERENTIAL DIAGNOSIS Viral diseases such as infectious mononucleosis; those due to cytomegalovirus, herpes simplex, and coxsackieviruses; and toxoplasmosis may share certain clinical features with viral hepatitis and cause elevations in serum aminotransferase and, less commonly, in serum bilirubin levels. Tests such as the differential heterophile and serologic tests for these agents may be helpful in the differential diagnosis if HBsAg, anti-HBc, IgM anti-HAV, and anti-HCV determinations are negative. Aminotransferase elevations can accompany almost any systemic viral infection; other rare causes of liver injury confused with viral hepatitis are infections with Leptospira, Candida, Brucella, Mycobacteria, and Pneumocystis. A complete drug history is particularly important because many drugs and certain anesthetic agents can produce a picture of either acute hepatitis or cholestasis (Chap. 361). Equally important is a past history of unexplained “repeated episodes” of acute hepatitis. This history should alert the physician to the possibility that the underlying disorder is chronic hepatitis. Alcoholic hepatitis must also be considered, but usually the serum aminotransferase levels are not as markedly elevated, and other stigmata of alcoholism may be present. The finding on liver biopsy of fatty infiltration, a neutrophilic inflammatory reaction, and “alcoholic hyaline” would be consistent with alcohol-induced rather than viral liver injury. Because acute hepatitis may present with right upper quadrant abdominal pain, nausea and vomiting, fever, and icterus, it is often confused with acute cholecystitis, common duct stone, or ascending cholangitis. Patients with acute viral hepatitis may tolerate surgery poorly; therefore, it is important to exclude this diagnosis, and in confusing cases, a percutaneous liver biopsy may be necessary before laparotomy. Viral hepatitis in the elderly is often misdiagnosed as obstructive jaundice resulting from a common duct stone or carcinoma of the pancreas. Because acute hepatitis in the elderly may be quite severe and the operative mortality high, a thorough evaluation including biochemical tests, radiographic studies of the biliary tree, and even liver biopsy may be necessary to exclude primary parenchymal liver disease. Another clinical constellation that may mimic acute hepatitis is right ventricular failure with passive hepatic congestion or hypoperfusion syndromes, such as those associated with shock, severe hypotension, and severe left ventricular failure. Also included in this general category is any disorder that interferes with venous return to the heart, such as right atrial myxoma, constrictive pericarditis, hepatic vein occlusion (Budd-Chiari syndrome), or venoocclusive disease. Clinical features are usually sufficient to distinguish among these vascular disorders and viral hepatitis. Acute fatty liver of pregnancy, cholestasis of pregnancy, eclampsia, and the HELLP (h emolysis, e levated l iver tests, and l ow p latelets) syndrome can be confused with viral hepatitis during pregnancy. Very rarely, malignancies metastatic to the liver can mimic acute or even fulminant viral hepatitis. Occasionally, genetic or metabolic liver disorders (e.g., Wilson’s disease, α1 antitrypsin deficiency) and nonalcoholic fatty liver disease are confused with acute viral hepatitis.
Acute Viral Hepatitis
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nor HEV causes chronic liver disease in immunocompetent hosts; 2019 however, cases of chronic hepatitis E have been observed in immunosuppressed organ-transplant recipients, persons receiving cytotoxic chemotherapy, and persons with HIV infection. Rare complications of viral hepatitis include pancreatitis, myocarditis, atypical pneumonia, aplastic anemia, transverse myelitis, and peripheral neuropathy. Persons with chronic hepatitis B, particularly those infected in infancy or early childhood and especially those with HBeAg and/or high-level HBV DNA, have an enhanced risk of hepatocellular carcinoma. The risk of hepatocellular carcinoma is increased as well in patients with chronic hepatitis C, almost exclusively in patients with cirrhosis, and almost always after at least several decades, usually after three decades of disease (Chap. 111). In children, hepatitis B may present rarely with anicteric hepatitis, a nonpruritic papular rash of the face, buttocks, and limbs, and lymphadenopathy (papular acrodermatitis of childhood or Gianotti-Crosti syndrome). Rarely, autoimmune hepatitis (Chap. 362) can be triggered by a bout of otherwise self-limited acute hepatitis, as reported after acute hepatitis A, B, and C.
CHAPTER 360
Documenting the disappearance of HBsAg after apparent clinical recovery from acute hepatitis B is particularly important. Before laboratory methods were available to distinguish between acute hepatitis and acute hepatitis-like exacerbations (spontaneous reactivations) of chronic hepatitis B, observations suggested that ~10% of previously healthy patients remained HBsAg-positive for >6 months after the onset of clinically apparent acute hepatitis B. One-half of these persons cleared the antigen from their circulations during the next several years, but the other 5% remained chronically HBsAg-positive. More recent observations suggest that the true rate of chronic infection after clinically apparent acute hepatitis B is as low as 1% in normal, immunocompetent, young adults. Earlier, higher estimates may have been confounded by inadvertent inclusion of acute exacerbations in chronically infected patients; these patients, chronically HBsAg-positive before exacerbation, were unlikely to seroconvert to HBsAg-negative thereafter. Whether the rate of chronicity is 10% or 1%, such patients have IgG anti-HBc in serum; anti-HBs is either undetected or detected at low titer against the opposite subtype specificity of the antigen (see “Laboratory Features”). These patients may (1) be inactive carriers; (2) have low-grade, mild chronic hepatitis; or (3) have moderate to severe chronic hepatitis with or without cirrhosis. The likelihood of remaining chronically infected after acute HBV infection is especially high among neonates, persons with Down’s syndrome, chronically hemodialyzed patients, and immunosuppressed patients, including persons with HIV infection. Chronic hepatitis is an important late complication of acute hepatitis B occurring in a small proportion of patients with acute disease but more common in those who present with chronic infection without having experienced an acute illness, as occurs typically after neonatal infection or after infection in an immunosuppressed host (Chap. 362). The following clinical and laboratory features suggest progression of acute hepatitis to chronic hepatitis: (1) lack of complete resolution of clinical symptoms of anorexia, weight loss, fatigue, and the persistence of hepatomegaly; (2) the presence of bridging/interface or multilobular hepatic necrosis on liver biopsy during protracted, severe acute viral hepatitis; (3) failure of the serum aminotransferase, bilirubin, and globulin levels to return to normal within 6–12 months after the acute illness; and (4) the persistence of HBeAg for >3 months or HBsAg for >6 months after acute hepatitis. Although acute hepatitis D infection does not increase the likelihood of chronicity of simultaneous acute hepatitis B, hepatitis D has the potential for contributing to the severity of chronic hepatitis B. Hepatitis D superinfection can transform inactive or mild chronic hepatitis B into severe, progressive chronic hepatitis and cirrhosis; it also can accelerate the course of chronic hepatitis B. Some HDV superinfections in patients with chronic hepatitis B lead to fulminant hepatitis. As defined in longitudinal studies over three decades, the annual rates of cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis D are 4% and 2.8%, respectively. Although HDV and HBV infections are associated with severe liver disease, mild hepatitis and even inactive carriage have been identified in some patients, and the disease may become indolent beyond the early years of infection. After acute HCV infection, the likelihood of remaining chronically infected approaches 85–90%. Although many patients with chronic hepatitis C have no symptoms, cirrhosis may develop in as many as 20% within 10–20 years of acute illness; in some series of cases reported by referral centers, cirrhosis has been reported in as many as 50% of patients with chronic hepatitis C. Although chronic hepatitis C accounts for at least 40% of cases of chronic liver disease and of patients undergoing liver transplantation for end-stage liver disease in the United States and Europe, in the majority of patients with chronic hepatitis C, morbidity and mortality are limited during the initial 20 years after the onset of infection. Progression of chronic hepatitis C may be influenced by advanced age of acquisition, long duration of infection, immunosuppression, coexisting excessive alcohol use, concomitant hepatic steatosis, other hepatitis virus infection, or HIV coinfection. In fact, instances of severe and rapidly progressive chronic hepatitis B and C are being recognized with increasing frequency in patients with HIV infection (Chap. 226). In contrast, neither HAV
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TREATMENT
Acute Viral Hepatitis
PART 14 Disorders of the Gastrointestinal System
In hepatitis B, among previously healthy adults who present with clinically apparent acute hepatitis, recovery occurs in ~99%; therefore, antiviral therapy is not likely to improve the rate of recovery and is not required. In rare instances of severe acute hepatitis B, treatment with a nucleoside analogue at oral doses used to treat chronic hepatitis B (Chap. 362) has been attempted successfully. Although clinical trials have not been done to establish the efficacy or duration of this approach, most authorities would recommend institution of antiviral therapy with a nucleoside analogue (entecavir or tenofovir, the most potent and least resistance-prone agents) for severe, but not mild–moderate, acute hepatitis B. Treatment should continue until 3 months after HBsAg seroconversion or 6 months after HBeAg seroconversion. In typical cases of acute hepatitis C, recovery is rare, progression to chronic hepatitis is the rule, and meta-analyses of small clinical trials suggest that antiviral therapy with interferon α monotherapy (3 million units SC three times a week) is beneficial, reducing the rate of chronicity considerably by inducing sustained responses in 30–70% of patients. In a German multicenter study of 44 patients with acute symptomatic hepatitis C, initiation of intensive interferon α therapy (5 million units SC daily for 4 weeks, then three times a week for another 20 weeks) within an average of 3 months after infection resulted in a sustained virologic response rate of 98%. Although treatment of acute hepatitis C is recommended, the optimum regimen, duration of therapy, and time to initiate therapy remain to be determined. Many authorities now opt for a 24-week course (beginning within 2–3 months after onset) of long-acting pegylated interferon plus the nucleoside analogue ribavirin, although the value of adding ribavirin has not been demonstrated (see Chap. 362 for doses). Patients with jaundice and women are more likely to recover from acute hepatitis C, and now that genetic markers associated with spontaneous recovery (IL28B CC haplotype) versus persistence (non-CC haplotypes) have been defined, such genetic testing can help determine the need for and immediacy of treating acute hepatitis C—maintaining a high threshold for treating patients with CC and a very low threshold for early intervention in patients with non-CC genotypes. Protease inhibitor–based antiviral therapy with telaprevir or boceprevir, now approved for chronic hepatitis C, genotype 1 (Chap. 362), has not been approved for acute hepatitis C. Moreover, given the high efficacy of pegylated interferon–based therapy for acute hepatitis C, in all likelihood, the addition of a protease inhibitor would add costs and side effects without incremental efficacy. When, however, after 2014, all-oral, brief-duration, low-resistance antiviral regimens replace the current standard of care, the new approaches will be applied to acute hepatitis C and, potentially (pending the outcome of clinical trials), could even be used immediately after exposure (e.g., occupational) to prevent infection and the onset of hepatitis. Because of the marked reduction over the past two decades in the frequency of acute hepatitis C, opportunities to identify and treat patients with acute hepatitis C are rare, except in injection drug users and health workers who sustain hepatitis C–contaminated needle sticks. After such occupational accidents, when monitoring for ALT elevations and the presence of HCV RNA identifies acute hepatitis C (risk only ~3%), therapy should be initiated. Notwithstanding these specific therapeutic considerations, in most cases of typical acute viral hepatitis, specific treatment generally is not necessary. Although hospitalization may be required for clinically severe illness, most patients do not require hospital care. Forced and prolonged bed rest is not essential for full recovery, but many patients will feel better with restricted physical activity. A high-calorie diet is desirable, and because many patients may experience nausea late in the day, the major caloric intake is best tolerated in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot maintain oral intake. Drugs capable of producing adverse reactions such as cholestasis and drugs metabolized by the liver should be avoided. If
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severe pruritus is present, the use of the bile salt-sequestering resin cholestyramine is helpful. Glucocorticoid therapy has no value in acute viral hepatitis, even in severe cases associated with bridging necrosis, and may be deleterious, even increasing the risk of chronicity (e.g., of acute hepatitis B). Physical isolation of patients with hepatitis to a single room and bathroom is rarely necessary except in the case of fecal incontinence for hepatitis A and E or uncontrolled, voluminous bleeding for hepatitis B (with or without concomitant hepatitis D) and hepatitis C. Because most patients hospitalized with hepatitis A excrete little, if any, HAV, the likelihood of HAV transmission from these patients during their hospitalization is low. Therefore, burdensome enteric precautions are no longer recommended. Although gloves should be worn when the bed pans or fecal material of patients with hepatitis A are handled, these precautions do not represent a departure from sensible procedure and contemporary universal precautions for all hospitalized patients. For patients with hepatitis B and hepatitis C, emphasis should be placed on blood precautions (i.e., avoiding direct, ungloved hand contact with blood and other body fluids). Enteric precautions are unnecessary. The importance of simple hygienic precautions such as hand washing cannot be overemphasized. Universal precautions that have been adopted for all patients apply to patients with viral hepatitis. Hospitalized patients may be discharged following substantial symptomatic improvement, a significant downward trend in the serum aminotransferase and bilirubin values, and a return to normal of the PT. Mild aminotransferase elevations should not be considered contraindications to the gradual resumption of normal activity. In fulminant hepatitis, the goal of therapy is to support the patient by maintenance of fluid balance, support of circulation and respiration, control of bleeding, correction of hypoglycemia, and treatment of other complications of the comatose state in anticipation of liver regeneration and repair. Protein intake should be restricted, and oral lactulose or neomycin administered. Glucocorticoid therapy has been shown in controlled trials to be ineffective. Likewise, exchange transfusion, plasmapheresis, human cross-circulation, porcine liver cross-perfusion, hemoperfusion, and extracorporeal liver-assist devices have not been proven to enhance survival. Meticulous intensive care that includes prophylactic antibiotic coverage is the one factor that does appear to improve survival. Orthotopic liver transplantation is resorted to with increasing frequency, with excellent results, in patients with fulminant hepatitis (Chap. 368). PROPHYLAXIS Because application of therapy for acute viral hepatitis is limited and because antiviral therapy for chronic viral hepatitis is cumbersome, costly, and not effective in all patients (Chap. 362), emphasis is placed on prevention through immunization. The prophylactic approach differs for each of the types of viral hepatitis. In the past, immunoprophylaxis relied exclusively on passive immunization with antibody-containing globulin preparations purified by cold ethanol fractionation from the plasma of hundreds of normal donors. Currently, for hepatitis A, B, and E, active immunization with vaccines is the preferable approach to prevention. Hepatitis A Both passive immunization with IG and active immunization with killed vaccines are available. All preparations of IG contain anti-HAV concentrations sufficient to be protective. When administered before exposure or during the early incubation period, IG is effective in preventing clinically apparent hepatitis A. For postexposure prophylaxis of intimate contacts (household, sexual, institutional) of persons with hepatitis A, the administration of 0.02 mL/kg is recommended as early after exposure as possible; it may be effective even when administered as late as 2 weeks after exposure. Prophylaxis is not necessary for those who have already received hepatitis A vaccine, for casual contacts (office, factory, school, or hospital), for most elderly persons, who are very likely to be immune, or for those known to have anti-HAV in their serum. In day care centers, recognition of hepatitis A in children or staff should provide a stimulus for immunoprophylaxis in the center and in the children’s family members. By the time most common-source outbreaks of hepatitis A are recognized, it is
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No. of Age, years Doses HAVRIX (GlaxoSmithKline)a 1–18 2 ≥19 2 VAQTA (Merck) 1–18 2 ≥19 2
Dose
Schedule, months
720 ELUb (0.5 mL) 1440 ELU (1 mL)
0, 6–12 0, 6–12
25 units (0.5 mL) 50 units (1 mL)
0, 6–18 0, 6–18
A combination of this hepatitis A vaccine and hepatitis B vaccine, TWINRIX, is licensed for simultaneous protection against both of these viruses among adults (age ≥18 years). Each 1-mL dose contains 720 ELU of hepatitis A vaccine and 20 μg of hepatitis B vaccine. These doses are recommended at months 0, 1, and 6. bEnzyme-linked immunoassay units.
a
Abbreviation: ELU, enzyme-linked immunoassay unit.
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Hepatitis B Until 1982, prevention of hepatitis B was based on passive immunoprophylaxis either with standard Ig, containing modest levels of anti-HBs, or hepatitis B immunoglobulin (HBIG), containing hightiter anti-HBs. The efficacy of standard IG has never been established and remains questionable; even the efficacy of HBIG, demonstrated in several clinical trials, has been challenged, and its contribution appears to be in reducing the frequency of clinical illness, not in preventing infection. The first vaccine for active immunization, introduced in 1982, was prepared from purified, noninfectious 22-nm spherical HBsAg particles derived from the plasma of healthy HBsAg carriers. In 1987, the plasma-derived vaccine was supplanted by a genetically engineered vaccine derived from recombinant yeast. The latter vaccine consists of HBsAg particles that are nonglycosylated but are otherwise indistinguishable from natural HBsAg; two recombinant vaccines are licensed for use in the United States. Current recommendations can be divided into those for pre-exposure and postexposure prophylaxis. For pre-exposure prophylaxis against hepatitis B in settings of frequent exposure (health workers exposed to blood; first-responder public safety workers; hemodialysis patients and staff; residents and staff of custodial institutions for the developmentally handicapped; injection drug users; inmates of long-term correctional facilities; persons with multiple sexual partners or who have had a sexually transmitted disease; men who have sex with men; persons such as hemophiliacs who require long-term, high-volume therapy with blood derivatives; household and sexual contacts of persons with chronic HBV infection; persons living in or traveling extensively in endemic areas; unvaccinated children under the age of 18; unvaccinated children who are Alaskan natives, Pacific Islanders, or residents in households of first-generation immigrants from endemic countries; persons born in countries with a prevalence of HBV infection ≥2%; patients with chronic liver disease; persons D (shown for PEG IFN-α2b but not for α-2a). Based on these results, some authorities concluded that PEG IFN monotherapy should be the first-line therapy of choice in HBeAgreactive chronic hepatitis B; however, this conclusion has been challenged. Although a finite, 1-year course of PEG IFN results in a higher
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2036 rate of sustained response (6 months after treatment) than is achieved
PART 14 Disorders of the Gastrointestinal System
with oral nucleoside/nucleotide analogue therapy, the comparison is confounded by the fact that oral agents are not discontinued at the end of 1 year. Instead, taken orally and free of side effects, therapy with oral agents is extended indefinitely or until after the occurrence of an HBeAg response. The rate of HBeAg responses after 2 years of oralagent nucleoside analogue therapy is at least as high as, if not higher than, that achieved with PEG IFN after 1 year; favoring oral agents is the absence of injections, difficult-to-tolerate side effects, and laboratory monitoring as well as lower direct and indirect medical care costs and inconvenience. The association of HBsAg responses with PEG IFN therapy occurs in such a small proportion of patients that subjecting everyone to PEG IFN for the marginal gain of HBsAg responses during or immediately after therapy in such a very small minority is questionable. Moreover, HBsAg responses occur in a comparable proportion of patients treated with early-generation nucleoside/nucleotide analogues in the years after therapy, and, with the newer, more potent nucleoside analogues, the frequency of HBsAg loss during the first year of therapy equals that of PEG IFN and is exceeded during year 2 and beyond (see below). Of course, resistance is not an issue during PEG IFN therapy, but the risk of resistance is much lower with new agents (≤1% up to 3−6 years in previously treatment-naïve, entecavirtreated and tenofovir-treated patients; see below). Finally, the level of HBV DNA inhibition that can be achieved with the newer agents, and even with lamivudine, exceeds that which can be achieved with PEG IFN, in some cases by several orders of magnitude. In HBeAg-negative chronic hepatitis B, a trial of PEG IFN-α 2a (180 μg weekly for 48 weeks versus comparison arms of lamivudine monotherapy and of combination therapy) in 564 patients showed that PEG IFN monotherapy resulted at the end of therapy in suppression of HBV DNA by a mean of 4.1 log10 copies/mL, undetectable HBV DNA (2 × 103 103
>2 × ULNd < or > ULN >ULN < or > ULN < or > ULN ≤ULN 1 to >2 × ULNd
>104 >2 × 103 2 × ULNd < or > ULN >ULN < or > ULN < or > ULN
Treate Treate with oral agents, not PEG IFN Consider treatmentf Treate with oral agentsg, not PEG IFN; refer for liver transplantation Observe; refer for liver transplantation Inactive carrier; treatment not necessary Consider liver biopsy; treath if biopsy shows moderate to severe inflammation or fibrosis Treath,i Treate with oral agents, not PEG IFN Consider treatmentf Treath with oral agentsg, not PEG IFN; refer for liver transplantation Observe; refer for liver transplantation
Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD). Except as indicated in footnotes, these guidelines are similar to those issued by the European Association for the Study of the Liver (EASL). bLiver disease tends to be mild or inactive clinically; most such patients do not undergo liver biopsy. cThis pattern is common during early decades of life in Asian patients infected at birth. dAccording to the EASL guidelines, treat if HBV DNA is >2 × 103 IU/mL and ALT >ULN. eOne of the potent oral drugs with a high barrier to resistance (entecavir or tenofovir) or PEG IFN can be used as first-line therapy (see text). These oral agents, but not PEG IFN, should be used for interferon-refractory/ intolerant and immunocompromised patients. PEG IFN is administered weekly by subcutaneous injection for a year; the oral agents are administered daily for at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion. fAccording to EASL guidelines, patients with compensated cirrhosis and detectable HBV DNA at any level, even with normal ALT, are candidates for therapy. Most authorities would treat indefinitely, even in HBeAg-positive disease after HBeAg seroconversion. gBecause the emergence of resistance can lead to loss of antiviral benefit and further deterioration in decompensated cirrhosis, a low-resistance regimen is recommended—entecavir or tenofovir monotherapy or combination therapy with the more resistance-prone lamivudine (or telbivudine) plus adefovir. Therapy should be instituted urgently. hBecause HBeAg seroconversion is not an option, the goal of therapy is to suppress HBV DNA and maintain a normal ALT. PEG IFN is administered by subcutaneous injection weekly for a year; caution is warranted in relying on a 6-month posttreatment interval to define a sustained response, because the majority of such responses are lost thereafter. Oral agents, entecavir or tenofovir, are administered daily, usually indefinitely or until, as very rarely occurs, virologic and biochemical responses are accompanied by HBsAg seroconversion. iFor older patients and those with advanced fibrosis, consider lowering the HBV DNA threshold to >2 × 103 IU/mL. a
Chronic Hepatitis
Cirrhosis decompensated
ALT ≤2 × ULNc,d
CHAPTER 362
HBeAg-negative
HBV DNA (IU/mL) >2 × 104
Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PEG IFN, pegylated interferon; ULN, upper limit of normal.
yields HBeAg responses (and even HBsAg responses) comparable in frequency to those achieved after 1 year of PEG IFN (and without the associated side effects) (Table 362-5). Although adefovir and tenofovir are safe, creatinine monitoring is recommended. Substantial experience with lamivudine during pregnancy (see above) has identified no teratogenicity. Although interferons do not appear to cause congenital anomalies, interferons have antiproliferative properties and should be avoided during pregnancy. Adefovir during pregnancy has not been associated with birth defects; however, there may be an increased risk of spontaneous abortion. Data on the safety of entecavir during pregnancy have not been published. Sufficient data in animals and limited data in humans suggest that telbivudine and tenofovir can be used safely during pregnancy. In general, except perhaps for lamivudine, and until additional data become available, the other antivirals for hepatitis B should be avoided or used with extreme caution during pregnancy. As noted above, some physicians prefer to begin with PEG IFN, while other physicians and patients prefer oral agents as first-line therapy. For patients with decompensated cirrhosis, the emergence of resistance can result in further deterioration and loss of antiviral effectiveness. Therefore, in this patient subset, the threshold for relying on therapy with a very favorable resistance profile (e.g., entecavir or tenofovir) or on combination therapy is low. PEG IFN should not be used in patients with compensated or decompensated cirrhosis. For patients with end-stage chronic hepatitis B who undergo liver transplantation, reinfection of the new liver is almost universal in the absence of antiviral therapy. The majority of patients become high-level viremic carriers with minimal liver injury. Before the availability of antiviral therapy, an unpredictable proportion experienced severe hepatitis B−related liver injury, sometimes a fulminant-like hepatitis and sometimes a rapid recapitulation of the original severe chronic hepatitis B (Chap. 360). Currently, however, prevention of
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recurrent hepatitis B after liver transplantation has been achieved definitively by combining hepatitis B immune globulin with one of the oral nucleoside or nucleotide analogues (Chap. 368); preliminary data suggest that the newer, more potent, and less resistanceprone oral agents may be used instead of hepatitis B immune globulin for posttransplantation therapy. Patients with HBV-HIV co-infection can have progressive HBVassociated liver disease and, occasionally, a severe exacerbation of hepatitis B resulting from immunologic reconstitution following ART. Lamivudine should never be used as monotherapy in patients with HBV-HIV infection because HIV resistance emerges rapidly to both viruses. Adefovir has been used successfully to treat chronic hepatitis B in HBV-HIV co-infected patients but is no longer considered a first-line agent for HBV. Entecavir has low-level activity against HIV and can result in selection of HIV resistance; therefore, it should be avoided in HBV-HIV co-infection. Tenofovir and the combination of tenofovir and emtricitabine in one pill are approved therapies for HIV and represent excellent choices for treating HBV infection in HBV-HIV co-infected patients. Generally, even for HBVHIV co-infected patients who do not yet meet treatment criteria for HIV infection, treating for both HBV and HIV is recommended. Patients with chronic hepatitis B who undergo cytotoxic chemotherapy for treatment of malignancies as well as patients treated with immunosuppressive, anticytokine, or antitumor necrosis factor therapies experience enhanced HBV replication and viral expression on hepatocyte membranes during chemotherapy coupled with suppression of cellular immunity. When chemotherapy is withdrawn, such patients are at risk for reactivation of hepatitis B, often severe and occasionally fatal. Such rebound reactivation represents restoration of cytolytic T cell function against a target organ enriched in HBV expression. Preemptive treatment with lamivudine prior to the initiation of chemotherapy has been shown to reduce the risk of such reactivation. The newer, more potent oral antiviral agents are
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2040 Table 362-5 Pegylated Interferon Versus Oral Nucleoside Analogues for the Treatment of Chronic Hepatitis B
Administration Tolerability
Duration of therapy
PEG IFN Weekly injection Poorly tolerated, intensive monitoring Finite 48 weeks
Nucleoside Analogues Daily, orally Well tolerated, limited monitoring
PART 14 Disorders of the Gastrointestinal System
Maximum mean HBV DNA suppression Effective in high-level HBV DNA (≥109 IU/mL) HBeAg seroconversion During 1 year of therapy During >1 year of therapy
4.5 log10
≥1 year, indefinite in most patients 6.9 log10
No
Yes
~30%
~20%
Not applicable
HBeAg-negative posttreatment HBV DNA suppression HBsAg loss During 1 year of therapy During >1 year of therapy After 1 year of therapy– HBeAg-negative Antiviral resistance
17% @ 5 years
30% (year 2) to up to 50% (year 5) 7% @ 4 years (lamivudine)
3–4% Not applicable 12% @ 5 years
0–3% 3–8% @ 5 years of therapy 3.5% @ 5 years
None
Lamivudine: ~30% year 1, ~70% year 5 Adefovir: 0% year 1, ~30% year 5 Telbivudine: up to 4% year 1, 22% year 2 Entecavir: ≤1.2% through year 6 Tenofovir: 0% through year 5 Yes
Use in cirrhosis, transplanta- No tion, immunosuppressed Cost, 1 year of therapy ++++
+ to ++
Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; PEG IFN, pegylated interferon.
even more effective in preventing hepatitis B reactivation and with a lower risk of antiviral drug resistance. The optimal duration of antiviral therapy after completion of chemotherapy is not known, but a suggested approach is 6 months for inactive hepatitis B carriers and longer-duration therapy in patients with baseline HBV DNA levels >2 × 103 IU/mL, until standard clinical endpoints are met (Table 362-4). CHRONIC HEPATITIS D (DELTA HEPATITIS) Chronic hepatitis D virus (HDV) may follow acute co-infection with HBV but at a rate no higher than the rate of chronicity of acute hepatitis B. That is, although HDV co-infection can increase the severity of acute hepatitis B, HDV does not increase the likelihood of progression to chronic hepatitis B. When, however, HDV superinfection occurs in a person who is already chronically infected with HBV, long-term HDV infection is the rule, and a worsening of the liver disease is the expected consequence. Except for severity, chronic hepatitis B plus D has similar clinical and laboratory features to those seen in chronic hepatitis B alone. Relatively severe and progressive chronic hepatitis, with or without cirrhosis, is the rule, and mild chronic hepatitis is the exception. Occasionally, however, mild hepatitis or even, rarely, inactive carriage occurs in patients with chronic hepatitis B plus D, and the disease may become indolent after several years of infection. A distinguishing serologic feature of chronic hepatitis D is the presence in the circulation of antibodies to liver-kidney microsomes (anti-LKM); however, the anti-LKM seen in hepatitis D, anti-LKM3, are directed against uridine diphosphate glucuronosyltransferase and are distinct from anti-LKM1 seen in patients with autoimmune hepatitis and in a subset of patients
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with chronic hepatitis C (see below). The clinical and laboratory features of chronic HDV infection are summarized in Chap. 360. TREATMENT
Chronic Hepatitis D
Management is not well defined. Glucocorticoids are ineffective and are not used. Preliminary experimental trials of IFN-α suggested that conventional doses and durations of therapy lower levels of HDV RNA and aminotransferase activity only transiently during treatment but have no impact on the natural history of the disease. In contrast, high-dose IFN-α (9 million units three times a week) for 12 months may be associated with a sustained loss of HDV replication and clinical improvement in up to 50% of patients. Moreover, the beneficial impact of treatment has been observed to persist for 15 years and to be associated with a reduction in grade of hepatic necrosis and inflammation, reversion of advanced fibrosis (improved stage), and clearance of HDV RNA in some patients. A suggested approach to therapy has been high-dose, long-term IFN for at least a year and, in responders, extension of therapy until HDV RNA and HBsAg clearance. PEG IFN has also been shown to be effective in the treatment of chronic hepatitis D (e.g., after 48 weeks of therapy, associated with undetectable HDV RNA, durable for at least 24 posttreatment weeks, in a quarter of patients) and is a more convenient replacement for standard IFN. None of the nucleoside analogue antiviral agents for hepatitis B are effective in hepatitis D. In patients with end-stage liver disease secondary to chronic hepatitis D, liver transplantation has been effective. If hepatitis D recurs in the new liver without the expression of hepatitis B (an unusual serologic profile in immunocompetent persons but common in transplant patients), liver injury is limited. In fact, the outcome of transplantation for chronic hepatitis D is superior to that for chronic hepatitis B; in such patients, combination hepatitis B immune globulin and nucleoside analogue therapy for hepatitis B is indicated (Chap. 368). CHRONIC HEPATITIS C Regardless of the epidemiologic mode of acquisition of hepatitis C virus (HCV) infection, chronic hepatitis follows acute hepatitis C in 50−70% of cases; chronic infection is common even in those with a return to normal in aminotransferase levels after acute hepatitis C, adding up to an 85% likelihood of chronic HCV infection after acute hepatitis C. Few clues had emerged to explain host differences associated with chronic infection until recently, when variation in a single nucleotide polymorphism (SNP) on chromosome 19, IL28B (which codes for IFN-λ3), was identified that distinguished between responders and nonresponders to antiviral therapy (see below). The same variants correlated with spontaneous resolution after acute infection: 53% in genotype C/C, 30% in genotype C/T, but only 23% in genotype T/T. The association with HCV clearance after acute infection is even stronger when IL28B haplotype is combined with haplotype G/G of an SNP near HLA class II DBQ1*03:01. In patients with chronic hepatitis C followed for 20 years, progression to cirrhosis occurs in about 20−25%. Such is the case even for patients with relatively clinically mild chronic hepatitis, including those without symptoms, with only modest elevations of aminotransferase activity, and with mild chronic hepatitis on liver biopsy. Even in cohorts of well-compensated patients with chronic hepatitis C referred for clinical research trials (no complications of chronic liver disease and with normal hepatic synthetic function), the prevalence of cirrhosis may be as high as 50%. Most cases of hepatitis C are identified initially in asymptomatic patients who have no history of acute hepatitis C (e.g., those discovered while attempting to donate blood, while undergoing lab testing as part of an application for life insurance, or as a result of routine laboratory tests). The source of HCV infection in many of these cases is not defined, although a long-forgotten percutaneous exposure (e.g., injection drug use) in the remote past can be elicited in a substantial proportion and probably accounts for most infections; most of these infections were acquired in the 1960s and 1970s, coming to clinical attention decades later.
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Chronic Hepatitis
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necroinflammatory activity or fibrosis, including septal or bridging 2041 fibrosis, progression to cirrhosis is highly likely over the course of 10−20 years. The pace of fibrosis progression may be accelerated by such factors as concomitant HIV infection, other causes of liver disease, excessive alcohol use, and hepatic steatosis. Among patients with compensated cirrhosis associated with hepatitis C, the 10-year survival rate is close to 80%; mortality occurs at a rate of 2−6% per year; decompensation at a rate of 4−5% per year; and, as noted above, HCC at a rate of 1−4% per year. A discussion of the pathogenesis of liver injury in patients with chronic hepatitis C appears in Chap. 360. Clinical features of chronic hepatitis C are similar to those described above for chronic hepatitis B. Generally, fatigue is the most common symptom; jaundice is rare. Immune complex−mediated extrahepatic complications of chronic hepatitis C are less common than in chronic hepatitis B (despite the fact that assays for immune complexes are often positive in patients with chronic hepatitis C), with the exception of essential mixed cryoglobulinemia (Chap. 360), which is linked to cutaneous vasculitis and membranoproliferative glomerulonephritis as well as lymphoproliferative disorders such as B-cell lymphoma and unexplained monoclonal gammopathy. In addition, chronic hepatitis C has been associated with extrahepatic complications unrelated to immune-complex injury. These include Sjögren’s syndrome, lichen planus, porphyria cutanea tarda, type 2 diabetes mellitus, and the metabolic syndrome (including insulin resistance and steatohepatitis). Laboratory features of chronic hepatitis C are similar to those in patients with chronic hepatitis B, but aminotransferase levels tend to fluctuate more (the characteristic episodic pattern of aminotransferase activity) and to be lower, especially in patients with long-standing disease. An interesting and occasionally confusing finding in patients with chronic hepatitis C is the presence of autoantibodies. Rarely, patients with autoimmune hepatitis (see below) and hyperglobulinemia have false-positive immunoassays for anti-HCV. On the other hand, some patients with serologically confirmable chronic hepatitis C have circulating anti-LKM. These antibodies are anti-LKM1, as seen in patients with autoimmune hepatitis type 2 (see below), and are directed against a 33-amino-acid sequence of cytochrome P450 IID6. The occurrence of anti-LKM1 in some patients with chronic hepatitis C may result from the partial sequence homology between the epitope recognized by anti-LKM1 and two segments of the HCV polyprotein. In addition, the presence of this autoantibody in some patients with chronic hepatitis C suggests that autoimmunity may be playing a role in the pathogenesis of chronic hepatitis C. Histopathologic features of chronic hepatitis C, especially those that distinguish hepatitis C from hepatitis B, are described in Chap. 360.
CHAPTER 362
Approximately one-third of patients with chronic hepatitis C have normal or near-normal aminotransferase activity; although one-third to one-half of these patients have chronic hepatitis on liver biopsy, the grade of liver injury and stage of fibrosis tend to be mild in the vast majority. In some cases, more severe liver injury has been reported— even, rarely, cirrhosis, most likely the result of previous histologic activity. Among patients with persistent normal aminotransferase activity sustained over ≥5−10 years, histologic progression has been shown to be rare; however, approximately one-fourth of patients with normal aminotransferase activity experience subsequent aminotransferase elevations, and histologic injury can be progressive once abnormal biochemical activity resumes. Therefore, continued clinical monitoring is indicated, even for patients with normal aminotransferase activity. Despite this substantial rate of progression of chronic hepatitis C, and despite the fact that liver failure can result from end-stage chronic hepatitis C, the long-term prognosis for chronic hepatitis C in a majority of patients is relatively benign. Mortality over 10−20 years among patients with transfusion-associated chronic hepatitis C has been shown not to differ from mortality in a matched population of transfused patients in whom hepatitis C did not develop. Although death in the hepatitis group is more likely to result from liver failure, and although hepatic decompensation may occur in ~15% of such patients over the course of a decade, the majority (almost 60%) of patients remain asymptomatic and well compensated, with no clinical sequelae of chronic liver disease. Overall, chronic hepatitis C tends to be very slowly and insidiously progressive, if at all, in the vast majority of patients, whereas in approximately one-fourth of cases, chronic hepatitis C will progress eventually to end-stage cirrhosis. In fact, because HCV infection is so prevalent, and because a proportion of patients progress inexorably to end-stage liver disease, hepatitis C is the most frequent indication for liver transplantation (Chap. 368). In the United States, hepatitis C accounts for up to 40% of all chronic liver disease, and, as of 2007, mortality caused by hepatitis C surpassed that associated with HIV/AIDS. Moreover, because the prevalence of HCV infection is so much higher in the “baby boomer” cohort borne between 1945 and 1965, three-quarters of the mortality associated with hepatitis C occurs in this age cohort. Referral bias may account for the more severe outcomes described in cohorts of patients reported from tertiary care centers (20-year progression of ≥20%) versus the more benign outcomes in cohorts of patients monitored from initial bloodproduct-associated acute hepatitis or identified in community settings (20-year progression of only 4−7%). Still unexplained, however, are the wide ranges in reported progression to cirrhosis, from 2% over 17 years in a population of women with hepatitis C infection acquired from contaminated anti-D immune globulin to 30% over ≤11 years in recipients of contaminated intravenous immune globulin. Progression of liver disease in patients with chronic hepatitis C has been reported to be more likely in patients with older age, longer duration of infection, advanced histologic stage and grade, more complex quasispecies diversity, increased hepatic iron, concomitant other liver disorders (alcoholic liver disease, chronic hepatitis B, hemochromatosis, α1 antitrypsin deficiency, and steatohepatitis), HIV infection, and obesity. Among these variables, however, duration of infection appears to be one of the most important, and some of the others probably reflect disease duration to some extent (e.g., quasispecies diversity, hepatic iron accumulation). No other epidemiologic or clinical features of chronic hepatitis C (e.g., severity of acute hepatitis, level of aminotransferase activity, level of HCV RNA, presence or absence of jaundice during acute hepatitis) are predictive of eventual outcome. Despite the relatively benign nature of chronic hepatitis C over time in many patients, cirrhosis following chronic hepatitis C has been associated with the late development, after several decades, of HCC (Chap. 111); the annual rate of HCC in cirrhotic patients with hepatitis C is 1−4%, occurring primarily in patients who have had HCV infection for 30 years or more. Perhaps the best prognostic indicator in chronic hepatitis C is liver histology; the rate of hepatic fibrosis may be slow, moderate, or rapid. Patients with mild necrosis and inflammation as well as those with limited fibrosis have an excellent prognosis and limited progression to cirrhosis. In contrast, among patients with moderate to severe
TREATMENT
Chronic Hepatitis C
Therapy for chronic hepatitis C has evolved substantially in the two decades since IFN-α was introduced for this indication. The therapeutic armamentarium has grown to include PEG IFN with ribavirin and, in 2011, the introduction of protease inhibitors telaprevir and boceprevir used in combination with PEG IFN and ribavirin in patients with HCV genotype 1. When first approved, IFN-α was administered via subcutaneous injection three times a week for 6 months but achieved a sustained virologic response (SVR) (Fig. 362-2) (a reduction of HCV RNA to undetectable levels by PCR when measured ≥6 months after completion of therapy) below 10%. Doubling the duration of therapy—but not increasing the dose or changing IFN preparations—increased the SVR rate to ~20%, and addition to the regimen of daily ribavirin, an oral guanosine nucleoside, increased the SVR rate to 40%. When used alone, ribavirin is ineffective and does not reduce HCV RNA levels appreciably, but ribavirin enhances the efficacy of IFN by reducing the likelihood of virologic relapse after the achievement of an end-treatment response (Fig. 362-2) (response measured during, and maintained to the end of, treatment). Proposed mechanisms to explain the role of ribavirin include subtle direct reduction of HCV replication, inhibition of host inosine monophosphate dehydrogenase activity (and associated depletion
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2042
Peginterferon and Ribavirin
HCV RNA log10 IU/ml
7 6
Null Nonresponse Partial
5 4
Relapse
3 2 1
RVR
Undetectable
PART 14
0 –8 –4 –2
0
EVR
ETR
SVR
4 8 12 16 20 24 32 40 48 52 60 72 Weeks after start of therapy
Disorders of the Gastrointestinal System
Figure 362-2 Classification of virologic responses based on outcomes during and after a 48-week course of pegylated interferon (PEG IFN) plus ribavirin antiviral therapy in patients with hepatitis C, genotype 1 or 4 (for genotype 2 or 3, the course would be 24 weeks). Nonresponders can be classified as null responders (hepatitis C virus [HCV] RNA reduction of 1 log10 or ≥1 log10 IU/mL) during the 4-week PEG IFN–ribavirin lead-in phase; (2) during boceprevir therapy, undetectable HCV RNA at week 8 (week 4 of triple-drug therapy; RVR); and (3) among telaprevir-treated patients, undetectable HCV RNA at week 4 and 12 (extended RVR). (Reproduced with permission, courtesy of Marc G. Ghany, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and the American Association for the Study of Liver Diseases. Hepatology 49:1335, 2009.) of guanosine pools), immune modulation, induction of virologic mutational catastrophe, and enhancement of IFN-stimulated gene expression. IFN therapy results in activation of the JAK-STAT signal transduction pathway, which culminates in the intracellular elaboration of genes and their protein products that have antiviral properties. Hepatitis C proteins inhibit JAK-STAT signaling at several steps along the pathway, and exogenous IFN restores expression of IFNstimulated genes and their antiviral effects. Treatment with the combination of PEG IFN and ribavirin increased responsiveness (frequency of SVR) to as high as 55% overall, to >40% in genotypes 1 and 4, and to >80% in genotypes 2 and 3. Still, many important lessons about antiviral therapy for chronic hepatitis C were learned from the experience with IFN monotherapy and combination IFN-ribavirin therapy. Even in the absence of biochemical and virologic responses, histologic improvement occurs in approximately three-fourths of all treated patients. In chronic hepatitis C, unlike the case in hepatitis B, responses to therapy are not accompanied by transient, acute hepatitis-like aminotransferase elevations. Instead, ALT levels fall precipitously during therapy. Up to 90% of virologic responses are achieved within the first 12 weeks of therapy; responses thereafter are rare. Most relapses occur within the first 12 weeks after treatment; therefore, an SVR at week 12 posttreatment is roughly equivalent to a 24-week SVR. SVRs are very durable; normal ALT, improved histology, and absence of HCV RNA in serum and liver have been documented a decade after successful
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therapy, and “relapses” 2 years after sustained responses are almost unheard of. Thus, an SVR to antiviral therapy of chronic hepatitis C is tantamount to a cure. Patient variables that tend to correlate with sustained virologic responsiveness to IFN-based therapy include favorable genotype (genotypes 2 and 3 as opposed to genotypes 1 and 4); low baseline HCV RNA level (85 kg) by raising the dose of PEG IFN (e.g., to as high as 270 μg of PEG IFN-α2a) and/or the dose of ribavirin to as high as 1600 mg daily (if tolerated or supplemented by erythropoietin) or by tailoring treatment based on viral response to prolong the duration of viral clearance before discontinuing therapy, i.e., extending therapy from 48 to 72 weeks for patients with genotype 1 and a slow virologic response (i.e., those whose HCV RNA has not fallen rapidly to undetectable levels within 4 weeks [absence of RVR]). Tailoring therapy based on the kinetics of HCV RNA reduction has also been applied to abbreviating the duration of therapy in patients with genotype 1 (and 4). The results of several clinical trials suggest that, in patients with genotype 1 (and 4) who have a 4-week RVR (which occurs in ≤20%), especially in the subset with low baseline HCV RNA, 24 weeks of therapy with PEG IFN and weight-based ribavirin suffices, yielding SVR rates of ~90% and comparable to those achieved in this cohort with 48 weeks of therapy. Although initial reports suggested that, for patients with genotype 2 and (somewhat less so) genotype 3, in rapid virologic responders with undetectable HCV RNA at week 4, the total duration of therapy required to achieve an SVR could be as short as 12−16 weeks, a very sizable, definitive subsequent trial showed that relapse is increased if treatment duration is curtailed and that a full 24 weeks is superior for these genotypes (except for the minority with very low baseline levels of HCV RNA). Persons with chronic HCV infection have been shown to suffer increased liver-related mortality. On the other hand, successful antiviral therapy of chronic hepatitis C resulting in an SVR has been shown to improve survival (and to reduce the need for liver transplantation), to lower the risk of liver failure and liver-related death and all-cause deaths, to slow the progression of chronic hepatitis C, and to reverse fibrosis and even cirrhosis. Although successful treatment reduces mortality in cirrhotic patients (and those with advanced fibrosis) and reduces the likelihood of HCC, the risk of liver-related death and HCC persists, albeit at a much reduced level, necessitating continued clinical monitoring and cancer surveillance after SVR in cirrhotics. On the other hand, in the absence of an SVR,
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routine-dose/duration IFN-based therapy does not reduce the risk of HCC. Similarly, for nonresponders to PEG IFN–ribavirin therapy, three trials of long-term maintenance therapy with PEG IFN have shown no benefit in reducing the risk of histologic progression or clinical decompensation, including the development of HCC. For PEG IFN–ribavirin nonresponders who have had a full, adequate course of therapy, the benefit of retreatment—with higher doses or a longer course of the original PEG IFN regimen or the alternative PEG IFN regimen or with a different type of IFN preparation (e.g., consensus IFN)—is marginal at best. Fortunately, such nonresponders can now be retreated with protease inhibitor-based therapy (see following). FIRST-GENERATION PROTEASE INHIBITORS (2011–2013) The HCV RNA genome encodes a single polyprotein, which is cleaved during and after translation by host and viral-encoded proteases. One protease involved in the cleavage of the viral polyprotein is an NS3-4A viral protein that has serine protease activity. Telaprevir and boceprevir are serine protease inhibitors that target NS3-4A. In 2011, telaprevir and boceprevir used in combination with PEG IFN and ribavirin were approved by the U.S. Food and Drug Administration (FDA) for the treatment of hepatitis C genotype 1 in adults with stable liver disease, both in patients who have not been treated before or who have failed previous treatment. Because the presently available HCV protease inhibitors have not been studied comprehensively in patients with genotypes other than 1, their use in these populations is not recommended. Because resistance develops rapidly, both telaprevir and boceprevir must be used in combination with a PEG IFN and ribavirin-based regimen and should never be used alone. Ribavirin in particular appears to reduce relapse rates significantly in protease inhibitor– based regimens, such that those who cannot take or are intolerant to ribavirin are unlikely to benefit from the addition of these agents. All current telaprevir and boceprevir regimens consist of periods of triple therapy (protease inhibitor plus PEG IFN plus ribavirin) and periods of dual therapy (PEG IFN plus ribavirin). Telaprevir regimens begin with 12 weeks of triple therapy followed by dual therapy of a duration based on HCV RNA status at weeks 4 and 12 (“responseguided therapy”) and prior treatment status. Boceprevir-based regimens consist of a 4-week lead-in period of dual (PEG IFN–ribavirin) therapy followed by triple therapy and, in some instances, a further extension of dual therapy, with duration of response-guided therapy based on HCV RNA status at weeks 4, 8, and 24 and prior treatment status (Table 362-7). For patients with HCV genotype 1, protease inhibitors have significantly improved the frequency of RVRs and SVRs as compared to PEG IFN plus ribavirin alone. In treatment-naïve patients treated with telaprevir, an SVR was seen in up to 79% of patients who received 12 weeks of triple therapy followed by 12–36 weeks of dual therapy, and among those with EVRs (undetectable HCV RNA at weeks 4 and 12) and response-guided therapy stopped at week 24 (12 weeks of triple therapy, then 12 weeks of dual therapy), the rate of SVRs was 83–89% (92% in a subsequent study). In studies with boceprevir in treatment-naïve patients, SVRs were seen in 59–66% of patients, and among those with undetectable HCV RNA at 8 weeks, the SVR rate increased to 86–88%. Protease inhibitors have also been studied in patients previously treated unsuccessfully with PEG IFN plus ribavirin. In studies with telaprevir, SVRs were seen in 83–88% of patients who had a previous relapse, 54–59% of partial responders (HCV RNA reduced by ≥2 log10 IU/mL but not to undetectable levels), and 29–33% of null responders (HCV RNA reduced by 85–105 kg), or 1400 mg/d (>105 kg) Plus response-guided therapy with a protease inhibitor consisting of either: Boceprevir 800 mg three times daily with food started after a lead-in treatment of 4 weeks with PEG IFN–ribavirin • Patients with undetectable HCV RNA at 8 and 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, boceprevir) through week 28 (4 weeks of PEG IFN–ribavirin then 24 weeks of triple-drug therapy). If HCV RNA is detectable at 4 weeks, continuing therapy through 48 weeks (4 weeks of PEG IFN–ribavirin then 44 weeks of triple-drug therapy) may increase the sustained response rate. • Patients with detectable HCV RNA at 8 weeks and undetectable at 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, boceprevir) through week 36 (4 weeks of PEG IFN–ribavirin then 32 weeks of triple-drug therapy) followed by a return to PEG IFN–ribavirin for 12 more weeks, for a total treatment duration of 48 weeks. • Patients with cirrhosis who are treatment-naive and have undetectable HCV RNA at weeks 8 and 24 should continue triple-drug therapy (PEG IFN, ribavirin, boceprevir) through 48 weeks (4 weeks of PEG IFN–ribavirin then 44 weeks of triple-drug therapy). • Stopping rules for futility: HCV RNA ≥100 IU/mL at week 12 or any detectable HCV RNA at week 24 or Telaprevir 750 mg three times daily with fatty food started at the beginning of therapy without a PEG IFN–ribavirin lead-in • Patients with undetectable HCV RNA at 4 and 12 weeks should receive triple-drug therapy (PEG IFN, ribavirin, telaprevir) for 12 weeks then PEG IFN and ribavirin for another 12 weeks, for a total of 24 weeks. • Patients with detectable HCV RNA at 4 or 12 weeks and undetectable at 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, telaprevir) for 12 weeks, then PEG IFN–ribavirin for another 36 weeks, for a total treatment duration of 48 weeks. • Patients with cirrhosis who are treatment-naïve and have undetectable HCV RNA at 4 and 12 weeks should receive triple-drug therapy for 12 weeks then PEG IFN–ribavirin for another 36 weeks, for a total treatment duration of 48 weeks. • Stopping rules for futility: HCV RNA >1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24 TREATMENT-EXPERIENCED PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) Plus a protease inhibitor consisting of either: Response-guided therapy with boceprevir 800 mg three times daily with food started after a lead-in treatment of 4 weeks with PEG IFN–ribavirin • For prior relapsers and partial responders (HCV RNA reduction of ≥2 log10 during previous therapy), follow the response-guided algorithm below; for prior null responders (HCV RNA reduction 1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24 HCV genotype 1 but protease inhibitors unavailable or contraindicated: 48 weeks of therapy PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) HCV genotype 4: 48 weeks of PEG IFN–ribavirin therapy PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) • Treatment should be discontinued in patients who do not achieve an early virologic response at week 12. • Patients who do achieve an early virologic response should be retested at week 24, and treatment should be discontinued if HCV RNA remains detectable. HCV genotypes 2 and 3: 24 weeks of therapy PEG IFN-α2a 180 μg weekly plus ribavirin 800 mg/d or PEG IFN-α2b 1.5 μg/kg weekly plus ribavirin 800 mg/d (for patients with genotype 3 who have advanced fibrosis and/or high-level HCV RNA, a full 48 weeks of therapy may be preferable) For HCV/HIV co-infected patients: 48 weeks, regardless of genotype, of weekly PEG IFN-α2a (180 μg) or PEG IFN-α2b (1.5 μg/kg) plus a daily ribavirin dose of at least 600–800 mg, up to full weight-based 1000–1400 mg dosing if tolerated. Protease inhibitors may be used for genotype 1; however, because of potential drug-drug interactions between HCV protease inhibitors and HIV antiretroviral drugs, HCV protease inhibitors should be used cautiously in HCV/HIV co-infected patients. If protease inhibitors are used, a full 48-week course is recommended without response-guided therapy. For boceprevir, 4 weeks of PEG IFN–ribavirin lead-in, followed by 44 weeks of triple-drug therapy (PEG IFN, ribavirin, boceprevir). For telaprevir, 12 weeks of triple-drug therapy (PEG IFN, ribavirin, telaprevir), followed by 36 weeks of PEG IFN–ribavirin therapy. Stopping rules for futility are as noted above. Features Associated with Reduced Responsiveness Single nucleotide polymorphism (SNP) T allele (as opposed to C allele) at IL28B locus Genotype 1a (compared to 1b) High-level HCV RNA (>800,000 IU/mL)b Advanced fibrosis (bridging fibrosis, cirrhosis) Long-duration disease Age >40b High HCV quasispecies diversity Immunosuppression African-American ethnicity Latino ethnicity Obesity Hepatic steatosis Insulin resistance, type 2 diabetes mellitusb Reduced adherence (lower drug doses and reduced duration of therapy) For boceprevir, black ethnicity), lower in prior partial responders, lower still in prior null responders, and lowest in cirrhotic prior null responders (Fig. 362-3). Responses to protease inhibitor triple-drug regimens are higher in patients with IL28B C than non-C genotypes, HCV genotype 1b than genotype 1a, less advanced than more advanced fibrosis stage, whites than blacks, lower body mass index (BMI) than elevated BMI, and, for boceprevir, achievement of a >1 log10 HCV RNA reduction during 4 weeks of
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PEG IFN–ribavirin lead-in therapy. Age and HCV RNA level are less influential and insulin resistance is noninfluential on response to these antiviral agents. Both protease inhibitors have potential toxicities. Telaprevir is associated with a severe, generalized (trunk and extremities), often confluent, maculopapular, pruritic rash in ~6% of treated patients. Other common side effects include pruritus, rectal burning, nausea, diarrhea, fatigue, and anemia, which may be relatively refractory,
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% with sustained virologic response
100% 80%
86%
79%
75% 66%
52%
60%
59% 38%
40%
31% 14%
20% 0% Treatmentnaïve
Partial responder
Null responder
Cirrhotic null responder
occasionally requiring transfusion. Complete blood counts should be obtained at baseline and then at 2, 4, 8, and 12 weeks after starting telaprevir. Anemia can occur in half of boceprevir-treated patients, as can neutropenia in up to 30% and thrombocytopenia in 3–4%. Complete blood counts should be obtained at baseline and then at 4, 8, and 12 weeks after starting boceprevir. Other side effects of boceprevir include fatigue, nausea, headache, dysgeusia (altered or unpleasant taste), dry mouth, vomiting, and diarrhea. Use of protease inhibitors is further complicated by numerous drug-drug interactions. As telaprevir and boceprevir are both eliminated by and inhibit CYP3A4, these agents should not be administered with other medications that induce CYP3A4 or are dependent on CYP3A4 for elimination. Care should be taken to examine for any potential interactions between protease inhibitors and other medications the patient may be taking, because serious adverse events can occur. A convenient website is available to check for such drugdrug interactions (www.hep-druginteractions.org). TREATMENT RECOMMENDATIONS* Prior to therapy, HCV genotype should be determined, because the genotype dictates the duration of therapy and potentially the agents to be used. PEG IFN plus ribavirin represents the foundation of treatment for all HCV genotypes; patients infected with genotype 1 should also receive a protease inhibitor (telaprevir or boceprevir) when these are available and not contraindicated (Table 362-7). For chronic HCV genotype 1 infection, the AASLD and EASL published treatment guidelines in 2011 reflecting FDA-approved indications for the new protease inhibitors, and in 2012, United Kingdom and French consensus guidelines were published. For treatment-naïve patients and prior relapsers, response-guided therapy with telaprevir or boceprevir is recommended. For telaprevir, the regimen consists of 12 weeks of triple therapy, followed by 12 or 36 weeks of PEG IFN–ribavirin consolidation, depending on whether extended RVR milestones (HCV RNA undetectable at weeks 4 and 12) are met. *As this chapter was going to press, two additional antiviral drugs, a second-generation protease inhibitor simeprevir and nucleoside analogue polymerase inhibitor sofosbuvir were approved for the treatment of hepatitis C. Simerprevir, which is effective for genotype 1, must be administered, like first-generation protease inhibitors, for 12 weeks with PEG IFN and ribavirin, followed by another 12 weeks of PEG IFN and ribavirin (no response-guided therapy). Sofosbuvir, the more convenient and broadly applicable of the two new drugs, must be administered with PEG IFN and ribavirin but for only 12 weeks in patients with genotyes 1, 4-6; for patients with genotypes 2 and 3, PEG IFN is not required. Sofosbuvir plus ribavirin are administered for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Antiviral therapy is evolving very rapidly; by the end of 2014, all-oral, interferon-free combinations (e.g., sofosbuvir plus the NS5a inhibitor ledipasvir) will supplant earlier treatment regimens. For updated treatment recommendations, please consult www.hcvguidelines.org.
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Chronic Hepatitis
Figure 362-3 Maximal efficacy (sustained virologic responses, SVR) of telaprevir (blue bars) and boceprevir (yellow bars) reported in phase III clinical trials. (Figure created using data from Bacon BR et al: N Engl J Med 364:1207, 2011; Jacobson IM et al: N Engl J Med 364:2405, 2011; Poordad F et al: N Engl J Med 364:1195, 2011; Zeuzem S et al: N Engl J Med 364:2417, 2011; Vierling JM et al: Hepatology 54 [Suppl 1]:796A-797A, 2011; Ghany MG et al: Hepatology 54:1433, 2011.)
CHAPTER 362
Relapsers
For boceprevir, the regimen consists of a 4-week PEG IFN–ribavirin 2047 lead-in period, followed by 24–32 weeks of triple-drug therapy, depending on whether HCV RNA milestones (undetectable at weeks 8 and 24) are met; if HCV RNA is detectable at week 8 but undetectable at week 24, after 36 weeks of therapy (4-week PEG IFN–ribavirin lead-in plus 32 weeks of triple-drug therapy), an additional 12 weeks of PEG IFN–ribavirin consolidation is recommended. For prior partial and null responders, a full 48-week course of telaprevir (no lead-in period, no response-guided therapy) is recommended; for boceprevir, a 4-week PEG IFN–ribavirin lead-in period is followed by response-guided therapy (32 weeks of triple-drug therapy if HCV RNA is undetectable at weeks 8 and 24 or, if HCV RNA is still detectable at week 8 [but undetectable at week 24], 32 weeks of tripledrug therapy followed by 12 weeks of PEG IFN–ribavirin consolidation). For cirrhotic patients (and for any boceprevir-treated patient whose HCV RNA does not fall by >1 log10 by week 4), a full 48-week course without response-guided therapy should be considered. Monitoring of HCV plasma RNA is crucial in assessing response to therapy. The goal of treatment is to eradicate HCV RNA, which is predicted by the absence of HCV RNA by PCR 6 months after stopping treatment (SVR). When therapy relied on PEG IFN and ribavirin, failure to achieve a 2-log10 drop in HCV RNA by week 12 of therapy (EVR) rendered it unlikely that further therapy would result in an SVR. When PEG IFN and ribavirin are part of a protease inhibitor regimen, HCV RNA should be measured at baseline and at weeks 4, 8 (for boceprevir), 12, and 24 to assess response to treatment and to aid in decisions regarding treatment duration (response-guided therapy), as well as 12 and 24 weeks after therapy. Stopping rules are important to prevent the emergence of resistance; if HCV RNA is >1000 IU/ mL at 4 or 12 weeks of telaprevir (or still detectable at week 24), or if HCV RNA is ≥100 IU/mL at week 12 of boceprevir (or detectable at week 24), all treatment should be stopped. INDICATIONS FOR ANTIVIRAL THERAPY* Patients with chronic hepatitis C who have detectable HCV RNA in serum, whether or not aminotransferase levels are increased, and chronic hepatitis of at least moderate grade and stage (portal or bridging fibrosis) are candidates for antiviral therapy with PEG IFN plus ribavirin. Most authorities recommend 800 mg of ribavirin for patients with genotypes 2 and 3 for both types of PEG IFN and weight-based 1000−1200 mg (when used with PEG IFN-α2a) or 800−1400 mg (when used with PEG IFN-α2b) ribavirin for patients with genotype 1 (and 4), unless ribavirin is contraindicated (Table 362-7). These PEG IFN and ribavirin doses are used with protease inhibitors for patients with genotype 1 (Table 362-7). Although patients with persistently normal ALT activity tend to progress histologically very slowly or not at all, they respond to antiviral therapy just as well as do patients with elevated ALT levels; therefore, although observation without therapy is an option, such patients are potential candidates for antiviral therapy. As noted above, therapy with IFN has been shown to improve survival and complication-free survival and to slow progression of (and to reverse) fibrosis. HCV genotype determines the duration of PEG IFN and ribavirin therapy: 24 weeks for those with genotypes 2 and 3 and 48 weeks for patients with genotypes 4 and 1 (in patients for whom protease inhibitors are not available or contraindicated). For patients with genotype 4, treatment should be discontinued in patients who do not achieve an EVR at week 12. For patients with genotypes 2 and 3, a full, 24-week course is most effective, although the duration may be reduced to 12−16 weeks for patients with genotype 2, a low baseline level of viremia, and an RVR, especially to be considered for patients who tolerate therapy poorly. Also, consideration should be given to increasing the duration of therapy to 48 weeks for patients with genotype 3 who have advanced fibrosis and/or a high baseline level of viremia. As noted above, the absence of a 2-log10 drop in HCV RNA at week 12 (EVR) weighs heavily against the likelihood of an SVR; therefore, measuring HCV RNA at 12 weeks is recommended routinely (Fig. 362-2), and therapy can be discontinued if an EVR is not achieved. Among patients with genotype 4 who achieve an
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2048 EVR (≥2-log10 HCV RNA reduction) but in whom HCV RNA remains
PART 14 Disorders of the Gastrointestinal System
detectable at week 24, an SVR is unlikely, and therapy can be discontinued. Although response rates are lower in patients with certain pretreatment variables, selection for treatment should not be based on symptoms, genotype, HCV RNA level, mode of acquisition of hepatitis C, or advanced hepatic fibrosis. Patients with cirrhosis can respond and should not be excluded as candidates for therapy. For patients being treated with telaprevir and boceprevir, treating physicians should explain the negative impact of non-C IL28B genotype and advanced fibrosis on outcome. Patients who have relapsed after, or failed to respond to (Fig. 362-2), a course of IFN monotherapy are potential candidates for retreatment with PEG IFN plus ribavirin (i.e., a more effective treatment regimen is required), and this approach remains current for patients with genotypes 2, 3, or 4; however, for patients with genotype 1, combination protease inhibitor/PEG IFN/ribavirin therapy is indicated. For patients with genotypes 2, 3, or 4 who were nonresponders to a prior course of IFN monotherapy, retreatment with IFN monotherapy or combination IFN plus ribavirin therapy is unlikely to achieve an SVR; however, a trial of combination PEG IFN plus ribavirin may be worthwhile, although an SVR is the outcome in 2.5 g/dL) is common in autoimmune hepatitis, as is the presence of rheumatoid factor. As noted above, circulating autoantibodies are also prevalent, most characteristically ANAs in a homogeneous staining pattern. Smooth-muscle antibodies are less specific, seen just as frequently in chronic viral hepatitis. Because of the high levels of globulins achieved in the circulation of some patients with autoimmune hepatitis, occasionally the globulins may bind nonspecifically in solid-phase binding immunoassays for viral antibodies. This has been recognized most commonly in tests for antibodies to hepatitis C virus, as noted above. In fact, studies of autoantibodies in autoimmune hepatitis have led to the recognition of new categories of autoimmune hepatitis. Type I autoimmune hepatitis is the classic syndrome prevalent in North America and northern Europe occurring in young women, associated with marked hyperglobulinemia, lupoid features, circulating ANAs, and HLA- DR3 or HLA-DR4 (especially B8-DRB1*03). Also associated with type I autoimmune hepatitis are autoantibodies against actin and atypical perinuclear antineutrophilic cytoplasmic antibodies (pANCA). Type II autoimmune hepatitis, often seen in children, more common in Mediterranean populations, and linked to HLA- DRB1 and HLA-DQB1 haplotypes, is associated not with ANA but with antiLKM. Actually, anti-LKM represent a heterogeneous group of antibodies. In type II autoimmune hepatitis, the antibody is anti-LKM1, directed against cytochrome P450 2D6. This is the same anti-LKM seen in some patients with chronic hepatitis C. Anti-LKM2 is seen in drug-induced hepatitis, and anti-LKM3 (directed against uridine diphosphate glucuronyltransferases) is seen in patients with chronic hepatitis D. Another autoantibody observed in type II autoimmune hepatitis is directed against liver cytosol formiminotransferase cyclodeaminase (anti-liver cytosol 1). More controversial is whether or not a third category of autoimmune hepatitis exists, type III autoimmune hepatitis. These patients lack ANA and anti-LKM1 but have circulating antibodies to soluble liver antigen. Most of these patients are women and have clinical features similar to, perhaps more severe than, those of patients with type I autoimmune hepatitis. Type III autoimmune hepatitis does not appear to represent a distinct category but, instead, is part of the spectrum of type I autoimmune hepatitis; this subcategory has not been adopted by a consensus of international experts. Liver biopsy abnormalities are similar to those described for chronic viral hepatitis. Expanding portal tracts and extending beyond the plate of periportal hepatocytes into the parenchyma (designated interface hepatitis or piecemeal necrosis) is a mononuclear cell infiltrate that, in autoimmune hepatitis, may include the presence of plasma cells. Necroinflammatory activity characterizes the lobular parenchyma, and evidence of hepatocellular regeneration is reflected by “rosette” formation, the occurrence of thickened liver cell plates, and regenerative “pseudolobules.” Septal fibrosis, bridging fibrosis, and cirrhosis are frequent. In patients with early autoimmune hepatitis presenting as an acute-hepatitis-like illness, lobular and centrilobular (as opposed to the more common periportal) necrosis has been reported. Bile duct injury and granulomas are uncommon; however,
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a subgroup of patients with autoimmune hepatitis has histologic, biochemical, and serologic features overlapping those of primary biliary cirrhosis (Chap. 365).
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The mainstay of management in autoimmune hepatitis is glucocorticoid therapy. Several controlled clinical trials have documented that such therapy leads to symptomatic, clinical, biochemical, and histologic improvement as well as increased survival. A therapeutic response can be expected in up to 80% of patients. Unfortunately, therapy has not been shown in clinical trials to prevent ultimate progression to cirrhosis; however, instances of reversal of fibrosis and cirrhosis have been reported in patients responding to treatment, and rapid treatment responses within 1 year do translate into a reduction in progression to cirrhosis. Although some advocate the use of prednisolone (the hepatic metabolite of prednisone), prednisone is just as effective and is favored by most authorities. Therapy may be initiated at 20 mg/d, but a popular regimen in the United States relies on an initiation dose of 60 mg/d. This high dose is tapered successively over the course of a month down to a maintenance level of 20 mg/d. An alternative, but equally effective, approach is to begin with half the prednisone dose (30 mg/d) along with azathioprine (50 mg/d). With azathioprine maintained at 50 mg/d, the prednisone dose is tapered over the course of a month down to a maintenance level of 10 mg/d. The advantage of the combination approach is a reduction, over the span of an 18-month course of therapy, in serious, life-threatening complications of steroid therapy (e.g., cushingoid features, hypertension, diabetes, osteoporosis) from 66% down to under 20%. Genetic analysis for thiopurine S-methyltransferase allelic variants does not correlate with azathioprine-associated cytopenias or efficacy and is not assessed routinely in patients with autoimmune hepatitis. In combination regimens, 6-mercaptopurine may be substituted for its prodrug azathioprine, but this is rarely required. Azathioprine alone, however, is not effective in achieving remission, nor is alternateday glucocorticoid therapy. Limited experience with budesonide in noncirrhotic patients suggests that this steroid side effect−sparing drug may be effective. Although therapy has been shown to be effective for severe autoimmune hepatitis (AST ≥10 × the upper limit of normal or ≥5 × the upper limit of normal in conjunction with serum globulin greater than or equal to twice normal; bridging necrosis or multilobular necrosis on liver biopsy; presence of symptoms), therapy is not indicated for mild forms of chronic hepatitis, and the efficacy of therapy in mild or asymptomatic autoimmune hepatitis has not been established. Improvement of fatigue, anorexia, malaise, and jaundice tends to occur within days to several weeks; biochemical improvement occurs over the course of several weeks to months, with a fall in serum bilirubin and globulin levels and an increase in serum albumin. Serum aminotransferase levels usually drop promptly, but improvements in AST and ALT alone do not appear to be reliable markers of recovery in individual patients; histologic improvement, characterized by a decrease in mononuclear infiltration and in hepatocellular necrosis, may be delayed for 6−24 months. Still, if interpreted cautiously, aminotransferase levels are valuable indicators of relative disease activity, and many authorities do not advocate for serial liver biopsies to assess therapeutic success or to guide decisions to alter or stop therapy. Rapidity of response is more common in older patients (≥69 years) and those with HLA DBR1*04; although rapid responders may progress less slowly to cirrhosis and liver transplantation, they are no less likely than slower responders to relapse after therapy. Therapy should continue for at least 12−18 months. After tapering and cessation of therapy, the likelihood of relapse is at least 50%, even if posttreatment histology has improved to show mild chronic hepatitis, and the majority of patients require therapy at maintenance doses indefinitely. Continuing azathioprine alone (2 mg/kg body weight daily) after cessation of prednisone therapy has been shown to reduce the frequency of relapse. Long-term maintenance with low-dose prednisone (≤10 mg daily) has also been shown to keep autoimmune hepatitis in check, but maintenance azathioprine is more effective in maintaining remission.
Chronic Hepatitis
DIFFERENTIAL DIAGNOSIS Early during the course of chronic hepatitis, autoimmune hepatitis may resemble typical acute viral hepatitis (Chap. 360). Without histologic assessment, severe chronic hepatitis cannot be readily distinguished based on clinical or biochemical criteria from mild chronic hepatitis. In adolescence, Wilson’s disease (Chaps. 365 and 429) may present with features of chronic hepatitis long before neurologic manifestations become apparent and before the formation of Kayser-Fleischer rings (copper deposition in Descemet’s membrane in the periphery of the cornea). In this age group, serum ceruloplasmin and serum and urinary copper determinations plus measurement of liver copper levels establish the correct diagnosis. Postnecrotic or cryptogenic cirrhosis and primary biliary cirrhosis (Chap. 365) share clinical features with autoimmune hepatitis, and both alcoholic hepatitis (Chap. 363) and nonalcoholic steatohepatitis (Chap. 367e) may present with many features common to autoimmune hepatitis; historic, biochemical, serologic, and histologic assessments are usually sufficient to allow these entities to be distinguished from autoimmune hepatitis. Of course, the distinction between autoimmune and chronic viral hepatitis is not always straightforward, especially when viral antibodies occur in patients with autoimmune disease or when autoantibodies occur in patients with viral disease. Furthermore, the presence of extrahepatic features such as arthritis, cutaneous vasculitis, or pleuritis—not to mention the presence of circulating autoantibodies—may cause confusion with rheumatologic disorders such as rheumatoid arthritis and systemic lupus erythematosus. The existence of clinical and biochemical features of progressive necroinflammatory liver disease distinguishes chronic hepatitis from these other disorders, which are not associated with severe liver disease. Rarely, hepatic venous outflow obstruction (Budd-Chiari syndrome) may present with features suggestive of autoimmune hepatitis, but painful hepatomegaly, ascites, and vascular imaging provide distinguishing diagnostic clues. Other diagnostic considerations would include celiac disease and ischemic liver disease, which would be readily distinguishable by clinical and laboratory features from autoimmune hepatitis. Finally, occasionally, features of autoimmune hepatitis overlap with features of autoimmune biliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis (Chaps. 365 and 369), or, even more rarely, mitochondrial antibody-negative autoimmune cholangitis. Such overlap syndromes are difficult to categorize, and often response to therapy may be the distinguishing factor that establishes the diagnosis.
2051
Autoimmune Hepatitis
CHAPTER 362
DIAGNOSTIC CRITERIA An international group has suggested a set of criteria for establishing a diagnosis of autoimmune hepatitis. Exclusion of liver disease caused by genetic disorders, viral hepatitis, drug hepatotoxicity, and alcohol are linked with such inclusive diagnostic criteria as hyperglobulinemia, autoantibodies, and characteristic histologic features. This international group has also suggested a comprehensive diagnostic scoring system that, rarely required for typical cases, may be helpful when typical features are not present. Factors that weigh in favor of the diagnosis include female gender; predominant aminotransferase elevation; presence and level of globulin elevation; presence of nuclear, smooth muscle, LKM1, and other autoantibodies; concurrent other autoimmune diseases; characteristic histologic features (interface hepatitis, plasma cells, rosettes); HLA-DR3 or -DR4 markers; and response to treatment (see below). A more simplified, more specific scoring system relies on four variables: autoantibodies, serum IgG level, typical or compatible histologic features, and absence of viral hepatitis markers. Weighing against the diagnosis are predominant alkaline phosphatase elevation, mitochondrial antibodies, markers of viral hepatitis, history of hepatotoxic drugs or excessive alcohol, histologic evidence of bile duct injury, or such atypical histologic features as fatty infiltration, iron overload, and viral inclusions.
TREATMENT
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In medically refractory cases, an attempt should be made to intensify treatment with high-dose glucocorticoid monotherapy (60 mg daily) or combination glucocorticoid (30 mg daily) plus high-dose azathioprine (150 mg daily) therapy. After a month, doses of prednisone can be reduced by 10 mg a month, and doses of azathioprine can be reduced by 50 mg a month toward ultimate, conventional maintenance doses. Patients refractory to this regimen may be treated with cyclosporine, tacrolimus, or mycophenolate mofetil; however, to date, only limited anecdotal reports support these approaches. If medical therapy fails, or when chronic hepatitis progresses to cirrhosis and is associated with life-threatening complications of liver decompensation, liver transplantation is the only recourse (Chap. 368); failure of the bilirubin to improve after 2 weeks of therapy should prompt early consideration of the patient for liver transplantation. Recurrence of autoimmune hepatitis in the new liver occurs rarely in most experiences but in as many as 35−40% of cases in others. Like all patients with chronic liver disease, patients with autoimmune hepatitis should be vaccinated against hepatitis A and B, ideally before immunosuppressive therapy is begun, if practical. Acknowledgment Kurt J. Isselbacher, MD, contributed to this chapter in previous editions of Harrison’s.
363
Alcoholic Liver Disease Mark E. Mailliard, Michael F. Sorrell
Chronic and excessive alcohol ingestion is one of the major causes of liver disease. The pathology of alcoholic liver disease consists of three major lesions, with the progressive injury rarely existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. Fatty liver is present in >90% of daily as well as binge drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; the mortality of patients with alcoholic hepatitis concurrent with cirrhosis is nearly 60% at 4 years. Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of alcoholics will develop alcoholic hepatitis. The explanation for this apparent paradox is unclear but involves the complex interaction of facilitating factors, such as drinking patterns, diet, obesity, and gender. There are no diagnostic tools that can predict individual susceptibility to alcoholic liver disease. GLOBAL CONSIDERATIONS Alcohol is the world’s third largest risk factor for disease burden. The harmful use of alcohol results in 2.5 million deaths each year. Most of the mortality attributed to alcohol is secondary to cirrhosis. Mortality from cirrhosis is declining in most Western countries, concurrent with a reduction in alcohol consumption, with the exceptions of the United Kingdom, Russia, Romania, and Hungary. These increases in cirrhosis and its complications are closely correlated with increased volume of alcohol consumed per capita population and are regardless of gender. ETIOLOGY AND PATHOGENESIS Quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver disease (Table 363-1). The roles of beverage type(s), i.e. wine, beer, or spirits, and pattern of drinking (daily versus binge drinking) are less clear. Progress beyond the fatty liver stage seems to require additional risk
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Table 363-1 Risk Factors for Alcoholic Liver Disease Risk Factor Quantity
Gender
Hepatitis C
Genetics
Fatty liver
Comment In men, 40–80 g/d of ethanol produces fatty liver; 160 g/d for 10–20 years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic liver disease. Women exhibit increased susceptibility to alcoholic liver disease at amounts >20 g/d; two drinks per day is probably safe. HCV infection concurrent with alcoholic liver disease is associated with younger age for severity, more advanced histology, and decreased survival. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been associated with alcoholic cirrhosis. Alcohol injury does not require malnutrition, but obesity and nonalcoholic fatty liver are risk factors. Patients should receive vigorous attention to nutritional support.
factors that remain incompletely defined. Although there are genetic predispositions for alcoholism (Chap. 467), gender is a strong determinant for alcoholic liver disease. Women are more susceptible to alcoholic liver injury when compared to men. They develop advanced liver disease with substantially less alcohol intake. In general, the time it takes to develop liver disease is directly related to the amount of alcohol consumed. It is useful in estimating alcohol consumption to understand that one beer, four ounces of wine, or one ounce of 80% spirits all contain ∼12 g of alcohol. The threshold for developing alcoholic liver disease is higher in men, while women are at increased risk for developing similar degrees of liver injury by consuming significantly less. Gender-dependent differences result from poorly understood effects of estrogen, proportion of body fat, and the gastric metabolism of alcohol. Obesity, a high-fat diet, and the protective effect of coffee have been postulated to play a part in the development of the pathogenic process. Chronic infection with hepatitis C virus (HCV) (Chap. 362) is an important comorbidity in the progression of alcoholic liver disease to cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of 20–50 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected individuals. Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. Increased liver iron stores and, rarely, porphyria cutanea tarda can occur as a consequence of the overlapping injurious processes secondary to alcohol abuse and HCV infection. In addition, alcohol intake of >50 g/d by HCVinfected patients decreases the efficacy of interferon-based antiviral therapy. The pathogenesis of alcoholic liver injury is unclear. The present conceptual foundation is that alcohol acts as a direct hepatotoxin and that malnutrition does not have a major role. Ingestion of alcohol initiates an inflammatory cascade by its metabolism to acetaldehyde, resulting in a variety of metabolic responses. Steatosis from lipogenesis, fatty acid synthesis, and depression of fatty acid oxidation appears secondary to effects on sterol regulatory transcription factor and peroxisome proliferator-activated receptor α (PPAR-α). Intestinalderived endotoxin initiates a pathogenic process through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that facilitates hepatocyte apoptosis and necrosis. The cell injury and endotoxin release initiated by ethanol and its metabolites also activate innate and adaptive immunity pathways releasing proinflammatory cytokines (e.g., TNF-α), chemokines, and proliferation of T and B cells. The production of toxic protein-aldehyde adducts, generation of reducing equivalents, and oxidative stress also contribute to the liver injury. Hepatocyte injury and impaired regeneration following chronic alcohol ingestion are ultimately associated with stellate cell activation and collagen production, which are key events in fibrogenesis. The resulting fibrosis from
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continuing alcohol use determines the architectural derangement of the liver and associated pathophysiology.
LABORATORY FEATURES Patients with alcoholic liver disease are often identified through routine screening tests. The typical laboratory abnormalities seen in fatty liver are nonspecific and include modest elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (GGTP), often accompanied by hypertriglyceridemia and hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of fatty liver, AST and ALT are usually elevated two- to sevenfold. They are rarely >400 IU, and the AST/ALT ratio is >1 (Table 363-2). Hyperbilirubinemia is accompanied by modest increases in the alkaline phosphatase level. Derangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liver injury. Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal venous collaterals indicates serious liver injury with less potential for complete reversal.
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ALT AST/ALT GGTP Bilirubin
Comment Increased two- to sevenfold, 50%. Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin time increased >5 s), anemia, serum albumin concentrations 137 μmol/L (8 mg/dL), renal failure, and ascites. A discriminant function calculated as 4.6 X (the prolongation of the prothrombin time above control [seconds]) + serum bilirubin (mg/dL) can identify patients with a poor prognosis (discriminant function >32). A Model for End-Stage Liver Disease (MELD) score (Chap. 368) ≥21 also is associated with significant mortality in alcoholic hepatitis. The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. The pathologic stage of the injury can be helpful in predicting prognosis. Liver biopsy should be performed whenever possible to establish the diagnosis and to guide the therapeutic decisions. TREATMENT
Alcoholic Liver Disease
CLINICAL FEATURES The clinical manifestations of alcoholic fatty liver are subtle and characteristically detected as a consequence of the patient’s visit for a seemingly unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally, patients with fatty liver will present with right upper quadrant discomfort, nausea, and, rarely, jaundice. Differentiation of alcoholic fatty liver from nonalcoholic fatty liver is difficult unless an accurate drinking history is ascertained. In every instance where liver disease is present, a thoughtful and sensitive drinking history should be obtained. Standard, validated questions accurately detect alcohol-related problems (Chap. 467). Alcoholic hepatitis is associated with a wide gamut of clinical features. Fever, spider nevi, jaundice, and abdominal pain simulating an acute abdomen represent the extreme end of the spectrum, while many patients will be entirely asymptomatic. Portal hypertension, ascites, or variceal bleeding can occur in the absence of cirrhosis. Recognition of the clinical features of alcoholic hepatitis is central to the initiation of an effective and appropriate diagnostic and therapeutic strategy. It is important to recognize that patients with alcoholic cirrhosis often exhibit clinical features identical to other causes of cirrhosis.
Test AST
CHAPTER 363
PATHOLOGY The liver has a limited repertoire in response to injury. Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excessive alcohol ingestion. The accumulation of fat within the perivenular hepatocytes coincides with the location of alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism. Continuing alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of hepatic architecture and fat content. Alcoholic fatty liver has traditionally been regarded as entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease (Chap. 367e), the appearance of steatohepatitis and certain pathologic features such as giant mitochondria, perivenular fibrosis, and macrovesicular fat may be associated with progressive liver injury. The transition between fatty liver and the development of alcoholic hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the perivenular and perisinusoidal space of Disse. Mallory-Denk bodies are often present in florid cases but are neither specific nor necessary to establish the diagnosis. Alcoholic hepatitis is thought to be a precursor to the development of cirrhosis. However, like fatty liver, it is potentially reversible with cessation of drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis, and its regression is uncertain, even with abstention.
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Table 363-2 Laboratory Diagnosis of Alcoholic Fatty Liver and Alcoholic Hepatitis
Alcoholic Liver Disease
Complete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologic injury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion. Referral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routine in the management of patients with alcoholic liver disease. Attention should be directed to the nutritional and psychosocial states during the evaluation and treatment periods. Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury by immunologic processes, glucocorticoids have been extensively evaluated in the treatment of alcoholic hepatitis. Patients with severe alcoholic hepatitis, defined as a discriminant function >32 or MELD >20, should be given prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks, followed by a steroid taper (Fig. 363-1). Exclusion criteria include active gastrointestinal bleeding, renal failure, or pancreatitis. Women with encephalopathy from severe alcoholic hepatitis may be particularly good candidates for glucocorticoids. A Lille score >0.45, at http://www.lillemodel.com, uses pretreatment variables plus the change in total bilirubin at day 7 of glucocorticoids to identify patients unresponsive to therapy. The role of TNF-α expression and receptor activity in alcoholic liver injury has led to an examination of TNF inhibition as an alternative to glucocorticoids for severe alcoholic hepatitis. The nonspecific TNF inhibitor, pentoxifylline, demonstrated improved survival in the therapy of severe alcoholic hepatitis, primarily due to a decrease in hepatorenal syndrome (Fig. 363-2). Monoclonal antibodies that neutralize serum TNF-α should not be used in alcoholic hepatitis because of studies reporting increased deaths secondary to infection and renal failure. Liver transplantation is an accepted indication for treatment in selected and motivated patients with end-stage cirrhosis. Outcomes are equal or superior to other indications for transplantation. In general, transplant candidacy should be reevaluated after a defined
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100
Cumulative survival, %
84.6 3.4% p = .001
75
65.1 4.8% 50
25
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0 0
7
14
21
28
Days
Disorders of the Gastrointestinal System
Figure 363-1 Effect of glucocorticoid therapy of severe alcoholic hepatitis on short-term survival: the result of a meta-analysis of individual data from three studies. Prednisolone, solid line; placebo, dotted line. (Adapted from P Mathurin et al: J Hepatol 36:480, 2002, with permission from Elsevier Science.) period of sobriety. Patients presenting with alcoholic hepatitis have been largely excluded from transplant candidacy because of the perceived risk of increased surgical mortality and high rates of recidivism following transplantation. Recently, a European multidisciplinary group has reported excellent long-term transplant outcomes in highly selected patients with florid alcoholic hepatitis. General application of transplantation in such patients must await confirmatory outcomes by others.
Alcoholic Hepatitis
Alcohol abstinence Nutritional support
Discriminant function ≥ 32 or MELD ≥ 21 (with absence of co-morbidity)
Treatment options Preferred
Prednisolone 32 mg p.o. daily for 4 weeks, then taper for 4 weeks
Alternative
Pentoxifylline 400 mg p.o. TID for 4 weeks
Figure 363-2 Treatment algorithm for alcoholic hepatitis. As identified by a calculated discriminant function >32 (see text), patients with severe alcoholic hepatitis, without the presence of gastrointestinal bleeding or infection, would be candidates for either glucocorticoids or pentoxifylline administration.
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Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis Manal F. Abdelmalek, Anna Mae Diehl
INCIDENCE, PREVALENCE, AND NATURAL HISTORY Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in many parts of the world, including the United States. Population-based abdominal imaging studies have demonstrated fatty liver in at least 25% of American adults. Because the vast majority of these subjects deny hazardous levels of alcohol consumption (defined as greater than one drink per day in women or two drinks per day in men), they are considered to have NAFLD. NAFLD is strongly associated with overweight/obesity and insulin resistance. However, it can also occur in lean individuals and is particularly common in those with a paucity of adipose depots (i.e., lipodystrophy). Ethnic/racial factors also appear to influence liver fat accumulation; the documented prevalence of NAFLD is lowest in African Americans (~25%), highest in Americans of Hispanic ancestry (~50%), and intermediate in American whites (~33%). NAFLD encompasses a spectrum of liver pathology with different clinical prognoses. The simple accumulation of triglyceride within hepatocytes (hepatic steatosis) is on the most clinically benign extreme of the spectrum. On the opposite, most clinically ominous extreme, are cirrhosis (Chap. 365) and primary liver cancer (Chap. 111). The risk of developing cirrhosis is extremely low in individuals with chronic hepatic steatosis, but increases as steatosis becomes complicated by histologically conspicuous hepatocyte death and inflammation (i.e., nonalcoholic steatohepatitis [NASH]). NASH itself is also a heterogeneous condition; sometimes it improves to steatosis or normal histology, sometimes it remains relatively stable for years, but sometimes it results in progressive accumulation of fibrous scar that eventuates in cirrhosis. Once NAFLD-related cirrhosis develops, the annual incidence of primary liver cancer is 1%. Abdominal imaging is not able to determine which individuals with NAFLD have associated liver cell death and inflammation (i.e., NASH), and specific blood tests to diagnose NASH are not yet available. However, population-based studies that have used elevated serum ALT as a marker of liver injury indicate that about 6–8% of American adults have serum ALT elevations that cannot be explained by excessive alcohol consumption, other known causes of fatty liver disease (Table 364-1), viral hepatitis, or drug-induced or congenital liver diseases. Because the prevalence of such “cryptogenic” ALT elevations increases with body mass index, it is presumed that they are due to NASH. Hence, at any given point in time, NASH is present in about 25% of individuals who have NAFLD (i.e., about 6% of the general U.S. adult population has NASH). Smaller cross-sectional studies in which liver biopsies have been performed on NASH patients at tertiary referral centers consistently demonstrate advanced fibrosis or cirrhosis in about 25% of those cohorts. By extrapolation, therefore, cirrhosis develops in about 6% of individuals with NAFLD (i.e., in about 1.5–2% of the general U.S. population). The risk for advanced liver fibrosis is highest in individuals with NASH who are older than 45–50 years of age and overweight/obese or afflicted with type 2 diabetes. To put these data in perspective, it is helpful to recall that the prevalence of hepatitis C–related cirrhosis in the United States is about 0.5%. Thus, NAFLD-related cirrhosis is about three to four times more common than cirrhosis caused by chronic hepatitis C infection. Consistent with these data, experts have predicted that NAFLD will surpass hepatitis C as the leading indication for liver transplantation in the United States within the next decade. Similar to cirrhosis caused by other liver diseases, cirrhosis caused by NAFLD increases the risk for primary liver cancer. Both hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC) have also been reported to occur in NAFLD patients without cirrhosis, suggesting that NAFLD per se may be a premalignant condition. NAFLD, NASH, and NAFLD-related cirrhosis are not limited to adults. All have been well documented in children. As in adults, obesity and insulin resistance are the main risk
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Table 364-1 Alternative Causes of Hepatic Steatosis
PATHOGENESIS The mechanisms underlying the pathogenesis and progression of NAFLD are not entirely clear. The best-understood mechanisms pertain to hepatic steatosis. This is proven to result when hepatocyte mechanisms for triglyceride synthesis (e.g., lipid uptake and de novo lipogenesis) overwhelm mechanisms for triglyceride disposal (e.g., degradative metabolism and lipoprotein export), leading to accumulation of fat (i.e., triglyceride) within hepatocytes. Obesity stimulates hepatocyte triglyceride accumulation by altering the intestinal microbiota to enhance both energy harvest from dietary sources and intestinal permeability. Reduced intestinal barrier function increases hepatic exposure to gut-derived products, which stimulate liver cells to generate inflammatory mediators that inhibit insulin actions. Obese adipose depots also produce excessive soluble factors (adipokines) that inhibit tissue insulin sensitivity. Insulin resistance promotes hyperglycemia. This drives the pancreas to produce more insulin to maintain glucose homeostasis. However, hyperinsulinemia also promotes lipid uptake, fat synthesis, and fat storage. The net result is hepatic triglyceride accumulation (i.e., steatosis). Triglyceride per se is not hepatotoxic. However, its precursors (e.g., fatty acids and diacylglycerols) and metabolic by-products (e.g., reactive oxygen species) may damage hepatocytes, leading to hepatocyte lipotoxicity. Lipotoxicity also triggers the generation of other factors (e.g., inflammatory cytokines, hormonal mediators) that deregulate systems that normally maintain hepatocyte viability. The net result is increased hepatocyte death. Dying hepatocytes, in turn, release various factors that trigger wound healing responses that aim to
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DIAGNOSIS Diagnosing NAFLD requires demonstration of increased liver fat in the absence of hazardous levels of alcohol consumption. Thresholds for potentially dangerous alcohol ingestion have been set at more than one drink per day in women and two drinks per day in men based on epidemiologic evidence that the prevalence of serum aminotransferase elevations increases when alcohol consumption habitually exceeds these levels. In those studies, one drink was defined as having 10 g of ethanol and, thus, is equivalent to one can of beer, 4 ounces of wine, or 1.5 ounces (one shot) of distilled spirits. Other causes of liver fat accumulation (particularly exposure to certain drugs; Table 364-2) and liver injury (e.g., viral hepatitis, autoimmune liver disease, iron or copper overload, α1 antitrypsin deficiency) must also be excluded. Thus, establishing the diagnosis of NAFLD does not require invasive testing: it can be accomplished by history and physical examination, liver imaging (ultrasound is an acceptable first-line test; computed tomography [CT] or magnetic resonance imaging [MRI] enhances sensitivity for liver fat detection but adds expense), and blood tests to exclude other liver diseases. It is important to emphasize that the liver may not be enlarged, and serum aminotransferases and liver function tests (e.g., bilirubin, albumin, prothrombin time) may be completely normal, in individuals with NAFLD. Because there is yet no one specific blood test for NAFLD, confidence in the diagnosis of NAFLD is increased by identification of NAFLD risk factors. The latter include increased body mass index, insulin resistance/type 2 diabetes mellitus, and other parameters indicative of the metabolic syndrome (e.g., systemic hypertension, dyslipidemia, hyperuricemia/gout, cardiovascular disease; Chap. 422) in the patient or family members. Establishing the severity of NAFLD-related liver injury and related scarring (i.e., staging NAFLD) is more difficult than simply diagnosing NAFLD. Staging is critically important, however, because it is necessary to define prognosis and thereby determine treatment recommendations. The goal of staging is to distinguish patients with NASH from those with simple steatosis and to identify which of the NASH patients have advanced fibrosis. The 10-year probability of developing liverrelated morbidity or mortality in steatosis is negligible, and hence, this subgroup of NAFLD patients tends to be managed conservatively (see below). In contrast, more intensive follow-up and therapy are justified in NASH patients, and the subgroup with advanced fibrosis merits the most intensive scrutiny and intervention because their 10-year risk of liver-related morbidity and mortality is clearly increased. Staging approaches can be separated into noninvasive testing (i.e., blood testing, physical examination, and imaging) and invasive approaches (i.e., liver biopsy). Blood test evidence of hepatic dysfunction (e.g., hyperbilirubinemia, hypoalbuminemia, prothrombin time
Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis
factors for pediatric NAFLD. Thus, the rising incidence and prevalence of childhood obesity suggests that NAFLD is likely to become an even greater contributor to society’s burden of liver disease in the future.
CHAPTER 364
• Alcoholic liver disease • Hepatitis C (particularly genotype 3) • Inborn errors of metabolism • Abetalipoproteinemia • Cholesterol ester storage disease • Galactosemia • Glycogen storage disease • Hereditary fructose intolerance • Homocystinuria • Systemic carnitine deficiency • Tyrosinemia • Weber-Christian syndrome • Wilson’s disease • Wolman’s disease • Medications (see Table 364–2) • Miscellaneous • Industrial exposure to petrochemical • Inflammatory bowel disease • Lipodystrophy • Bacterial overgrowth • Starvation • Parenteral nutrition • Surgical procedures • Bilopancreatic diversion • Extensive small-bowel resection • Gastric bypass • Jejunoileal bypass • Reye’s syndrome • Acute fatty liver of pregnancy • HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet count)
replace (regenerate) lost hepatocytes. Such repair involves transient 2055 expansion of other cell types, such as myofibroblasts and progenitor cells, that make and degrade matrix, remodel the vasculature, and generate replacement hepatocytes, as well as the recruitment of immune cells that release factors that modulate liver injury and repair. NASH is the morphologic manifestation of lipotoxicity and resultant wound healing responses. Because the severity and duration of lipotoxic liver injury dictate the intensity and duration of repair, the histologic features and outcomes of NASH are variable. Cirrhosis and liver cancer are potential outcomes of chronic NASH. Cirrhosis results from futile repair, i.e., progressive accumulation of wound healing cells, fibrous matrix, and abnormal vasculature (scarring), rather than efficient reconstruction/regeneration of healthy hepatic parenchyma. Primary liver cancers develop when malignantly transformed liver cells escape mechanisms that normally control regenerative growth. The mechanisms responsible for futile repair (cirrhosis) and liver carcinogenesis are not well understood. Because normal liver regeneration is a very complex process, there are multiple opportunities for deregulation and, thus, pathogenic heterogeneity. To date, this heterogeneity has confounded development of both diagnostic tests and treatments for defective/deregulated liver repair (i.e., cirrhosis and cancer). Hence, current strategies focus on circumventing misrepair by preventing and/or reducing lipotoxic liver injury.
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2056 Table 364-2 Medications Associated with Hepatic Steatosis
PART 14 Disorders of the Gastrointestinal System
• Cytotoxic and cytostatic drugs • l-Asparaginase • Azacitidine • Azaserine • Bleomycin • Methotrexate • Puromycin • Tetracycline • Doxycycline • Metals • Antimony • Barium salts • Chromates • Phosphorus • Rare earths of low atomic number • Thallium compounds • Uranium compounds • Other drugs and toxins • Amiodarone • 4,4’-Diethylaminoethoxyhexesterol • Ethionine • Ethyl bromide • Estrogens • Glucocorticoids • Highly active antiretroviral therapy • Hydralazine • Hypoglycin • Orotate • Perhexiline maleate • Safrole • Tamoxifen
prolongation) or portal hypertension (e.g., thrombocytopenia) and stigmata of portal hypertension on physical examination (e.g., spider angiomata, palmar erythema, splenomegaly, ascites, clubbing, encephalopathy) suggest a diagnosis of advanced NAFLD. Currently, however, liver biopsy is the gold standard for establishing the severity of liver injury and fibrosis because it is both more sensitive and specific than these other tests for establishing NAFLD severity. Although invasive, liver biopsy is seldom complicated by serious adverse sequelae such as significant bleeding, pain, or inadvertent puncture of other organs and thus is relatively safe. However, biopsy suffers from potential sampling error unless tissue cores of 2 cm or longer are acquired. Also, examination of tissue at a single point in time is not reliable for determining whether the pathologic processes are progressing or regressing. The risk of serial liver biopsies within short time intervals is generally deemed as unacceptable outside of research studies. These limitations of liver biopsy have stimulated efforts to develop noninvasive approaches to stage NAFLD. As is true for many other types of chronic liver disease, in NAFLD the levels of serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) do not reliably reflect the severity of liver cell injury, extent of liver cell death, or related liver inflammation and fibrosis. Thus, they are imperfect for determining which individuals with NAFLD have NASH. This has stimulated research to identify superior markers of liver injury. Serum levels of keratin 8 and keratin 18 appear to be promising surrogates. Keratins 8 and 18 (K8/18) are epithelial cytoskeletal proteins that undergo cleavage during programmed cell death (apoptosis). Both cleaved and full-length K8/18 are released into the blood as hepatocytes die, and studies suggest that serum levels of K8/18 differentiate individuals with NASH from those with simple steatosis or normal livers more reliably than do serum aminotransferase levels. Moreover, K8/18 levels appear to parallel the severity of liver fibrosis, with higher levels marking individuals who are likely to have worse
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scarring (i.e., advanced liver fibrosis or cirrhosis). While promising, testing for K8/18 has not yet become standard clinical practice. Other blood tests and imaging approaches that quantify liver fibrosis are also being developed. Recently, the U.S. Food and Drug Administration (FDA) approved an ultrasound-based test that measures liver stiffness as a surrogate marker of fibrosis (FibroScan®) (Chap. 358). This new tool will likely be used serially to monitor fibrosis progression and regression in NAFLD patients. Studies that compare the receiver operator characteristics of K8/18 plus FibroScan® versus liver biopsy for monitoring NAFLD evolution are forthcoming. CLINICAL FEATURES OF NAFLD Most subjects with NAFLD are asymptomatic. The diagnosis is often made when abnormal liver aminotransferases or features of fatty liver are noted during an evaluation performed for other reasons. NAFLD may also be diagnosed during the workup of vague right upper quadrant abdominal pain, hepatomegaly, or an abnormal-appearing liver at time of abdominal surgery. Obesity is present in 50–90% of subjects. Most patients with NAFLD also have other features of the metabolic syndrome (Chap. 422). Some have subtle stigmata of chronic liver disease, such as spider angiomata, palmer erythema, or splenomegaly. In a small minority of patients with advanced NAFLD, complications of end-stage liver disease (e.g., jaundice, features of portal hypertension such as ascites or variceal hemorrhage) may be the initial findings. The association of NAFLD with obesity, diabetes, hypertriglyceridemia, hypertension, and cardiovascular disease is well known. Other associations include chronic fatigue, mood alterations, obstructive sleep apnea, thyroid dysfunction, and chronic pain syndrome. NAFLD is an independent risk factor for metabolic syndrome (Chap. 422). Longitudinal studies suggest that patients with NASH are at two- to threefold increased risk for the development of metabolic syndrome. Similarly, studies have shown that patients with NASH have a higher risk for the development of hypertension and diabetes mellitus. The presence of NAFLD is also independently associated with endothelial dysfunction, increased carotid intimal thickness, and the number of plaques in carotid and coronary arteries. Such data indicate that NAFLD has many deleterious effects on health in general. TREATMENT OF NAFLD Treatment of NAFLD can be divided into three components: (1) specific therapy of NAFLD-related liver disease; (2) treatment of NAFLDassociated comorbidities; and (3) treatment of the complications of advanced NAFLD. The subsequent discussion focuses on specific therapies for NAFLD, with some mention of their impact on major NAFLD comorbidities (insulin resistance/diabetes, obesity, and dyslipidemia). Treatment of the complications of advanced NAFLD involves management of the complications of cirrhosis and portal hypertension, including primary liver cancers. Approaches to accomplish these objectives are similar to those used in other chronic liver diseases and are covered elsewhere in the textbook (Chaps. 365 and 111). At present, there are no FDA-approved therapies for the treatment of NAFLD. Thus, the current approach to NAFLD management focuses on treatment to improve the risk factors for NASH (i.e., obesity, insulin resistance, metabolic syndrome, dyslipidemia). Based on our understanding of the natural history of NAFLD, only patients with NASH or those with features of hepatic fibrosis on liver biopsy are considered currently for targeted pharmacologic therapies. This approach may change as our understanding of disease pathophysiology improves and potential targets of therapy evolve. Diet and Exercise Lifestyle changes and dietary modification are the foundation for NAFLD treatment. Many studies indicate that lifestyle modification can improve serum aminotransferases and hepatic steatosis, with loss of at least 3–5% of body weight improving steatosis, but greater weight loss (up to 10%) necessary to improve steatohepatitis. The benefits of different dietary macronutrient contents (e.g., low-carbohydrate vs low-fat diets, saturated vs unsaturated fat diets) and different intensities of calorie restriction appear to be comparable. In adults with NAFLD, exercise regimens that improve fitness may be sufficient to reduce hepatic steatosis, but their impact on other aspects
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Bariatric Surgery Although interest in bariatric surgery as a treatment for NAFLD exists, a recently published Cochrane review concluded that lack of randomized clinical trials or adequate clinical studies prevents definitive assessment of benefits and harms of bariatric surgery as a treatment for NASH. Most studies of bariatric surgery have shown that bariatric surgery is generally safe in individuals with wellcompensated chronic liver disease and improves hepatic steatosis and necroinflammation (i.e., features of NAFLD/NASH); however, effects on hepatic fibrosis have been variable. Concern lingers because some of the largest prospective studies suggest that hepatic fibrosis might progress after bariatric surgery. Thus, the Cochrane review deemed it premature to recommend bariatric surgery as a primary treatment for NASH. There is also general agreement that patients with NAFLDrelated cirrhosis and portal hypertension should be excluded as candidates for bariatric surgery. However, given growing evidence for the benefits of bariatric surgery on metabolic syndrome complications in individuals with refractory obesity, it is not contraindicated in otherwise eligible patients with NAFLD or NASH. Liver Transplantation Patients with NAFLD in whom end-stage liver disease develops should be evaluated for liver transplantation (Chap. 368). The outcomes of liver transplantation in well-selected patients with NAFLD are generally good, but comorbid medical conditions associated with NAFLD, such as diabetes mellitus, obesity, and cardiovascular disease, often limit transplant candidacy. NAFLD may recur after liver transplantation. The risk factors for recurrent or de novo NAFLD after liver transplantation are multifactorial and include hypertriglyceridemia, obesity, diabetes mellitus, and immunosuppressive therapies, particularly glucocorticoids.
Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis
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dipeptidyl IV antagonists); however, sufficient data do not yet exist to 2057 justify their use as NASH treatments in standard clinical practice. Statins are an important class of agents to treat dyslipidemia and decrease cardiovascular risk. There is no evidence to suggest that statins cause liver failure in patients with any chronic liver disease, including NAFLD. The incidence of liver enzyme elevations in NAFLD patients taking statins is also no different than that of healthy controls or patients with other chronic liver diseases. Moreover, several studies have suggested that statins may improve aminotransferases and histology in patients with NASH. Yet, there is continued reluctance to use statins in patients with NAFLD. The lack of evidence that statins harm the liver in NAFLD patients, combined with the increase risk for cardiovascular morbidity and mortality in NAFLD patients, warrants the use of statins to treat dyslipidemia in patients with NAFLD/NASH.
CHAPTER 364
of liver histology remains unknown. Unfortunately, most NAFLD patients are unable to achieve sustained weight loss. Although pharmacologic therapies such as orlistat, topiramate, and phentermine to facilitate weight loss are available, their role in the treatment of NAFLD remains experimental. Pharmacologic Therapies Several drug therapies have been tried in both research and clinical settings. No agent has yet been approved by the FDA for the treatment of NAFLD. Hence, this remains an area of active research. Because NAFLD is strongly associated with the metabolic syndrome and type 2 diabetes (Chaps. 417 and 418), the efficacy of various insulin-sensitizing agents has been examined. Metformin, an agent that mainly improves hepatic insulin sensitivity, has been evaluated in several small, open-label studies in adults and a recent larger, prospectively randomized trial in children (dubbed the TONIC study). Although several of the adult NASH studies suggested improvements in aminotransferases and/or liver histology, metformin did not improve liver histology in the TONIC study of children with NASH. Thus, it is not currently recommended as a treatment for NASH. Uncontrolled open-label studies have also investigated thiazolidinediones (pioglitazone and rosiglitazone) in adults with NASH. This class of drugs is known to improve systemic insulin resistance. Both pioglitazone and rosiglitazone reduced aminotransferases and improved some of the histologic features of NASH in small, uncontrolled studies. A large, National Institutes of Health–sponsored, randomized placebo-controlled clinical trial, the PIVENs Study (Pioglitazone vs Vitamin E vs Placebo for the Treatment of 247 Nondiabetic Adults with NASH), demonstrated that resolution of histologic NASH occurred more often in subjects treated with pioglitazone (30 mg/d) than with placebo for 18 months (47 vs 21%, p = .001). However, many subjects in the pioglitazone group gained weight, and liver fibrosis did not improve. Also, it should be noted that the longterm safety and efficacy of thiazolidinediones in patients with NASH has not been established. Five-year follow-up of subjects treated with rosiglitazone demonstrated no reduction in liver fibrosis, and rosiglitazone has been associated with increased long-term risk for cardiovascular mortality. Hence, it is not recommended as a treatment for NAFLD. Pioglitazone may be safer because in a recent large meta-analysis it was associated with reduced overall morality, myocardial infarction, and stroke. However, caution must be exercised when considering its use in patients with impaired myocardial function. Antioxidants have also been evaluated for the treatment of NAFLD because oxidant stress is thought to contribute to the pathogenesis of NASH. Vitamin E, an inexpensive yet potent antioxidant, has been examined in several small pediatric and adult studies with varying results. In all of those studies, vitamin E was well tolerated, and most showed modest improvements in aminotransferase levels, radiographic features of hepatic steatosis, and/or histologic features of NASH. Vitamin E (800 IU/d) was also compared to placebo in the PIVENs and TONIC studies. In PIVENs, vitamin E was the only agent that achieved the predetermined primary endpoint (i.e., improvement in steatohepatitis, lobular inflammation, and steatosis score, without an increase in the fibrosis score). This endpoint was met in 43% of patients in the vitamin E group (p = .001 vs placebo), 34% in the pioglitazone group (p = .04 vs placebo), and 19% in the placebo group. Vitamin E also improved NASH histology in pediatric patients with NASH (TONIC trial). However, a recent population-based study suggested that chronic vitamin E therapy may increase the risk for cardiovascular mortality. Thus, vitamin E should only be considered as a first-line pharmacotherapy for nondiabetic NASH patients. Also, given its potentially negative effects on cardiovascular health, caution should be exercised until the risk-to-benefit ratio and long-term therapeutic efficacy of vitamin E are better defined. Ursodeoxycholic acid (a bile acid that improves certain cholestatic liver diseases) and betaine (metabolite of choline that raises SAM levels and decreases cellular oxidative damage) offer no histologic benefit over placebo in patients with NASH. Experimental evidence to support the use of omega-3 fatty acids in NAFLD exists; however, a recent large, multicenter, placebo-controlled study failed to demonstrate a histologic benefit. Other pharmacotherapies are also being evaluated in NAFLD (e.g., probiotics, farnesoid X receptor agonists, anticytokine agents, glucagon-like peptide agonists,
GLOBAL HEALTH CONSIDERATIONS The epidemic of obesity is now a global and accelerating phenomenon. Worldwide, there are over 1 billion overweight adults, of whom at least 300 million are obese. In the wake of the obesity epidemic follow numerous comorbidities, including NAFLD. NAFLD is the most common liver disease identified in Western countries and the fastest rising form of chronic liver disease worldwide. Present understanding of NAFLD natural history is based mainly on studies in whites who became overweight/obese and developed the metabolic syndrome in adulthood. The impact of the global childhood obesity epidemic on NAFLD pathogenesis/progression is unknown. Emerging evidence demonstrates that advanced NAFLD, including cirrhosis and primary liver cancer, can occur in children, prompting concerns that childhood-onset NAFLD might follow a more aggressive course than typical adult-acquired NAFLD. Some of the most populated parts of the world are in the midst of industrial revolutions, and certain environmental pollutants seem to exacerbate NAFLD. Some studies also suggest that the risk for NASH and NAFLD-related cirrhosis may be higher in certain ethnic groups such as Asians, certain Hispanics, and Native Americans and lower in others such as African Americans, compared with whites. Although all of these variables confound efforts to predict the net impact of this obesity-related liver disease on global health, it seems likely that NAFLD will remain a major cause of chronic liver disease worldwide for the foreseeable future.
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Cirrhosis and Its Complications Bruce R. Bacon
PART 14 Disorders of the Gastrointestinal System
Cirrhosis is a condition that is defined histopathologically and has a variety of clinical manifestations and complications, some of which can be life-threatening. In the past, it has been thought that cirrhosis was never reversible; however, it has become apparent that when the underlying insult that has caused the cirrhosis has been removed, there can be reversal of fibrosis. This is most apparent with the successful treatment of chronic hepatitis C; however, reversal of fibrosis is also seen in patients with hemochromatosis who have been successfully treated and in patients with alcoholic liver disease who have discontinued alcohol use. Regardless of the cause of cirrhosis, the pathologic features consist of the development of fibrosis to the point that there is architectural distortion with the formation of regenerative nodules. This results in a decrease in hepatocellular mass, and thus function, and an alteration of blood flow. The induction of fibrosis occurs with activation of hepatic stellate cells, resulting in the formation of increased amounts of collagen and other components of the extracellular matrix. Clinical features of cirrhosis are the result of pathologic changes and mirror the severity of the liver disease. Most hepatic pathologists provide an assessment of grading and staging when evaluating liver biopsy samples. These grading and staging schemes vary between disease states and have been developed for most conditions, including chronic viral hepatitis, nonalcoholic fatty liver disease, and primary biliary cirrhosis. Advanced fibrosis usually includes bridging fibrosis with nodularity designated as stage 3 and cirrhosis designated as stage 4. Patients who have cirrhosis have varying degrees of compensated liver function, and clinicians need to differentiate between those who have stable, compensated cirrhosis and those who have decompensated cirrhosis. Patients who have developed complications of their liver disease and have become decompensated should be considered for liver transplantation. Many of the complications of cirrhosis will require specific therapy. Portal hypertension is a significant complicating feature of decompensated cirrhosis and is responsible for the development of ascites and bleeding from esophagogastric varices, two complications that signify decompensated cirrhosis. Loss of hepatocellular function results in jaundice, coagulation disorders, and hypoalbuminemia and contributes to the causes of portosystemic encephalopathy. The complications of cirrhosis are basically the same regardless of the etiology. Nonetheless, it is useful to classify patients by the cause of their liver disease (Table 365-1); patients can be divided into broad groups with alcoholic cirrhosis, cirrhosis due to chronic viral hepatitis, biliary cirrhosis, and other, less common causes such as cardiac cirrhosis, cryptogenic cirrhosis, and other miscellaneous causes.
ALCOHOLIC CIRRHOSIS Excessive chronic alcohol use can cause several different types of chronic liver disease, including alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Furthermore, use of excessive alcohol can
Table 365-1 Causes of Cirrhosis Alcoholism Chronic viral hepatitis Hepatitis B Hepatitis C Autoimmune hepatitis Nonalcoholic steatohepatitis Biliary cirrhosis Primary biliary cirrhosis Primary sclerosing cholangitis Autoimmune cholangiopathy
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Cardiac cirrhosis Inherited metabolic liver disease Hemochromatosis Wilson’s disease α1 Antitrypsin deficiency Cystic fibrosis Cryptogenic cirrhosis
contribute to liver damage in patients with other liver diseases, such as hepatitis C, hemochromatosis, and fatty liver disease related to obesity. Chronic alcohol use can produce fibrosis in the absence of accompanying inflammation and/or necrosis. Fibrosis can be centrilobular, pericellular, or periportal. When fibrosis reaches a certain degree, there is disruption of the normal liver architecture and replacement of liver cells by regenerative nodules. In alcoholic cirrhosis, the nodules are usually 32. The DF is calculated as the serum total bilirubin plus the difference in the patient’s prothrombin time compared to control (in seconds) multiplied by 4.6. In patients for whom this value is >32, there is improved survival at 28 days with the use of glucocorticoids. Other therapies that have been used include oral pentoxifylline, which decreases the production of tumor necrosis factor α (TNF-α) and other proinflammatory cytokines. In contrast to glucocorticoids, with which complications can occur, pentoxifylline is relatively easy to administer and has few, if any, side effects. A variety of nutritional therapies have been tried with either parenteral or enteral feedings; however, it is unclear whether any of these modalities have significantly improved survival. Recent studies have used parenterally administered inhibitors of TNF-α such as infliximab or etanercept. Early results have shown no adverse events; however, there was no clear-cut improvement in survival. Anabolic steroids, propylthiouracil, antioxidants, colchicine, and penicillamine have all been used but do not show clear-cut benefits and are not recommended. As mentioned above, the cornerstone to treatment is cessation of alcohol use. Recent experience with medications that reduce craving for alcohol, such as acamprosate calcium, has been favorable. Patients may take other necessary medications even in the presence of cirrhosis. Acetaminophen use is often discouraged in patients with liver disease; however, if no more than 2 g of acetaminophen per day are consumed, there generally are no problems.
Cirrhosis and Its Complications
alcoholic cirrhosis, menstrual irregularities usually occur, and some women may be amenorrheic. These changes are often reversible following cessation of alcohol. Laboratory tests may be completely normal in patients with early compensated alcoholic cirrhosis. Alternatively, in advanced liver disease, many abnormalities usually are present. Patients may be anemic either from chronic GI blood loss, nutritional deficiencies, or hypersplenism related to portal hypertension, or as a direct suppressive effect of alcohol on the bone marrow. A unique form of hemolytic anemia (with spur cells and acanthocytes) called Zieve’s syndrome can occur in patients with severe alcoholic hepatitis. Platelet counts are often reduced early in the disease, reflective of portal hypertension with hypersplenism. Serum total bilirubin can be normal or elevated with advanced disease. Direct bilirubin is frequently mildly elevated in patients with a normal total bilirubin, but the abnormality typically progresses as the disease worsens. Prothrombin times are often prolonged and usually do not respond to administration of parenteral vitamin K. Serum sodium levels are usually normal unless patients have ascites and then can be depressed, largely due to ingestion of excess free water. Serum alanine and aspartate aminotransferases (ALT, AST) are typically elevated, particularly in patients who continue to drink, with AST levels being higher than ALT levels, usually by a 2:1 ratio.
TREATMENT
CHAPTER 365
abuse alcohol. Furthermore, other forms of chronic liver disease (e.g., 2059 chronic viral hepatitis or metabolic or autoimmune liver diseases) must be considered or ruled out, or if present, an estimate of relative causality along with the alcohol use should be determined. Liver biopsy can be helpful to confirm a diagnosis, but generally when patients present with alcoholic hepatitis and are still drinking, liver biopsy is withheld until abstinence has been maintained for at least 6 months to determine residual, nonreversible disease. In patients who have had complications of cirrhosis and who continue to drink, there is a 12 mmHg are at risk for variceal hemorrhage.
TREATMENT
Cirrhosis and Its Complications
Clinical Features The three primary complications of portal hypertension are gastroesophageal varices with hemorrhage, ascites, and
hypersplenism. Thus, patients may present with upper GI bleeding, 2063 which, on endoscopy, is found to be due to esophageal or gastric varices; with the development of ascites along with peripheral edema; or with an enlarged spleen with associated reduction in platelets and white blood cells on routine laboratory testing.
CHAPTER 365
flow through the liver due to cirrhosis and regenerative nodules, and (2) increased splanchnic blood flow secondary to vasodilation within the splanchnic vascular bed. Portal hypertension is directly responsible for the two major complications of cirrhosis: variceal hemorrhage and ascites. Variceal hemorrhage is an immediate life-threatening problem with a 20–30% mortality rate associated with each episode of bleeding. The portal venous system normally drains blood from the stomach, intestines, spleen, pancreas, and gallbladder, and the portal vein is formed by the confluence of the superior mesenteric and splenic veins. Deoxygenated blood from the small bowel drains into the superior mesenteric vein along with blood from the head of the pancreas, the ascending colon, and part of the transverse colon. Conversely, the splenic vein drains the spleen and the pancreas and is joined by the inferior mesenteric vein, which brings blood from the transverse and descending colon as well as from the superior two-thirds of the rectum. Thus, the portal vein normally receives blood from almost the entire GI tract. The causes of portal hypertension are usually subcategorized as prehepatic, intrahepatic, and posthepatic (Table 365-3). Prehepatic causes of portal hypertension are those affecting the portal venous system before it enters the liver; they include portal vein thrombosis and splenic vein thrombosis. Posthepatic causes encompass those affecting the hepatic veins and venous drainage to the heart; they include BCS, venoocclusive disease, and chronic right-sided cardiac congestion. Intrahepatic causes account for over 95% of cases of portal hypertension and are represented by the major forms of cirrhosis. Intrahepatic causes of portal hypertension can be further subdivided into presinusoidal, sinusoidal, and postsinusoidal causes. Postsinusoidal causes include venoocclusive disease, whereas presinusoidal causes include congenital hepatic fibrosis and schistosomiasis. Sinusoidal causes are related to cirrhosis from various causes. Cirrhosis is the most common cause of portal hypertension in the United States, and clinically significant portal hypertension is present in >60% of patients with cirrhosis. Portal vein obstruction may be idiopathic or can occur in association with cirrhosis or with infection, pancreatitis, or abdominal trauma. Coagulation disorders that can lead to the development of portal vein thrombosis include polycythemia vera; essential thrombocytosis; deficiencies in protein C, protein S, antithrombin 3, and factor V Leiden; and abnormalities in the gene-regulating prothrombin production. Some patients may have a subclinical myeloproliferative disorder.
Variceal Hemorrhage
Treatment for variceal hemorrhage as a complication of portal hypertension is divided into two main categories: (1) primary prophylaxis and (2) prevention of rebleeding once there has been an initial variceal hemorrhage. Primary prophylaxis requires routine screening by endoscopy of all patients with cirrhosis. Once varices that are at increased risk for bleeding are identified, primary prophylaxis can be achieved either through nonselective beta blockade or by variceal band ligation. Numerous placebo-controlled clinical trials of either propranolol or nadolol have been reported in the literature. The most rigorous studies were those that only included patients with significantly enlarged varices or with hepatic vein pressure gradients >12 mmHg. Patients treated with beta blockers have a lower risk of variceal hemorrhage than those treated with placebo over 1 and 2 years of follow-up. There is also a decrease in mortality related to variceal hemorrhage. Unfortunately, overall survival was improved in only one study. Further studies have demonstrated that the degree of reduction of portal pressure is a significant feature to determine success of therapy. Therefore, it has been suggested that repeat measurements of hepatic vein pressure gradients may be used to guide pharmacologic therapy; however, this may be cost-prohibitive. Several studies have evaluated variceal band ligation and variceal sclerotherapy as methods for providing primary prophylaxis. Endoscopic variceal ligation (EVL) has achieved a level of success and comfort with most gastroenterologists who see patients with these complications of portal hypertension. Thus, in patients with cirrhosis who are screened for portal hypertension and are found to have large varices, it is recommended that they receive either beta blockade or primary prophylaxis with EVL.
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PART 14 Disorders of the Gastrointestinal System
The approach to patients once they have had a variceal bleed is first to treat the acute bleed, which can be life-threatening, and then to prevent further bleeding. Prevention of further bleeding is usually accomplished with repeated variceal band ligation until varices are obliterated. Treatment of acute bleeding requires both fluid and blood-product replacement as well as prevention of subsequent bleeding with EVL. The medical management of acute variceal hemorrhage includes the use of vasoconstricting agents, usually somatostatin or octreotide. Vasopressin was used in the past but is no longer commonly used. Balloon tamponade (Sengstaken-Blakemore tube or Minnesota tube) can be used in patients who cannot get endoscopic therapy immediately or who need stabilization prior to endoscopic therapy. Control of bleeding can be achieved in the vast majority of cases; however, bleeding recurs in the majority of patients if definitive endoscopic therapy has not been instituted. Octreotide, a direct splanchnic vasoconstrictor, is given at dosages of 50–100 µg/h by continuous infusion. Endoscopic intervention is used as first-line treatment to control bleeding acutely. Some endoscopists will use variceal injection therapy (sclerotherapy) as initial therapy, particularly when bleeding is vigorous. Variceal band ligation is used to control acute bleeding in over 90% of cases and should be repeated until obliteration of all varices is accomplished. When esophageal varices extend into the proximal stomach, band ligation is less successful. In these situations, when bleeding continues from gastric varices, consideration for a transjugular intrahepatic portosystemic shunt (TIPS) should be made. This technique creates a portosystemic shunt by a percutaneous approach using an expandable metal stent, which is advanced under angiographic guidance to the hepatic veins and then through the substance of the liver to create a direct portocaval shunt. This offers an alternative to surgery for acute decompression of portal hypertension. Encephalopathy can occur in as many as 20% of patients after TIPS and is particularly problematic in elderly patients and in patients with preexisting encephalopathy. TIPS should be reserved for individuals who fail endoscopic or medical management or who are poor surgical risks. TIPS can sometimes be used as a bridge to transplantation. Surgical esophageal transsection is a procedure that is rarely used and generally is associated with a poor outcome. PREVENTION OF RECURRENT BLEEDING (Fig. 365-3) Once patients have had an acute bleed and have been managed successfully, attention should be paid to preventing recurrent bleeding. This usually requires repeated variceal band ligation until varices are obliterated. Beta blockade may be of adjunctive benefit in patients who are having recurrent variceal band ligation; however, once varices have been obliterated, the need for beta blockade is lessened. Despite successful variceal obliteration, many patients will still have portal hypertensive gastropathy from which bleeding can occur. Nonselective beta blockade may be helpful to prevent further bleeding from portal hypertensive gastropathy once varices have been obliterated. Portosystemic shunt surgery is less commonly performed with the advent of TIPS; nonetheless, this procedure should be considered for patients with good hepatic synthetic function who could benefit by having portal decompressive surgery. SPLENOMEGALY AND HYPERSPLENISM Congestive splenomegaly is common in patients with portal hypertension. Clinical features include the presence of an enlarged spleen on physical examination and the development of thrombocytopenia and leukopenia in patients who have cirrhosis. Some patients will have fairly significant left-sided and left upper quadrant abdominal pain related to an enlarged and engorged spleen. Splenomegaly itself usually requires no specific treatment, although splenectomy can be successfully performed under very special circumstances. Hypersplenism with the development of thrombocytopenia is a common feature of patients with cirrhosis and is usually the first indication of portal hypertension.
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MANAGEMENT OF RECURRENT VARICEAL HEMORRHAGE Recurrent acute bleeding Endoscopic therapy +/– Pharmacologic therapy Control of bleeding
Compensated cirrhosis Child’s class A
Decompensated cirrhosis Child’s class B or C
Surgical shunt vs TIPS
Transplant evaluation
Liver transplantation
Endoscopic therapy or beta blockers Consider TIPS Liver transplantation
Figure 365-3 Management of recurrent variceal hemorrhage. This algorithm describes an approach to management of patients who have recurrent bleeding from esophageal varices. Initial therapy is generally with endoscopic therapy often supplemented by pharmacologic therapy. With control of bleeding, a decision needs to be made as to whether patients should go on to a surgical shunt or TIPS (if they are Child’s class A) and be considered for transplant, or if they should have TIPS and be considered for transplant (if they are Child’s class B or C). TIPS, transjugular intrahepatic portosystemic shunt. ASCITES Definition Ascites is the accumulation of fluid within the peritoneal cavity. Overwhelmingly, the most common cause of ascites is portal hypertension related to cirrhosis; however, clinicians should remember that malignant or infectious causes of ascites can be present as well, and careful differentiation of these other causes are obviously important for patient care. Pathogenesis The presence of portal hypertension contributes to the development of ascites in patients who have cirrhosis (Fig. 365-4). There is an increase in intrahepatic resistance, causing increased portal pressure, but there is also vasodilation of the splanchnic arterial system, which, in turn, results in an increase in portal venous inflow. Both of these abnormalities result in increased production of splanchnic lymph. Vasodilating factors such as nitric oxide are responsible for the vasodilatory effect. These hemodynamic changes result in sodium retention by causing activation of the renin-angiotensin-aldosterone system with the development of hyperaldosteronism. The renal effects of increased aldosterone leading to sodium retention also contribute to the development of ascites. Sodium retention causes fluid accumulation and expansion of the extracellular fluid volume, which results in the formation of peripheral edema and ascites. Sodium retention is the consequence of a homeostatic response caused by underfilling of the arterial circulation secondary to arterial vasodilation in the splanchnic vascular bed. Because the retained fluid is constantly leaking out of the intravascular compartment into the peritoneal cavity, the sensation of vascular filling is not achieved, and the process continues. Hypoalbuminemia and reduced plasma oncotic pressure also contribute to the loss of fluid from the vascular compartment into the
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DEVELOPMENT OF ASCITES IN CIRRHOSIS Cirrhosis Portal hypertension Splanchnic vasodilation
Lymph formation Formation of ascites Plasma volume expansion
Arterial underfilling Activation of vasoconstrictors and antinatriuretic factors* Sodium retention
peritoneal cavity. Hypoalbuminemia is due to decreased synthetic function in a cirrhotic liver. Clinical Features Patients typically note an increase in abdominal girth that is often accompanied by the development of peripheral edema. The development of ascites is often insidious, and it is surprising that some patients wait so long and become so distended before seeking medical attention. Patients usually have at least 1–2 L of fluid in the abdomen before they are aware that there is an increase. If ascitic fluid is massive, respiratory function can be compromised, and patients will complain of shortness of breath. Hepatic hydrothorax may also occur in this setting, contributing to respiratory symptoms. Patients with massive ascites are often malnourished and have muscle wasting and excessive fatigue and weakness. Diagnosis Diagnosis of ascites is by physical examination and is often aided by abdominal imaging. Patients will have bulging flanks, may have a fluid wave, or may have the presence of shifting dullness. This is determined by taking patients from a supine position to lying on either their left or right side and noting the movement of the dullness to percussion. Subtle amounts of ascites can be detected by ultrasound or CT scanning. Hepatic hydrothorax is more common on the right side and implicates a rent in the diaphragm with free flow of ascitic fluid into the thoracic cavity. When patients present with ascites for the first time, it is recommended that a diagnostic paracentesis be performed to characterize the fluid. This should include the determination of total protein and albumin content, blood cell counts with differential, and cultures. In the appropriate setting, amylase may be measured and cytology performed. In patients with cirrhosis, the protein concentration of the ascitic fluid is quite low, with the majority of patients having an ascitic fluid protein concentration 1.1 g/dL, the cause of the ascites is most likely due to portal hypertension; this is usually in the setting of cirrhosis. When the gradient is 250/µL, the question of ascitic fluid infection should be strongly considered. Ascitic fluid cultures should be obtained using bedside inoculation of culture media.
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Patients with small amounts of ascites can usually be managed with dietary sodium restriction alone. Most average diets in the United States contain 6–8 g of sodium per day, and if patients eat at restaurants or fast-food outlets, the amount of sodium in their diet can exceed this amount. Thus, it is often extremely difficult to get patients to change their dietary habits to ingest 1000 μg/L, the patient should be considered for liver biopsy because there is an increased frequency of advanced fibrosis in these individuals. If liver biopsy is performed, iron deposition is found in a periportal distribution with a periportal to pericentral gradient; iron is found predominantly in parenchymal cells, and Kupffer cells are spared.
Table 367e-3 Symptoms of Hereditary Hemochromatosis Symptom Weakness, lethargy, fatigue Apathy, lack of interest Abdominal pain Weight loss Arthralgias Loss of libido, impotence Amenorrhea Congestive heart failure symptoms
% 40–85 40–85 30–60 30–60 40–60 30–60 20–60 0–40
367e-1
CHAPTER 367e Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver
There are a number of disorders of the liver that fit within the categories of genetic, metabolic, and infiltrative disorders (Table 367e-1). Inherited disorders include hemochromatosis, Wilson’s disease, α1 antitrypsin (α1AT) deficiency, and cystic fibrosis (CF). Hemochromatosis is the most common inherited disorder affecting white populations, with the genetic susceptibility for the disease being identified in 1 in 250 individuals. Over the past 15 years, it has become increasingly apparent that nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes found in the U.S. population. This disorder is discussed in greater detail in Chap. 364. Infiltrative disorders of the liver are relatively rare.
Table 367e-2 Classification of Iron Overload Syndromes
367e-2
Table 367e-4 Physical Findings in Hereditary Hemochromatosis
PART 14
Finding Hepatomegaly Cirrhosis Skin pigmentation Arthritis (second, third metacarpophalangeal joints) Clinical diabetes Splenomegaly Loss of body hair Testicular atrophy Dilated cardiomyopathy
TREATMENT
% 60–85 50–95 40–80 40–60 10–60 10–40 10–30 10–30 0–30
Hereditary Hemochromatosis
Disorders of the Gastrointestinal System
Treatment of HH is relatively straightforward with weekly phlebotomy aimed to reduce iron stores, recognizing that each unit of blood contains 200–250 mg of iron. If patients are diagnosed and treated before the development of hepatic fibrosis, all complications of the disease can be avoided. Maintenance phlebotomy is required in most patients and usually can be achieved with 1 unit of blood removed every 2–3 months. Family studies should be performed with transferrin saturation, ferritin, and genetic testing offered to all first-degree relatives. Wilson’s Disease Wilson’s disease is an inherited disorder of copper homeostasis first described in 1912 (Chap. 429). The Wilson’s disease gene was discovered in 1993, with the identification of ATP7B. This P-type ATPase is involved in copper transport and is necessary for the export of copper from the hepatocyte. Thus, in patients with mutations in ATP7B, copper is retained in the liver, leading to increased copper storage and ultimately liver disease as a result. The clinical presentation of Wilson’s disease is variable and includes chronic hepatitis, hepatic steatosis, and cirrhosis in adolescents and young adults. Neurologic manifestations indicate that liver disease is present and include speech disorders and various movement disorders. Diagnosis includes the demonstration of a reduced ceruloplasmin level, increased urinary excretion of copper, the presence of Kayser-Fleischer rings in the corneas of the eyes, and an elevated hepatic copper level, in the appropriate clinical setting. The genetic diagnosis of Wilson’s disease is difficult because >500 mutations in ATP7B have been described with different degrees of frequency and penetration in certain populations. TREATMENT
Wilson’s Disease
Treatment consists of copper-chelating medications such as D-penicillamine and trientine. A role for zinc acetate has also been established. Medical treatment is lifelong, and severe relapses leading to liver failure and death can occur with cessation of therapy. Liver transplantation is curative with respect to the underlying metabolic defect and restores the normal phenotype with respect to copper homeostasis. α1 Antitrypsin Deficiency α1AT deficiency was first described in the late 1960s in patients with severe pulmonary disease. α1AT is a 52-kDa glycoprotein produced in hepatocytes, phagocytes, and epithelial cells in the lungs, which inhibits serine proteases, primarily neutrophil elastase. In α1AT deficiency, increased amounts of neutrophil elastase can result in progressive lung injury from degradation of elastin, leading to premature emphysema. In the 1970s, α1AT deficiency was discovered as a cause of neonatal liver disease, so-called “neonatal hepatitis.” It is now known to be a cause of liver disease in infancy, early childhood, and adolescence, and in adults.
In α1AT deficiency, variants in the proteinase inhibitor (Pi) gene located on chromosome 14 alter α1AT structure, interfering with hepatocellular export. Aggregated, deformed polymers of α1AT accumulate in the hepatocyte endoplasmic reticulum. There are over 75 different α1AT variants. Conventional nomenclature identifies normal variants as PiMM; these individuals have normal blood levels of α1AT. The most common abnormal variants are called S and Z. Individuals homozygous for the Z mutation (PiZZ) have low levels of α1AT (about 15% of normal), and these patients are susceptible to liver and/or lung disease, yet only a proportion (about 25%) of PiZZ patients develop disease manifestations. Null variants have undetectable levels of α1AT and are susceptible to premature lung disease. α1AT deficiency has been identified in all populations; however, the disorder is most common in patients of northern European and Iberian descent. The disorder affects about 1 in 1500 to 2000 individuals in North America. The natural history of α1AT deficiency is quite variable because many individuals with the PiZZ variant never develop disease, whereas others can develop childhood cirrhosis leading to liver transplantation. In adults, the diagnosis often comes in the course of evaluation of patients with abnormal liver test abnormalities or in a workup for cirrhosis. A hint to diagnosis may be coexistent lung disease at a relatively young age or a family history of liver and/or lung disease. Patients may have symptoms of pulmonary disease with cough and dyspnea. Liver disease may be asymptomatic other than fatigue, or patients may present with complications of decompensated liver disease. Diagnosis of α1AT deficiency is confirmed by blood tests showing reduced levels of serum α1AT, accompanied by Pi determinations. Most patients with liver disease have either PiZZ or PiSZ; occasionally, patients with PiMZ have reduced levels of α1AT, but they usually do not have a low enough level to cause disease. Liver biopsy is often performed to determine stage of hepatic fibrosis and shows characteristic PAS-positive, diastase-resistant globules in the periphery of the hepatic lobule. TREATMENT
α1 Antitrypsin Deficiency
Treatment of α1AT deficiency is usually nonspecific and supportive. For patients with liver involvement, other sources of liver injury, such as alcohol, should be avoided. Evidence for other liver diseases (e.g., viral hepatitis B and C, hemochromatosis, NAFLD) should be sought and treated if possible. Smoking can worsen lung disease progression in α1AT deficiency and should be discontinued. Patients with lung disease may be eligible to receive infusions of α1AT, which has been shown to halt further damage to the lungs. If liver disease becomes decompensated, transplantation should be pursued and is curative. Following transplant, patients express the Pi phenotype of the donor. Finally, risk of hepatocellular carcinoma is significantly increased in patients with cirrhosis due to α1AT deficiency. Cystic Fibrosis CF should also be considered as an inherited form of chronic liver disease, although the principal manifestations of CF include chronic lung disease and pancreatic insufficiency (Chap. 313). A small percentage of patients with CF who survive to adulthood have a form of biliary cirrhosis characterized by cholestatic liver enzyme abnormalities and the development of chronic liver disease. Ursodeoxycholic acid is occasionally helpful in improving liver test abnormalities and in reducing symptoms. The disease is slowly progressive. METABOLIC LIVER DISEASES Nonalcoholic Fatty Liver Disease NAFLD and NASH are common liver diseases causing abnormal liver test results and progressing to cirrhosis. NAFLD and NASH are discussed in detail in Chap. 364. Lipid Storage Diseases There are a number of rare lipid storage diseases that involve the liver, including the inherited disorders of Gaucher’s disease and Niemann-Pick disease (Chap. 433e). Other rare disorders
Table 367e-5 Lipid Storages Diseases Gaucher’s Niemann-Pick Abetalipoproteinemia Tangier Fabry’s Types I and IV hyperlipoproteinemia
Porphyrias The porphyrias are a group of metabolic disorders in which there are defects in the biosynthesis of heme necessary for incorporation into numerous hemoproteins such as hemoglobin, myoglobin, catalase, and the cytochromes (Chap. 430). Porphyrias can present as either acute or chronic diseases, with the acute disorder causing recurring bouts of abdominal pain, and the chronic disorders characterized by painful skin lesions. Porphyria cutanea tarda (PCT) is the most commonly encountered porphyria. Patients present with characteristic vesicular lesions on sun-exposed areas of the skin, principally the dorsum of the hands, the tips of the ears, or the cheeks. About 40% of patients with PCT have mutations in the gene for hemochromatosis (HFE), and ~50% have hepatitis C; thus, iron studies and HFE mutation analysis as well as hepatitis C testing should be considered in all patients who present with PCT. PCT is also associated with excess alcohol use and some medications, most notably estrogens. TREATMENT
Porphyrias
The mainstay of treatment of PCT is iron reduction by therapeutic phlebotomy, which is successful in reversing the skin lesions in the majority of patients. If hepatitis C is present, this should be treated as well. Acute intermittent porphyria presents with abdominal pain, with the diagnosis made by avoidance of certain precipitating factors such as starvation or certain diets. Intravenous heme as hematin has been used for treatment. INFILTRATIVE DISORDERS Amyloidosis Amyloidosis is a metabolic storage disease that results from deposition of insoluble proteins that are aberrantly folded and assembled and then deposited in a variety of tissues (Chap. 136).
Granulomas Granulomas are frequently found in the liver when patients are being evaluated for cholestatic liver enzyme abnormalities. Granulomas can be seen in primary biliary cirrhosis, but there are other characteristic clinical (e.g., pruritus, fatigue) and laboratory findings (cholestatic liver tests, antimitochondrial antibody) that allow for a definitive diagnosis of that disorder. Granulomatous infiltration can also be seen as the principal hepatic manifestation of sarcoidosis, and this is the most common presentation of hepatic granulomas (Chap. 390). The vast majority of these patients do not require any specific treatment other than what would normally be used for treatment of their sarcoidosis. A small subset, however, can develop a particularly bothersome desmoplastic reaction with a significant increase in fibrosis, which can progress to cirrhosis and liver failure. These patients may require treatment with immunosuppressive therapy and may require liver transplantation. In patients who have granulomas in the liver not associated with sarcoidosis, treatment is rarely needed. Diagnosis requires liver biopsy, and it is important to establish a diagnosis so that a cause for the elevated liver enzymes is carefully identified. Some medications can cause granulomatous infiltration of the liver, the most notable of which is allopurinol. Lymphoma Involvement of the liver with lymphoma can sometimes be with bulky mass lesions but can also be as a difficult-to-diagnose infiltrative disorder that does not show any characteristic findings on abdominal imaging studies (Chap. 134). Patients may present with severe liver disease, jaundice, hypoalbuminemia, mild to moderately elevated aminotransferases, and an elevated alkaline phosphatase. A liver biopsy is required for diagnosis and should be considered when routine blood testing does not lead to a diagnosis of the liver dysfunction.
367e-3
CHAPTER 367e Genetic, Metabolic, and Infiltrative Diseases Affecting the Liver
include abetalipoproteinemia, Tangier disease, Fabry’s disease, and types I and V hyperlipoproteinemia (Table 367e–5). Hepatomegaly is present due to increased fat deposition, and increased glycogen is found in the liver.
Amyloidosis is divided into two types, primary and secondary, based on the broad concepts of association with myeloma (primary) or chronic inflammatory illnesses (secondary). The disease is generally considered rare, although, in certain disease states or in certain populations, it can be more common. For example, when associated with familial Mediterranean fever, it is seen in high frequency in Sephardic Jews and Armenians living in Armenia and less frequently in Ashkenazi Jews, Turks, and Arabs. Amyloidosis frequently affects patients suffering from tuberculosis and leprosy and can be seen in upwards of 10–15% of patients with ankylosing spondylitis, rheumatoid arthritis, or Crohn’s disease. In one surgical pathology series, amyloid was found in 90% today. These improved prospects for prolonged survival resulted from refinements in operative technique, improvements in organ procurement and preservation, advances in immunosuppressive therapy, and, perhaps most influentially, more enlightened patient selection and timing. Despite the perioperative morbidity and mortality, the technical and management challenges of the procedure, and its costs, liver transplantation has become the approach of choice for selected patients whose chronic or acute liver disease is progressive, life-threatening, and unresponsive to medical therapy. Based on the current level of success, the number of liver transplants has continued to grow each year; in 2012, 6256 patients received liver allografts in the United States. Still, the demand for new livers continues to outpace availability; as of mid-2013, 15,806 patients in the United States were on a waiting list for a donor liver. In response to this drastic shortage of donor organs, many transplantation centers supplement cadaver-organ liver transplantation with living-donor transplantation.
INDICATIONS Potential candidates for liver transplantation are children and adults who, in the absence of contraindications (see below), suffer from severe, irreversible liver disease for which alternative medical or surgical treatments have been exhausted or are unavailable. Timing of the operation is of critical importance. Indeed, improved timing and better patient selection are felt to have contributed more to the increased
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2068 success of liver transplantation in the 1980s and beyond than all the
PART 14
impressive technical and immunologic advances combined. Although the disease should be advanced, and although opportunities for spontaneous or medically induced stabilization or recovery should be allowed, the procedure should be done sufficiently early to give the surgical procedure a fair chance for success. Ideally, transplantation should be considered in patients with end-stage liver disease who are experiencing or have experienced a life-threatening complication of hepatic decompensation or whose quality of life has deteriorated to unacceptable levels. Although patients with well-compensated cirrhosis can survive for many years, many patients with quasi-stable chronic liver disease have much more advanced disease than may be apparent. As discussed below, the better the status of the patient prior to transplantation, the higher will be its anticipated success rate. The decision about when to transplant is complex and requires the combined judgment of an experienced team of hepatologists, transplant surgeons, anesthesiologists, and specialists in support services, not to mention the well-informed consent of the patient and the patient’s family.
Disorders of the Gastrointestinal System
TRANSPLANTATION IN CHILDREN Indications for transplantation in children are listed in Table 368-1. The most common is biliary atresia. Inherited or genetic disorders of metabolism associated with liver failure constitute another major indication for transplantation in children and adolescents. In CriglerNajjar disease type I and in certain hereditary disorders of the urea cycle and of amino acid or lactate-pyruvate metabolism, transplantation may be the only way to prevent impending deterioration of central nervous system function, despite the fact that the native liver is structurally normal. Combined heart and liver transplantation has yielded dramatic improvement in cardiac function and in cholesterol levels in children with homozygous familial hypercholesterolemia; combined liver and kidney transplantation has been successful in patients with primary hyperoxaluria type I. In hemophiliacs with transfusion-associated hepatitis and liver failure, liver transplantation has been associated with recovery of normal factor VIII synthesis. TRANSPLANTATION IN ADULTS Liver transplantation is indicated for end-stage cirrhosis of all causes (Table 368-1). In sclerosing cholangitis and Caroli’s disease (multiple cystic dilatations of the intrahepatic biliary tree), recurrent infections and sepsis associated with inflammatory and fibrotic obstruction of the biliary tree may be an indication for transplantation. Because prior biliary surgery complicates and is a relative contraindication for liver transplantation, surgical diversion of the biliary tree has been all but abandoned for patients with sclerosing cholangitis. In patients who Table 368-1 Indications for Liver Transplantation Children Biliary atresia Neonatal hepatitis Congenital hepatic fibrosis Alagille’s syndromeα Byler’s diseaseb α1-Antitrypsin deficiency Inherited disorders of metabolism Wilson’s disease Tyrosinemia Glycogen storage diseases Lysosomal storage diseases Protoporphyria Crigler-Najjar disease type I Familial hypercholesterolemia Primary hyperoxaluria type I Hemophilia
Adults Primary biliary cirrhosis Secondary biliary cirrhosis Primary sclerosing cholangitis Autoimmune hepatitis Caroli’s diseasec Cryptogenic cirrhosis Chronic hepatitis with cirrhosis Hepatic vein thrombosis Fulminant hepatitis Alcoholic cirrhosis Chronic viral hepatitis Primary hepatocellular malignancies Hepatic adenomas Nonalcoholic steatohepatitis Familial amyloid polyneuropathy
α Arteriohepatic dysplasia, with paucity of bile ducts, and congenital malformations, including pulmonary stenosis. bIntrahepatic cholestasis, progressive liver failure, and mental and growth retardation. cMultiple cystic dilatations of the intrahepatic biliary tree.
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undergo transplantation for hepatic vein thrombosis (Budd-Chiari syndrome), postoperative anticoagulation is essential; underlying myeloproliferative disorders may have to be treated but are not a contraindication to liver transplantation. If a donor organ can be located quickly, before life-threatening complications—including cerebral edema—set in, patients with acute liver failure are candidates for liver transplantation. Routine candidates for liver transplantation are patients with alcoholic cirrhosis, chronic viral hepatitis, and primary hepatocellular malignancies. Although all three of these categories are considered to be high risk, liver transplantation can be offered to carefully selected patients. Currently, chronic hepatitis C and alcoholic liver disease are the most common indications for liver transplantation, accounting for over 40% of all adult candidates who undergo the procedure. Patients with alcoholic cirrhosis can be considered as candidates for transplantation if they meet strict criteria for abstinence and reform; however, these criteria still do not prevent recidivism in up to a quarter of cases. In highly selected cases in a limited number of centers, transplantation for severe acute alcoholic hepatitis has been performed with success; however, because patients with acute alcoholic hepatitis are still actively using alcohol, and because continued alcohol abuse remains a concern, acute alcoholic hepatitis is not a routine indication for liver transplantation. Patients with chronic hepatitis C have early allograft and patient survival comparable to those of other subsets of patients after transplantation; however, reinfection in the donor organ is universal, recurrent hepatitis C is insidiously progressive, allograft cirrhosis develops in 20–30% at 5 years, and cirrhosis and late organ failure occur at a higher frequency beyond 5 years. With the introduction of highly effective direct acting antiviral agents targeting HCV, it is expected that allograft outcomes will improve significantly in the coming years. In patients with chronic hepatitis B, in the absence of measures to prevent recurrent hepatitis B, survival after transplantation is reduced by approximately 10–20%; however, prophylactic use of hepatitis B immune globulin (HBIg) during and after transplantation increases the success of transplantation to a level comparable to that seen in patients with nonviral causes of liver decompensation. Specific oral antiviral drugs (e.g., entecavir, tenofovir disoproxil fumarate) (Chap. 362) can be used both for prophylaxis against and for treatment of recurrent hepatitis B, facilitating further the management of patients undergoing liver transplantation for endstage hepatitis B; most transplantation centers rely on antiviral drugs with or without HBIg to manage patients with hepatitis B. Issues of disease recurrence are discussed in more detail below. Patients with nonmetastatic primary hepatobiliary tumors—primary hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, epithelioid hemangioendothelioma, and multiple or massive hepatic adenomata—have undergone liver transplantation; however, for some hepatobiliary malignancies, overall survival is significantly lower than that for other categories of liver disease. Most transplantation centers have reported 5-year recurrence-free survival rates in patients with unresectable HCC for single tumors 70
adequate oxygenation, absence of bacterial or fungal infection, absence 2069 of abdominal trauma, absence of hepatic dysfunction, and serologic exclusion of hepatitis B (HBV) and C viruses and HIV. Occasionally, organs from donors with hepatitis B and C are used (e.g., for recipients with prior hepatitis B and C, respectively). Organs from donors with antibodies to hepatitis B core antigen (anti-HBc) can also be used when the need is especially urgent, and recipients of these organs are treated prophylactically with antiviral drugs. Cardiovascular and respiratory functions are maintained artificially until the liver can be removed. Transplantation of organs procured from deceased donors who have succumbed to cardiac death can be performed successfully under selected circumstances, when ischemic time is minimized and liver histology preserved. Compatibility in ABO blood group and organ size between donor and recipient are important considerations in donor selection; however, ABO-incompatible, split liver, or reduceddonor-organ transplants can be performed in emergencies or marked donor scarcity. Tissue typing for human leukocyte antigen (HLA) matching is not required, and preformed cytotoxic HLA antibodies do not preclude liver transplantation. Following perfusion with cold electrolyte solution, the donor liver is removed and packed in ice. The use of University of Wisconsin (UW) solution, rich in lactobionate and raffinose, has permitted the extension of cold ischemic time up to 20 h; however, 12 h may be a more reasonable limit. Improved techniques for harvesting multiple organs from the same donor have increased the availability of donor livers, but the availability of donor livers is far outstripped by the demand. Currently in the United States, all donor livers are distributed through a nationwide organ-sharing network (United Network for Organ Sharing [UNOS]) designed to allocate available organs based on regional considerations and recipient acuity. Recipients who have the highest disease severity generally have the highest priority, but allocation strategies that balance highest urgency against best outcomes continue to evolve to distribute cadaver organs most effectively. Allocation based on the Child-Turcotte-Pugh (CTP) score, which uses five clinical variables (encephalopathy stage, ascites, bilirubin, albumin, and prothrombin time) and waiting time, has been replaced by allocation based on urgency alone, calculated by the Model for End-Stage Liver Disease (MELD) score. The MELD score is based on a mathematical model that includes bilirubin, creatinine, and prothrombin time expressed as international normalized ratio (INR) (Table 368-3). Neither waiting time (except as a tie breaker between two potential recipients with the same MELD scores) nor posttransplantation outcome is taken into account, but use of the MELD score
Table 368-3 United Network for Organ Sharing (UNOS) Liver Transplantation Waiting List Criteria Status 1
Fulminant hepatic failure (including primary graft nonfunction and hepatic artery thrombosis within 7 days after transplantation as well as acute decompensated Wilson’s disease)α The Model for End-Stage Liver Disease (MELD) score, on a continuous scale,b determines allocation of the remainder of donor organs. This model is based on the following calculation: 3.78 × loge bilirubin (mg/100 mL) ± 11.2 × loge international normalized ratio (INR) ± 9.57 × loge creatinine (mg/100 mL) ± 6.43 (v 0 for alcoholic and cholestatic liver disease, × 1 for all other types of liver disease).c,d,e Online calculators to determine MELD scores are available, such as the following: http://optn.transplant.hrsa.gov/resources/professionalresources .asp?index=9. For children 95%) Simultaneous scanning of GB, liver, bile ducts, pancreas “Real-time” scanning allows assessment of GB volume, contractility Not limited by jaundice, pregnancy May detect very small stones Plain Abdominal X-Ray Low cost Readily available
Figure 369-2 Examples of ultrasound and radiologic studies of the biliary tract. A. An ultrasound study showing a distended gallbladder (GB) containing a single large stone (arrow), which casts an acoustic shadow. B. Endoscopic retrograde cholangiopancreatogram (ERCP) showing normal biliary tract anatomy. In addition to the endoscope and large vertical gallbladder filled with contrast dye, the common hepatic duct (CHD), common bile duct (CBD), and pancreatic duct (PD) are shown. The arrow points to the ampulla of Vater. C. Endoscopic retrograde cholangiogram (ERC) showing choledocholithiasis. The biliary tract is dilated and contains multiple radiolucent calculi. D. ERCP showing sclerosing cholangitis. The common bile duct shows areas that are strictured and narrowed.
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2080 but are not specific for biliary calculi. Biliary colic may be precipitated
by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a normal meal; it is frequently nocturnal, occurring within a few hours of retiring.
PART 14 Disorders of the Gastrointestinal System
Natural History Gallstone disease discovered in an asymptomatic patient or in a patient whose symptoms are not referable to cholelithiasis is a common clinical problem. Sixty to 80% of persons with asymptomatic gallstones remain asymptomatic over follow-up periods of up to 25 years. The probability of developing symptoms within 5 years after diagnosis is 2–4% per year and decreases in the years thereafter to 1–2%. The yearly incidence of complications is about 0.1–0.3%. Patients remaining asymptomatic for 15 years were found to be unlikely to develop symptoms during further follow-up, and most patients who did develop complications from their gallstones experienced prior warning symptoms. Similar conclusions apply to diabetic patients with silent gallstones. Decision analysis has suggested that (1) the cumulative risk of death due to gallstone disease while on expectant management is small, and (2) prophylactic cholecystectomy is not warranted. Complications requiring cholecystectomy are much more common in gallstone patients who have developed symptoms of biliary pain. Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients >60 years at the time of initial diagnosis. Patients with diabetes mellitus and gallstones may be somewhat more susceptible to septic complications, but the magnitude of risk of septic biliary complications in diabetic patients is incompletely defined. TREATMENT
Gallstones
SURGICAL THERAPY In asymptomatic gallstone patients, the risk of developing symptoms or complications requiring surgery is quite small (see above). Thus, a recommendation for cholecystectomy in a patient with gallstones should probably be based on assessment of three factors: (1) the presence of symptoms that are frequent enough or severe enough to interfere with the patient’s general routine; (2) the presence of a prior complication of gallstone disease, i.e., history of acute cholecystitis, pancreatitis, gallstone fistula, etc.; or (3) the presence of an underlying condition predisposing the patient to increased risk of gallstone complications (e.g., calcified or porcelain gallbladder and/or a previous attack of acute cholecystitis regardless of current symptomatic status). Patients with very large gallstones (>3 cm in diameter) and patients harboring gallstones in a congenitally anomalous gallbladder might also be considered for prophylactic cholecystectomy. Although young age is a worrisome factor in asymptomatic gallstone patients, few authorities would now recommend routine cholecystectomy in all young patients with silent stones. Laparoscopic cholecystectomy is a minimalaccess approach for the removal of the gallbladder together with its stones. Its advantages include a markedly shortened hospital stay, minimal disability, and decreased cost, and it is the procedure of choice for most patients referred for elective cholecystectomy. From several studies involving >4000 patients undergoing laparoscopic cholecystectomy, the following key points emerge: (1) complications develop in ∼4% of patients, (2) conversion to laparotomy occurs in 5%, (3) the death rate is remarkably low (i.e., 6 weeks after diagnosis) cholecystectomy. Delayed surgical intervention is probably best reserved for (1) patients in whom the overall medical condition imposes an unacceptable risk for early surgery and (2) patients in whom the diagnosis of acute cholecystitis is in doubt. Thus, early cholecystectomy (within 72 h) is the treatment of choice for most
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patients with acute cholecystitis. Mortality figures for emergency cholecystectomy in most centers range from 1–3%, whereas the mortality risk for early elective cholecystectomy is ∼0.5% in patients under age 60. Of course, the operative risks increase with agerelated diseases of other organ systems and with the presence of long- or short-term complications of gallbladder disease. Seriously ill or debilitated patients with cholecystitis may be managed with cholecystostomy and tube drainage of the gallbladder. Elective cholecystectomy may then be done at a later date. Postcholecystectomy Complications Early complications following cholecystectomy include atelectasis and other pulmonary disorders, abscess formation (often subphrenic), external or internal hemorrhage, biliary-enteric fistula, and bile leaks. Jaundice may indicate absorption of bile from an intraabdominal collection following a biliary leak or mechanical obstruction of the CBD by retained calculi, intraductal blood clots, or extrinsic compression. Overall, cholecystectomy is a very successful operation that provides total or near-total relief of preoperative symptoms in 75–90% of patients. The most common cause of persistent postcholecystectomy symptoms is an overlooked symptomatic nonbiliary disorder (e.g., reflux esophagitis, peptic ulceration, pancreatitis, or—most often— irritable bowel syndrome). In a small percentage of patients, however, a disorder of the extrahepatic bile ducts may result in persistent symptomatology. These so-called postcholecystectomy syndromes may be due to (1) biliary strictures, (2) retained biliary calculi, (3) cystic duct stump syndrome, (4) stenosis or dyskinesia of the sphincter of Oddi, or (5) bile salt–induced diarrhea or gastritis. Cystic duct stump syndrome In the absence of cholangiographically demonstrable retained stones, symptoms resembling biliary pain or cholecystitis in the postcholecystectomy patient have frequently been attributed to disease in a long (>1 cm) cystic duct remnant (cystic duct stump syndrome). Careful analysis, however, reveals that postcholecystectomy complaints are attributable to other causes in almost all patients in whom the symptom complex was originally thought to result from the existence of a long cystic duct stump. Accordingly, considerable care should be taken to investigate the possible role of other factors in the production of postcholecystectomy symptoms before attributing them to cystic duct stump syndrome. Papillary dysfunction, papillary stenosis, spasm of the sphincter of Oddi, and biliary dyskinesia Symptoms of biliary colic accompanied by signs of recurrent, intermittent biliary obstruction may be produced by acalculous cholecystopathy, papillary stenosis, papillary dysfunction, spasm of the sphincter of Oddi, and biliary dyskinesia. Papillary stenosis is thought to result from acute or chronic inflammation of the papilla of Vater or from glandular hyperplasia of the papillary segment. Five criteria have been used to define papillary stenosis: (1) upper abdominal pain, usually RUQ or epigastric; (2) abnormal liver tests; (3) dilatation of the CBD upon ERCP examination; (4) delayed (>45 min) drainage of contrast material from the duct; and (5) increased basal pressure of the sphincter of Oddi, a finding that may be of only minor significance. An alternative to ERCP is magnetic resonance cholangiography (MRC) if ERCP and/or biliary manometry are either unavailable or not feasible. After exclusion of acalculous cholecystopathy, treatment consists of endoscopic or surgical sphincteroplasty to ensure wide patency of the distal portions of both the bile and pancreatic ducts. The greater the number of the preceding criteria present, the greater is the likelihood that a patient does have a degree of papillary stenosis sufficient to justify correction. The factors usually considered as indications for sphincterotomy include (1) prolonged duration of symptoms, (2) lack of response to symptomatic treatment, (3) presence of severe disability, and (4) the patient’s choice of sphincterotomy over surgery (given a clear understanding on his or her part of the risks involved in both procedures). Criteria for diagnosing dyskinesia of the sphincter of Oddi are even more controversial than those for papillary stenosis. Proposed mechanisms include spasm of the sphincter, denervation sensitivity resulting
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THE HYPERPLASTIC CHOLECYSTOSES The term hyperplastic cholecystoses is used to denote a group of disorders of the gallbladder characterized by excessive proliferation of normal tissue components. Adenomyomatosis is characterized by a benign proliferation of gallbladder surface epithelium with glandlike formations, extramural sinuses, transverse strictures, and/or fundal nodule (“adenoma” or “adenomyoma”) formation. Cholesterolosis is characterized by abnormal deposition of lipid, especially cholesteryl esters, within macrophages in the lamina propria of the gallbladder wall. In its diffuse form (“strawberry gallbladder”), the gallbladder mucosa is brick red and speckled with bright yellow flecks of lipid. The localized form shows solitary or multiple “cholesterol polyps” studding the gallbladder wall. Cholesterol stones of the gallbladder are found in nearly half the cases. Cholecystectomy is indicated in both adenomyomatosis and cholesterolosis when symptomatic or when cholelithiasis is present. The prevalence of gallbladder polyps in the adult population is ∼5%, with a marked male predominance. Few significant changes have been found over a 5-year period in asymptomatic patients with gallbladder polyps 50 years of age, or in those whose polyps are >10 mm in diameter or associated with gallstones or polyp growth on serial ultrasonography.
DISEASES OF THE BILE DUCTS CONGENITAL ANOMALIES Biliary Atresia and Hypoplasia Atretic and hypoplastic lesions of the extrahepatic and large intrahepatic bile ducts are the most common biliary anomalies of clinical relevance encountered in infancy. The clinical picture is one of severe obstructive jaundice during the first month of life, with pale stools. When biliary atresia is suspected on the basis of clinical, laboratory, and imaging findings, the diagnosis is confirmed by surgical exploration and operative cholangiography. Approximately 10% of cases of biliary atresia are treatable with Roux-en-Y choledochojejunostomy, with the Kasai procedure (hepatic portoenterostomy) being attempted in the remainder in an effort to restore some bile flow. Most patients, even those having successful biliary-enteric anastomoses, eventually develop chronic cholangitis, extensive hepatic fibrosis, and portal hypertension.
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Congenital Biliary Ectasia Dilatation of intrahepatic bile ducts may involve either the major intrahepatic radicles (Caroli’s disease), the inter- and intralobular ducts (congenital hepatic fibrosis), or both. In Caroli’s disease, clinical manifestations include recurrent cholangitis, abscess formation in and around the affected ducts, and, often, brown pigment gallstone formation within portions of ectatic intrahepatic biliary radicles. Ultrasound, MRC, and CT are of great diagnostic value in demonstrating cystic dilatation of the intrahepatic bile ducts. Treatment with ongoing antibiotic therapy is usually undertaken in an effort to limit the frequency and severity of recurrent bouts of cholangitis. Progression to secondary biliary cirrhosis with portal hypertension, extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent episodes of sepsis with hepatic abscess formation is common. CHOLEDOCHOLITHIASIS Pathophysiology and Clinical Manifestations Passage of gallstones into the CBD occurs in ∼10–15% of patients with cholelithiasis. The incidence of common duct stones increases with increasing age of the patient, so that up to 25% of elderly patients may have calculi in the common duct at the time of cholecystectomy. Undetected duct stones are left behind in ∼1–5% of cholecystectomy patients. The overwhelming majority of bile duct stones are cholesterol stones formed in the gallbladder, which then migrate into the extrahepatic biliary tree through the cystic duct. Primary calculi arising de novo in the ducts are usually brown pigment stones developing in patients with (1) hepatobiliary parasitism or chronic, recurrent cholangitis; (2) congenital anomalies of the bile ducts (especially Caroli’s disease); (3) dilated, sclerosed, or strictured ducts; or (4) an MDR3 (ABCB4) gene defect leading to impaired biliary phospholipids secretion (low phospholipid–associated cholesterol cholelithiasis). Common duct stones may remain asymptomatic for years, may pass spontaneously into the duodenum, or (most often) may present with biliary colic or a complication.
Diseases of the Gallbladder and Bile Ducts
Bile salt–induced diarrhea and gastritis Postcholecystectomy patients may develop symptoms of dyspepsia, which have been attributed to duodenogastric reflux of bile. However, firm data linking these symptoms to bile gastritis after surgical removal of the gallbladder are lacking. Cholecystectomy induces persistent changes in gut transit, and these changes effect a noticeable modification of bowel habits. Cholecystectomy shortens gut transit time by accelerating passage of the fecal bolus through the colon with marked acceleration in the right colon, thus causing an increase in colonic bile acid output and a shift in bile acid composition toward the more diarrheagenic secondary bile acids, i.e. deoxycholic acid. Diarrhea that is severe enough, i.e., three or more watery movements per day, can be classified as postcholecystectomy diarrhea, and this occurs in 5–10% of patients undergoing elective cholecystectomy. Treatment with bile acid–sequestering agents such as cholestyramine or colestipol is often effective in ameliorating troublesome diarrhea.
Choledochal Cysts Cystic dilatation may involve the free portion of the 2083 CBD, i.e., choledochal cyst, or may present as diverticulum formation in the intraduodenal segment. In the latter situation, chronic reflux of pancreatic juice into the biliary tree can produce inflammation and stenosis of the extrahepatic bile ducts leading to cholangitis or biliary obstruction. Because the process may be gradual, ∼50% of patients present with onset of symptoms after age 10. The diagnosis may be made by ultrasound, abdominal CT, MRC, or cholangiography. Only one-third of patients show the classic triad of abdominal pain, jaundice, and an abdominal mass. Ultrasonographic detection of a cyst separate from the gallbladder should suggest the diagnosis of choledochal cyst, which can be confirmed by demonstrating the entrance of extrahepatic bile ducts into the cyst. Surgical treatment involves excision of the “cyst” and biliary-enteric anastomosis. Patients with choledochal cysts are at increased risk for the subsequent development of cholangiocarcinoma.
CHAPTER 369
in hypertonicity, and abnormalities of the sequencing or frequency rates of sphincteric-contraction waves. When thorough evaluation has failed to demonstrate another cause for the pain, and when cholangiographic and manometric criteria suggest a diagnosis of biliary dyskinesia, medical treatment with nitrites or anticholinergics to attempt pharmacologic relaxation of the sphincter has been proposed. Endoscopic biliary sphincterotomy (EBS) or surgical sphincteroplasty may be indicated in patients who fail to respond to a 2- to 3-month trial of medical therapy, especially if basal sphincter of Oddi pressures are elevated. EBS has become the procedure of choice for removing bile duct stones and for other biliary and pancreatic problems.
Complications • Cholangitis Cholangitis may be acute or chronic, and symptoms result from inflammation, which usually is caused by at least partial obstruction to the flow of bile. Bacteria are present on bile culture in ∼75% of patients with acute cholangitis early in the symptomatic course. The characteristic presentation of acute cholangitis involves biliary pain, jaundice, and spiking fevers with chills (Charcot’s triad). Blood cultures are frequently positive, and leukocytosis is typical. Nonsuppurative acute cholangitis is most common and may respond relatively rapidly to supportive measures and to treatment with antibiotics. In suppurative acute cholangitis, however, the presence of pus under pressure in a completely obstructed ductal system leads to symptoms of severe toxicity—mental confusion, bacteremia, and septic shock. Response to antibiotics alone in this setting is relatively poor, multiple hepatic abscesses are often present, and the mortality rate approaches 100% unless prompt endoscopic or surgical relief of the obstruction and drainage of infected bile are carried out. Endoscopic management of bacterial cholangitis is as effective as surgical intervention. ERCP with endoscopic sphincterotomy is safe and the preferred initial procedure for both establishing a definitive diagnosis and providing effective therapy.
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(3) ultrasonographic or MRCP evidence of a dilated CBD or stones in the duct. Alternatively, if intraoperative cholangiography reveals retained stones, postoperative ERCP can be carried out. The need for preoperative ERCP is expected to decrease further as laparoscopic techniques for bile duct exploration improve. The widespread use of laparoscopic cholecystectomy and ERCP has decreased the incidence of complicated biliary tract disease and the need for choledocholithotomy and T-tube drainage of the bile ducts. EBS followed by spontaneous passage or stone extraction is the treatment of choice in the management of patients with common duct stones, especially in elderly or poor-risk patients.
PART 14
TRAUMA, STRICTURES, AND HEMOBILIA Most benign strictures of the extrahepatic bile ducts result from surgical trauma and occur in about 1 in 500 cholecystectomies. Strictures may present with bile leak or abscess formation in the immediate postoperative period or with biliary obstruction or cholangitis as long as 2 years or more following the inciting trauma. The diagnosis is established by percutaneous or endoscopic cholangiography. Endoscopic brushing of biliary strictures may be helpful in establishing the nature of the lesion and is more accurate than bile cytology alone. When positive exfoliative cytology is obtained, the diagnosis of a neoplastic stricture is established. This procedure is especially important in patients with primary sclerosing cholangitis (PSC) who are predisposed to the development of cholangiocarcinomas. Successful operative correction of non-PSC bile duct strictures by a skillful surgeon with duct-to-bowel anastomosis is usually possible, although mortality rates from surgical complications, recurrent cholangitis, or secondary biliary cirrhosis are high. Hemobilia may follow traumatic or operative injury to the liver or bile ducts, intraductal rupture of a hepatic abscess or aneurysm of the hepatic artery, biliary or hepatic tumor hemorrhage, or mechanical complications of choledocholithiasis or hepatobiliary parasitism. Diagnostic procedures such as liver biopsy, PTC, and transhepatic biliary drainage catheter placement may also be complicated by hemobilia. Patients often present with a classic triad of biliary pain, obstructive jaundice, and melena or occult blood in the stools. The diagnosis is sometimes made by cholangiographic evidence of blood clot in the biliary tree, but selective angiographic verification may be required. Although minor episodes of hemobilia may resolve without operative intervention, surgical ligation of the bleeding vessel is frequently required.
Disorders of the Gastrointestinal System
2084 Obstructive jaundice Gradual obstruction of the CBD over a period
of weeks or months usually leads to initial manifestations of jaundice or pruritus without associated symptoms of biliary colic or cholangitis. Painless jaundice may occur in patients with choledocholithiasis, but is much more characteristic of biliary obstruction secondary to malignancy of the head of the pancreas, bile ducts, or ampulla of Vater. In patients whose obstruction is secondary to choledocholithiasis, associated chronic calculous cholecystitis is very common, and the gallbladder in this setting may be unable to distend. The absence of a palpable gallbladder in most patients with biliary obstruction from duct stones is the basis for Courvoisier’s law, i.e., that the presence of a palpably enlarged gallbladder suggests that the biliary obstruction is secondary to an underlying malignancy rather than to calculous disease. Biliary obstruction causes progressive dilatation of the intrahepatic bile ducts as intrabiliary pressures rise. Hepatic bile flow is suppressed, and reabsorption and regurgitation of conjugated bilirubin into the bloodstream lead to jaundice accompanied by dark urine (bilirubinuria) and light-colored (acholic) stools. CBD stones should be suspected in any patient with cholecystitis whose serum bilirubin level is >85.5 μmol/L (5 mg/dL). The maximum bilirubin level is seldom >256.5 μmol/L (15.0 mg/dL) in patients with choledocholithiasis unless concomitant hepatic or renal disease or another factor leading to marked hyperbilirubinemia exists. Serum bilirubin levels ≥342.0 μmol/L (20 mg/dL) should suggest the possibility of neoplastic obstruction. The serum alkaline phosphatase level is almost always elevated in biliary obstruction. A rise in alkaline phosphatase often precedes clinical jaundice and may be the only abnormality in routine liver function tests. There may be a two- to tenfold elevation of serum aminotransferases, especially in association with acute obstruction. Following relief of the obstructing process, serum aminotransferase elevations usually return rapidly to normal, while the serum bilirubin level may take 1–2 weeks to return to normal. The alkaline phosphatase level usually falls slowly, lagging behind the decrease in serum bilirubin. Pancreatitis The most common associated entity discovered in patients with nonalcoholic acute pancreatitis is biliary tract disease. Biochemical evidence of pancreatic inflammation complicates acute cholecystitis in 15% of cases and choledocholithiasis in >30%, and the common factor appears to be the passage of gallstones through the common duct. Coexisting pancreatitis should be suspected in patients with symptoms of cholecystitis who develop (1) back pain or pain to the left of the abdominal midline, (2) prolonged vomiting with paralytic ileus, or (3) a pleural effusion, especially on the left side. Surgical treatment of gallstone disease is usually associated with resolution of the pancreatitis. Secondary biliary cirrhosis Secondary biliary cirrhosis may complicate prolonged or intermittent duct obstruction with or without recurrent cholangitis. Although this complication may be seen in patients with choledocholithiasis, it is more common in cases of prolonged obstruction from stricture or neoplasm. Once established, secondary biliary cirrhosis may be progressive even after correction of the obstructing process, and increasingly severe hepatic cirrhosis may lead to portal hypertension or to hepatic failure and death. Prolonged biliary obstruction may also be associated with clinically relevant deficiencies of the fat-soluble vitamins A, D, E, and K. Diagnosis and Treatment The diagnosis of choledocholithiasis is usually made by cholangiography (Table 369-3), either preoperatively by endoscopic retrograde cholangiogram (ERC) (Fig. 369-2C) or MRCP or intraoperatively at the time of cholecystectomy. As many as 15% of patients undergoing cholecystectomy will prove to have CBD stones. When CBD stones are suspected prior to laparoscopic cholecystectomy, preoperative ERCP with endoscopic papillotomy and stone extraction is the preferred approach. It not only provides stone clearance but also defines the anatomy of the biliary tree in relationship to the cystic duct. CBD stones should be suspected in gallstone patients who have any of the following risk factors: (1) a history of jaundice or pancreatitis, (2) abnormal tests of liver function, and
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EXTRINSIC COMPRESSION OF THE BILE DUCTS Partial or complete biliary obstruction may be produced by extrinsic compression of the ducts. The most common cause of this form of obstructive jaundice is carcinoma of the head of the pancreas. Biliary obstruction may also occur as a complication of either acute or chronic pancreatitis or involvement of lymph nodes in the porta hepatis by lymphoma or metastatic carcinoma. The latter should be distinguished from cholestasis resulting from massive replacement of the liver by tumor. HEPATOBILIARY PARASITISM Infestation of the biliary tract by adult helminths or their ova may produce a chronic, recurrent pyogenic cholangitis with or without multiple hepatic abscesses, ductal stones, or biliary obstruction. This condition is relatively rare but does occur in inhabitants of southern China and elsewhere in Southeast Asia. The organisms most commonly involved are trematodes or flukes, including Clonorchis sinensis, Opisthorchis viverrini or Opisthorchis felineus, and Fasciola hepatica. The biliary tract also may be involved by intraductal migration of adult Ascaris lumbricoides from the duodenum or by intrabiliary rupture of hydatid cysts of the liver produced by Echinococcus spp. The diagnosis is made by cholangiography and the presence of characteristic ova on stool examination. When obstruction is present, the treatment of choice is laparotomy under antibiotic coverage, with common duct exploration and a biliary drainage procedure. SCLEROSING CHOLANGITIS Primary or idiopathic sclerosing cholangitis is characterized by a progressive, inflammatory, sclerosing, and obliterative process
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2085
Table 369-3 Diagnostic Evaluation of the Bile Ducts Diagnostic Limitations Bowel gas Massive obesity Ascites Barium Partial bile duct obstruction Poor visualization of distal CBD
Percutaneous Transhepatic Cholangiogram Extremely successful when bile Nondilated or ducts dilated sclerosed ducts Best visualization of proximal biliary tract Bile cytology/culture Percutaneous transhepatic drainage Endoscopic Ultrasound Most sensitive method to detect ampullary stones
Complications
Comment
None
None
Initial procedure of choice in investigating possible biliary tract obstruction
Pregnancy
Reaction to iodinated contrast, if used
Indicated for evaluation of hepatic or pancreatic masses Procedure of choice in investigating possible biliary obstruction if diagnostic limitations prevent HBUS
Claustrophobia Certain metals (iron)
None
Pregnancy ? Acute pancreatitis ? Severe cardiopulmonary disease
Pancreatitis Cholangitis, sepsis Infected pancreatic pseudocyst Perforation (rare) Hypoxemia, aspiration
Cholangiogram of choice in: Absence of dilated ducts ? Pancreatic, ampullary or gastroduodenal disease Prior biliary surgery Endoscopic sphincterotomy a treatment possibility
Pregnancy Uncorrectable coagulopathy Massive ascites ? Hepatic abscess
Bleeding Hemobilia Bile peritonitis Bacteremia, sepsis
Indicated when ERCP is contraindicated or failed
Diseases of the Gallbladder and Bile Ducts
Computed Tomography Simultaneous scanning of GB, liver, Extreme cachexia bile ducts, pancreas Movement artifact Accurate identification of dilated Ileus bile ducts, masses Partial bile duct Not limited by jaundice, gas, obesity, obstruction ascites High-resolution image Guidance for fine-needle biopsy Magnetic Resonance Cholangiopancreatography Useful modality for visualizing Cannot offer pancreatic and biliary ducts therapeutic intervention Has excellent sensitivity for bile duct dilatation, biliary stricture, High cost and intraductal abnormalities Can identify pancreatic duct dilatation or stricture, pancreatic duct stenosis, and pancreas divisum Endoscopic Retrograde Cholangiopancreatography Simultaneous pancreatography Gastroduodenal obstruction Best visualization of distal biliary tract ? Roux-en-Y Bile or pancreatic cytology biliary-enteric Endoscopic sphincterotomy and stone anastomosis removal Biliary manometry
Contraindications
CHAPTER 369
Diagnostic Advantages Hepatobiliary Ultrasound Rapid Simultaneous scanning of GB, liver, bile ducts, pancreas Accurate identification of dilated bile ducts Not limited by jaundice, pregnancy Guidance for fine-needle biopsy
Abbreviations: CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography; GB, gallbladder; HBUS, hepatobiliary ultrasound.
affecting the extrahepatic and/or the intrahepatic bile ducts. The disorder occurs up to 75% in association with inflammatory bowel disease, especially ulcerative colitis. It may also be associated with autoimmune pancreatitis; multifocal fibrosclerosis syndromes such as retroperitoneal, mediastinal, and/or periureteral fibrosis; Riedel’s struma; or pseudotumor of the orbit. Immunoglobulin G4 (IgG4)–associated cholangitis is a recently described biliary disease of unknown etiology that presents with biochemical and cholangiographic features indistinguishable from PSC, is often associated with autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts and liver tissue. In contrast to PSC, it is not associated with inflammatory bowel disease and should be suspected if associated with increased serum IgG4 and
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unexplained pancreatic disease. Glucocorticoids are regarded as the initial treatment of choice. Relapse is common after steroid withdrawal, especially with proximal strictures. Long-term treatment with glucocorticoids and/or azathioprine may be needed after relapse or for inadequate response (Chap. 371). Patients with primary sclerosing cholangitis often present with signs and symptoms of chronic or intermittent biliary obstruction: RUQ abdominal pain, pruritus, jaundice, or acute cholangitis. Late in the course, complete biliary obstruction, secondary biliary cirrhosis, hepatic failure, or portal hypertension with bleeding varices may occur. The diagnosis is usually established by finding multifocal, diffusely distributed strictures with intervening segments of normal or dilated ducts, producing a beaded appearance on cholangiography (Fig. 369-2D). The cholangiographic techniques of choice in suspected
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2086 cases are MRCP and ERCP. When a diagnosis of sclerosing cholangitis
PART 14 Disorders of the Gastrointestinal System
has been established, a search for associated diseases, especially for chronic inflammatory bowel disease, should be carried out. A recent study describes the natural history and outcome for 305 patients of Swedish descent with primary sclerosing cholangitis; 134 (44%) of the patients were asymptomatic at the time of diagnosis and, not surprisingly, had a significantly higher survival rate. The independent predictors of a bad prognosis were advanced age, serum bilirubin concentration, and liver histologic changes. Cholangiocarcinoma was found in 24 patients (8%). Inflammatory bowel disease was closely associated with primary sclerosing cholangitis and had a prevalence of 81% in this study population. Small duct PSC is defined by the presence of chronic cholestasis and hepatic histology consistent with PSC but with normal findings on cholangiography. Small duct PSC is found in ∼5% of patients with PSC and may represent an earlier stage of PSC associated with a significantly better long-term prognosis. However, such patients may progress to classic PSC and/or end-stage liver disease with consequent necessity of liver transplantation. In patients with AIDS, cholangiopancreatography may demonstrate a broad range of biliary tract changes as well as pancreatic duct obstruction and occasionally pancreatitis (Chap. 226). Further, biliary tract lesions in AIDS include infection and cholangiopancreatographic changes similar to those of PSC. Changes noted include: (1) diffuse involvement of intrahepatic bile ducts alone, (2) involvement of both intra- and extrahepatic bile ducts, (3) ampullary stenosis, (4) stricture of the intrapancreatic portion of the CBD, and (5) pancreatic duct involvement. Associated infectious organisms include Cryptosporidium, Mycobacterium avium-intracellulare, cytomegalovirus, Microsporidia,
and Isospora. In addition, acalculous cholecystitis occurs in up to 10% of patients. ERCP sphincterotomy, while not without risk, provides significant pain reduction in patients with AIDS-associated papillary stenosis. Secondary sclerosing cholangitis may occur as a long-term complication of choledocholithiasis, cholangiocarcinoma, operative or traumatic biliary injury, or contiguous inflammatory processes.
TREATMENT
Sclerosing Cholangitis
Therapy with cholestyramine may help control symptoms of pruritus, and antibiotics are useful when cholangitis complicates the clinical picture. Vitamin D and calcium supplementation may help prevent the loss of bone mass frequently seen in patients with chronic cholestasis. Glucocorticoids, methotrexate, and cyclosporine have not been shown to be efficacious in PSC. UDCA in high dosage (20 mg/kg) improves serum liver tests, but an effect on survival has not been documented. In cases where high-grade biliary obstruction (dominant strictures) has occurred, balloon dilatation or stenting may be appropriate. Only rarely is surgical intervention indicated. Efforts at biliary-enteric anastomosis or stent placement may, however, be complicated by recurrent cholangitis and further progression of the stenosing process. The prognosis is unfavorable, with a median survival of 9–12 years following the diagnosis, regardless of therapy. Four variables (age, serum bilirubin level, histologic stage, and splenomegaly) predict survival in patients with PSC and serve as the basis for a risk score. PSC is one of the most common indications for liver transplantation.
Section 3 Disorders of the Pancreas
370
Approach to the Patient with Pancreatic Disease D arwin L. Conwell, Norton J. Greenberger, Peter A. Banks
GENERAL CONSIDERATIONS As emphasized in Chap. 371, the etiologies as well as clinical manifestations of pancreatitis are quite varied. Although it is well-appreciated that pancreatitis is frequently secondary to biliary tract disease and alcohol abuse, it can also be caused by drugs, genetic mutations, trauma, and viral infections and is associated with metabolic and connective tissue disorders. In ~30% of patients with acute pancreatitis and 25–40% of patients with chronic pancreatitis, the etiology initially can be obscure. The incidence of acute pancreatitis is about 5–35/100,000 new cases per year worldwide, with a mortality rate of about 3%. The incidence of chronic pancreatitis is about 4–8 new cases per 100,000 per year with a prevalence of 26–42 cases per 100,000. The number of patients admitted to the hospital who suffer with both acute and chronic pancreatitis in the United States is largely increasing and is now estimated to be 274,119 for acute pancreatitis and 19,724 for chronic pancreatitis. Acute pancreatitis is now the most common gastrointestinal diagnosis requiring hospitalization in the United States. Acute and chronic pancreatic disease costs an estimated 3 billion dollars annually in health care expenditures. These numbers may underestimate the true incidence and prevalence, because non–alcohol-induced pancreatitis has been largely ignored. At autopsy, the prevalence of chronic pancreatitis ranges from 0.04 to 5%.
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The diagnosis of acute pancreatitis is generally clearly defined based on a combination of laboratory, imaging, and clinical symptoms. The diagnosis of chronic pancreatitis, especially in mild disease, is hampered by the relative inaccessibility of the pancreas to direct examination and the nonspecificity of the abdominal pain associated with chronic pancreatitis. Many patients with chronic pancreatitis do not have elevated blood amylase or lipase levels. Some patients with chronic pancreatitis develop signs and symptoms of pancreatic exocrine insufficiency, and thus, objective evidence for pancreatic disease can be demonstrated. However, there is a very large reservoir of pancreatic exocrine function. More than 90% of the pancreas must be damaged before maldigestion of fat and protein is manifested. Noninvasive, indirect tests of pancreatic exocrine function (fecal elastase) are much more likely to give abnormal results in patients with obvious advanced pancreatic disease (i.e., pancreatic calcification, steatorrhea, or diabetes mellitus) than in patients with occult disease. Invasive, direct tests of pancreatic secretory function (secretin tests) are the most sensitive and specific tests to detect early chronic pancreatic disease when imaging is equivocal or normal.
TESTS USEFUL IN THE DIAGNOSIS OF PANCREATIC DISEASE Several tests have proved of value in the evaluation of pancreatic disease. Examples of specific tests and their usefulness in the diagnosis of acute and chronic pancreatitis are summarized in Table 370-1 and Fig. 370-1. At some institutions, pancreatic function tests are available and performed if the diagnosis of chronic pancreatic disease remains a possibility after noninvasive tests (ultrasound, computed tomography [CT], magnetic resonance cholangiopancreatography [MRCP]) or invasive tests (endoscopic retrograde cholangiopancreatography [ERCP], endoscopic ultrasonography [EUS]) have given normal or
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Table 370-1 Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Tumors
4. Pleural fluid
Exudative pleural effusion with pancreatitis
Comment Enzyme measurement of choice for diagnosis of acute pancreatitis
Simple; reliable if test results are three times the upper limit of normal Infrequently used Can help establish source of ascites; false positives occur with intestinal obstruction and perforated ulcer; can also measure lipase False positives occur with carcinoma of the lung and esophageal perforation
Infrequently used Infrequently used Simple, noninvasive; sequential studies quite feasible; useful in diagnosis of gallstones; pancreas visualization limited by interference from overlying bowel gas 4. Computed tomography Permits detailed visualization of pancreas and surrounding Useful in the diagnosis of pancreatic calcification, dilated (CT) scan structures, pancreatic fluid collection, pseudocyst; pancreatic ducts, and pancreatic tumors; may not be able to assessment of necrosis or interstitial disease distinguish between inflammatory and neoplastic mass lesions 5. Magnetic resonance Three-dimensional imaging has been used to produce very Has replaced ERCP as a diagnostic test; noninvasive cholangiopancreatography good images of the pancreatic-biliary ductal system by a (MRCP) noninvasive technique 6. Endoscopic ultrasonography High-frequency transducer used with EUS can produce Can be used to assess gallstones, chronic pancreatitis, and (EUS) very high-resolution images and depict changes in the pancreatic carcinoma pancreatic duct and parenchyma with great detail 7. Endoscopic retrograde Cannulation of pancreatic and common bile duct permits Primarily a therapeutic procedure; invasive cholangiopancreatography visualization of pancreatic-biliary ductal system (ERCP) Pancreatic biopsy with US or Percutaneous aspiration biopsy of mass-forming lesions of High diagnostic yield; laparotomy avoided; can be done with CT guidance the pancreas EUS for the evaluation of chronic pancreatitis, autoimmune pancreatitis, and pancreatic carcinoma Tests of Exocrine Pancreatic Function Direct stimulation of the pancreas with analysis of duodenal contents 1. Secretin test Secretin leads to increased output of pancreatic juice Sensitive enough to detect occult disease; involves duodenal and HCO3–; pancreatic secretory response is related to the intubation and fluoroscopic placement of gastroduodenal tube; functional mass of pancreatic tissue poorly defined normal enzyme response; overlap in chronic pancreatitis; large secretory reserve capacity of the pancreas; currently done at only a few medical centers 2. Endoscopic secretin test Replaces need for tube placement duodenum Sensitive enough to detect occult disease; high negative predictive value; avoids intubation and fluoroscopy; requires sedation Measurement of intraluminal digestion products 1. Quantitative stool fat Lack of lipolytic enzymes brings about impaired fat Reliable reference standard for defining severity of malabsorption; determination digestion does not distinguish between maldigestion and malabsorption Measurement of pancreatic enzymes in feces 1. Elastase Pancreatic secretion of proteolytic enzymes; not degraded Diagnostic accuracy best if value is 200 mg/g are normal; levels of 100–200 mg/g are considered mild, and levels 250,000 hospitalizations per year. The median length of hospital stay is 4 days, with a median hospital cost of $6,096 and a mortality of 1%. The estimated cost annually approaches $2.6 billion. Hospitalization rates increase with age, are 88% higher among blacks, and are higher among males than females. The age-adjusted rate of hospital discharges with an acute pancreatitis diagnosis increased 62% between 1988 and 2004. From 2000 to 2009, the rate increased 30%. Thus, acute pancreatitis is increasing and is a significant burden on health care costs and resource utilization. ETIOLOGY AND PATHOGENESIS There are many causes of acute pancreatitis (Table 371-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been fully elucidated. Gallstones continue to be the leading cause of acute pancreatitis in most series (30–60%). The risk
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Acute and Chronic Pancreatitis
ENTEROPANCREATIC AXIS AND FEEDBACK INHIBITION Pancreatic enzyme secretion is controlled, at least in part, by a negative feedback mechanism induced by the presence of active serine proteases in the duodenum. To illustrate, perfusion of the duodenal lumen with phenylalanine (stimulates early digestion) causes a prompt increase in plasma CCK levels as well as increased secretion of chymotrypsin and other pancreatic enzymes. However, simultaneous perfusion with trypsin (stimulates late digestion) blunts both responses. Conversely, perfusion of the duodenal lumen with protease inhibitors actually leads to enzyme hypersecretion. The available evidence supports the concept that the duodenum contains a peptide called CCK-releasing factor (CCK-RF) that is involved in stimulating CCK release. It appears that serine proteases inhibit pancreatic secretion by inactivating a CCK-releasing peptide in the lumen of the small intestine. Thus, the integrative result of both bicarbonate and enzyme secretion depends on a feedback process for both bicarbonate and pancreatic enzymes. Acidification of the duodenum releases secretin, which stimulates vagal and other neural pathways to activate pancreatic duct cells, which secrete bicarbonate. This bicarbonate then neutralizes the duodenal acid, and the feedback loop is completed. Dietary proteins bind proteases, thereby leading to an increase in free CCK-RF. CCK is then released into the blood in physiologic concentrations, acting primarily through the neural pathways (vagal-vagal). This leads to acetylcholinemediated pancreatic enzyme secretion. Proteases continue to be secreted from the pancreas until the protein within the duodenum is digested. At this point, pancreatic protease secretion is reduced to basic levels, thus completing this step in the feedback process.
Common Causes Gallstones (including microlithiasis) Alcohol (acute and chronic alcoholism) Hypertriglyceridemia Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, anti-HIV medications, 5-aminosalicylic acid [5-ASA]) Trauma (especially blunt abdominal trauma) Postoperative (abdominal and nonabdominal operations) Uncommon Causes Vascular causes and vasculitis (ischemic-hypoperfusion states after cardiac surgery) Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP) Cancer of the pancreas Hypercalcemia Periampullary diverticulum Pancreas divisum Hereditary pancreatitis Cystic fibrosis Renal failure Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites) Autoimmune (e.g., type 1 and type 2) Causes to Consider in Patients with Recurrent Bouts of Acute Pancreatitis Without an Obvious Etiology Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis, biliary sludge Drugs Alcohol abuse Metabolic: Hypertriglyceridemia, hypercalcemia Anatomic: Pancreas divisum Pancreatic cancer Intraductal papillary mucinous neoplasm (IPMN) Hereditary pancreatitis Cystic fibrosis Autoimmune Idiopathic
CHAPTER 371
AUTOPROTECTION OF THE PANCREAS Autodigestion of the pancreas is prevented by (1) the packaging of pancreatic proteases in precursor (proenzyme) form, (2) intracellular calcium homeostasis (low intracellular calcium in the cytosol of the acinar cell promotes the destruction of spontaneously activated trypsin), (3) acid-base balance, and (4) the synthesis of protective protease inhibitors (pancreatic secretory trypsin inhibitor [PSTI] or SPINK1), which can bind and inactivate about 20% of intracellular trypsin activity. Chymotrypsin C can also lyse and inactivate trypsin. These protease inhibitors are found in the acinar cell, the pancreatic secretions, and the α1- and α2-globulin fractions of plasma. Loss of any of these four protective mechanisms leads to premature enzyme activation, autodigestion, and acute pancreatitis.
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Table 371-1 Causes of Acute Pancreatitis
of acute pancreatitis in patients with at least one gallstone 11.3 mmol/L (>1000 mg/dL). Most patients with hypertriglyceridemia, when subsequently examined, show evidence of an underlying derangement in lipid metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g., drugs or alcohol) that causes an abrupt increase in serum triglycerides can precipitate a bout of acute pancreatitis. Patients with a deficiency of apolipoprotein CII have an increased incidence of pancreatitis; apolipoprotein CII
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2092 activates lipoprotein lipase, which is important in clearing chylomi-
PART 14 Disorders of the Gastrointestinal System
crons from the bloodstream. Patients with diabetes mellitus who have developed ketoacidosis and patients who are on certain medications such as oral contraceptives may also develop high triglyceride levels. Approximately 0.1–2% of cases of acute pancreatitis are drug related. Drugs cause pancreatitis either by a hypersensitivity reaction or by the generation of a toxic metabolite, although in some cases, it is not clear which of these mechanisms is operative (Table 371-1). Pathologically, acute pancreatitis varies from interstitial pancreatitis (pancreas blood supply maintained), which is generally self-limited to necrotizing pancreatitis (pancreas blood supply interrupted), in which the extent of necrosis may correlate with the severity of the attack and its systemic complications. Autodigestion is a currently accepted pathogenic theory; according to this theory, pancreatitis results when proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, and lipolytic enzymes such as phospholipase A2) are activated in the pancreas acinar cell rather than in the intestinal lumen. A number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, oxidative stress, lysosomal calcium, and direct trauma) are believed to facilitate premature activation of trypsin. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also can activate other enzymes, such as elastase and phospholipase A2. Spontaneous activation of trypsin also can occur.
ACTIVATION OF PANCREATIC ENZYMES IN THE PATHOGENESIS OF ACUTE PANCREATITIS Several recent studies have suggested that pancreatitis is a disease that evolves in three phases. The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. Trypsin activation appears to be mediated by lysosomal hydrolases such as cathepsin B that become colocalized with digestive enzymes in intracellular organelles; it is currently believed that acinar cell injury is the consequence of trypsin activation. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction. Neutrophil depletion induced by prior administration of an antineutrophil serum has been shown to reduce the severity of experimentally induced pancreatitis. There is also evidence to support the concept that neutrophils can activate trypsinogen. Thus, intrapancreatic acinar cell activation of trypsinogen could be a two-step process (i.e., an early neutrophil-independent and a later neutrophil-dependent phase). The third phase of pancreatitis is due to the effects of activated proteolytic enzymes and cytokines, released by the inflamed pancreas, on distant organs. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also activate other enzymes such as elastase and phospholipase A2. The active enzymes and cytokines then digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal cell necrosis. Cellular injury and death result in the liberation of bradykinin peptides, vasoactive substances, and histamine that can produce vasodilation, increased vascular permeability, and edema with profound effects on many organs. The systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS), as well as multiorgan failure, may occur as a result of this cascade of local and distant effects. A number of genetic factors can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis, recurrent pancreatitis, and chronic pancreatitis. All of the major genetic susceptibility factors center on the control of trypsin activity within the pancreatic acinar cell, in part because they were identified as candidate genes linked to intrapancreatic trypsin control. Five genetic variants have been identified as being associated with susceptibility to pancreatitis. The genes that have been identified include (1) cationic trypsinogen gene (PRSS1), (2) pancreatic secretory trypsin inhibitor (SPINK1), (3) the cystic fibrosis transmembrane conductance regulator gene (CFTR), (4) the chymotrypsin C gene (CTRC), and (5) the calcium-sensing receptor (CASR). Investigations of other genetic variants are currently under way, and new genes will be added to this list
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in the future. Multiple medical, ethical, and psychological issues arise when these genes are discovered, and referral to genetic counselors is recommended.
APPROACH TO THE PATIENT: Abdominal Pain Abdominal pain is the major symptom of acute pancreatitis. Pain may vary from a mild discomfort to severe, constant, and incapacitating distress. Characteristically, the pain, which is steady and boring in character, is located in the epigastrium and periumbilical region, and may radiate to the back, chest, flanks, and lower abdomen. Nausea, vomiting, and abdominal distention due to gastric and intestinal hypomotility and chemical peritonitis are also frequent complaints. Physical examination frequently reveals a distressed and anxious patient. Low-grade fever, tachycardia, and hypotension are fairly common. Shock is not unusual and may result from (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space; (2) increased formation and release of kinin peptides, which cause vasodilation and increased vascular permeability; and (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation. Jaundice occurs infrequently; when present, it usually is due to edema of the head of the pancreas with compression of the intrapancreatic portion of the common bile duct or passage of a biliary stone or sludge. Erythematous skin nodules due to subcutaneous fat necrosis may rarely occur. In 10–20% of patients, there are pulmonary findings, including basilar rales, atelectasis, and pleural effusion, the latter most frequently left sided. Abdominal tenderness and muscle rigidity are present to a variable degree, but compared with the intense pain, these signs may be less impressive. Bowel sounds are usually diminished or absent. An enlarged pancreas from acute fluid collection, walled off necrosis, or a pseudocyst may be palpable in the upper abdomen later in the course of the disease (i.e., 4–6 weeks). A faint blue discoloration around the umbilicus (Cullen’s sign) may occur as the result of hemoperitoneum, and a blue-red-purple or green-brown discoloration of the flanks (Turner’s sign) reflects tissue catabolism of hemoglobin from severe necrotizing pancreatitis with hemorrhage. LABORATORY DATA Serum amylase and lipase values threefold or more above normal virtually clinch the diagnosis if gut perforation, ischemia, and infarction are excluded. Serum lipase is the preferred test. However, it should be noted that there is no correlation between the severity of pancreatitis and the degree of serum lipase and amylase elevations. After 3–7 days, even with continuing evidence of pancreatitis, total serum amylase values tend to return toward normal. However, pancreatic isoamylase and lipase levels may remain elevated for 7–14 days. It should be recognized that amylase elevations in serum and urine occur in many conditions other than pancreatitis (see Chap. 370, Table 370-2). Importantly, patients with acidemia (arterial pH ≤7.32) may have spurious elevations in serum amylase. This finding explains why patients with diabetic ketoacidosis may have marked elevations in serum amylase without any other evidence of acute pancreatitis. Serum lipase activity increases in parallel with amylase activity and is more specific than amylase. A serum lipase measurement can be instrumental in differentiating a pancreatic or nonpancreatic cause for hyperamylasemia. Leukocytosis (15,000–20,000 leukocytes/μL) occurs frequently. Patients with more severe disease may show hemoconcentration with hematocrit values >44% and/or prerenal azotemia with a blood urea nitrogen (BUN) level >22 mg/dL resulting from loss of plasma into the retroperitoneal space and peritoneal cavity. Hemoconcentration may be the harbinger of more severe disease (i.e., pancreatic necrosis), whereas azotemia is a significant risk factor for mortality. Hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and
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Table 371-2 Revised Atlanta Definitions of Morphologic Features of Acute Pancreatitis Morphologic Feature Interstitial pancreatitis
Acute pancreatic fluid collection
Lack of pancreatic parenchymal enhancement by IV contrast agent and/or presence of findings of peripancreatic necrosis (see below—ANC and WON) Occurs in the setting of interstitial edematous pancreatitis Homogeneous collection with fluid density Confined by normal peripancreatic fascial planes No definable wall encapsulating the collection Adjacent to pancreas (no intrapancreatic extension)
Well circumscribed, usually round or oval Homogeneous fluid density No nonliquid component Well-defined wall; that is, completely encapsulated Maturation usually requires >4 weeks after onset of acute pancreatitis; occurs after interstitial edematous pancreatitis Acute necrotic A collection containing Occurs only in the setting of collection (ANC) variable amounts of acute necrotizing pancreatitis both fluid and necrosis Heterogeneous and nonliquid associated with necrodensity of varying degrees tizing pancreatitis; the in different locations (some necrosis can involve the appear homogeneous early in pancreatic parenchyma their course) and/or the peripancreNo definable wall encapsulatatic tissues. ing the collection Location—intrapancreatic and/or extrapancreatic Walled-off A mature, encapsulated Heterogeneous with liquid and necrosis (WON) collection of pancreatic nonliquid density with varying and/or peripancreatic degrees of loculations (some necrosis that has devel- may appear homogeneous) oped a well-defined Well-defined wall; that is, cominflammatory wall. WON pletely encapsulated usually occurs >4 weeks Location—intrapancreatic after onset of necrotizand/or extrapancreatic ing pancreatitis. Maturation usually requires 4 weeks after onset of acute necrotizing pancreatitis
Source: Modified from P Banks et al: Gut 62:102, 2013.
an increased output of adrenal glucocorticoids and catecholamines. Hypocalcemia occurs in ~25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathyroid gland to a decrease in serum calcium is impaired, subsequent observations have failed to confirm this phenomenon. Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs occasionally, with large amounts (up to 6.0 g) dissolved or suspended in ascitic fluid. Such “soap formation” may also be significant in patients with pancreatitis, mild hypocalcemia, and
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DIAGNOSIS Any severe acute pain in the abdomen or back should suggest the possibility of acute pancreatitis. The diagnosis is established by two of the following three criteria: (1) typical abdominal pain in the epigastrium that may radiate to the back, (2) threefold or greater elevation in serum lipase and/or amylase, and (3) confirmatory findings of acute pancreatitis on cross-sectional abdominal imaging. Patients also have associated nausea, emesis, fever, tachycardia, and abnormal findings on abdominal examination. Laboratory studies may reveal leukocytosis, hypocalcemia, and hyperglycemia. Although not required for diagnosis, markers of severity may include hemoconcentration (hematocrit >44%), admission azotemia (BUN >22 mg/dL), SIRS, and signs of organ failure (Table 371-3). The differential diagnosis should include the following disorders: (1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis and biliary colic; (3) acute intestinal obstruction; (4) mesenteric vascular occlusion; (5) renal colic; (6) inferior myocardial infarction; (7) dissecting aortic aneurysm; (8) connective tissue disorders with vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. It may be difficult to differentiate acute cholecystitis from acute pancreatitis, because an elevated serum amylase may be found in both disorders. Pain of biliary tract origin is more right sided or epigastric than periumbilical or left upper quadrant and can be more severe; ileus is usually absent. Ultrasound is helpful in establishing the diagnosis of cholelithiasis and cholecystitis. Intestinal obstruction due to mechanical factors can be differentiated from pancreatitis by the history of crescendodecrescendo pain, findings on abdominal examination, and CT of the abdomen showing changes characteristic of mechanical obstruction. Acute mesenteric vascular occlusion is usually suspected in elderly debilitated patients with brisk leukocytosis, abdominal distention, and bloody diarrhea, confirmed by CT or magnetic resonance angiography. Vasculitides secondary to systemic lupus erythematosus and polyarteritis nodosa may be confused with pancreatitis, especially because pancreatitis may develop as a complication of these diseases. Diabetic ketoacidosis is often accompanied by abdominal pain and elevated total serum amylase levels, thus closely mimicking acute pancreatitis. However, the serum lipase level is not elevated in diabetic ketoacidosis.
Acute and Chronic Pancreatitis
Pancreatic pseudocyst
Peripancreatic fluid associated with interstitial edematous pancreatitis with no associated peripancreatic necrosis. This term applies only to areas of peripancreatic fluid seen within the first 4 weeks after onset of interstitial edematous pancreatitis and without the features of a pseudocyst. An encapsulated collection of fluid with a welldefined inflammatory wall usually outside the pancreas with minimal or no necrosis. This entity usually occurs >4 weeks after onset of interstitial edematous pancreatitis.
Computed Tomography Criteria Pancreatic parenchyma enhancement by IV contrast agent No findings of peripancreatic necrosis
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Necrotizing pancreatitis
Definition Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but without recognizable tissue necrosis Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis
little or no obvious ascites. Hyperbilirubinemia (serum bilirubin >68 2093 mmoL or >4.0 mg/dL) occurs in ~10% of patients. However, jaundice is transient, and serum bilirubin levels return to normal in 4–7 days. Serum alkaline phosphatase and aspartate aminotransferase levels are also transiently elevated, and they parallel serum bilirubin values and may point to gallbladder-related disease or inflammation in the pancreatic head. Hypertriglyceridemia occurs in 5–10% of patients, and serum amylase levels in these individuals are often spuriously normal (Chap. 370). Approximately 5–10% of patients have hypoxemia (arterial PO2 ≤60 mmHg), which may herald the onset of ARDS. Finally, the electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia. An abdominal ultrasound is recommended in the emergency ward as the initial diagnostic imaging modality and is most useful to evaluate for gallstone disease and the pancreatic head. The revised Atlanta criteria have clearly outlined the morphologic features of acute pancreatitis on computed tomography (CT) scan as follows: (1) interstitial pancreatitis, (2) necrotizing pancreatitis, (3) acute pancreatic fluid collection, (4) pancreatic pseudocyst, (5) acute necrotic collection (ANC), and (6) walled-off pancreatic necrosis (WON) (Table 371-2 and Fig. 371-1). Radiologic studies useful in the diagnosis of acute pancreatitis are discussed in Chap. 370 and listed in Table 370-1.
CLINICAL COURSE, DEFINITIONS, AND CLASSIFICATIONS The Revised Atlanta Classification (1) defines phases of acute pancreatitis, (2) defines severity of acute pancreatitis, and (3) clarifies imaging definitions as outlined below. Phases of Acute Pancreatitis Two phases of acute pancreatitis have been defined, early (2 weeks), which primarily
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Disorders of the Gastrointestinal System
Figure 371-1 Acute pancreatitis: computed tomography (CT) evolution. A. Contrast-enhanced CT scan of the abdomen performed on admission for a patient with clinical and biochemical parameters suggestive of acute pancreatitis. Note the abnormal enhancement of the pancreatic parenchyma (arrow) suggestive of interstitial pancreatitis. B. Contrast-enhanced CT scan of the abdomen performed on the same patient 6 days later for persistent fever and systemic inflammatory response syndrome. The pancreas now demonstrates significant areas of nonenhancement consistent with development of necrosis, particularly in the body and neck region (arrow). Note that an early CT scan obtained within the first 48 h of hospitalization may underestimate or miss necrosis. C. Contrast-enhanced CT scan of the abdomen performed on the same patient 2 months after the initial episode of acute pancreatitis. CT now demonstrates evidence of a fluid collection consistent with walledoff pancreatic necrosis (arrow). (Courtesy of Dr. KJ Mortele, Brigham and Women’s Hospital; with permission.) describes the hospital course of the disease. In the early phase of acute pancreatitis, which lasts 1–2 weeks, severity is defined by clinical parameters rather than morphologic findings. Most patients exhibit SIRS, and if this persists, patients are predisposed to organ failure. Three organ systems should be assessed to define organ failure: respiratory, cardiovascular, and renal. Organ failure is defined as a score of 2 or more for one of these three organ systems using the modified Marshall scoring system. Persistent organ failure (>48 h) is the most important clinical finding in regard to severity of the acute pancreatitis Table 371-3 Severe Acute Pancreatitis Risk Factors for Severity • Age >60 years • Obesity, BMI >30 • Comorbid disease (Charlson Comorbidity Index) Markers of Severity at Admission or Within 24 h • SIRS—defined by presence of 2 or more criteria: • Core temperature 38°C • Heart rate >90 beats/min • Respirations >20/min or Pco2 12,000/μL, 44%) • Admission BUN (>22 mg/dL) • BISAP Score • (B) BUN >25 mg/dL • (I) Impaired mental status • (S) SIRS: ≥2 of 4 present • (A) Age >60 years • (P) Pleural effusion • Organ failure (Modified Marshall Score) • Cardiovascular: systolic BP 130 beats/min • Pulmonary: Pao2 2.0 mg% Markers of Severity During Hospitalization • Persistent organ failure • Pancreatic necrosis Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; BISAP, Bedside Index of Severity in Acute Pancreatitis; BP, blood pressure; BUN, blood urea nitrogen; SIRS, systemic inflammatory response syndrome.
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episode. Organ failure that affects more than one organ is considered multisystem organ failure. CT imaging is usually not needed or recommended during the first 48 h of admission in acute pancreatitis. The late phase is characterized by a protracted course of illness and may require imaging to evaluate for local complications. The important clinical parameter of severity, as in the early phase, is persistent organ failure. These patients may require supportive measures such as renal dialysis, ventilator support, or need for supplemental nutrition via the nasojejunal or parenteral route. The radiographic feature of greatest importance to recognize in this phase is the development of necrotizing pancreatitis on CT imaging. Necrosis generally prolongs hospitalization and, if infected, may require operative, endoscopic, or percutaneous intervention. Severity of Acute Pancreatitis Three severity classifications have also been defined: mild, moderately severe, and severe. Mild acute pancreatitis is without local complications or organ failure. Most patients with interstitial acute pancreatitis have mild pancreatitis. In mild acute pancreatitis, the disease is self-limited and subsides spontaneously, usually within 3–7 days after treatment is instituted. Oral intake can be resumed if the patient is hungry, has normal bowel function, and is without nausea and vomiting. Typically, a clear or full liquid diet has been recommended for the initial meal; however, a low-fat solid diet is a reasonable choice following recovery from mild acute pancreatitis. Moderately severe acute pancreatitis is characterized by transient organ failure (resolves in 48 h). Organ failure can be single or multiple. A CT scan or magnetic resonance imaging (MRI) should be obtained to assess for necrosis and/or complications. If a local complication is encountered, management is dictated by clinical symptoms, evidence of infection, maturity of fluid collection, and clinical stability of the patient. Prophylactic antibiotics are not recommended. Imaging in Acute Pancreatitis Two types of pancreatitis are recognized on imaging as interstitial or necrotizing based on pancreatic perfusion. CT imaging is best evaluated 3–5 days into hospitalization when patients are not responding to supportive care to look for local complications such as necrosis. Recent studies report the overutilization of CT imaging in acute pancreatitis and its inability to be better than clinical judgment in the early days of acute pancreatitis management. The revised criteria also outline the terminology for local
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Figure 371-2 A. Acute necrotizing pancreatitis: computed tomography (CT) scan. Contrast-enhanced CT scan showing acute pancreatitis with necrosis. Arrow shows partially enhancing body/tail of pancreas surrounded by fluid with decreased enhancement in the neck/body of the pancreas. B. Acute fluid collection: CT scan. Contrast-enhanced CT scan showing fluid collection in the retroperitoneum (arrow) compressing the air-filled stomach arising from the pancreas in a patient with asparaginase-induced acute necrotizing pancreatitis. C. Walled-off pancreatic necrosis: CT scan. CT scan showing marked walled-off necrosis of the pancreas and peripancreatic area (arrow) in a patient with necrotizing pancreatitis. Addendum: In past years, both of these CT findings (Figs. 371-2B and 371-2C ) would have been misinterpreted as pseudocysts. D. Spiral CT showing a pseudocyst (small arrow) with a pseudoaneurysm (light area in pseudocyst). Note the demonstration of the main pancreatic duct (big arrow), even though this duct is minimally dilated by endoscopic retrograde cholangiopancreatography. (A, B, C, courtesy of Dr. KJ Mortele, Brigham and Women’s Hospital; D, courtesy of Dr. PR Ros, Brigham and Women’s Hospital; with permission.)
Acute and Chronic Pancreatitis
ACUTE PANCREATITIS MANAGEMENT We will briefly describe the management of patients with acute pancreatitis from the time of diagnosis in the emergency ward to ongoing hospital admission and, finally, to time of discharge, highlighting salient features based on severity and complications. It is important to note that 85–90% of cases of acute pancreatitis are self-limited and subside spontaneously, usually within 3–7 days after initiation of treatment, and do not exhibit organ failure or local complications. The management of acute pancreatitis begins in the emergency ward. After a diagnosis has been
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complications and fluid collections along with a CT imaging template to guide reporting of findings. Local morphologic features are summarized in Table 371-1. Interstitial pancreatitis occurs in 90–95% of admissions for acute pancreatitis and is characterized by diffuse gland enlargement, homogenous contrast enhancement, and mild inflammatory changes or peripancreatic stranding. Symptoms generally resolve with a week of hospitalization. Necrotizing pancreatitis occurs in 5–10% of acute pancreatitis admissions and does not evolve until several days of hospitalization. It is characterized by lack of pancreatic parenchymal enhancement by intravenous contrast agent and/ or presence of findings of peripancreatic necrosis. According to the revised Atlanta criteria, the natural history of pancreatic and peripancreatic necrosis is variable because it may remain solid or liquefy, remain sterile or become infected, and persist or disappear over time. CT identification of local complications, particularly necrosis, is critical in patients who are not responding to therapy because patients with infected and sterile necrosis are at greatest risk of mortality (Figs. 371-1B, 3712, and 371-3). The median prevalence of organ failure is 54% in necrotizing pancreatitis. The prevalence of organ failure is perhaps slightly higher in infected versus sterile necrosis. With single-organ system failure, the mortality is 3–10% but increases to 47% with multisystem organ failure.
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Figure 371-3 A. Pancreaticopleural fistula: pancreatic duct leak on endoscopic retrograde cholangiopancreatography. Pancreatic duct leak (arrow) demonstrated at the time of retrograde pancreatogram in a patient with acute exacerbation of alcohol-induced acute or chronic pancreatitis. B. Pancreaticopleural fistula: computed tomography (CT) scan. Contrast-enhanced CT scan (coronal view) with arrows showing fistula tract from pancreatic duct disruption in the pancreatic pleural fistula. C. Pancreaticopleural fistula: chest x-ray. Large pleural effusion in the left hemithorax from a disrupted pancreatic duct. Analysis of pleural fluid revealed elevated amylase concentration. (Courtesy of Dr. KJ Mortele, Brigham and Women’s Hospital; with permission.)
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PART 14 Disorders of the Gastrointestinal System
gesics are administered, severity is assessed, and a search for etiologies that may impact acute care is begun. Patients who do not respond to aggressive fluid resuscitation in the emergency ward should be considered for admission to a step-down or intensive care unit for aggressive fluid resuscitation, hemodynamic monitoring, and management of necrosis or organ failure. Fluid Resuscitation and Monitoring Response to Therapy The most important treatment intervention for acute pancreatitis is safe, aggressive intravenous fluid resuscitation. The patient is made NPO to rest the pancreas and is given intravenous narcotic analgesics to control abdominal pain and supplemental oxygen (2 L) via nasal cannula. Intravenous fluids of lactated Ringer’s or normal saline are initially bolused at 15–20 cc/kg (1050–1400 mL), followed by 3 mg/kg per hour (200–250 mL/h), to maintain urine output >0.5 cc/kg per hour. Serial bedside evaluations are required every 6–8 h to assess vital signs, oxygen saturation, and change in physical examination. Lactated Ringer’s solution has been shown to decrease systemic inflammation and may be a better crystalloid than normal saline. A targeted resuscitation strategy with measurement of hematocrit and BUN every 8–12 h is recommended to ensure adequacy of fluid resuscitation and monitor response to therapy, noting less aggressive resuscitation strategy may be needed in milder forms of pancreatitis. A rising BUN during hospitalization is not only associated with inadequate hydration but also higher in-hospital mortality. A decrease in hematocrit and BUN during the first 12–24 h is strong evidence that sufficient fluids are being administered. Serial measurements and bedside assessment for fluid overload are continued, and fluid rates are maintained at the current rate. Adjustments in fluid resuscitation may be required in patients with cardiac, pulmonary, or renal disease. A rise in hematocrit or BUN during serial measurement should be treated with a repeat volume challenge with a 2-L crystalloid bolus followed by increasing the fluid rate by 1.5 mg/kg per hour. If the BUN or hematocrit fails to respond (i.e., remains elevated or does not decrease) to this bolus challenge and increase in fluid rate, consideration of transfer to an intensive care unit is strongly recommended for hemodynamic monitoring. Assessment of Severity and Hospital Triage Severity of acute pancreatitis should be determined in the emergency ward to assist in patient triage to a regular hospital ward or step-down unit or direct admission to an intensive care unit. The Bedside Index of Severity in Acute Pancreatitis (BISAP) incorporates five clinical and laboratory parameters obtained within the first 24 h of hospitalization (Table 371-3)—BUN >25 mg/dL, impaired mental status (Glasgow coma score 60 years, and pleural effusion on radiography—that can be useful in assessing severity. Presence of three or more of these factors was associated with substantially increased risk for in-hospital mortality among patients with acute pancreatitis. In addition, an elevated hematocrit >44% and admission BUN >22 mg/dL are also associated with more severe acute pancreatitis. Incorporating these indices with the overall patient response to initial fluid resuscitation in the emergency ward can be useful at triaging patients to the appropriate hospital acute care setting. In general, patients with lower BISAP scores, hematocrits, and admission BUNs tend to respond to initial management and are triaged to a regular hospital ward for ongoing care. If SIRS is not present at 24 h, the patient is unlikely to develop organ failure or necrosis. Therefore, patients with persistent SIRS at 24 h or underlying comorbid illnesses (e.g., chronic obstructive pulmonary disease, congestive heart failure) should be considered for a step-down unit setting if available. Patients with higher BISAP scores and elevations in hematocrit and admission BUN that do not respond to initial fluid resuscitation and exhibit evidence of respiratory failure, hypotension, or organ failure should be considered for direct admission to an intensive care unit. Special Considerations Based on Etiology A careful history, review of medications, selected laboratory studies (liver profile, serum triglycerides, serum calcium), and an abdominal ultrasound are recommended in the emergency ward to assess for etiologies that may impact acute
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management. An abdominal ultrasound is the initial imaging modality of choice and will evaluate the gallbladder and common duct and assess the pancreatic head. Gallstone pancreatitis Patients with evidence of ascending cholangitis (rising white blood cell count, increasing liver enzymes) should undergo ERCP within 24–48 h of admission. Patients with gallstone pancreatitis are at increased risk of recurrence, and consideration should be given to performing a cholecystectomy during the same admission or within 4–6 weeks of discharge. An alternative for patients who are not surgical candidates would be to perform an endoscopic biliary sphincterotomy before discharge. Hypertriglyceridemia Serum triglycerides >1000 mg/dL are associated with acute pancreatitis. Initial therapy may include insulin, heparin, or plasmapheresis. Outpatient therapies include control of diabetes if present, administration of lipid-lowering agents, weight loss, and avoidance of drugs that elevate lipid levels. Other potential etiologies that may impact acute hospital care include hypercalcemia, autoimmune pancreatitis, post-ERCP pancreatitis, and drug-induced pancreatitis. Treatment of hyperparathyroidism or malignancy is effective at reducing serum calcium. Autoimmune pancreatitis is responsive to glucocorticoid administration. Pancreatic duct stenting and rectal indomethacin administration are effective at decreasing pancreatitis after ERCP. Drugs that cause pancreatitis should be discontinued. Multiple drugs have been implicated, but only about 30 have been challenged (Class 1A) and found to be causative. Nutritional Therapy A low-fat solid diet can be administered to subjects with mild acute pancreatitis after the abdominal pain has resolved. Enteral nutrition should be considered 2–3 days after admission in subjects with more severe pancreatitis instead of total parenteral nutrition (TPN). Enteral feeding maintains gut barrier integrity, limits bacterial translocation, is less expensive, and has fewer complications than TPN. The choice of gastric versus nasojejunal enteral feeding is currently under investigation. Management of Local Complications (Table 371-4) Patients exhibiting signs of clinical deterioration despite aggressive fluid resuscitation and hemodynamic monitoring should be assessed for local complications, which may include necrosis, pseudocyst formation, pancreas duct disruption, peripancreatic vascular complications, and extrapancreatic infections. A multidisciplinary team approach is recommended including gastroenterology, surgery, interventional radiology, and intensive care specialists, and consideration should also be made for transfer to a pancreas center. Necrosis The management of necrosis requires a multidisciplinary team approach. Percutaneous aspiration of necrosis with Gram stain and culture should be performed if there are ongoing signs of possible pancreatic infection such as sustained leukocytosis, fever, or organ failure. There is currently no role for prophylactic antibiotics in necrotizing pancreatitis. It is reasonable to start broad-spectrum antibiotics in a patient who appears septic while awaiting the results of Gram stain and cultures. If cultures are negative, the antibiotics should be discontinued to minimize the risk of developing opportunistic or fungal superinfection. Repeated fine-needle aspiration and Gram stain with culture of pancreatic necrosis may be done every 5–7 days in the presence of persistent fever. Repeated CT or MRI imaging should also be considered with any change in clinical course to monitor for complications (e.g., thromboses, hemorrhage, abdominal compartment syndrome). In general, sterile necrosis is most often managed conservatively unless complications arise. Once a diagnosis of infected necrosis is established and an organism identified, targeted antibiotics should be instituted. Pancreatic debridement (necrosectomy) should be considered for definitive management of infected necrosis, but clinical decisions are generally influenced by response to antibiotic treatment and overall clinical condition. Symptomatic local complications as outlined in the revised Atlanta criteria may require definitive therapy.
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Table 371-4 Complications of Acute Pancreatitis
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Pancreatic duct disruption Pancreatic duct disruption may present with symptoms of increasing abdominal pain or shortness of breath in the setting of an enlarging fluid collection. Diagnosis can be confirmed on magnetic resonance cholangiopancreatography (MRCP) or ERCP. Placement of a bridging pancreatic stent for at least 6 weeks is >90% effective at resolving the leak. Nonbridging stents are less effective. Perivascular complications Perivascular complications may include splenic vein thrombosis with gastric varices and pseudoaneurysms. Gastric varices bleed less than 5% of the time. Life-threatening bleeding from a ruptured pseudoaneurysm can be diagnosed and treated with mesenteric angiography and embolization. Extrapancreatic infections Hospital-acquired infections occur in up to 20% of patients with acute pancreatitis. Patients should be continually monitored for the development pneumonia, urinary tract infection, and line infection. Continued culturing of urine, monitoring of chest x-rays, and routine changing of intravenous lines are important during hospitalization.
Acute and Chronic Pancreatitis
A step-up approach (percutaneous or endoscopic transgastric drainage followed, if necessary, by open necrosectomy) has been successfully reported by some pancreatic centers. One-third of the patients successfully treated with the step-up approach did not require major abdominal surgery. A recent randomized trial reported advantages
Pseudocyst The incidence of pseudocyst is low, and most acute collections resolve over time. Less than 10% of patients have persistent fluid collections after 6 weeks that would meet the definition of a pseudocyst. Only symptomatic collections should be drained with surgery or endoscopy or by percutaneous route.
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Local Necrosis Sterile Infected Walled-off necrosis Pancreatic fluid collections Pancreatic pseudocyst Disruption of main pancreatic duct or secondary branches Pancreatic ascites Involvement of contiguous organs by necrotizing pancreatitis Thrombosis of blood vessels (splenic vein, portal vein) Pancreatic enteric fistula Bowel infarction Obstructive jaundice Systemic Pulmonary Pleural effusion Atelectasis Mediastinal fluid Pneumonitis Acute respiratory distress syndrome Hypoxemia (unrecognized) Cardiovascular Hypotension Hypovolemia Nonspecific ST-T changes in electrocardiogram simulating myocardial infarction Pericardial effusion Hematologic Disseminated intravascular coagulation Gastrointestinal hemorrhage Peptic ulcer disease Erosive gastritis Hemorrhagic pancreatic necrosis with erosion into major blood vessels Portal vein thrombosis, splenic vein thrombosis, variceal hemorrhage Renal Oliguria (280 mg/dL in those with AIP. CT scans reveal abnormalities in the majority of patients and include diffuse enlargement, focal enlargement, and a distinct enlargement at the head of the pancreas. ERCP or MRCP reveals strictures in the bile duct in more than one-third of patients with AIP; these may include common bile duct strictures, intrahepatic bile duct strictures, or proximal bile duct strictures, with accompanying narrowing of the pancreatic portion of the bile duct. This has been termed autoimmune IgG4 cholangitis. Characteristic histologic findings include extensive lymphoplasmacytic infiltrates
with dense fibrosis around pancreatic ducts, as well as a lymphoplas- 2099 macytic infiltration, resulting in an obliterative phlebitis. The Mayo Clinic HISORt criteria indicate that AIP can be diagnosed by the presence of at least two of the following: (1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels); (4) other organ involvement; and (5) response to glucocorticoid therapy, with improvement in pancreatic and extrapancreatic manifestations. Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the size of the pancreas, and reversing histopathologic features in patients with AIP. Patients may respond dramatically to glucocorticoid therapy within a 2- to 4-week period. Prednisone is usually administered at an initial dose of 40 mg/d for 4 weeks followed by a taper of the daily dosage by 5 mg/wk based on monitoring of clinical parameters. Relief of symptoms, serial changes in abdominal imaging of the pancreas and bile ducts, decreased serum γ-globulin and IgG4 levels, and improvements in liver tests are parameters to follow. A poor response to glucocorticoids over a 2- to 4-week period should raise suspicion of pancreatic cancer or other forms of chronic pancreatitis. A recent multicenter international report reviewed 1064 patients with AIP. Clinical remission was achieved in 99% of type I and 92% of type II AIP patients with steroids. However, disease relapse occurred in 31% of type I and 9% of type II AIP patients. For treatment of disease relapse in type 1 AIP, glucocorticoids were successful in 201 of 295 (68%) patients, and azathioprine was successful in 52 of 58 patients (85%). A small number of patients responded favorably to 6-mercaptapurine, rituximab, cyclosporine, and cyclophosphamide. Types 1 and 2 AIP are highly responsive to initial glucocorticoid treatment. Relapse is common in type 1 patients, especially those with biliary tract strictures. Most relapses occur after glucocorticoids are discontinued. Patients with refractory symptoms and strictures generally require immunomodulator therapy as noted above. Appearance of interval cancers following a diagnosis of AIP is uncommon. Clinical Features of Chronic Pancreatitis Patients with chronic pancreatitis seek medical attention predominantly because of two symptoms: abdominal pain or maldigestion and weight loss. The abdominal pain may be quite variable in location, severity, and frequency. The pain can be constant or intermittent with frequent pain-free intervals. Eating may exacerbate the pain, leading to a fear of eating with consequent weight loss. The spectrum of abdominal pain ranges from mild to quite severe, with narcotic dependence as a frequent consequence. Maldigestion is manifested as chronic diarrhea, steatorrhea, weight loss, and fatigue. Patients with chronic abdominal pain may or may not progress to maldigestion, and ~20% of patients will present with symptoms of maldigestion without a history of abdominal pain. Patients with chronic pancreatitis have significant morbidity and mortality and use appreciable amounts of societal resources. Despite steatorrhea, clinically apparent deficiencies of fat-soluble vitamins are surprisingly uncommon. Physical findings in these patients are usually unimpressive, so that there is a disparity between the severity of abdominal pain and the physical signs that usually consist of some mild tenderness. The diagnosis of early or mild chronic pancreatitis can be challenging because there is no biomarker for the disease. In contrast to acute pancreatitis, the serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis. Elevation of serum bilirubin and alkaline phosphatase may indicate cholestasis secondary to common bile duct stricture caused by chronic inflammation. Many patients have impaired glucose tolerance with elevated fasting blood glucose levels. The fecal elastase-1 and small-bowel biopsy are useful in the evaluation of patients with suspected pancreatic steatorrhea. The fecal elastase level will be abnormal and small-bowel histology will be normal in such patients. A decrease of fecal elastase level to
