Osmosis High-Yield Notes Pathology Volume 1 - ATF [PDF]

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BURNS & FROSTBITE GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Damage to skin, underlying structures due to overexposure to harmful conditions ▪ Burn/frostbite injury → loss of skin function ▫ Impaired thermoregulation → loss of body heat ▫ Impaired fluid retention → large water, protein losses from skin, affected tissues ▫ Loss of microbial barrier function → high risk of infection



SIGNS & SYMPTOMS ▪ Pain, erythema, blistering, skin layers slough off



DIAGNOSIS OTHER DIAGNOSTICS



▪ Clinical presentation ▫ Nature of exposure, appearance of wound, depth of damage



TREATMENT MEDICATIONS ▪ Analgesia



SURGERY



▪ Debridement of dead tissue



ACTINIC KERATOSIS osms.it/actinic_keratosis PATHOLOGY & CAUSES ▪ Repeated prolonged sun exposure → small, ill-defined, rough, scaly patches of skin ▪ Once initial lesions develop, more may follow without additional sun exposure ▪ UVB radiation → damage to keratinocytes → accumulation of oncogenic changes (e.g. p53 gene mutation) → unchecked proliferation of dysplastic keratinocytes → precancerous lesion



RISK FACTORS



▪ Fair-skinned individuals; facial distribution, sun-exposed limbs; increased age;



immunosuppression; albinism; xeroderma pigmentosum; human papillomavirus (HPV) infection



COMPLICATIONS



▪ Malignant transformation to squamous cell carcinoma (0.03–20% likelihood)



SIGNS & SYMPTOMS ▪ Small, rough, scaly skin lesions ▪ Sandpaper-like sensation felt on palpation ▪ Induration, tenderness, bleeding → possible malignant transformation



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DIAGNOSIS LAB RESULTS



▪ Skin biopsy ▫ Exclude malignancy



TREATMENT MEDICATIONS Figure 1.1 The clinical appearance of an actinic keratosis.



▪ Topical pharmacotherapy: 5-Fluorouracil, imiquimod, ingenol mebutate



SURGERY



▪ Scraping, excision



OTHER INTERVENTIONS Prevention ▪ Avoid excessive sun exposure, use sunscreen Dermatologic ▪ Cryotherapy (liquid nitrogen), photodynamic therapy, electrodessication Figure 1.2 The histological appearance of actinic keratosis. There is full thickness epidermal atypia with hyperchromatic basal cells and nuclei in the stratum corneum (parakeratosis).



BURNS osms.it/burns PATHOLOGY & CAUSES ▪ Tissue destruction due to exposure ▫ Heat, electricity, chemicals, radiation ▪ Burn injury → loss of skin function ▪ Impaired thermoregulation → loss of body heat ▪ Impaired fluid retention → large water, protein losses from skin, affected tissues ▪ Loss of microbial barrier function → high risk of infection



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▪ Cell survival favoured by moist environment, aseptic conditions, good blood supply



TYPES Thermal burns ▪ Contact with heat/heated objects, fluids ▪ > 44°C/111.2°F ▫ Proteins denature, break down → cell damage ▪ Amount of tissue destruction determined



Chapter 1 Burns & Frostbite by temperature, duration → injury diminishes outwards as heat disperses around central site ▪ Zone of coagulation (ischemia): area of maximal damage; no remaining tissue perfusion → irreversible cell damage → coagulative necrosis ▪ Zone of stasis (edematous): surrounds coagulation area, microvascular sludging, thrombosis → decreased perfusion → progressive tissue necrosis; cellular death within 24–48 hours without treatment; early intervention may save significant amounts of tissue ▪ Zone of hyperemia: surrounds zone of stasis; inflammation → vasodilation, increased capillary permeability → erythema; tissues still viable → recovery likely Chemical burns ▪ Exposure to corrosive substances (e.g. acids, bases, oxidizing/reducing agents, solvents, alkylants, chemical weapons) ▪ Severity ▫ Alkali > acid; warmer temperature; greater volume, concentration, contact duration; specific mechanism of chemical action; degree of tissue penetration ▪ Occur immediately on contact, may continue to progress for some time ▪ May not be immediately evident ▪ May diffuse to deeper structures without initial damage to skin surface Electrical burns ▪ Passage of electricity through tissue → rapid injury ▪ Subdermal damage significantly greater than superficial injury ▪ Extent of injury determined by ▫ Current: higher current → increased lethality/tissue damage ▫ Voltage: higher voltage → more damage; higher voltage → dielectric breakdown of skin → lowered resistance, greater current flows



▫ Frequency: very high frequencies → tissue burning; doesn’t penetrate deep enough to affect heart ▫ Duration: longer duration → more tissue damage ▫ Pathway: current flowing through heart → lethal ▫ Tissue resistance (pathway, depth dependant): nerves < blood vessels < muscle < skin < tendon < fat < bone Radiation burns ▪ Excessive exposure to radiation ▫ Ultraviolet (UV) light: sunlight most common cause of radiation, superficial burns ▫ Ionizing radiation (e.g. radiation therapy, X-rays, radioactive fallout): skin effects vary from hair loss at 3Gy to necrosis at 30Gy ▫ Microwave burns



Figure 1.3 An adult male with superficial partial thickness burns to the arms and torso, secondary to sun overexposure.



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RISK FACTORS



▪ Complicated injury ▫ Age (< 3, > 60), location (e.g. face, neck, hands, feet, perineum), inhalational injury, associated injuries (e.g. fractures), comorbid disease (e.g. chronic renal failure)



COMPLICATIONS



▪ Wound contracture/hypertrophic scarring, infection ▫ Most common organisms: S. aureus, P. aeruginosa, C. albicans ▪ Systemic effects of severe burns ▫ Large burns > 30% of total body



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surface area → significant inflammatory response → impaired organ perfusion → gastrointestinal (GI) bleeding, renal failure, progressive pulmonary insufficiency ▫ Increased levels of catecholamines, cortisol → hypermetabolism. immunosuppression ▪ Additional injury ▫ Singeing of airways → inflammation → eventual compromised airway ▫ Carbon monoxide inhalation



Chapter 1 Burns & Frostbite



DIAGNOSIS OTHER DIAGNOSTICS



▪ % of total body surface area (TBSA) affected ▫ Doesn’t include areas with first degree/ superficial burns ▫ Palm size estimation: size of individual’s hand print (palm, fingers) 1% of TBSA ▫ Wallace rule of nines: each major body part assigned value corresponding to approx. proportion of body surface area



American Burn Association severity classification ▪ Minor ▫ < 2% full thickness burn ▫ < 10% TBSA (young/old < 5% TBSA) ▪ Moderate ▫ 2–5% full thickness burn ▫ 10–20% TBSA (young/old 5–10% TBSA) ▫ high voltage injury, possible inhalation injury, circumferential burn, comorbidities ▪ Major ▫ > 5% full thickness burn ▫ > 20% TBSA (young/old > 10% TBSA) ▫ high voltage burn, known inhalation injury, significant burns to face/joints/ hands/feet, associated injuries



Figure 1.4 A full-thickness superficial burn to the hand.



TREATMENT OTHER INTERVENTIONS Intravenous (IV) fluids ▪ Parkland formula ▫ Estimated IV fluid replacement required over initial 24 hours ▫ Volume required in 24 hours = 4 x mass (kg) x (% TBSA x 100) ▫ Half of requirement given over first eight hours; remainder over following 16 hours Wound care ▪ First degree: maintain moist skin barrier with antimicrobial burn dressings ▪ Second degree: daily burn dressing change with topical antimicrobial, leave blisters intact unless circulation impaired/overlying joint, inhibiting movement ▪ Deep second degree: prevention of sepsis → antibiotics



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▪ Remove dead tissue ▫ Surgical debridement, excise to viable (bleeding) tissue Chemical burn ▪ Remove contaminated clothing, brush off dry powder ▪ Irrigate with water for 1–2 hours under low pressure; if elemental metal burn (e.g. sodium, potassium, magnesium, lithium) avoid exothermic reaction with water, soak in mineral oil instead ▪ Acid ▫ Water irrigation, followed by dilute solution of sodium bicarbonate Electrical burn ▪ Debride non-viable tissue, repeat every two days ▪ Monitor for cardiac complications



Figure 1.5 A full thickness burn to the medial aspect of the foot.



FROSTBITE osms.it/frostbite PATHOLOGY & CAUSES ▪ Exposure to low temperatures for significant periods of time, subsequent rewarming → tissue damage Freezing ▪ Temperatures < −4°C/24.8°F → formation of ice crystals within tissues → damage to cellular membranes, small blood vessels ▪ Cooling → vasoconstriction, impaired circulation → further cooling, warm blood unable to effectively perfuse freezing extremities Thawing ▪ Rewarming → vasodilation → edema ▪ Poor blood flow through damaged



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capillaries → ischemia, inflammation, blood coagulation → tissue death ▪ Thawing → formation of blood clots in small vessels



RISK FACTORS



▪ Frequently exposed/thermally vulnerable skin (e.g. hands, feet, face); occupational/ hobby exposure to low temperature environments (e.g. winter sports enthusiasts, military personnel); circulationimpairing disorders (e.g. Raynaud’s phenomenon, diabetes), substance use (e.g. smoking)



COMPLICATIONS



▪ Hypothermia, compartment syndrome



Chapter 1 Burns & Frostbite



SIGNS & SYMPTOMS ▪ Numbness prior to thawing ▪ White/bluish discolouration of skin ▪ Swelling/blistering after treatment



DIAGNOSIS ▪ Clinical presentation: physical assessment, classification



DIAGNOSTIC IMAGING



Figure 1.6 The clinical appearance of frostbitten fingers.



▪ Technetium (Tc)-99m scintigraphy (SPECT scan)/CT scan ▪ Assess salvageable tissue; earlier debridement of nonviable soft tissue ▪ Perfusion/metabolic imaging identifies viable bone, tissue/location autoamputation likely to occur



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activator, heparin for risk of amputation ▫ Blood vessel dilator: iloprost ▫ Sympatholytic drugs → counteract peripheral vasoconstriction ▫ High risk of infection → antibiotic prophylaxis (e.g. penicillin G)



SURGERY



▪ Debride dead tissue ▪ Escharotomy: release restrictive eschars ▪ Fasciotomy: compartment syndrome



Figure 1.7 Toes three weeks following frost bite.



TREATMENT MEDICATIONS Initial thawing ▪ Analgesia ▫ Nonsteroidal anti-inflammatory drugs (NSAIDs)/opioids ▪ Pharmacological adjuvants (severe cases, grade 2+) ▫ Antithrombotics: tissue plasminogen



OTHER INTERVENTIONS General measures ▪ Do not rewarm if possibility of refreezing exists (worse tissue damage) ▪ Do not walk on frostbitten feet/rub frostbitten hands (worse tissue damage) ▪ Avoid using stoves/fires to reheat insensate limbs (avoid thermal damage) Initial thawing ▪ Temperature: immerse in 37–39°C/98.6– 102.2°F agitated water; maintain steady temperature ▪ Duration: 10–30 min with povidone iodine/ chlorhexidine antiseptic



SUNBURN osms.it/sunburn PATHOLOGY & CAUSES ▪ Radiation burn of living tissue due to excessive exposure to UV radiation ▫ Burning may occur in 15 minutes of sunlight exposure in high UV radiation areas/seconds of non-shielded welding arcs ▪ UV light radiation overexposure ▫ Initial direct DNA damage (formation of thymine dimer) → activates cellular response mechanisms → DNA repair/ inflammatory response, cell death via apoptosis



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▫ Within one hour mast cells degranulate → release of histamine, serotonin, tumor necrosis factor (TNF) → prostaglandin, leukotriene synthesis → neutrophilic, lymphocytic infiltrate → further inflammation ▪ UV exposure → activation of genes to produce melanin → absorbs UV wavelength light → acts as photoprotectant



RISK FACTORS



▪ Outdoor work/sports, fair skin, very young/ old age, genetic defects in DNA repair, use of photosensitizing medication



Chapter 1 Burns & Frostbite



COMPLICATIONS



▪ Increased risk of skin cancers (e.g. melanoma; basal-cell, squamous-cell carcinoma)



SIGNS & SYMPTOMS ▪ Initial erythema, heat given off by increased blood flow to area due to vasodilation ▪ Pain proportional to severity of exposure ▪ Blistering, swelling, edema, peeling skin, fever, chills



DIAGNOSIS OTHER DIAGNOSTICS



▪ Clinical presentation (similar to thermal burn) ▫ Superficial (first degree) → affects only epidermis (erythematous) ▫ Superficial partial thickness (second degree) → affects dermis (forms blisters)



TREATMENT MEDICATIONS Analgesia ▪ hydrocortisone cream, NSAIDs



OTHER INTERVENTIONS ▪ Protect burnt skin with loose fitting clothing when outside to prevent further damage Analgesia ▪ Cool baths/showers, soothing skin moisturizers Figure 1.8 Desquamation (peeling) of the skin following sunburn.



Prevention ▪ Avoid peak UV radiation intervals (10:00 AM to 4:00 PM), wear appropriate clothing (e.g. long-sleeved shirts, long trousers, wide-brimmed hats, sunglasses), broadspectrum sunscreen on any exposed skin



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DERMATITIS & ECZEMA GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inflammatory skin disorders ▪ Immune-mediated skin damage



SIGNS & SYMPTOMS ▪ Rashes ▫ Pruritus (itching), burning, pain



OTHER DIAGNOSTICS ▪ Rash ▫ Appearance, distribution



TREATMENT MEDICATIONS ▪ Corticosteroids ▪ Immunosuppressants



DIAGNOSIS LAB RESULTS ▪ Skin biopsy, blood tests



ATOPIC DERMATITIS (ECZEMA) osms.it/atopic-dermatitis



▪ Allergic, inflammatory skin condition ▪ Common for children; may affect adults ▪ Associated with elevated serum IgE levels ▫ Atopy: predisposition to IgE antibody release after trigger exposure



Type 4 hypersensitivity ▪ Primary immune dysfunction ▫ T cell subset imbalance → Th2 predominance → increased inflammatory cytokine production (IL-4, 5, 13) → increased release of IgE from plasma B-cells, recruitment of mast cells, eosinophils



TYPES



RISK FACTORS



PATHOLOGY & CAUSES



Type 1 hypersensitivity ▪ Epidermal barrier dysfunction ▫ Skin barrier defects (e.g. filaggrin mutation) → antigen entry → inflammatory cytokines



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▪ Family history of atopy (eczema, asthma, allergic rhinitis) ▪ Environmental allergen sensitivities ▪ Loss of function mutation in filaggrin gene (skin barrier function)



Chapter 2 Dermatitis & Eczema ▪ Higher incidence in urban populations, high-income countries ▪ Low levels of early life exposure to endotoxin (immunogenic component of gram-negative bacteria)



COMPLICATIONS ▪ Skin infections ▫ Staphylococcus aureus common commensal organism → impetigo ▪ Eczema herpeticum ▫ Rapid spread of herpes simplex virus on affected skin ▪ Social stigma, anxiety



SIGNS & SYMPTOMS ▪ Acute ▫ Pruritic erythematous papules, vesicles with exudate, crusting ▪ Chronic ▫ Dry, excoriated erythematous papules with scaling; lichenification (hyperplasia) ▪ Dry skin ▪ Pruritus → chronic scratching → skin thickening, increased infection risk ▪ Cutaneous hyperreactivity to environmental antigens/stimuli (e.g. stress) ▪ 0–2 years old ▫ Erythematous, pruritic, scaly, crusted lesions +/- vesicles, serous exudate ▫ Extensor surfaces, cheeks, scalp ▪ 2–16 years old ▫ Lichenified plaques (thickened epidermis) ▫ Flexural distribution (e.g. antecubital, popliteal fossae); volar aspect of wrists, ankles, neck ▪ Adults ▫ Localized lichenified plaques ▫ Flexural surface involvement ▫ Uncommonly involves face/neck/hands



DIAGNOSIS LAB RESULTS ▪ Elevated level of Serum IgE



OTHER DIAGNOSTICS ▪ Morphology, distribution of lesions United Kingdom working group atopic dermatitis criteria ▪ Mandatory ▫ Evidence of pruritic skin with rubbing/ scratching ▪ ≥ three following criteria ▫ Skin crease involvement (antecubital fossa, popliteal fossae, neck, around eyes, ankles) ▫ History/first degree relative with asthma/hay fever ▫ Dry skin in past year ▫ < two years old before symptoms arose (not applicable to children < four years old) ▫ Visible dermatitis of flexural surfaces (< four years old → examine cheeks, forehead, outer aspects of extremities)



Figure 2.1 Atopic dermatitis affecting the flexural surfaces of the forearms.



TREATMENT MEDICATIONS ▪ Control pruritus ▫ Antihistamines ▫ Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) ▫ Antibiotics to treat associated skin infections ▪ Immune suppression ▫ Topical → systemic corticosteroids



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▫ Topical calcineurin inhibitors ▫ Oral cyclosporine ▫ Dupilumab (IL-4 receptor antagonist)



OTHER INTERVENTIONS ▪ Reduce exposure to environmental allergens ▪ Avoid triggers ▫ Heat, low humidity ▪ Manage stress/anxiety



▪ Maintain skin hydration ▫ Thick, unscented creams with low water content/ointments without water ▫ Apply after bathing/hand washing ▫ Avoid lotions with high water/low oil content (evaporation dries out skin, triggers outbreak) ▪ Control pruritus ▫ Prevent scratching; keep fingernails short (esp. young children)



CONTACT DERMATITIS osms.it/contact-dermatitis PATHOLOGY & CAUSES ▪ Inflammation of skin after contact exposure to allergens/irritants ▪ Localized ▪ Exposure to foreign substance triggers immune response ▪ Most common form: irritant contact dermatitis



CAUSES ▪ Exposure to irritant (irritation may be mechanical/chemical/physical) ▫ Acute: strong irritant ▫ Chronic: recurring exposure to weak irritant ▪ Detergents, surfactants, extreme pH, organic solvents, water ▫ Altered epidermal barrier function: Fat emulsion → defatting of dermal lipids → cellular damage to epithelium → DNA damage, transepidermal water loss → cytotoxic cell damage → cytokine release from keratinocytes → activation of innate immunity ▪ Plants with spines/irritant hairs ▪ Low humidity ▫ Skin loses moisture more easily



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Allergic contact dermatitis ▪ Anacardiaceae family plants ▫ Poison ivy, poison oak, poison sumac ▪ Nickel, fragrances, dyes ▫ Induction phase: immune system primed for allergic response to antigen ▫ Elicitation phase: contact allergens are typically haptens → small, can cross stratum corneum of skin to associate with epidermal proteins → form complete reactive antigen → dendritic cells recognise antigen → internalise antigen, transport to lymph nodes → present to T lymphocytes → trigger immune response → cell mediated immune response (Type IV delayed hypersensitivity) → memory cells remain within skin. Future exposure → triggers memory cells → immune response (cytokines, chemokines, TNF, lymphocytes, granulocytes migrate)



RISK FACTORS ▪ Age ▫ Infants: highest risk ▫ > 65 years old: lowest risk ▪ Body site exposure ▫ Difference in thickness of stratum corneum, barrier function ▫ Face, dorsum of hands, finger webs are prone to irritation ▪ Atopy



Chapter 2 Dermatitis & Eczema ▫ Chronically impaired barrier function ▪ Occupational exposure ▫ Continuous moisture exposure, repeated cycles of wet-to-dry from frequent handwashing ▪ Allergic contact dermatitis ▫ Occupation (health professionals, chemical industry, beauticians, hairdressers, machinists, construction) ▫ Increases with age ▫ History of atopic dermatitis



SIGNS & SYMPTOMS ▪ Erythematous rash (can develop ≤ 72hrs after exposure) ▪ Vesicles/bullae/wheals occur at exposure site ▪ Glaze/parched/scaled presentation ▪ Scaling, hyperkeratosis, fissuring ▪ Itching (favors allergic etiology); burning (favors irritant)



TREATMENT MEDICATIONS ▪ Pruritus ▫ Calamine lotion ▪ Mild topical corticosteroid (hydrocortisone) ▪ Oral antihistamine ▪ Allergic contact dermatitis ▫ High potency topical corticosteroids ▫ Oral corticosteroids ▫ Topical calcineurin inhibitors (tacrolimus/ pimecrolimus) ▫ Systemic immunosuppression (azathioprine, mycophenolate mofetil, cyclosporine)



OTHER INTERVENTIONS ▪ Remove/avoid trigger ▪ Treat blistering ▫ Cold compress ▪ Avoid scratching ▪ Retain moisture, protect skin ▫ Barrier cream (e.g. zinc oxide) ▪ Irritant contact dermatitis ▫ Mild acidic solutions (e.g. acetic acid) may neutralize alkali irritants/vice versa ▫ Emollients (e.g. Aquaphor) ▫ Gloves ▪ Allergic contact dermatitis ▫ Phototherapy (narrow band UVB radiation)



Figure 2.2 Contact dermatitis secondary to poison ivy exposure.



DIAGNOSIS OTHER DIAGNOSTICS ▪ History of possible exposure to irritant/ allergen ▪ Patch allergen testing



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SEBORRHOEIC DERMATITIS osms.it/seborrhoeic-dermatitis PATHOLOGY & CAUSES ▪ Sebaceous gland-centered skin inflammation ▪ Response to fungal antigens/irritants ▪ Chronic/relapsing ▪ Typically mild form of dermatitis



CAUSES ▪ Occurs in sites with greater density of sebaceous glands ▪ Not a disease of sebaceous glands, nor increased sebum production ▪ Suspected connection to lipid-dependent fungal genus Malassezia ▫ Immune response to fungus ▫ Local irritants produced by fungus ▪ Children ▫ Nutritional deficiencies of biotin, pyridoxine (vitamin B6), riboflavin (vitamin B2)



Distribution ▪ Areas containing significant number of sebaceous glands ▫ External ear, center of face, upper trunk, areas where skin rubs together ▪ Scalp ▫ Infants: aka cradle cap; self-resolving ▫ Adults: aka dandruff (pityriasis sicca); mildest form ▫ Fine, white scaliness without erythema +/- pruritus ▫ Severe cases: inflammation; patchy orange plaques with yellow, oily scales (pityriasis steatoides); may progress to oozing/crusting fissures affecting outer canal, concha of ear (vulnerable to superinfection) ▪ Face ▫ Forehead, eyebrows, glabella, nasolabial folds; may affect cheeks/malar area in butterfly distribution ▫ Frequently affects areas of facial hair distribution



RISK FACTORS ▪ Age (biphasic incidence: 2–12 months of age to adolescence; adulthood: peaks 30s–40s) ▪ Hyperandrogenism ▪ Biological males > biological females ▪ HIV ▪ Parkinson’s ▪ Stress ▪ Cold, dry weather ▪ Sleep deprivation ▪ Poor general health



SIGNS & SYMPTOMS ▪ Scaling erythematous plaques ▪ Scales yellow, oily in appearance Figure 2.3 Seborrhoeic dermatitis affecting both nasal folds.



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Chapter 2 Dermatitis & Eczema ▪ Periocular ▫ Blepharitis, free margin redness ▫ Yellow crusting between lashes ▫ Can occur in isolation/part of larger distribution ▪ Trunk (five distinct patterns of distribution) ▫ Moist, skin-contact regions: axillae, inframammary folds, umbilicus, genitocrural ▫ Petaloid pattern: fine, scaling plaques over sternum/interscapular ▫ Annular/arcuate: round, scaly plaques, may have hypopigmented central clearing ▫ Pityriasiform pattern: mimics pityriasis rosea, 5–15mm oval, scaly lesions along lines of skin tension ▫ Psoriasiform pattern: large, rounded erythematous plaques with thick scales



DIAGNOSIS OTHER DIAGNOSTICS ▪ History, appearance, distribution



TREATMENT MEDICATIONS ▪ ▪ ▪ ▪ ▪ ▪



Topical antifungals Antifungal shampoo Topical corticosteroids Topical calcineurin inhibitors Oral antifungals Antiandrogens ▫ Reserved for individuals for whom feminization/male infertility is unproblematic ▫ Sexually-active, uterus-bearing people: combine with contraception to avoid risk to fetus



OTHER INTERVENTIONS ▪ Cradle cap ▫ Apply emollient (petroleum jelly, vegetable oil, baby oil) to scalp overnight to loosen scales → remove scales with soft toothbrush ▫ Frequent shampooing with mild, nonmedicated baby shampoo → remove scales with soft toothbrush ▫ Extensive/persistent cases → medical therapy ▪ Topical ▫ Coal tar shampoo/ointment



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ERYTHEMA MULTIFORME & DRUG ERUPTION



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



DIAGNOSIS



▪ Skin, mucous membrane conditions ▪ Associated with medication use/infection



LAB RESULTS



CAUSES



OTHER DIAGNOSTICS



▪ Exact mechanism unclear, severe immune reaction against foreign antigen



▪ Skin biopsy



▪ Clinical history



TREATMENT



COMPLICATIONS



▪ Initial rash may → epidermal layer loss



▪ Identify/remove/treat offending agent/ infection



SIGNS & SYMPTOMS ▪ Desquamating skin, mucous membrane rash



ERYTHEMA MULTIFORME osms.it/erythema-multiforme PATHOLOGY & CAUSES ▪ Immune-mediated, acute, self-limiting skin condition ▪ Type IV hypersensitivity



CAUSES



▪ Suspected deposition of primarily IgMbound immune complexes in superficial skin, oral mucous membranes



Infection (most) ▪ Viral ▫ Herpes simplex primary cause



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▪ Bacterial ▫ Hemolytic Streptococci, Legionella, Mycobacterium, Mycoplasma pneumoniae, Neisseria meningitidis, Pneumococcus, Salmonella, Staphylococcus ▪ Parasitic ▫ Trichomonas, Toxoplasma gondii Drugs (rarely) ▪ Non-steroidal anti-inflammatories (NSAIDs), sulfonamides, phenytoin, barbiturates, phenylbutazone, penicillin, allopurinol



Chapter 3 Erythema Multiforme & Drug Eruption Physical factors ▪ Sunlight, radiotherapy, cold Autoimmune disease ▪ Vasculitides Hematological malignancy ▪ Non-Hodgkin lymphoma, leukemia, myeloid metaplasia



RISK FACTORS



▪ < 20 years old ▪ ↑ frequency in biological males



SIGNS & SYMPTOMS ▪ “Multiforme” denotes wide associated lesion variety ▪ Target lesions ▫ Initially round erythematous papules → dusky central area/blister, surrounded by dark red inflammation, surrounded by pale edematous ring, erythematous region on periphery ▪ Pruritus in affected area ▪ Painful lesions ▪ If severe ▫ Fever, weakness, malaise



Erythema multiforme minor ▪ Often herpes simplex ▪ Involves skin (little/no mucous membrane involvement) ▪ Favors skin of extremities, face ▪ Symmetrical circular lesions ▪ Lesions become classic “target” lesions (red border, small white center) ▪ Rash spreads towards body center Erythema multiforme major ▪ Often drug-related ▪ Epidermal detachment/skin loss progression ▪ Erythematous, confluent, bullous lesions ▪ Involves mucous membranes ▪ Nikolsky’s sign (lightly rub skin with firm object for few seconds → blister forms)



DIAGNOSIS LAB RESULTS



▪ Biopsy to exclude other skin disorders



OTHER DIAGNOSTICS



▪ Identify offending agent/infection ▫ Identification: target lesions, symmetrical distribution



TREATMENT ▪ Often self-resolving in 1–2 weeks



MEDICATIONS



▪ Control primary cause ▫ Treat/remove identifiable causes ▫ Herpes simplex suspected: oral acyclovir/valaciclovir/famciclovir ▫ Eliminate possible offending drugs



Figure 3.1 The abdomen of a child displaying numerous target lesions in a case of erythema multiforme.



Mild disease ▪ Topical corticosteroids ▪ Antihistamines Severe Disease ▪ Glucocorticoids ▪ In severe cases, prednisone considered



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Recurrent disease ▪ Systemic antivirals (up to 6 months) ▪ Immunosuppression if antivirals fail



STEVENS–JOHNSON SYNDROME & TOXIC EPIDERMAL NECROLYSIS osms.it/stevens-johnson_syndrome osms.it/toxic-epidermal-necrolysis PATHOLOGY & CAUSES ▪ Same underlying pathology (severity spectrum) ▫ Stevens–Johnson syndrome (lower end), toxic epidermal necrolysis (upper end) ▪ Severity, classification ▫ Body surface involvement % ▪ Severe mucocutaneous reaction → epidermal detachment



COMPLICATIONS



▪ Dehydration, sepsis, pneumonia, multiple organ failure, renal tubular necrosis, acute renal failure, phimosis, vaginal synechiae (adhesions), inside eyelid-tissue scarring → corneal vascularisation → vision loss



CAUSES



▪ Cytotoxic T cell mediated destruction of keratinocytes expressing foreign antigen



Medications ▪ Most common ▪ Allopurinol, sulfa drugs (e.g. sulfonamide antibiotics), lamotrigine, carbamazepine, nevirapine, phenylbutazone, thiacetazone, oxicam NSAIDS Infections ▪ Mycoplasma pneumoniae most common infective agent



RISK FACTORS



HIV/AIDS Systemic lupus erythematosus > 40 years old Genetic carbamazepine interaction predisposition (HLA-B*15:02, HLAA*31:01 alleles) ▪ ↑ frequency in biological females ▪ ▪ ▪ ▪



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Figure 3.2 An individual with Stevens– Johnson syndrome.



Chapter 3 Erythema Multiforme & Drug Eruption



DIAGNOSIS



SIGNS & SYMPTOMS Systemic ▪ Before skin eruptions occur ▪ Fever, sore throat, fatigue, cough Mucocutaneous ▪ Burning eyes, skin ▪ Red-purple macules → skin blisters → peels, forms painful raw areas ▪ Mucous membranes (often) → painful crusts, erosions ▪ Starts on trunk → rest of body ▪ Spontaneous ulceration of skin, mucous membranes (often eyes/lips) ▪ Conjunctivitis (often accompanied by purulent discharge) ▪ Round ulcerating lesions (approx. 2.5cm/1in diameter) ▫ Arise on face, trunk, arms, legs, soles of feet (scalp spared) ▪ Nikolsky’s sign



▪ Stevens–Johnson syndrome: < 10% skin involvement ▪ SJS/TEN overlap: 10–30% ▪ Toxic epidermal necrolysis: > 30%



LAB RESULTS ▪ Skin biopsy



OTHER DIAGNOSTICS



▪ Clinical history, suspected agents



TREATMENT MEDICATIONS



▪ Analgesics (non-opioid for non-severe, opioids for severe pain) ▪ Antihistamines ▪ Intravenous immunoglobulin



Infection control ▪ Culture-specific antibiotic initiation



OTHER INTERVENTIONS ▪ ▪ ▪ ▪



Transfer to burn/intensive care unit Fluid support Oral feeding, nasogastric tube Room temperature 30–32°C/86–90°F (minimize heat loss)



Infection control ▪ Sterile handling ▪ Skin disinfection ▫ Antiseptic solution ▪ 48 hourly skin, blood, indwelling line culture



Figure 3.3 An individual with toxic epidermal necrolysis ten days after the onset of symptoms.



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Figure 3.4 A histological section of skin demonstrating epidermal necrolysis. The epidermis is detached from the dermis and the keratinocytes have undergone necrosis. This can be seen in erythema multiforma, Stevens-Johnson syndrom and toxic epidermal necrolysis.



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HAIR–RELATED DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Conditions affecting either total number of hairs/thickness of hair on body ▪ Scalp most commonly affected



SIGNS & SYMPTOMS ▪ See individual diseases



DIAGNOSIS ▪ See individual diseases



TREATMENT ▪ See individual diseases



ALOPECIA AREATA osms.it/alopecia-areata PATHOLOGY & CAUSES ▪ Chronic localized hair loss, generally on scalp; autoimmune-related ▪ May occur at any age, but > 30 years old in most cases; lifetime prevalence 2%



CAUSES



▪ Exact mechanism unclear; hypothesized ▫ T cells release cytokines, chemokines → normal hair cycle disrupted → hair loss ▪ Spontaneous regrowth of hair possible, often within one year



RISK FACTORS



▪ Genetic ▫ Close family members, history of autoimmune conditions



SIGNS & SYMPTOMS ▪ Usually smooth, circular patches of hair loss, but can be any shape ▪ Can be accompanied by nail changes ▫ Nail pitting, roughening/longitudinal fissuring of nail plate ▪ Associated with other autoimmune conditions ▫ Psoriasis, vitiligo, thyroid disease



DIAGNOSIS LAB RESULTS



▪ Biopsy (unclear cases) ▫ Peribulbar lymphocytic inflammatory infiltrates characteristic ▫ Follicular edema, cellular necrosis, microvesiculation, pigment incontinence



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OTHER DIAGNOSTICS



▪ Based on timeline of events, physical examination (exclamation point hairs) ▫ Short, broken hairs around area of hair loss ▫ Narrower proximal than distal end ▫ Dermatoscope may make hairs easier to spot



TREATMENT ▪ Treatment unreliable, temporary; no cure



MEDICATIONS



▪ Intralesional steroid injections of triamcinolone acetonide ▪ Topical agents including 5% minoxidil solution/topical steroids



Figure 4.1 The clinical appearance of the scalp in a case of alopecia areata.



TELOGEN EFFLUVIUM osms.it/telogen-effluvium PATHOLOGY & CAUSES ▪ Periodic episodes of increased hair thinning/shedding due to altered follicle growth cycle ▫ Occurs during follicles’ telogen (resting) phase



CAUSES



▪ May be related to ▫ Recent stressor (e.g. major illness/ surgery) ▫ Drugs/toxins ▫ Nutritional deficiencies



SIGNS & SYMPTOMS ▪ Non-scarring, diffuse < 50% hair loss ▪ Nail changes ▫ Deep grooved lines running from side to side may be present



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DIAGNOSIS OTHER DIAGNOSTICS



▪ Determine timeline of stressors, recent events, drug/medication usage, course/ characteristics of hair loss ▪ Hair-pull test ▫ Grasp 50–60 hairs → tug lightly ▫ If > 6–10 hairs extracted, test = positive ▫ Telogen hairs confirmed by microscopic examination



TREATMENT ▪ Sometimes self-correcting



OTHER INTERVENTIONS



▪ Reduce stressors, improve diet, handle hair carefully



Chapter 4 Hair-related Diseases



Figure 4.2 The clinical appearance of the nails in a case of telogen effluvium.



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NOTES



NOTES



MALIGNANT TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Malignant cutaneous lesions due to abnormal/uncontrolled growth of epithelial cells



SIGNS & SYMPTOMS ▪ ≥ one multiple visible cutaneous tumors ▪ Melanoma can present noncutaneously (e.g. ocular, mucosal)



DIAGNOSIS TREATMENT



LAB RESULTS Histological analysis ▪ Confirms diagnosis, establishes tumor grade



MEDICATIONS



Biopsy ▪ Confirms diagnosis, establishes tumor grade



SURGERY



OTHER DIAGNOSTICS



OTHER INTERVENTIONS



▪ Dermatological examination with dermatoscope, TNM staging ▪ Breslow thickness ▫ Distance of tumor cell from basal layer of epidermis



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▪ Immunomodulators



▪ Surgical excision ▪ Electrodesiccation, curettage of lesion



▪ Radiation therapy



Chapter 5 Malignant Skin Tumors



BASAL-CELL CARCINOMA osms.it/basal-cell_carcinoma PATHOLOGY & CAUSES



CAUSES



▪ Most common type of skin cancer; emerges from basal cells found in lower epidermis ▪ Slow growing, can infiltrate surrounding tissue, rarely metastasizes



▪ UV radiation: direct DNA damage (pyrimidine dimers) → alters DNA structure → mutations, carcinogenesis if tumor suppressor gene involved ▪ Gorlin syndrome: numerous basal cell carcinomas due to mutation of PTCH1 gene



TYPES



RISK FACTORS



Nodular ▪ Pearly circular cystic pigmented nodule



▪ Arsenic exposure; immunodeficiency; fair skin, albinism; xeroderma pigmentosum; risk increases with age; high exposure to UV radiation



Infiltrative ▪ Invades dermis Micronodular ▪ Solid white-coloured lesion Morpheaform ▪ Flat white-yellowish waxy lesion Superficial ▪ Erythematous plaque, usually on upper trunk



SIGNS & SYMPTOMS ▪ Presents on face, periocular, neck, scalp (i.e. sun-exposed areas) ▪ Newly discovered lesion ▫ Pearly elevated patch of skin ▪ Does not heal within four weeks ▪ Dimpled at midpoint ▪ Grows slowly ▪ May bleed (esp. when poked/knocked) ▪ Painless, may itch ▪ Dilated blood vessels (telangiectasia) ▪ Ulcerated lesion ▫ Brown-black pigmentation in crater of lesion



DIAGNOSIS LAB RESULTS Figure 5.1 The clinical appearance of a basal-cell carcinoma on the nose of an elderly individual. The tumor is nodular with central ulceration and pearly borders.



Skin biopsy/histopathology ▪ Basal cells form clusters called islands with peripheral palisading nuclei



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TREATMENT MEDICATIONS



▪ Topical 5-fluorouracil/imiquimod



SURGERY



▪ Electrodesiccation, curettage; complete surgical excision; cryosurgery; Mohs surgery



Figure 5.2 The histological appearance of a basal-cell carcinoma. Malignant darkstaining, basaloid cells infiltrate the dermis. There is clefting at the junction between the tumor and the dermis.



OTHER DIAGNOSTICS



▪ Radiation, photodynamic therapy



OTHER DIAGNOSTICS



▪ Dermatoscopy ▫ Scattered vascular pattern, telangiectasias, hemorrhage-ulceration, hypopigmented areas with blue-grey ovoid nests, red dots/globules



MELANOMA osms.it/melanoma PATHOLOGY & CAUSES ▪ Malignant skin cancer, arises from melanocytes ▪ Occurs most commonly on skin ▫ Rarely: mouth, eyes, gastrointestinal (GI) tract ▪ Can arise from ▫ Preexisting mole ▫ De novo lump: nodular melanoma (most dangerous) Variants ▪ Superficial spreading melanoma ▪ Lentigo maligna melanoma ▪ Nodular melanoma ▪ Acral lentiginous melanoma



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Figure 5.3 A malignant melanoma exhibiting pigment production.



Chapter 5 Malignant Skin Tumors Growth phases ▪ Radial growth phase (< 1mm thick) ▫ Grows laterally along epidermis, superficial dermis; does not spread ▫ Rarely metastasizes; good prognosis if detected ▪ Vertical growth phase (> 1mm thick) ▫ Grows deeper into dermis, beyond ▫ Invasive, able to metastasize through lymph/blood vessels



CAUSES ▪ DNA damage caused by ultraviolet (UV) light exposure (e.g. sun, tanning beds) ▪ Genetic mutations in MC1R, CDKN2A, BRAF genes



RISK FACTORS



Immunosuppression Numerous moles Family history of melanoma Syndromes ▫ Dysplastic nevus syndrome, xeroderma pigmentosum, albinism, Gorlin syndrome ▪ Exposure/overexposure to UV light (e.g. sun, tanning beds) ▫ Esp. if blistering/occurring early in life; more common in people with fair skin



▪ ▪ ▪ ▪



▫ See tables: American Joint Committee on Cancer Guideline for TMN staging of melanoma ▪ Histopathological evaluation for tumor grade



OTHER DIAGNOSTICS



▪ Dermatological examination using dermatoscope ▫ Classic melanoma: mnemonic ABCDE ▫ Nodular melanoma: mnemonic EFG



MNEMONIC: ABCDE



Appearance of classic melanoma Asymmetry Border irregularities Color variation Diameter: 6 mm Enlargement



MNEMONIC: EFG



Appearance of nodular melanoma Elevated Firm to touch Growing



COMPLICATIONS



▪ Metastazes most commonly to lymph nodes, skin, subcutaneous tissue → lungs, liver, brain



SIGNS & SYMPTOMS ▪ New skin lesion/change pre-existing lesion: color, shape, size irregularities; ulcerations, pruritus, bleeding ▪ Nausea, vomiting, loss of appetite, fatigue



DIAGNOSIS LAB RESULTS



Figure 5.4 The clinical appearance of a malignant melanoma. It is darkly pigmented with an irregular border.



Full-thickness, sentinel node biopsy ▪ Tumor staging



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TREATMENT MEDICATIONS



▪ Immunotherapy in case of metastases



SURGERY



▪ Surgical excision ▫ Wide margin excision (1–3cm of normal tissue depending on depth of invasion) ▪ Excision if sentinel node biopsy is positive



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OTHER INTERVENTIONS



▪ Early detection for good prognosis (depends directly on depth of invasion) ▪ Radiation/chemotherapy in case of metastases



Chapter 5 Malignant Skin Tumors



Figure 5.5 The gross pathology of the heart in a case of metastatic melanoma.



SQUAMOUS-CELL CARCINOMA (SCC) osms.it/squamous-cell_carcinoma PATHOLOGY & CAUSES ▪ Second most common type of skin cancer ▪ Epidermal keratinocytes acquire antiapoptotic properties → frequent mitosis



RISK FACTORS



▪ Immunosuppression, chronic UV exposure, fair skin, albinism, xeroderma pigmentosa, tobacco use (increases risk of lip/oral SCC), arsenic exposure (rare)



CAUSES



▪ UV radiation (e.g. sun, tanning beds) ▪ HPV infection ▪ Genetic mutations ▫ Deletion of tumor progression locus 2 (Tpl2) gene ▪ Preceding skin lesions (e.g. actinic keratosis, other melanomas) ▫ Actinic keratosis: precancerous skin lesion; rough, scaly patch caused by chronic, long-term sun exposure ▪ Bowen’s disease (AKA squamous cell carcinoma in situ)



Figure 5.6 An ulcerated squamous cell carcinoma on the nose of a middle-aged individual.



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COMPLICATIONS ▪ Significant risk of metastasis



SIGNS & SYMPTOMS ▪ Most commonly found on sun-exposed areas (e.g. head, nose, neck) ▪ Small rough scaly nodule (slow growing) ▫ Nodule expands → center necroses → evolves into ulcer covered by red growing plaque → frequently scales, easily bleeds ▪ Chronic draining sinuses



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Assess surrounding tissue invasion (soft tissue, bones, lymph nodes), metastasis Dermatoscopy, excisional/incisional biopsy of subcutaneous tissue ▪ Microscopic features: hyperkeratosis, nuclear atypia ▪ See tables: American Joint Committee on Cancer Guideline for TMN staging of cutaneous squamous-cell carcinoma MRI ▪ Evaluate vital structures (neural, vascular invasions)



TREATMENT MEDICATIONS



▪ Topical immunomodulators



SURGERY



▪ Surgical excision ▪ Mohs surgery: microscopic procedure removing thin layers of affected tissue, examining under microscope until cancerfree tissue reached ▪ Electrodessication, curettage



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OTHER INTERVENTIONS



▪ Chemotherapy, radiotherapy, photodynamic therapy



Chapter 5 Malignant Skin Tumors



Figure 5.7 The histological appearance of well-differentiated squamous cell carcinoma of the skin. It is composed of polygonal cells with eosinophilic cytoplasm which produce keratin pearls.



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NOTES



NOTES



PAPULOSQUAMOUS DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Heterogeneous skin disorders; scaly papules, plaques ▫ Papule: circumscribed, solid elevation of skin < 1cm/0.39in ▫ Plaque: broad papule/confluence of papules ≥ 1cm/0.39in ▫ Scale: dry/greasy laminated masses of keratin



CAUSES ▪ Inflammation



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS OTHER DIAGNOSTICS ▪ Rash patterns



TREATMENT ▪ May spontaneously resolve



MEDICATIONS



▪ Topical (e.g. corticosteroids), nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines ▪ Immunosuppressants, retinoids (e.g. acitretin)



OTHER INTERVENTIONS ▪ Phototherapy, colloid baths



LICHEN PLANUS osms.it/lichen-planus PATHOLOGY & CAUSES ▪ Self-limiting chronic dermatosis ▪ Multifactorial pathogenesis ▫ Environmental factors → genetic aberrations of immune system ▫ CD8+ T cells respond to altered antigens in basal epidermidis/ dermoepidermal junction ▫ Causal agent identified: lichenoid reaction (e.g. drugs)



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▪ Chronic inflammation in mucosal lesions → squamous cell carcinoma



SIGNS & SYMPTOMS ▪ Shiny, flat-topped, pink-purple, polygonal papules coalesce, form plaques with red scales ▪ Wickham striae (pathognomonic) ▫ Interspersed grey-white lace-like pattern of lines



Chapter 6 Papulosquamous Disorders ▪ Symmetrical peripheral distribution, esp. on flexural surfaces (e.g. wrists, elbows, ankles, shins) ▪ Severe pruritus ▪ Koebner phenomenon ▫ Skin lesions induced by local trauma ▪ Nail involvement ▫ 10% of individuals; subungual thickening/hyperpigmentation, thinning/ ridging/ grooving of nail plate, pterygium formation, onycholysis ▪ Mucosal involvement ▪ Oral mucosa ▫ Asymptomatic/burning sensation,severe pain ▫ Mostly bilateral, inner cheeks ▫ Various types may coexist; oral variant of Wickham’s striae, erosive/ulcerative, papular, plaque-like, atrophic, bullous ▫ Possible secondary Candida infections ▪ Esophageal mucosa ▫ Dysphagia/odynophagia ▪ Genital mucosa (glans penis, vulva/vagina) ▫ Lower urinary tract symptoms, dyspareunia, itching in individuals who are biologically female



MNEMONIC: 6 Ps



▫ Basal keratinocytes degenerate, appear like stratum spinosum cells (squamatization)/undergo necrosis, become incorporated into inflamed papillary dermis (Civatte bodies)



OTHER DIAGNOSTICS ▪ Rash pattern distinctive at skin examination ▪ Skin biopsy ▫ Rule out secondary malignancies



TREATMENT ▪ Cutaneous lesions spontaneously resolve in nine months, longer for mucosal lesions ▫ Leaves area of hyperpigmentation



MEDICATIONS



▪ Reduce symptoms, shorten duration ▪ Antihistamines (pruritus), corticosteroids ▪ Retinoids, immunosuppressants



OTHER INTERVENTIONS ▪ Occlusive dressings ▪ Phototherapy ▫ Ultraviolet A radiation



Clinical presentation of lichen planus Planar Purple Polygonal Pruritic Papules Plaques



DIAGNOSIS LAB RESULTS



▪ Typical microscopic features ▫ Acanthosis: epidermidis thickening ▫ Interface dermatitis: continuous infiltrate of lymphocytes along dermoepidermal junction → sawtoothing (dermoepidermal interface with zig-zag contour)



Figure 6.1 Lesions on the shins of an individual with lichen planus.



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33



Figure 6.2 The histological appearance of lichen planus. There is a lymphocytic infiltrate at the junction between the dermis and epidermis which is known as interface dermatitis.



PITYRIASIS ROSEA osms.it/pityriasis-rosea PATHOLOGY & CAUSES ▪ Self-limiting acute dermatosis ▪ Unknown etiology; may be viral in origin, related to human herpesvirus 7 (HHV7)



SIGNS & SYMPTOMS ▪ Upper respiratory tract infection may precede rash ▪ “Herald patch” ▫ Solitary oval red plaque, usually located on trunk ▫ First skin lesion ▫ Spreads with central clearing, fading in 2–10 days ▪ 1–2 weeks after herald patch, multiple round/oval pink (white individuals of European descent)/dark brown (black individuals of sub-Saharan African descent) plaques with central scale appear



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▪ Trunk, neck, upper arms, thighs; “Christmas tree” progression ▫ Across chest, then rib-line ▪ Pruritus ▪ Systemic ▫ Low-grade fever, headache, nausea, fatigue



Figure 6.3 A herald patch is often seen at the onset of pityriasis rosea. It is a slightly raised, erythematous patch with superficial scaling.



Chapter 6 Papulosquamous Disorders



DIAGNOSIS LAB RESULTS



▪ Skin biopsy (rare) ▪ Microscopic features ▫ Dyskeratosis: abnormal premature keratinization ▫ Extravasated erythrocytes within dermal papillae



OTHER DIAGNOSTICS



▪ Rash pattern ▫ Distinctive at skin examination



TREATMENT ▪ May spontaneously disappear in 6–8 weeks Figure 6.4 The clinical appearance of pityriasis rosea on the torso of an adult male.



MEDICATIONS ▪ Antihistamines for pruritis



OTHER INTERVENTIONS ▪ May spontaneously disappear in 6–8 weeks ▪ Colloid baths for pruritis



PSORIASIS osms.it/psoriasis PATHOLOGY & CAUSES ▪ Chronic dermatosis of skin, nails, joints ▪ Multifactorial pathogenesis ▫ Environmental factors → genetic abnormalities of immune system ▫ CD4+ TH1, TH17, CD8+ T cells collect in epidermis, secrete cytokines (e.g. IFN-gamma, TNF-alpha, IL-17, IL22), growth factors → abnormal microenvironment (“cytokine soup”) accelerates keratinocyte proliferation → defective keratinization, epidermal thickening ▪ Unpredictable progression with



spontaneous remissions, sudden exacerbations (e.g. may worsen in winter— lack of sun, humidity) ▫ Skin abrasion, infection, drugs (e.g. lithium, beta blockers, chloroquine), psychosocial stress → exacerbations ▪ 10–15% of individuals develop psoriatic arthritis ▫ Inflammatory cells in joint tissue → synoviocyte proliferation ▫ Surrounding connective tissue also involved (e.g. enthesitis)



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TYPES ▪ Plaque psoriasis, AKA vulgar psoriasis; 90% ▪ Guttate (eruptive), inverse (flexural), pustular, erythrodermic



SIGNS & SYMPTOMS ▪ Plaque ▫ Pink, salmon-colored papules/plaques covered by loosely adherent silver-white scales ▫ Any area of body, esp. extensor surfaces (e.g. knees, elbows), lumbosacral area, scalp, glans penis ▫ Itching is mild/absent ▪ Nail involvement in 30% of individuals ▫ Subungual thickening ▫ Yellow-brown discolorations of nail plate (resembling oil slicks) ▫ Crumbling/ridging/pitting of nail plate ▫ Onycholysis: separation of nail plate from bed ▪ Guttate (eruptive) ▫ Drop-like appearance, associated with group A streptococcus ▪ Inverse (flexural) ▫ Skin folds ▪ Pustular ▫ Blisters filled with non-infectious pus ▪ Erythrodermic ▫ Total body inflammation, skin exfoliation, severe itching, swelling, pain; ability to regulate temperature, perform barrier functions impaired; possibly fatal ▫ May develop from any type (e.g. plaque during corticosteroid rebound phenomenon) ▪ Auspitz sign ▫ Pinpoint bleeding appears when scale removed ▪ Koebner phenomenon ▫ Characteristic skin lesions induced by local trauma ▪ Psoriatic arthritis ▫ Inflammatory arthritis: pain, red overlying area, swelling, hot to touch ▫ Frequently occurs after onset of rash ▫ Asymmetric peripheral oligoarthritis;



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joints of hands, feet most affected, followed by sacroiliac bone, spine ▫ Fusiform swelling of digits (dactylitis); aka “sausage digits” ▫ Aggressive disease with joint damage, malformations not common



DIAGNOSIS DIAGNOSTIC IMAGING ▪ For psoriatic arthritis



X-ray ▪ Erosive changes, “fluffy” periostitis, presence of new bone formation MRI ▪ Inflammation in adjacent bone marrow and soft tissues



LAB RESULTS



▪ Skin biopsy (rare) ▪ Acanthosis ▫ Epidermidis thickening ▪ Parakeratosis ▫ Keratinization (retention of nuclei in stratum corneum) ▪ Neoangiogenesis with tortuous blood vessels below stratum corneum ▪ Accumulation of neutrophils in superficial epidermis (spongiform pustules), in stratum corneum (Munro microabscesses) ▪ Clinical diagnosis ▫ Psoriasis features, clinical pattern of joint involvement ▪ Confirmation ▫ Elevated inflammatory markers, negative rheumatoid factor (RF), anticyclic citrullinated peptide antibody (anti-CCP)



OTHER DIAGNOSTICS



▪ Rash pattern ▫ Distinctive at skin examination ▪ Differentiation from rheumatoid arthritis ▫ Minority show polyarthritic pattern with no skin lesions; note asymmetry, distal interphalangeal joint involvement, mild joint destruction



Chapter 6 Papulosquamous Disorders



TREATMENT ▪ No definitive cure ▪ Avoid triggers



MEDICATIONS



▪ Topical corticosteroids → antiinflammatory, antiproliferative ▪ Vitamin D derivatives (calcipotriene, calcipotriol) → limit keratinocyte proliferation ▪ Anthralin → suppresses proliferation ▪ Combination therapy is most effective (e.g. betamethasone dipropionate + calcipotriene) ▪ Affected area > 10%, unsuccessful topical treatment, involves face, hands, genitals ▪ Immunosuppressant ▫ Methotrexate, cyclosporine ▪ Systemic retinoids ▫ Acitretin → inhibits pro-inflammatory cytokines ▪ Biologic therapy ▫ Anti-TNF (infliximab, etanercept, adalimumab), T-cells (alefacept), IL12/23 (ustekinumab) ▪ NSAIDs, immunosuppressant/biologic therapy ▫ For psoriatic arthritis



Figure 6.5 A large psoriatic plaque on the upper limb.



OTHER INTERVENTIONS



▪ Topical ▫ Coal tar → inhibits cellular mitotic activity, proliferation ▫ Moisturizers, emollients ▪ Phototherapy ▫ Ultraviolet A radiation ▫ Often combined with topical tar/ systemic acitretin/psoralen/methoxsalen ▫ Immunosuppressive, antiproliferative



Figure 6.6 Psoriasis affecting the hand.



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NOTES



NOTES



PIGMENTATION DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Skin loses pigment, becomes lighter/darker ▪ Pigment-producing cells (melanocytes) ▫ Expected number, overproduce pigment (melanin) ▫ Higher in number, produce expected melanin ▫ Destroyed, no melanin produced



DIAGNOSIS LAB RESULTS ▪ Skin biopsy ▪ Genetic testing



OTHER DIAGNOSTICS



▪ Dermatological physical examination (e.g. dermoscopy)



CAUSES



▪ Autoimmune disorders → melanocyte destruction ▪ Long periods of sun exposure ▪ Genetic mutations



SIGNS & SYMPTOMS ▪ Changes in skin pigmentation only symptom ▪ Some disorders (esp. produced by sun overexposure) heighten risk of skin cancer



TREATMENT ▪ Usually no cure



MEDICATIONS



▪ Topical medication ▫ Most respond to steroids ▫ Depigmentation agents effective for hyperpigmentation disorders



SURGERY



▪ For some lesions



OTHER INTERVENTIONS



▪ Sun avoidance, if caused by ultraviolet (UV) overexposure



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Chapter 7 Pigmentation Disorders



ALBINISM osms.it/albinism PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Congenital condition; skin, eyes, hair partially (hypomelanistic albinism)/ completely (amelanistic albinism) devoid of pigment ▪ Lack of pigment → dermatological problems ▫ Increased risk of sunburn, skin cancer



▪ Complete/partial absence of skin pigmentation ▪ Light yellow/white hair ▪ Light eye colour ▫ Light blue (partial pigment production) ▫ Pink (complete absence of pigment production) ▪ Visual problems ▫ Visual development in fetus highly dependent on melanin production; abnormal arrangements in optic nerves fibres (e.g. abnormal optic chiasm) ▫ Severe sensitivity to light ▫ Poor visual acuity due to foveal hypoplasia ▫ Amblyopia/nystagmus: poor coordination between eye, brain



TYPES Oculocutaneous albinism (OCA) ▪ Eyes, skin; possibly hair ▪ Autosomal recessive transmission ▪ Seven different subtypes; OCA1, OCA2 most common ▫ OCA1: defect in gene for enzyme tyrosinase (TYR) ▫ OCA2: defect in P gene (membrane transporter, moves amino acid tyrosine) ▪ Rufous oculocutaneous albinism ▫ Specific subtype of OCA ▫ Common in people of sub-Saharan African descent Ocular albinism (OA) ▪ Only eyes ▪ OA1 most common subtype (AKA Nettleship–Falls syndrome) ▫ X-linked recessive inheritance ▫ Lack of pigment in retinal epithelium



DIAGNOSIS LAB RESULTS



▪ Genetic testing ▫ Identify defective gene, allotype



OTHER DIAGNOSTICS ▪ Physical examination ▪ Family history



CAUSES



▪ Hereditary/genetic ▫ Autosomal/X-linked ▫ Recessive inheritance pattern → defect leading to lack/absence of enzyme in melanin synthesis pathway → hypopigmentation/depigmentation ▪ Chediak–Higashi syndrome ▫ Rare; malfunctions in lysosomal trafficking regulator gene (CHS1/LYST)



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39



TREATMENT ▪ No cure



SURGERY



▪ Manage strabismus, nystagmus



OTHER INTERVENTIONS



▪ Lifestyle management ▫ Avoid sunburn ▫ Regular dermatological, ophthalmological check-ups ▫ Visual rehabilitation ▫ Glasses/contact lenses



Figure 7.1 A baby with albinism.



PITYRIASIS ALBA osms.it/pityriasis-alba PATHOLOGY & CAUSES ▪ Common, irregularly hypopigmented skin condition: slightly scaly patches, macules ▫ Lesion diameter: 0.5–5cm/0.2–2in ▫ Irregular borders ▫ Most common on face, neck, shoulders, upper arms ▫ May resolve spontaneously after puberty



CAUSES



▪ Unknown etiology: eczema-related postinflammatory hypopigmentation (possible relation)



RISK FACTORS ▪ ▪ ▪ ▪ ▪



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Atopy Sun exposure Frequent bathing Biologically male Children/adolescents > adults



COMPLICATIONS ▪ Benign condition



SIGNS & SYMPTOMS ▪ Often asymptomatic, may itch/burn



DIAGNOSIS OTHER DIAGNOSTICS



▪ Wood’s lamp examination: hypomelanosis patches ▪ Microscopy: ↓ melanocyte number, size



TREATMENT MEDICATIONS



▪ Hydrocortisone (topical), calcineurin inhibitors, emollients



Chapter 7 Pigmentation Disorders



VITILIGO osms.it/vitiligo PATHOLOGY & CAUSES ▪ Pigmentation disorder; parts of skin, hair lose pigment ▪ Melanocytes destroyed → white patches of depigmented skin ▫ Sharp margins on depigmented patches ▪ May be autoimmune condition



SIGNS & SYMPTOMS ▪ Depigmented skin patches only symptom, usually on extremities ▪ Patches grow over time (non-segmental subtype) ▪ Can be associated with alopecia



DIAGNOSIS



TYPES Segmental ▪ Areas innervated by dorsal roots of spinal cord ▪ Unilateral; stable over time Non-segmental ▪ Symmetrical; appearance of new patches ▪ Multiple subtypes ▫ Vitiligo universalis: most severe, almost no pigmented skin remains ▫ Generalized: most common ▫ Focal: smaller, localised patches ▫ Acrofacial: hands, face ▫ Mucosal: only mucous membranes



CAUSES



▪ Autoimmune disorder → melanocyte destruction



RISK FACTORS



▪ Medical/family history of autoimmune conditions ▫ Hashimoto’s thyroiditis ▫ Type I diabetes mellitus ▫ Systemic lupus erythematosus ▫ Celiac disease ▫ Addison’s disease



▪ Rule out autoimmune/inflammatory disorders



OTHER DIAGNOSTICS



▪ Ultraviolet light (Wood’s lamp): lesions; vitiligo turns blue



TREATMENT ▪ No cure



MEDICATIONS



▪ Topical immune system suppressing medication ▪ Glucocorticoids ▪ Calcineurin inhibitors



OTHER INTERVENTIONS



▪ Ultraviolet light therapy (phototherapy) ▪ Skin camouflage (e.g. makeup)



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Figure 7.2 The clinical appearance of vitiligo affecting the hands.



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NOTES



NOTES



SKIN & SOFT TISSUE INFLAMMATION & INFECTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



DIAGNOSIS



▪ Inflammation of epidermis, dermis, underlying tissues



LAB RESULTS



CAUSES



OTHER DIAGNOSTICS



▪ Infections, autoimmune response



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Impaired skin barrier Pressure Friction Exposure to infectious agents Immunosuppression



COMPLICATIONS ▪ Infection ▫ Local or systemic disease



▪ Tissue cultures, Gram stain



▪ Mostly clinical, based on presentation



TREATMENT MEDICATIONS



▪ Infections: antimicrobials



OTHER INTERVENTIONS ▪ Dressings, ointments ▪ Cryotherapy ▪ Curettage



SIGNS & SYMPTOMS ▪ See individual disorders



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ACNE VULGARIS osms.it/acne_vulgaris PATHOLOGY & CAUSES ▪ Common inflammatory skin disorder affecting hair follicles, sebaceous glands ▪ May involve comedones, papules, pustules, cysts, scars ▪ Especially affects individuals who are ▫ Biologically male, with hormonal disorders producing androgens (e.g. polycystic ovarian syndrome), adolescent ▫ Symptoms decrease with age



TYPES Mild ▪ Occasional, comedones, inflammatory papules, pustules



▪ Infection ▫ Follicle colonization by Propionibacterium acnes ▪ Medications ▫ Lithium, glucocorticoids, anabolic steroids ▪ Polycystic ovarian syndrome ▪ Stress



COMPLICATIONS ▪ Cosmetic ▫ Scars, hyperpigmentation, pyogenic granulomas, osteoma cutis ▪ Psychiatric ▫ Low self esteem, depression



Moderate ▪ Multiple pustules, nodules occur on trunk Severe ▪ Cystic, large nodules predominant, with persistent involvement of trunk; scarring



CAUSES ▪ Androgen stimulates sebaceous follicles to overproduce sebum → follicles become blocked ▪ Hyperkeratinization of epithelium → accumulation → follicular blocking → debris accumulates further → skin follicles rupture ▪ Propionibacterium acnes replicates within follicle → releases lipase → sebum converted to free fatty acids → release of cytokines → inflammation



RISK FACTORS ▪ Genetic predisposition ▪ Oil-based skin products ▪ Hormonal imbalance



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Figure 8.1 Acne vulgaris affecting the face of an adolescent male.



Chapter 8 Skin & Soft Tissue Inflammation & Infections



SIGNS & SYMPTOMS ▪ Papules, pustules, painful nodules (cysts) on face, neck, chest, back ▪ Closed comedones ▪ Erythema



DIAGNOSIS



▪ In case of comedonal acne, use azelaic acid, salicylic acid as anti-inflammatory, antibacterial, antiproliferative agent Mild to moderate ▪ Benzoyl peroxide, retinoid ▪ Add topical antibiotic (clindamycin) for synergistic effect with benzoyl peroxide Severe ▪ Oral isotretinoin decreases sebum production, bacterial proliferation, inflammation ▪ Avoid using tetracycline due to sun sensitivity



OTHER DIAGNOSTICS ▪ Clinical presentation



TREATMENT



OTHER INTERVENTIONS



MEDICATIONS ▪ Target sebum production, inflammation, bacterial/follicular proliferation Mild ▪ Benzoyl peroxide treats Propionibacterium acnes ▪ Add topical retinoids to prevent follicular proliferation



▪ Clean skin with gentle agents ▪ Comedones extraction ▪ Pigmentation ▫ Topical retinoid, azelaic acid, chemical peels ▫ Photodynamic treatment with lasers (removes superficial layers of skin) ▫ Dermabrasion (treatment of scars; may irritate skin)



CELLULITIS osms.it/cellulitis PATHOLOGY & CAUSES ▪ Non-necrotizing inflammation of dermis, subcutaneous tissue, typically caused by streptococci (S. aureus, S. pyogenes); usually unilateral ▪ Skin breach: trauma; dry, fissuring skin; ulcers → bacteria invade skin, subcutaneous tissue ▪ Common locations: face, legs; may affect arms ▪ Other locations: causes vary ▫ Orbital cellulitis: originates from trauma, sinuses, hematogenous spread



▫ Abdominal wall cellulitis: morbid obesity causes bacteria to enter skin sores ▫ Buccal cellulitis: spread from tooth infection ▫ Perianal cellulitis: affects all demographics



TYPES ▪ Purulent ▫ Furuncles (inflamed follicles), carbuncles (accumulation of furuncles), abscesses, cysts ▪ Non-purulent ▫ Superficial cellulitis, erysipelas



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RISK FACTORS ▪ Skin inflammation ▫ Abrasion: wounds, eczema, radiation, broken skin between toes ▪ Lowered immunity ▫ Diabetes mellitus, alcohol abuse, HIV, older age ▪ Skin infection ▫ Tinea, impetigo, varicella, rash ▪ Edema ▫ Lymphatic obstruction, venous insufficiency ▪ Obesity



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Subcutaneous fat separates into lobules ▫ Cobblestone appearance



COMPLICATIONS ▪ Recurrence, abscess formation, necrotizing fasciitis, osteomyelitis, sepsis



SIGNS & SYMPTOMS ▪ Fever, chills ▪ Localized inflammation ▫ Swelling ▫ Warmth ▫ Erythema with unclear borders (contrast to erysipelas—clear demarcations) ▫ Often painful ▪ Enlarged lymph nodes ▪ Purulent cellulitis associated with S. aureus infection



Figure 8.2 An ultrasound scan of the right lower limb demonstrating the cobblestone appearance of subcutaneous edema, in this case secondary to cellulitis.



LAB RESULTS ▪ Complete blood count (CBC) ▫ ↑ inflammatory markers: ↑ C-reactive protein (CRP), ↑ erythrocyte sedimentation rate (ESR), ↑ WBC count ▪ Wound, blood cultures ▫ Identify causative microbe



OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Spreading inflammation of skin/ subcutaneous tissues



TREATMENT MEDICATIONS



Figure 8.3 An individual with cellulitis of the left leg.



▪ Antibiotics: second generation penicillins, first generation cephalosporins; vancomycin for MRSA



OTHER INTERVENTIONS ▪ Immobilization, elevation, dressings ▪ Drain abscess



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Chapter 8 Skin & Soft Tissue Inflammation & Infections



ERYSIPELAS osms.it/erysipelas PATHOLOGY & CAUSES ▪ Acute, non-necrotizing infection of upper dermis, superficial lymphatics; usually unilateral ▪ Well-defined demarcation between normal, infected tissue; non-purulent ▪ Usually caused by streptococci; most often Streptococcus pyogenes



▪ Elevated, warm, painful rash called “forest fire rash” (because it’s reddest at border) ▪ Vesicles may be present; may be bright, salmon red ▪ Inflammation of regional lymph nodes, lymphangitis in chronic infection



RISK FACTORS ▪ Very young/old age ▪ Breaks in skin ▫ Abrasions, trauma, eczema, radiation, bites ▪ Lowered immunity ▫ Diabetes mellitus, alcohol abuse, HIV, older age ▪ Skin infection ▫ Tinea, impetigo, varicella, rash ▪ Edema ▫ Lymphatic obstruction, venous insufficiency ▪ Obesity



COMPLICATIONS ▪ Lymphedema due to impaired lymphatic drainage ▪ Necrosis ▪ If spread hematogenously to other areas ▫ Arthritis, osteomyelitis, necrotizing fasciitis, glomerulonephritis



SIGNS & SYMPTOMS ▪ Initially, general infection symptoms ▫ Fever, chills, headache, fatigue ▪ Lesions ▫ Mostly on legs, but may be found on face, arms, fingers, toes



Figure 8.4 Erysipelas affecting the face of an elderly individual.



DIAGNOSIS LAB RESULTS ▪ Blood test ▫ CBC: ↑ CRP, ↑ ESR, ↑ WBCs; antistreptolysin titer O shows streptococcal involvement ▪ Wound, blood culture



OTHER DIAGNOSTICS ▪ Clinical presentation



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TREATMENT MEDICATIONS



▪ Antibiotics: oral penicillins/macrolides, vancomycin for MRSA, intravenous (IV) route in severe infection



FOLLICULITIS osms.it/folliculitis PATHOLOGY & CAUSES ▪ Hair follicle inflammation (pyoderma), usually infectious cause ▪ May also be due to persistent trauma (mechanical folliculitis) ▪ Pathogen enters hair follicle → inflammatory inflammatory response → infection causes a perifollicular infiltrate of lymphocytes, neutrophils, macrophages → pustule formation



CAUSES ▪ Bacterial ▫ S. aureus, Pseudomonas aeruginosa (hot-tub folliculitis) ▪ Viral ▫ Herpes simplex virus (HSV) ▪ Fungal ▫ Tinea barbae ▪ Rarely ▫ Autoimmune; oily skin in factory workers



RISK FACTORS ▪ Swimming pools, hot tubs ▪ Shaving against hair growth, tight clothes causing friction, profuse sweating (hyperhidrosis) ▪ Use of antibiotics, acne medication, topical corticosteroids ▪ Upper respiratory presence of S. aureus



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COMPLICATIONS ▪ Recurrence ▪ Furunculosis ▫ Deep infection of hair follicle → evolves into swollen nodule, may coalesce into carbuncles



SIGNS & SYMPTOMS ▪ Many small pustules, papules in areas of hair growth (e.g. face, legs, arms, back) ▫ Typical in groin, armpits ▫ Gram-negative infections more common on the face (areas of acne) ▫ Methicillin resistant S. aureus (MRSA) more common on the front trunk ▪ Itching, redness; often tender ▪ Does not appear in areas without hair growth (palms of hands, soles of feet) ▪ Sycosis vulgaris ▫ Multiple pustules on chin, upper lip; caused by S. aureus infection after shaving



DIAGNOSIS LAB RESULTS ▪ Gram stain, wound culture performed for treatment-resistant individuals ▪ Skin biopsy ▫ Differentiation from other skin disorders in persistent folliculitis



Chapter 8 Skin & Soft Tissue Inflammation & Infections



OTHER DIAGNOSTICS ▪ History ▫ Risk behavior/predisposition ▪ Clinical presentation



TREATMENT MEDICATIONS



▪ Topical antibiotics: mupirocin, clindamycin ▪ Oral antibiotics: tetracycline, cephalosporin ▫ Used in extensive involvement ▪ MRSA treatment: trimethoprim/ sulfamethoxazole, clindamycin, tetracycline ▪ Fungal treatment: fluconazole, itraconazole ▪ Viral treatment: acyclovir, valacyclovir, famciclovir



Figure 8.5 The clinical appearance of folliculitis.



OTHER INTERVENTIONS ▪ May resolve spontaneously ▪ Warm compress with antiseptic use ▪ Loose fitting clothing; avoiding shaving



HIDRADENITIS SUPPURATIVA osms.it/hidradenitis-suppurativa PATHOLOGY & CAUSES ▪ Chronic, pus-producing dermatological disorder ▫ AKA acne inversa ▪ Dysfunctional hair follicles/apocrine sweat glands → pore clogging → inflammation → painful abscesses



CAUSES Environmental ▪ Skin/clothes friction, hormonal changes, sweating, humidity Genetic ▪ Apocrine gland dysfunction, cellular disorders



RISK FACTORS ▪ Obesity, tight clothes, smoking, deodorant use, shaving ▪ More common for biologically-female individuals



COMPLICATIONS ▪ Scarring, bacterial infection, interstitial keratitis, sinus formation, fistula formation; squamous cell carcinoma (chronic lesions); depression



SIGNS & SYMPTOMS ▪ Red inflamed areas, painful bumps that drain with pus ▪ Presence of double comedones ▪ Mostly in axilla, groin, under breasts



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DIAGNOSIS



TREATMENT



OTHER DIAGNOSTICS



MEDICATIONS



Clinical presentation ▪ Sartorius/Hurley’s staging systems (determines severity; guides treatment) ▫ Stage I: solitary/multiple isolated abscess formation without scarring/ sinus tracts ▫ Stage II: recurrent abscesses; lesions may be single/multiple, widely separated; sinus tract formation ▫ Stage III: diffuse, regional involvement across; multiple interconnected sinus tracts, abscesses



▪ Corticosteroids, anti-androgen medication, oral antibiotics, tumor necrosis factor (TNF) inhibitors to ↓ inflammation



SURGERY ▪ Incision, drainage; sinus tract opening



OTHER INTERVENTIONS ▪ Clean affected area ▪ Laser treatments remove lesions, scarring Behavioral ▪ Smoking cessation, weight loss



IMPETIGO osms.it/impetigo PATHOLOGY & CAUSES ▪ Highly infectious skin infection; affects superficial epidermis ▫ Commonly affects children ▫ Skin-to-skin spread possible ▪ Contact with carrier → pathogen enters intact/non-intact skin → incubation → lesion formation, spread over body through scratching ▪ Commonly caused by S. aureus, S. pyogenes



TYPES ▪ Nonbullous ▪ Bullous ▪ Ecthyma



RISK FACTORS ▪ Higher incidence in warm, humid climates ▪ Eczema, HSV, diabetes mellitus, malnutrition ▪ School, daycare



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COMPLICATIONS ▪ Cellulitis, poststreptococcal glomerulonephritis



SIGNS & SYMPTOMS ▪ Nonbullous ▫ Most common ▫ Red bump → blister → blisters rupture, ooze, form crusts → characteristic yellow scab formation ▪ Bullous ▫ Bullae on limbs, trunk ▫ Not painful ▫ Ruptured bullae become covered with thin, brown crust ▪ Ecthyma ▫ Deeper nonbullous impetigo appears on limbs ▫ Painful ▫ Evolves into yellow scabs ▪ Fever (rare); blisters may be painful, itchy



Chapter 8 Skin & Soft Tissue Inflammation & Infections



DIAGNOSIS LAB RESULTS ▪ Lesion culture ▫ Identify pathogen, adjust treatment



OTHER DIAGNOSTICS ▪ History ▪ Physical exam



TREATMENT MEDICATIONS ▪ Topical antibiotic ▪ Penicillins ▪ In case of MRSA, use trimethoprim/ sulfamethoxazole



OTHER INTERVENTIONS ▪ Clean with antiseptic to prevent spreading ▪ Topical antibiotic ▫ Penicillins ▫ In case of MRSA use trimethoprim/ sulfamethoxazole



Figure 8.6 Impetigo on the back of the neck of an adult male.



NECROTIZING FASCIITIS osms.it/necrotizing_fasciitis PATHOLOGY & CAUSES ▪ Potentially life-threatening infection ▫ Progressive destruction of deep soft tissue (subcutaneous fat, muscle fascia) ▪ Bacteria spread via subcutaneous tissue → release exotoxins → tissue destruction spreads along fascial planes



TYPES Type I: polymicrobial ▪ Causes: combination of aerobic, anaerobic bacteria ▫ Most common anaerobes: Bacteroides,



Clostridium, Peptostreptococcus ▫ Enterobacteriaceae: Escherichia coli, Klebsiella, Proteus, Enterobacter ▫ Facultative anaerobic streptococci ▪ Common sites ▫ Perineum (Fournier’s gangrene): impaired gastrointestinal/urethral mucosal integrity → spreads to anterior abdominal wall; gluteal muscles; scrotum, penis (in biological male); labia (in biological female) ▫ Cervical (head, neck): impaired oropharynx mucosa (often related to dental/odontogenic infection) → spreads to face, neck, mediastinum



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Type II: monomicrobial ▪ Causes: Group A Streptococcus, other beta-hemolytic streptococci, Staphylococcus aureus Type III: saltwater infection ▪ Cause: Vibrio vulnificus ▪ Rare Type IV: fungal infection



RISK FACTORS ▪ Immunosuppression ▫ HIV, diabetes, cirrhosis, corticosteroid use ▪ Peripheral vascular disease ▪ Trauma ▫ Injury, surgery ▪ IV drug abuse ▪ Childbirth ▪ Exposure of open wound to fresh/salt water, swimming pools, hot tubs ▪ Ludwig’s angina (submandibular region infection) ▪ Lemierre syndrome (septic thrombophlebitis located in jugular vein)



COMPLICATIONS ▪ Shock ▪ Organ failure ▪ Potentially fatal



SIGNS & SYMPTOMS Overlying skin ▪ May appear normal initially ▪ Later ▫ Warmth, erythema/violet/purple (violaceous), woody induration, edema, necrosis ▪ Bullae; may fill with serosanguinous fluid ▪ Subcutaneous emphysema (if infection with anaerobes) Systemic findings ▪ Pain ▫ Often out of proportion to exam findings ▪ Fever ▪ ↑ pulse ▪ ↓ perfusion (motling, pallor, altered level of consciousness) ▪ Hemodynamic instability (↓ BP)



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Subcutaneous gas visualized in fascial planes



LAB RESULTS Blood ▪ ↑ WBCs, left shift; ↑ creatine phosphokinase; ↓ hemoglobin, ↑ glucose, ↓ sodium Urine ▪ Proteinuria Gram stain, cultures of skin ▪ Debrided tissue identifies organism(s)



Figure 8.7 Necrotizing fasciitis on the left leg. The dark areas represent progression to necrosis.



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OTHER DIAGNOSTICS ▪ Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score ▫ Score = 6: ↑ suspicion of necrotizing fasciitis ▫ Score = 8: strongly predictive



Chapter 8 Skin & Soft Tissue Inflammation & Infections



Figure 8.9 A histological section of subcutaneous tissue in a case of necrotizing fasciitis showing an inflammatory infiltrate in the fascia leading to necrosis.



TREATMENT MEDICATIONS



Figure 8.8 A CT scan in the coronal plane demonstrating the presence of gas in the fascial planes of the leg, consistent with a diagnosis of necrotizing fasciitis.



▪ Empiric IV antibiotics ▫ Carbapenem/beta-lactam-betalactamase inhibitor + vancomycin/ linezolid + clindamycin ▪ Hemodynamic support ▫ Fluids, vasopressors



SURGERY ▪ Direct surgical examination of skin, subcutaneous tissue, fascial planes, muscle → debridement of all devitalized, necrotic tissue ▪ Fasciotomy



OTHER INTERVENTIONS ▪ Hyperbaric oxygen



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ONYCHOMYCOSIS osms.it/onychomycosis PATHOLOGY & CAUSES ▪ Chronic fungal infection ▫ Nail bed, matrix, plate of toes/fingers ▪ Infection spread by direct contact from people, animals, soil, fomites (upholstery, hairbrushes, hats) ▪ Causative agents ▫ Dermatophytes (tinea unguium): most commonly Trichophyton rubrum ▫ Nondermatophyte molds: Aspergillus spp. ▫ Yeasts: most commonly Candida albicans ▪ Dermatophyte hyphae penetrate stratum corneum of skin, nails → manufacture keratinolytic proteases → invade living cells ▪ Spores of nondermatophyte (e.g. Aspergillus) lodge under nail/at lateral nail folds → colonization, spread toward cuticle Candida spp. → infect soft tissue around nail, penetrate nail plate



TYPES



Mixed pattern ▪ Combination of other types



RISK FACTORS ↑ age Biological male > female Communal showers, swimming pools Contributory/predisposing factors ↑ warmth, humidity Occlusive footwear Occupational ▫ Jobs that involve frequent hand washing; dishwashers, housekeepers ▪ Immunocompromised state (HIV, diabetes) ▪ Living with others affected by onychomycosis ▪ Chronic mucocutaneous fungal infection



▪ ▪ ▪ ▪ ▪ ▪ ▪



COMPLICATIONS ▪ ▪ ▪ ▪



Pain ↑ risk of bacterial coinfection, cellulitis Nail disfigurement Recurrence



Distal lateral subungual ▪ Initially affects distal corner of nail; eventually spreads toward cuticle ▪ Most common Proximal subungual ▪ Affects nail plate near cuticle; extends distally ▪ Sign of severely immunocompromised state White superficial ▪ Affects nail surface; may spread to cover entire nail Endonyx ▪ Affects interior of nail plate Total dystrophic ▪ Nail plate is completely destroyed



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Figure 8.10 Onychomycosis of the toe nails.



Chapter 8 Skin & Soft Tissue Inflammation & Infections



TREATMENT



SIGNS & SYMPTOMS ▪ Distal lateral subungual ▫ Yellow, brown, white discoloration; subungual hyperkeratosis; mild inflammation; onycholysis ▪ Proximal subungual ▫ Diffuse patches/transverse striate of white to yellow patches on nail plate ▪ Endonyx ▫ Discoloration, onycholysis ▪ White superficial ▫ Soft white spots on nail surface ▪ Total dystrophic ▫ Keratotic debris on thick, rigid nail bed ▪ Other associated features ▫ Coexisting tinea pedis infection (common) ▫ Chronic paronychia (proximal/lateral fold inflammation) ▫ Dermatophytoma (linear, yellow/white band of dermatophyte hyphae) ▫ Fungal melanonychia (black/brown discoloration; caused by pigmentproducing molds, fungi)



MEDICATIONS ▪ Topical triazole ▫ Efinaconazole ▪ Systemic ▫ Terbinafine (dermatophyte infections); itraconazole (yeast, non-dermatophyte infections) ▪ Coexisting tinea capitis ▫ Griseofulvin ▪ Keratolytic (urea) ▫ Reduces nail thickening



SURGERY ▪ Nail removal in some cases (nail avulsion)



OTHER INTERVENTIONS ▪ Laser (Nd:YAG) ▪ Photodynamic therapy



DIAGNOSIS LAB RESULTS ▪ Potassium hydroxide (KOH) microscopy ▫ Identifies fungal elements (e.g. fungal hyphae, pseudohyphae, yeast) ▪ Histopathological analysis using periodic acid-Schiff (PAS) stain ▫ Identifies fungal elements ▪ Fungal culture (e.g. dermatophyte test medium/DTM) ▫ Identifies organism



OTHER DIAGNOSTICS ▪ History, physical examination with characteristic findings



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PRESSURE ULCER osms.it/pressure-ulcer PATHOLOGY & CAUSES ▪ Localized skin, underlying-tissue injury ▫ Caused by unrelieved pressure/pressure in combination with friction, shearing forces ▪ AKA bedsores/decubitus ▪ Blood flow diminishes ▫ Pressure → ischemia → necrosis ▪ Bony prominences most commonly affected ▫ Sacrum, heels, hips, elbows



RISK FACTORS ▪ Reduced mobility ▫ Chronic/acute disease (e.g. hip fracture, stroke, Parkinson disease) ▫ Central/peripheral neural damage, altered level of consciousness, advanced age ▪ Reduced perfusion ▫ Atherosclerosis, peripheral vascular disease, hypotension, smoking ▪ Factors affecting skin structure ▫ Malnutrition, protein deficiency, skin moisture (incontinence, sweating) ▪ Diabetes mellitus



STAGING



▪ Stage I: nonblanchable erythema; skin intact, localized ▪ Stage II: partial thickness dermis loss; red wound bed; serum-filled blister; no skin sloughing ▪ Stage III: full thickness tissue loss; visible subcutaneous fat; raised wound edges (epibole); skin sloughs ▪ Stage IV: full thickness tissue loss; bone, muscle, tendon exposed; raised wound edges; skin sloughs/eschar formation



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▪ Unstageable: if filled with sloughed skin, scabs; diagnosis difficult ▪ Deep tissue injury: nonblanchable erythema, skin separation; no skin disruption



COMPLICATIONS ▪ Biofilm formation on wound → inflammation → delayed healing → wound dehiscence ▪ Wound, bone, joint infection; sepsis; fistulas; gangrene ▪ Malignant transformation rare



SIGNS & SYMPTOMS ▪ Ulceration (skin in contact with underlying surface) ▪ Fever, foul odor (if complicated by infection) ▪ May be painful



DIAGNOSIS LAB RESULTS ▪ Swab culture ▫ May help determine treatment in healing-resistant ulcers



OTHER DIAGNOSTICS ▪ Clinical presentation



TREATMENT MEDICATIONS ▪ Topical sulfadiazine cream



OTHER INTERVENTIONS ▪ Debridement of biofilm, dressing replacement, negative pressure therapy



Chapter 8 Skin & Soft Tissue Inflammation & Infections Prevention ▪ If bedridden, reposition at least every two hours (reduces chance of ulcer development) ▪ Use of special mattresses



ROSACEA osms.it/rosacea PATHOLOGY & CAUSES ▪ Chronic inflammatory cutaneous disorder ▫ Usually affects face (may extend to neck, upper chest, ears) ▫ Ocular involvement: dry, burning, itching, foreign-body sensation ▪ Typical onset: 30–50 years ▪ Defining features ▫ Persistent central facial erythema; intensity may be intermittent ▫ Phymatous changes (irregular, nodular skin), usually affecting nose (biologically-male > biologically-female individuals) ▪ Hyperactive vascular response, may extend to eyes (ocular rosacea) ▪ Triggered by warm weather, alcohol, certain foods, sun, stress



CAUSES ▪ Unknown ▪ May be innate immune system dysfunction; response to bacteria, UV → chronic inflammation



COMPLICATIONS ▪ Skin thickening, scarring, rhinophyma, ocular rosacea (blepharitis)



RISK FACTORS ▪ Genetic predisposition ▪ More common in biologically-female individuals, especially of Celtic/NorthernEuropean descent



SIGNS & SYMPTOMS ▪ Telangiectasia with erythema, papules, pustules ▪ Flushing Characteristics of different types ▪ Papulopustular ▫ Similar to acne, no comedones ▪ Phymatous ▫ Thick oily skin; mostly on nose, in biologically-male individuals ▪ Ocular (common) ▫ Conjunctivitis, keratitis, tearing, burning, telangiectasias ▪ Granulomatous ▫ Papules around eyes, cheeks ▪ Pediatric (rare) ▫ Never phymatous ▪ Neurogenic ▫ Pain, neurologic symptoms



DIAGNOSIS OTHER DIAGNOSTICS ▪ History; clinical exam with characteristic findings



TREATMENT MEDICATIONS ▪ Antibiotic (topical metronidazole) ▪ Topical azelaic acid ▪ Oral doxycycline



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OTHER INTERVENTIONS ▪ Avoid exacerbating factors (e.g. spicy food, alcohol, sun, stress) ▪ Regular sunscreen use ▪ Laser therapy ▫ Telangiectasia ablation



STAPHYLOCOCCAL SCALDED SKIN SYNDROME (SSS) osms.it/SSS PATHOLOGY & CAUSES ▪ Infectious, superficial skin disorder ▫ Skin blistering, desquamation ▪ AKA Ritter’s disease



CAUSES



▪ S. aureus produces epidermolytic exotoxin → enters skin → breaks down desmosomes between cells → peeling skin



COMPLICATIONS ▪ Cellulitis, sepsis



RISK FACTORS ▪ ▪ ▪ ▪



S. aureus infection Immunocompromised state Immature renal function/kidney disease Affects children < six years



SIGNS & SYMPTOMS ▪ Tender erythema with large desquamation areas, moist patches ▪ Nikolsky sign: skin peels at gentle touch ▪ Fever, malaise, appetite loss



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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Check for pneumonia as infectious cause; lobar infiltrates



LAB RESULTS Biopsy ▪ Epidermal splitting in stratum granulosum near skin surface Blood culture ▪ S. aureus



OTHER DIAGNOSTICS ▪ Clinical presentation



TREATMENT MEDICATIONS ▪ Antibiotics



NOTES



NOTES



URTICARIA & ERYTHEMA NODOSUM



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vascular reaction of the skin triggered by allergic reaction, irritation, or infection ▪ Vasodilation, increased vascular permeability → fluid leaks into interstitium → swelling/edema ▪ Possible elicitation of hypersensitivity reaction (immune system involved) ▪ Can be acquired (e.g. medications), associated with underlying illness (e.g. malignancies, autoimmune disorders), or have genetic predisposition



SIGNS & SYMPTOMS ▪ Range of dermatological manifestations: ▫ Erythema ▫ Swelling



▫ Urticaria, pruritus ▫ Raised or flat lesions



DIAGNOSIS ▪ Physical examination ▫ Based on appearance ▪ Patch testing to confirm and determine the allergy ▪ Screening for autoimmune or neoplastic etiologies



TREATMENT ▪ Identify/avoid triggers ▪ Address underlying cause ▪ Symptomatic management



ERYTHEMA NODOSUM osms.it/erythema-nodosum PATHOLOGY & CAUSES ▪ Acute skin eruption due to inflammation in the subcutaneous adipose tissue ▫ Most common form of acute panniculitis ▪ Chronic or recurrent forms are rare but may occur ▪ Presumably caused by a delayed hypersensitivity type IV reaction to a variety of antigens



CAUSES



▪ 30–50% unknown etiology ▪ Infections: Streptococcus spp., M. tuberculosis complex, M. leprae, M. pneumoniae, Yersinia spp., Histoplasma capsulatum, Coccidioides immitis ▪ Autoimmune disorders: inflammatory bowel disease, sarcoidosis, Behçet’s disease, medium-vessel vasculitis ▪ Medications: sulfonamides, oral contraceptives, amiodarone



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▪ Malignancies: hematological malignancies, carcinoid tumours, pancreatic cancer



SIGNS & SYMPTOMS ▪ Pre-eruptive phase ▫ Fever, malaise, and arthralgia ▪ Eruptions of red, painful, poorly defined plaques and nodules, most commonly located on shins, knees, arms, thighs, and torso → skin lesions gradually get softer and smaller until they completely disappear over the course of about two weeks



DIAGNOSTIC IMAGING Chest X-ray ▪ Additional evaluation to determine the underlying cause



TREATMENT MEDICATIONS



▪ Potassium iodide, corticosteroids and colchicine can be used in severe refractory cases



OTHER INTERVENTIONS



▪ Address underlying cause ▪ Symptomatic management ▫ Bedrest, leg elevation, compressive bandages, wet dressings, and nonsteroidal anti-inflammatory agents



Figure 9.1 A single area of erythema nodosum.



DIAGNOSIS ▪ Observation of typical skin lesions



LAB RESULTS



▪ Biopsy in uncertain cases ▪ Additional evaluation to determine the underlying cause ▫ Complete blood count, erythrocyte sedimentation rate, antistreptolysin-O titer, throat culture, urinalysis, intradermal tuberculin test, venereal disease research laboratory (VDRL), and cultures, as appropriate



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Figure 9.2 Erythema nodosum affecting the shins; a common site for this disease.



Chapter 9 Urticaria & Erythema



HEREDITARY ANGIOEDEMA (HAE) osms.it/hereditary-angioedema PATHOLOGY & CAUSES ▪ Small but important number of all cases of angioedema ▫ Increased vasodilation and vascular permeability → fluid leakage from deep blood vessels → angioedema ▫ Urticaria and pruritus are not present



▪ Attacks begin during childhood and become increasingly frequent and severe ▪ Frequency of attacks differs greatly, varying from weekly episodes to intervals longer than a year; discrepancies can occur among different individuals and at different times in the same individual



CAUSES



▪ Inherited in an autosomal dominant manner involving mutation of genes associated with C1-inhibitor (C1INH) that inhibits the complement pathway and is associated with coagulation factor XII ▫ Results in unregulated levels of bradykinin and other vasoactive substances → inflammation, vasodilation, and cellular injury ▫ Attack triggers may include minor trauma, mood and temperature changes, but often no obvious inciting event can be established



SIGNS & SYMPTOMS ▪ Recurrent attacks of angioedema ▪ Painless, nonpruritic, nonpitting swelling of extremities, genitalia, buttocks, eyelids, lips, tongue, larynx or gastrointestinal tract ▫ Gastrointestinal tract → nausea, vomiting, intense colicky abdominal pain, diarrhea, dehydration, and intense exhaustion → mimics a surgical emergency and unnecessary surgery could be performed ▫ Larynx → life-threatening airway obstruction → without treatment, death by asphyxia occurs in about 25% ▪ Tightness, tingling, or erythema marginatum corresponding to the affected area may precede the swelling ▪ Each episode usually resolves within 72 hours



Figure 9.3 Angioedema of the lips.



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Imaging studies may be useful during attacks of gastrointestinal edema



LAB RESULTS



▪ Complement testing to assess alterations in the system



TREATMENT MEDICATIONS



▪ Management of attacks ▫ Intravenous C1-inhibitor concentrates, kallikrein inhibitors (ecallantide), bradykinin B2 receptor antagonists (icatibant) or, if those are unavailable, fresh-frozen plasma as an alternative



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▪ More than one episode in a month or high risk of developing laryngeal edema → longterm prevention ▫ Danazol (an androgen that increases levels of C4) ▫ C1-inhibitor concentrates



OTHER INTERVENTIONS ▪ Avoid specific stimuli that have previously led to attacks ▪ Avoid medications associated with attacks ▫ ACE inhibitors; medications containing estrogen



URTICARIA (HIVES) osms.it/urticaria PATHOLOGY & CAUSES ▪ Acute (< six weeks) or, rarely, chronic (> six weeks) skin eruption ▪ Acute form most common dermatologic disorder seen in emergency department ▫ Most often benign and self-limiting, though may rarely progress to lifethreatening angioedema or anaphylactic shock; strong tendency to recur ▪ Hypersensitivity reaction → mast cell degranulation and release of inflammatory mediators → increased vascular permeability → fluid leakage from superficial blood vessels → cutaneous lesion



TYPES



▪ Acute urticaria ▫ Single lesions usually last less than 24 hours ▪ Chronic urticaria ▫ May last six weeks or more



▪ Precipitants include psychological and physical stress, cold or hot temperature, pressure or vibration ▪ Physical urticaria is urticaria is induced by an exogenous physical stimulus such as scratching or firm stroking of the skin ▫ The most common type of physical urticaria is called a dermatographism



SIGNS & SYMPTOMS ▪ Wheals: skin eruption characterized by itchy, burning or stinging, red, raised plaques with well-defined erythematous margins and pale centers ▫ Individual lesions may coalesce ▫ New lesions may appear as others resolve ▪ Can occur anywhere, but common sites are areas exposed to pressure (e.g., trunk, distal extremities, ears)



CAUSES



▪ Assessment for potential causes includes “5 Is” ▫ Infection (bacterial/viral/fungal/parasitic) ▫ Injection of a drug/insect venom ▫ Inhaled substances (pollen, mold, dust) ▫ Ingestion of foods, drugs, chemicals ▫ Internal disease process such as an autoimmune disorder ▪ Vasculitis urticaria associated with autoimmune and malignant diseases



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Figure 9.4 Urticaria of the forearm.



Chapter 9 Urticaria & Erythema



DIAGNOSIS ▪ Typically based on appearance ▪ Patch testing to confirm and determine the allergy



LAB RESULTS



▪ Complete blood count ▪ Erythrocyte sedimentation rate ▪ Thyroid-stimulating hormone (rule out thyroid disease) ▪ Autoimmune screening



TREATMENT ▪ Avoid triggers ▪ Symptomatic management ▫ Antihistamines ▫ In severe cases, corticosteroids or leukotriene inhibitors ▫ Monoclonal antibodies and immunosuppressants may be used in refractory cases



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NOTES



NOTES



VESICULOBULLOUS DISEASES



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Chronic skin blistering diseases; associated with underlying autoimmune, genetic pathology ▪ Destruction/malfunction of structural, anchoring proteins of skin



SIGNS & SYMPTOMS ▪ Skin blistering ▪ Mucosal erosions pruritus



DIAGNOSIS LAB RESULTS



▪ Skin biopsy ▪ Immunofluorescence testing



TREATMENT MEDICATIONS ▪ Corticosteroids



OTHER INTERVENTIONS ▪ Lifestyle modifications



BULLOUS PEMPHIGOID osms.it/bullous-pemphigoid PATHOLOGY & CAUSES ▪ Autoimmune skin disease; bubble-like blisters ▫ Bulla- = blister, pemphig- = bubble, oid= similar ▪ Chronic, relapsing, remitting, autoimmune subepithelial blistering disease ▫ Epithelial lesions (unlike pemphigus vulgaris) ▫ Can affect mucous membranes ▪ Presents with cutaneous bullae, mucosal erosions ▪ Rare disease, most common autoimmune blistering disorder



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CAUSES



▪ Autoantibodies against hemidesmosomal proteins ▫ Bullous pemphigoid antigen 2 (BPAg2) ▫ Collagen type XVII ▪ Autoantibodies may develop in response to certain drugs/infections ▪ Autoantibody activation → abnormal IgG/complement deposition in basement membrane zone → separation of dermis, epidermis → inflammatory reaction → formation of blisters, inflammatory mucosal erosions



RISK FACTORS



▪ More common in individuals > 60 years



Chapter 10 Vesiculobullous Diseases



SIGNS & SYMPTOMS ▪ Trunk, skin folds, extremities most affected ▪ May exhibit prodromal phase ▫ Pruritic papular lesions, resemble eczema ▪ Oral, ocular mucositis ▪ Blisters with inflammatory/noninflammatory base ▪ Unlike pemphigus vulgaris, bullae tense, difficult to rupture → negative Nikolsky sign ▪ After rupture, scarring uncommon



TREATMENT MEDICATIONS



▪ Topical/systemic corticosteroids ▫ Decrease blister formation, promote blister healing, improve quality of life



DIAGNOSIS LAB RESULTS ▪ Histopathological studies (confirm) ▫ Skin biopsies, immunofluorescent staining techniques ▪ Complete blood count (CBC) ▫ Eosinophilia ▪ ↑ IgG antibodies



Figure 10.1 The histological appearance of the skin in a case of bullous pemphigoid. In contrast to pemphigus vulgaris, the bullae are subepithelial. The bullae contain an infiltrate of eosinophils.



EPIDERMOLYSIS BULLOSA osms.it/epidermolysis-bullosa PATHOLOGY & CAUSES ▪ Skin breakdown → blisters ▫ Epidermo- = skin, lysis- = breakdown, bullosa- = blistering ▪ Rare condition, inherited group of disorders; blisters, erosions after minor skin trauma due to fragility of epithelial tissue ▪ May also affect mucous membranes, nails



CAUSES



▪ Mutations in structural proteins of skin responsible for tissue integrity ▫ Keratin, desmosomes, cell junctions, intermediate filaments, etc. ▫ Presence of some or all → determine



disease severity, clinical presentation



RISK FACTORS



▪ Genetic inheritance



SIGNS & SYMPTOMS ▪ Localized/systemic ▪ Skin blistering following minor trauma/ friction ▪ Nail dystrophy, loss (common) ▪ Oral lesions



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DIAGNOSIS LAB RESULTS



▪ Skin biopsy ▪ Immunofluorescence testing



OTHER DIAGNOSTICS ▪ Family history



TREATMENT ▪ No specific therapy



OTHER INTERVENTIONS



Figure 10.2 The hands of an individual with epidermolysis bullosa. Numerous consecutive bullae have caused scarring and induration of the skin, leading to contractures.



▪ Symptomatic care, wound care, infection prophylaxis, pain management



PEMPHIGUS VULGARIS osms.it/pemphigus-vulgaris PATHOLOGY & CAUSES ▪ Autoimmune, life-threatening blistering disorders of skin, mucous membranes ▪ Epithelial lesions ▫ Unlike bullous pemphigoid, which presents with subepithelial lesions ▪ Acantholysis: defining mechanism (acanthus- = thorny, lysis- = breakdown) ▫ Impaired adhesion between cells in spinous layer of epidermis



CAUSES



▪ Autoantibodies against desmoglein ▪ Autoantibody activation → attack of adhesion molecules → breakdown of intercellular adhesion → inflammatory reaction → blister formation



RISK FACTORS



▪ Adults ▪ Jewish people of Middle Eastern origin



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SIGNS & SYMPTOMS ▪ Oral mucosa (most common); can affect all mucosal surfaces ▪ Nikolsky sign → blister ruptures with pressure/friction ▫ Unlike bullous pemphigoid, where blisters difficult to rupture ▪ Easily-eroding painful blisters over erythematous skin ▪ No pruritus



DIAGNOSIS LAB RESULTS



▪ Skin biopsy ▪ Immunofluorescent staining ▪ Serum antibodies



Chapter 10 Vesiculobullous Diseases



TREATMENT MEDICATIONS



▪ Systemic steroids ▪ Immunosuppressive agents



Figure 10.3 A histological section of the skin in a case of pemphigus vulgaris. There is intraepidermal bulla formation in the superficial epidermis and characteristic tombstoning of the dermoepidermal junction.



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NOTES



NOTES



ADRENAL HYPERFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Overproduction of ≥ one adrenal hormones → complex systemic disorders



CAUSES ▪ Pituitary/adrenal endocrine tumors ▪ Idiopathic, iatrogenic ▪ Increased aldosterone → hyperaldosteronism ▪ Increased cortisol → Cushing syndrome



SIGNS & SYMPTOMS



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Image tumors



LAB RESULTS ▪ Blood/urine tests; measure hormone levels



TREATMENT ▪ See individual disorders



▪ Diffuse systemic symptoms due to systemic endocrine effects



CONN'S SYNDROME osms.it/conns-syndrome PATHOLOGY & CAUSES ▪ Type of primary hyperaldosteronism



CAUSES ▪ Adrenal glands produce too much aldosterone due to benign tumor (adrenal adenoma) ▫ Forms in zona glomerulosa in adrenal gland



RISK FACTORS ▪ Individuals who are biologically female, 20–60 years old, with family history



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SIGNS & SYMPTOMS ▪ Headache, facial flushing (due to hypertension) ▪ Constipation, muscle weakness, arrhythmias (if severe, due to hypokalemia) ▫ Low potassium, high blood pressure (BP); unresponsive to treatment



Chapter 11 Adrenal Hyperfunction



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Abdominal CT scan to differentiate tumor from idiopathic hyperaldosteronism



LAB RESULTS ▪ Adrenal vein sampling (CT scans do not detect lesions < 1cm/0.39in)



TREATMENT SURGERY ▪ Unilateral adrenalectomy



Figure 11.1 The gross pathological appearance of an adrenal cortical adenoma in an individual with Conn’s syndrome.



CUSHING'S SYNDROME osms.it/cushings-syndrome PATHOLOGY & CAUSES ▪ Endocrine disorder caused by increased cortisol ▪ Can be endogenous (caused by cortisol production inside body)/exogenous (iatrogenic) ▪ Pseudo Cushing’s syndrome: estrogencontaining oral contraceptive pills → increased cortisol-binding globulin → increased total cortisol ▫ Active hormone total free cortisol levels found in a 24-hour urine sample normal



CAUSES Primary ▪ Tumor in zona fasciculata of adrenal gland secretes cortisol ▪ Adenoma (benign)/adenocarcinoma (malignant) Secondary ▪ Iatrogenic



▫ Glucocorticoid steroid medications to treat inflammatory, autoimmune disorders (e.g. asthma, rheumatoid arthritis, eczema, immunosuppression); most common ▪ Pituitary adenoma (benign) ▫ Leads to excess adrenocorticotropic hormone (ACTH), adrenal cortisol secretion ▪ Adrenal Cushing’s disease ▫ Adrenal gland tumors/hyperplastic adrenal glands/nodular adrenal hyperplasia of adrenal glands produce excess cortisol ▪ Ectopic ACTH ▫ Increased ACTH secreted from benign bronchial carcinoid tumors/malignant oat-cell carcinoma



COMPLICATIONS ▪ Metabolic syndrome, diabetes, infection due to immunosuppression, fragility fractures due to osteoporosis



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SIGNS & SYMPTOMS ▪ Fat redistribution due to glucose release → insulin release ▪ Muscle, bone, skin breakdown due to protein breakdown ▪ Hypertension due to corticosteroids crossreacting with mineralocorticoid receptors ▪ High cortisol → feedback inhibition of GH-releasing hormone (GRH) → disrupts ovarian, testicular function



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Adrenal glands (primary Cushing’s) ▪ Chest, abdomen, pelvis (ectopic ACTH production) MRI ▪ Pituitary gland (Cushing’s disease)



LAB RESULTS ▪ ↑ free cortisol in 24-hour urine sample ▪ Cortisol blood/saliva test: ↑ cortisol ▫ Performed in evening when cortisol levels are normally low



OTHER DIAGNOSTICS



Figure 11.2 Abdominal striae in an individual with Cushing’s syndrome.



MNEMONIC: BAM CUSHINGOID



Signs & symptoms of Cushing’s syndrome Buffalo hump: fat redistribution Amenorrhea Moon face: fat redistribution Psychosis/agitation: previously, Crazed Ulcers Skin changes: acne, purple striae/stretch marks Hypertension Infection: due to immunosuppression Necrosis of femoral head Glaucoma Osteoporosis: causing fragility fractures Immunosuppression Diabetes



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Dexamethasone suppression test ▪ Differentiates endogenous, exogenous Cushing’s syndrome ▪ Measure cortisol change after dexamethasone (exogenous steroid) ▪ Endogenous Cushing’s syndrome: cortisol unchanged, negative feedback cycle broken by autonomous endocrine tumor in pituitary, adrenal, etc. (ectopic ACTH) ▪ Positive dexamethasone test ▫ High ACTH: ACTH-producing tumor ▫ Low ACTH: adrenal tumor, causing pituitary ACTH suppression Long dexamethasone suppression test ▪ If high ACTH ▪ Differentiates ACTH-producing pituitary tumor, ectopic ACTH-producing tumor (e.g. small cell lung cancer) ▫ Cushing’s disease (pituitary adenoma): cells partly responsive to negative feedback → cortisol decrease ▫ Ectopic ACTH-producing tumor: no negative feedback → cortisol unchanged



Chapter 11 Adrenal Hyperfunction



TREATMENT MEDICATIONS ▪ Cortisol inhibitors ▫ Esp. if surgery ruled out by ectopic ACTH production/metastatic adrenal carcinoma ▪ Wean steroid medications ▫ For Iatrogenic Cushing’s ▫ Sudden withdrawal → adrenal crisis



SURGERY ▪ Transphenoidal resection of pituitary gland ▫ For Cushing disease ▪ Surgical resection ▫ For adrenal adenoma



Figure 11.3 A large fat deposit at the upper back in an individual with Cushing’s syndrome.



HYPERALDOSTERONISM osms.it/hyperaldosteronism PATHOLOGY & CAUSES ▪ Adrenal gland produces excess aldosterone → hypertension (high blood pressure), hypokalemia (decreased blood potassium) ▪ Increased aldosterone → sodium, water retention → increased blood volume → hypertension



TYPES Primary ▪ Idiopathic (2/3 of cases): overproduction from both adrenal glands ▪ Conn’s syndrome (1/3 of cases): benign adrenal tumor → excess aldosterone ▪ Familial hyperaldosteronism: rare genetic condition, adrenocorticotropic hormone (ACTH) → adrenal aldosterone, renin secretion



angiotensin-aldosterone axis activation → hyperaldosteronism ▪ Decreased blood flow to kidneys (e.g. renal stenosis) ▪ Renal-secreting neoplasms



COMPLICATIONS ▪ Hypertension, hypokalemia ▫ Heart disease (ischemic heart disease, arrhythmias), vascular disease, renal disease, stroke, alkalosis (due to increased hydrogen ion excretion)



SIGNS & SYMPTOMS ▪ Headache, facial flushing (due to hypertension) ▪ Constipation, muscle weakness, arrhythmias (if severe, due to hypokalemia)



Secondary ▪ Hypotension (e.g. congestive heart failure, cor pulmonale, hypoalbuminemia, cirrhosis, ascites, coarctation of aorta) → renin-



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DIAGNOSIS LAB RESULTS ▪ Renin, aldosterone levels in blood and urine ▪ Primary ▫ Increased aldosterone, decreased renin; potassium decreased/normal ▫ Metabolic acidosis secondary to hypokalemia ▪ Secondary ▫ Increased renin, aldosterone in blood



OTHER DIAGNOSTICS ▪ Increased blood pressure



TREATMENT ▪ Goal: prevent complications of hyperaldosteronism on organs (e.g. ventricular hypertrophy, heart failure, stroke, myocardial infarction, atrial fibrillation, metabolic syndrome)



MEDICATIONS ▪ Potassium-sparing diuretic/aldosterone antagonist ▫ Spironolactone ▪ Additionally ▫ Thiazide diuretics, angiotensin converting enzyme inhibitors (ACE) inhibitors, calcium channel antagonists, angiotensin II blockers



OTHER INTERVENTIONS ▪ Control BP via lifestyle ▫ Sodium restriction, weight management, regular exercise ▪ Second-line ▫ Thiazide diuretics, ACE inhibitors, calcium channel antagonists, angiotensin II blockers



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NOTES



ADRENAL HYPERPLASIA



CONGENITAL ADRENAL HYPERPLASIA osms.it/congenital-adrenal-hyperplasia PATHOLOGY & CAUSES ▪ Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive metabolic disorders characterized by defects in certain genes resulting in a partial/total lack of an enzyme involved in steroidogenesis within the adrenal cortex ▫ ↓ steroid hormone production → compensatory ↑ ACTH → adrenal hyperplasia ▫ ↓ cortisol → cortisol precursor accumulation → steroid precursors shunted to overproduction of other ACTH-dependent adrenal steroids



TYPES 21-hydroxylase deficiency ▪ Defective gene: CYP21A2 ▪ Most common type of CAH ▫ Classic: neonatal/early infancy genital ambiguity in females, adrenal insufficiency; classic non-salt-losing (simple virilizing): female fetus virilization; classic salt-losing ▫ Non-classic (late onset): presents later in life (child-adult) with androgen excess signs; non-salt-losing 17-alpha hydroxylase deficiency ▪ Defective gene: CYP17A1 ▪ Rare ▪ Steroid precursors for testosterone, cortisol synthesis shunted to aldosterone



11-beta-hydroxylase deficiency ▪ Defective gene: CYP11B1 ▪ 7% of CAH cases ▪ Lack of enzyme prevents conversion of 11-deoxycortisol to cortisol ▪ 11-deoxycortisol (aldosterone precursor) has mild mineralocorticoid effect → biphasic effect on mineralocorticoid balance



SIGNS & SYMPTOMS 21-hydroxylase deficiency ▪ Varies by subtype 17-alpha hydroxylase deficiency ▪ ↓ cortisol → corticosterone presence prevents adrenal crisis ▪ Mineralocorticoid excess → secondary hypertension; hypokalemic alkalosis ▪ Gonadocorticoid deficiency (males: mildly underdeveloped genitalia, hypergonadotropic hypogonadism; females: abnormal pubertal sexual development, infertility) 11-beta-hydroxylase deficiency ▪ Androgen excess → external genitalia virilization, sexual ambiguity (females) ▪ Biphasic mineralocorticoid balance → possible salt-wasting crisis in early infancy; secondary hypertension and hypokalemia in childhood and adult life



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TREATMENT MEDICATIONS



Figure 12.1 Clitoromegaly with normal labia and introitus in a biologically female individual with 21-hydroxylase deficiency.



DIAGNOSIS ▪ Clinical presentation ▫ Steroid imbalance evidence ▪ Most cases identified via newborn screening



SURGERY



LAB RESULTS



▪ Address complications (e.g., fluid, electrolyte imbalance) ▪ Monitor ▫ Serum 17-hydroxyprogesterone, renin, electrolytes ▫ Blood pressure ▫ Bone age and density ▫ Tanner staging ▫ Weight ▫ Growth velocity



Serum hormone levels ▪ 21-hydroxylase deficiency ▫ ↓ sodium (salt-losing type), ↑ potassium (salt-losing type) ▫ Serum markers: ↑↑ serum 17-hydroxyprogesterone, ↑ 21-deoxycortisol) ▪ 17-alpha hydroxylase deficiency ▫ ↑ sodium, ↓ potassium ▫ Serum markers: ↑ pregnenolone, ↑ progesterone, ↑ 11-deoxycorticosterone, ↑ 11-deoxycortisol ▪ 11-beta-hydroxylase deficiency ▫ ↑ sodium, ↓ potassium ▫ Serum markers: ↑ 11-deoxycorticosterone, ↑ 11-deoxycortisol) Genetic testing Prenatal diagnosis ▪ By chorionic villus sampling at 10–12 weeks



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▪ 21-hydroxylase deficiency ▫ Exogenous glucocorticoid (hydrocortisone), mineralocorticoid (fludrocortisone) ▪ 11-beta-hydroxylase deficiency ▫ Exogenous glucocorticoid (hydrocortisone), antihypertensives ▪ 17-alpha hydroxylase deficiency ▫ Exogenous glucocorticoid (hydrocortisone), sex steroid replacement beginning at puberty, antihypertensives ▪ If CAH diagnosed prenatally ▫ Dexamethasone



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▪ Potential atypical genitalia correction



OTHER INTERVENTIONS



Chapter 12 Adrenal Hyperplasia



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NOTES



ADRENAL HYPOFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders of adrenal cortex resulting in loss of essential steroid hormones (corticosteroids, mineralocorticoids, androgens)



CAUSES



▪ Addison’s disease ▫ Multiple causes; primarily autoimmune ▪ Waterhouse–Friderichsen syndrome (WFS) ▫ Primarily caused by meningococcal infection, sepsis



COMPLICATIONS



▪ Adrenal crisis ▫ Addison’s, WFS ▪ Disseminated intravascular coagulation ▫ WFS



SIGNS & SYMPTOMS ▪ Hypoglycemia, hypotension, electrolyte imbalance ▪ Adrenal crisis: dehydration, electrolyte imbalance, shock



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DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, CT scan ▪ Visualizes enlarged, calcified, solid/ hemorrhagic glands



OTHER DIAGNOSTICS



▪ Rapid adrenocorticotropic hormone (ACTH) test confirms adrenal hypofunction



TREATMENT MEDICATIONS



▪ Hormone replacement: hydrocortisone, fludrocortisone ▫ Dehydroepiandrosterone (DHEA) in some cases



OTHER INTERVENTIONS ▪ Treat underlying cause



Chapter 13 Adrenal Hypofunction



ADDISON'S DISEASE osms.it/addisons-disease PATHOLOGY & CAUSES ▪ Endocrine disorder characterized by primary adrenal insufficiency due to bilateral adrenal cortex destruction ▪ Adrenal cortex destruction → ↓ production of adrenocortical hormones → glucocorticoid, mineralocorticoid, androgen deficiency ▫ Adrenals only source of androgens in biologically-female individuals; testicles supply androgens in biologically-male individuals ▪ ↓ cortisol → ↓ adrenal medullary epinephrine synthesis → ↓ serum epinephrine, compensatory norepinephrine production



CAUSES



▪ Autoimmune destruction (e.g. polyglandular autoimmune syndrome type 2) ▪ Infection (e.g. tuberculosis, fungal infections) ▪ Adrenal hemorrhage (e.g. WFS) ▪ Adrenal vein thrombotic infarction ▪ Metastatic infiltration ▪ Drugs that inhibit cortisol biosynthesis (e.g. ketoconazole, suramin)



norepinephrine ▪ Hyponatremia ▫ Mineralocorticoid deficiency → sodium loss + ↓ volume due to ↑ vasopressin secretion secondary to ↓ cortisol ▪ Hyperkalemia, mild hyperchloremic acidosis due to mineralocorticoid deficiency ▪ Hypoglycemia due to ↓ gluconeogenesis ▪ Gastrointestinal ▫ Abdominal pain, anorexia, nausea, vomiting → weight loss ▪ Intolerance of temperature extremes ▪ Hyperpigmentation due to ACTH stimulation of melanocyte activity ▪ Vitiligo due to autoimmune destruction of melanocytes ▪ Salt cravings due to hyponatremia ▪ ↓ libido, ↓ pubic, axillary hair in biologicallyfemale individuals due to ↓ adrenal androgens ▪ Psychiatric symptoms (e.g. confusion, depression) ▪ Addisonian crisis triggered by stress ▫ Hypoglycemia ▫ Vasomotor/circulatory collapse; shock may be unresponsive to vasopressors due to ↓↓ cortisol, potentially fatal



COMPLICATIONS



▪ Addisonian crisis precipitated by physiologically stressful events (e.g. surgical procedures, trauma, infection, dehydration)



SIGNS & SYMPTOMS ▪ Fatigue, weakness are common initial symptoms ▪ Hypotension, postural hypotension, syncope ▫ ↓ glucocorticoids → ↓ vascular responsiveness to angiotensin II and



Figure 13.1 An example of increased skin pigmentation in an individual with Addison’s disease (left) and resolution post-treatment (right).



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▪ ↑ serum ACTH ▪ Plasma renin activity ▫ ↑ renin, compensatory to ↓ aldosterone ▪ ↓ serum sodium, ↑ serum potassium, mild hyperchloremic acidosis



OTHER DIAGNOSTICS



Figure 13.2 Hyperpigmentation of the gums in an individual with Addison’s disease.



DIAGNOSIS DIAGNOSTIC IMAGING Abdominal CT scan ▪ Enlarged adrenal glands with tuberculosis/ malignant mass; small if autoimmune adrenalitis/advanced tuberculosis; calcifications if infectious cause ▪ Visualizes adrenal gland hemorrhage/ thrombosis Abdominal X-ray ▪ Adrenal calcifications if infectious cause



LAB RESULTS



▪ ↓ serum cortisol ▫ Blood draw in AM when cortisol levels should peak



▪ History, physical examination with characteristic findings ▪ Rapid ACTH test ▫ Administer 250µg synthetic ACTH (cosyntropin) intravenous (IV)/ intramuscular (IM) → insufficient/no cortisol produced in response



TREATMENT MEDICATIONS



▪ Life-long glucocorticoid replacement; e.g. hydrocortisone, mineralocorticoid replacement ▫ E.g. fludrocortisone ▪ Biologically-female individuals may need low dose dehydroepiandrosterone (DHEA) ▪ Addisonian crisis ▫ Glucocorticoids, epinephrine, glucose, isotonic fluids ▪ Stress dose of glucocorticoid during any surgical intervention/significant trauma ▫ Premedication/induction-maintenancegradual titration to baseline dose



WATERHOUSE–FRIDERICHSEN SYNDROME osms.it/waterhouse-friderichsen PATHOLOGY & CAUSES ▪ Uncommon, severe syndrome characterized by adrenal failure related to overwhelming infection, adrenal gland hemorrhage



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▪ Bacterial infection → septicemia → release of bacterial endotoxins → endothelial dysfunction → seeding of bacterial emboli into adrenals → bleeding into one/both



Chapter 13 Adrenal Hypofunction adrenal glands → hemorrhagic necrosis → adrenocortical insufficiency → adrenal crisis



CAUSES



▪ Associated with sepsis caused by organisms (e.g. Neisseria meningitidis (80% of cases), Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae, Staphylococcus aureus)



COMPLICATIONS



▪ Disseminated intravascular coagulation (DIC) ▪ Profound shock ▪ Potentially life-threatening



SIGNS & SYMPTOMS ▪ Initial presentation: malaise, fever, chills, headache, vomiting ▪ Signs of shock (e.g. hypotension, tachycardia, tachypnea) ▪ Widespread petechial lesions → purpura → plaques ▪ Cyanosis, AKA dusky gray color of skin



DIAGNOSIS



OTHER DIAGNOSTICS



▪ History, physical examination with characteristic findings ▪ Rapid ACTH test ▫ Insufficient/no cortisol produced indicates adrenal insufficiency



TREATMENT MEDICATIONS ▪ Adrenal insufficiency ▫ IV glucocorticoids ▪ Infection ▫ Antibiotics (e.g. IV penicillin, cefotaxime/ ceftriaxone if meningococcal infection) ▪ Shock ▫ IV fluids, vasopressors, supplemental oxygen ▪ DIC ▫ Packed red blood cells (RBCs), cryoprecipitate, fresh frozen plasma, platelets



OTHER INTERVENTIONS



▪ Prevention ▫ Routine vaccination against meningococcal disease



DIAGNOSTIC IMAGING CT scan ▪ Identifies blood collection within adrenals Ultrasound ▪ Adrenal hemorrhage appears solid, diffusely echogenic



LAB RESULTS



▪ Blood culture ▫ Identifies causative organism ▪ Adrenal insufficiency ▫ ↓ serum sodium, ↓ glucose, ↑ potassium, ↓ serum cortisol ▪ DIC ▫ ↑ fibrinogen degradation products, ↑ D-dimer levels, prolonged PT, aPTT



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NOTES



NOTES



DIABETES MELLITUS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ A group of chronic disorders characterized by abnormal glucose metabolism resulting in elevated blood glucose levels



CAUSES



▪ Genetic predisposition, lifestyle factors



COMPLICATIONS



▪ Hyper/hypoglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS), vascular and neurological pathology, renal disease



SIGNS & SYMPTOMS ▪ Symptomatic hyperglycemia



DIAGNOSIS LAB RESULTS Urinalysis ▪ Albuminuria, glycosuria Blood tests ▪ ↑ Non-fasting/fasting glucose tests ▪ ↑ HbA1c ▪ Diabetic ketoacidosis (DKA) ▫ Glucose > 250mg/dL ▪ Hyperosmolar hyperglycemic state (HHS) ▫ Glucose >600mg/dL



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OTHER DIAGNOSTICS Physical examination ▪ Fundoscopic exam ▫ Cotton wools spots, flare hemorrhages ▪ Monofilament testing ▫ ↓ sensation ▪ Lower extremities ▫ ↓ pedal pulses, presence of ulcers



TREATMENT MEDICATIONS



▪ Diabetes mellitus type I ▫ Insulin ▪ Diabetes mellitus type II ▫ Oral antidiabetic agents, insulin



OTHER INTERVENTIONS



▪ Metabolism regulation with diet ▪ Weight loss, exercise ▪ Smoking cessation



Chapter 14 Diabetes Mellitus



DIABETES MELLITUS TYPE 1 osms.it/diabetes-mellitus-type-1 PATHOLOGY & CAUSES ▪ Chronic metabolic disease; destroys pancreatic beta cells → insulin deficiency, hyperglycemia ▪ Diabetes (going through) mellitus (honey/ sweet) ▪ ↓ insulin → glucose unable to enter cells → hyperglycemia ▫ Cells “starve” due to no glucose for energy generation → polyphagia, fatigue ▫ Glucose exceeds renal threshold → glycosuria → osmotic diuresis → polyuria → hypovolemia ▫ ↑ serum osmolality + hypovolemia → polydipsia ▫ Endothelial glycosylation (endothelial cells unable to downregulate glucose transport in setting of extracellular hyperglycemia) → damage to endothelial cells → microvascular damage + accelerated atherosclerosis in large vessels ▫ Narrowing of vascular lumens → ↓ microcirculation → tissue ischemia, cellular loss ▫ ↓ blood supply to nerves → segmental demyelination → slowing of nerve conduction neuropathy



Latent autoimmune diabetes ▪ Progressive form of autoimmune diabetes ▪ Onset at > 30 years old



RISK FACTORS



▪ Genetic predisposition ▪ Multiple gene polymorphisms associated with DM Type I ▫ HLA-DQalpha, HLA-DQbeta, HLA-DR, PTPN22 gene, CTLA-4



COMPLICATIONS



▪ ↑ risk of infection, delayed wound healing; ↑ risk of amputations ▪ Diabetic ketoacidosis ▫ Hyperglycemia (> 250mg/dL), ketonemia, metabolic acidosis ▪ Neuropathy ▫ Autonomic, somatic



Microvascular ▪ Retinopathy, nephropathy, erectile dysfunction Macrovascular ▪ Cardiovascular, cerebrovascular, and peripheral vascular disease



TYPES Type IA: immune-mediated diabetes ▪ Most common ▪ Autoimmune destruction of pancreatic beta-cells ▪ Type IV hypersensitivity response Type IB: idiopathic diabetes ▪ No evidence of autoimmunity ▪ Varying degrees of low insulin, episodes of ketoacidosis



Figure 14.1 A retinal photograph of an individual who has received laser treatment for proliferative retinopathy as a consequence of diabetes mellitus.



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DIAGNOSIS LAB RESULTS Non-fasting/random glucose test ▪ 200mg/dL Fasting glucose test ▪ Prediabetes: 110–125mg/dL ▪ Diabetes: ≥ 126mg/dL HbA1c glycated hemoglobin test ▪ Indicates glucose level control over prolonged period ▪ Prediabetes: 5.7–6.4% HbA1c ▪ Diabetes: > 6.5% HbA1c Urinalysis ▪ Albuminuria, glycosuria



Figure 14.2 An individual with diabetes mellitus and charcot arthropathy of the left ankle. Lack of sensation to the joint causes results in repetitive microtrauma which eventually leads to bony destruction and joint malformation.



SIGNS & SYMPTOMS ▪ Classic presentation: polyuria, polydipsia, polyphagia (3Ps) ▫ Dehydration → dry mucous membranes/ decreased skin turgor ▪ Fatigue, lethargy ▪ Blurred vision ▪ Gastroparesis → constipation ▪ Paresthesias ▪ Unexplained weight loss ▪ Mild hyperglycemia, may be asymptomatic ▪ Volume depletion: symptomatic moderate to severe hyperglycemia ▫ Dry mucous membranes, hypotension, poor skin turgor



Differentiation from Type II diabetes ▪ Autoantibodies against beta cells: glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated-2 autoantibodies (IA-2A), islet cell autoantibodies, insulin autoantibodies (IAA), zinc transporter 8 (ZnT8Ab) ▪ C-peptide: insulin low



OTHER DIAGNOSTICS Physical examination ▪ Fundoscopic exam: cotton wools spots, flare hemorrhages ▪ Monofilament testing: ↓ sensation ▪ Lower extremities: ↓ pedal pulses, presence of ulcers



Figure 14.3 A neuropathic ulcer on the heel of an individual with diabetes mellitus.



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Chapter 14 Diabetes Mellitus



TREATMENT MEDICATIONS



▪ Lifelong insulin therapy (short-acting insulin/insulin pump)



Figure 14.4 The histological appearance of a glomerulus in an individual with diabetes mellitus. The glomerular basement membrane is thickened and there is mesangial proliferation leading to the appearance of a Kimmelstiel–Wilson nodule.



DIABETES MELLITUS TYPE II osms.it/diabetes-mellitus-type-2 PATHOLOGY & CAUSES ▪ Metabolic disorder; varying degrees of resistance to insulin ▪ Most common type of diabetes in adults (90–95%)



CAUSES



▪ Insulin resistance (inherited, acquired) → beta cell hyperplasia, hypertrophy → ↑ beta cell secretion of insulin + amylin production → hyperinsulinemia, amyloid deposits within beta cells → beta cell exhaustion, dysfunction, atrophy → ↓ insulin production → hyperglycemia ▪ Genetic polymorphisms associated with DM Type II ▫ TCF7L2, GCK, HNF1B, WFS1, KCNJ11, PPARG, IRS1



▪ Family history, physical inactivity, poor diet, obesity, > 45 years old, history of gestational diabetes, prediabetes, polycystic ovary syndrome (PCOS), medications that adversely affect glucose tolerance/↑ blood glucose levels (e.g. glucocorticoids, atypical antipsychotics, thiazide diuretics)



COMPLICATIONS



▪ ↑ risk of cardiovascular, peripheral artery disease



Hyperosmolar hyperglycemic state (HHS) ▪ Profound hyperglycemia (>600mg/dL) → ↑ plasma osmolarity (>320mOsm/kg) → systemic, cellular dehydration ▪ Mental status changes; thrombotic events; polyuria; mild ketonemia, acidosis; high mortality rate



RISK FACTORS



▪ Multifactorial; interaction between genetic, environmental, behavioral factors



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SIGNS & SYMPTOMS ▪ Polyuria, polydipsia, polyphagia; glycosuria, weakness, unexplained weight loss, blurred vision; acanthosis nigricans (hyperpigmented cutaneous patches) related to insulin resistance



DIAGNOSIS LAB RESULTS Non-fasting/random glucose test ▪ 200mg/dl Fasting glucose test ▪ Prediabetes: 110–125mg/dl ▪ Diabetes: 126mg/dl Oral glucose tolerance test ▪ Prediabetes: 99–140mg/dl ▪ Diabetes: ≥ 200 HbA1c glycated hemoglobin ▪ Prediabetes: 5.7–6.4% ▪ Diabetes: > 6.5%



Differentiation from Type I ▪ Autoantibodies ▫ Absent ▪ C peptide ▫ Normal/elevated



OTHER DIAGNOSTICS Physical examination ▪ Fundoscopic exam: cotton wool spots, flare hemorrhages ▪ Monofilament testing: ↓ sensation ▪ Lower extremities: ↓ pedal pulses, presence of ulcers



TREATMENT MEDICATIONS



▪ Metformin; sulfonylureas, meglitinides ▪ Long/short-acting insulin



OTHER INTERVENTIONS



▪ Weight loss, exercise, diet management



DIABETIC KETOACIDOSIS osms.it/diabetic-ketoacidosis PATHOLOGY & CAUSES ▪ Medical emergency due to cell starvation → altered mental status ▪ Arises with stress/infection, individuals with poorly regulated glucose levels ▪ Epinephrine → glucagon → lipolysis → free fatty acids → ketone bodies, acetoacetic, hydroxybutyric acid → ↑ blood acidity ▪ Occurs in Type I, long-standing Type II DM when body completely stops producing insulin



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COMPLICATIONS



▪ Acute cerebral edema ▫ High glucose → osmotic shift of water to extracellular fluid ▪ Hyperkalemia due to H+/K+ exchange mechanisms in regulating acidosis → arrhythmias



RISK FACTORS



▪ Infection, stress, irregular insulin use



Chapter 14 Diabetes Mellitus



SIGNS & SYMPTOMS ▪ Anion gap metabolic acidosis, bicarbonate low → insulin stops letting potassium into cells, potassium acts as buffer by letting hydrogen into cells → hyperkalemia → ultimately lost in urine ▪ Dehydration (individual extremely thirsty), nausea, vomiting, mental status change ▪ Kussmaul respiration ▫ Deep, labored breathing to move carbon dioxide out of blood ▪ Acetone breath ▫ Ketone bodies break down into acetone → excrete as gas through lungs



DIAGNOSIS LAB RESULTS



▪ Hyperkalemia (> 5.2mg/dl), initially with hypokalemia (< 3.5mg/dl) ▪ Glucose > 250mg/dL



TREATMENT MEDICATIONS Insulin ▪ Lower blood glucose ▪ Monitor carefully ▫ Rapid decrease in serum glucose → osmotic shift of water intracellularly → risk for cerebral edema → increased ICP ▪ Treat cerebral edema with hypertonic solution (3% saline, mannitol) Fluid, electrolyte replacement ▪ 0.9% normal saline + potassium (KCl); serum K+ levels drop as insulin shifts potassium intracellularly → risk for hypokalemia ▪ Bicarbonates ▫ Reverse acidosis



OTHER INTERVENTIONS ▪ Fluids, rehydration



Acid base status ▪ Ketones present in urine; arterial gas, bicarbonates measured; pH < 7.3



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NOTES



ENDOCRINE TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Tumors arising from endocrine gland tissue ▪ May be functional (excess secretion of one/ more hormones); nonfunctional (clinically silent)



LAB RESULTS



▪ Measure hypersecretion degree



OTHER DIAGNOSTICS



▪ History, physical examination with characteristic findings



TREATMENT



SIGNS & SYMPTOMS ▪ Depends on degree of hypersecretion, mass effect



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Tumor visualization, staging



MEDICATIONS



▪ Chemotherapy ▪ Hormone replacement/suppression



SURGERY ▪ Resection



OTHER INTERVENTIONS ▪ Radiation therapy ▪ Address complications



ADRENAL CORTICAL CARCINOMA osms.it/adrenal-cortical-carcinoma PATHOLOGY & CAUSES ▪ Rare, malignant adrenal cortex tumor ▪ Usually functional, with excess hormone secretion ▫ Glucocorticoids → Cushing’s syndrome ▫ Androgens → virilization (biologicallyfemale individuals), feminization (biologically-male individuals) ▫ Aldosterone (rare) → hyperkalemia



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RISK FACTORS



▪ Biologically female ▪ Bimodal distribution: ages 0–5, 40–50 ▫ Adults: more aggressive ▪ Associated with hereditary cancer syndromes (e.g. MEN1, Li–Fraumeni syndrome)



COMPLICATIONS



▪ Metastasis (renal vein, para-aortic nodes, lungs), diabetes



Chapter 15 Endocrine Tumors



SIGNS & SYMPTOMS ▪ Rapidly progressing hypercortisolism signs ▫ ↑ weight, muscle wasting, fat redistribution, skin atrophy ▪ Hyperandrogenism ▫ Female: hirsutism, male-pattern baldness, oligomenorrhea ▫ Male: gynecomastia, testicular atrophy, erectile dysfunction ▪ Mass effect ▫ Abdominal, flank pain; nausea; vomiting



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Usually unilateral, irregular shape, heterogeneous; presence of necrosis, calcification; tumor staging (local invasion/ distant metastases)



LAB RESULTS



▪ Measure hypersecretion degree ▫ Fasting blood glucose, potassium, basal cortisol, corticotropin (ACTH), 24-hour urinary free cortisol, sex hormones (e.g. dehydroepiandrosterone, androstenedione, testosterone, 17-hydroxyprogesterone, 17-betaestradiol)



TREATMENT MEDICATIONS ▪ Chemotherapy



SURGERY ▪ Resection



OTHER INTERVENTIONS ▪ Radiation therapy



PITUITARY ADENOMA osms.it/pituitary-adenoma PATHOLOGY & CAUSES ▪ Benign anterior pituitary tumor arising from specific cell types ▫ Eventual normal pituitary tissue destruction → hypopituitarism ▪ Associated with genetic mutations ▫ Loss-of-function mutations (MEN1) ▫ Activating mutation in guanine nucleotide stimulatory protein (Gsalpha) ▫ Overexpression of pituitary tumor transforming gene (PTTG) ▫ Expression of truncated form of fibroblast growth factor receptor (FGF4) ▪ Monoclonal tumor formation → adjacent structure compression (e.g. meninges,



optic nerve/chiasm) + specific hormone hypersecretion Classification ▪ Microadenoma: < 1cm/0.4in ▪ Macroadenoma: > 1cm/0.4in ▪ Functional, non-functional



TYPES



▪ Gonadotroph adenomas usually nonsecreting/may cause hypogonadism ▪ Prolactinomas → hyperprolactinemia, galactorrhea, hypogonadism ▫ Lactotroph/somatotroph adenoma (rare plurihormonal adenomas) secrete prolactin, growth hormone (GH) ▪ Somatotroph adenomas secrete GH → acromegaly (adults); gigantism (children) ▪ Corticotropin (adrenocorticotropic hormone



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[ACTH])-secreting adenomas → Cushing’s syndrome ▪ Thyrotropin-secreting tumors → hyperthyroidism



RISK FACTORS



▪ Genetic predisposition, sporadic development



SURGERY



▪ Transsphenoidal tumor resection ▪ Stereotactic radiosurgery (gamma knife)



OTHER INTERVENTIONS ▪ Radiation therapy



COMPLICATIONS



▪ Mass effect, pituitary apoplexy (hemorrhage into pituitary), sella turcica erosion, hormone-related disease development (e.g. Cushing syndrome), panhypopituitarism



SIGNS & SYMPTOMS ▪ Adjacent structure compression ▫ Visual changes (e.g. diplopia, bitemporal hemianopsia), headache



DIAGNOSIS DIAGNOSTIC IMAGING



Figure 15.1 An MRI scan of the head in the sagittal plane demonstrating a large pituitary adenoma.



Gadolinium-enhanced MRI ▪ Delineates tumor boundary; proximity to optic chiasm, cavernous sinus; tumor consistency; hemorrhage/cystic lesion presence ▫ T1-weighted: hypointense ▫ T2-weighted: hyperintense



LAB RESULTS



▪ Pituitary hormone hyper-/hyposecretion



TREATMENT MEDICATIONS



▪ Replacement hormones (e.g. hydrocortisone, synthroid for hypopituitarism) ▪ Hormone suppression (e.g. somatostatin analogs for GH-secreting hormones; dopamine agonists for lactotrophs)



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Figure 15.2 The histological appearance of a pituitary adenoma. The finely granular eosinophilic cytoplasm seen here is characteristic of a growth hormone producing adenoma. The lobular architecture of normal pituitary tissue is lost.



Chapter 15 Endocrine Tumors



PROLACTINOMA osms.it/prolactinoma PATHOLOGY & CAUSES



DIAGNOSIS



▪ Functional, usually benign lactotroph cell tumor in anterior pituitary → prolactin (PL) secretion, prolactinemia ▫ Rarely: tumors arise from both lactotroph, somatotroph cells → secrete growth hormone (GH), and PL ▫ Malignant pituitary PRL-secreting carcinomas (rare) ▪ Monoclonal tumor formation → adjacent structure compression (e.g. meninges, optic nerve/chiasm) + prolactin hypersecretion → milk production stimulation; secondary gonadal function effects



DIAGNOSTIC IMAGING



Classification ▪ Microadenoma: < 1cm/0.4in ▪ Macroadenoma: > 1cm/0.4in



MEDICATIONS



RISK FACTORS



▪ Biologically female ▪ Peak incidence during childbearing years ▪ May be associated with MEN1



COMPLICATIONS



Gadolinium-enhanced MRI ▪ Delineates tumor boundary; proximity to optic chiasm, cavernous sinus; tumor consistency; hemorrhage/cystic lesion presence



LAB RESULTS



▪ ↑ serum prolactin



TREATMENT ▪ Dopamine agonists



SURGERY



▪ Transsphenoidal resection ▪ Stereotactic radiosurgery (gamma knife)



OTHER INTERVENTIONS ▪ Radiation therapy



▪ Hypothalamic-pituitary stalk compression → hypopituitarism ▪ Gonadal steroidogenesis impairment → infertility ▪ Hypogonadism-induced ↓ bone-mineral density → osteoporosis (biologically-female individuals) ▪ Male/female infertility



SIGNS & SYMPTOMS ▪ Microprolactinomas may be asymptomatic ▪ Biologically-female individuals: galactorrhea, amenorrhea, vaginal dryness ▪ Biologically-male individuals: gynecomastia, erectile dysfunction ▪ Mass effects → visual problems, headaches



Figure 15.3 The histological appearance of a prolactinoma. The cells have moderate amounts of eosinophilic cytoplasm and finely granular nuclear chromatin.



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THYROID CANCER osms.it/thyroid-cancer PATHOLOGY & CAUSES ▪ Uncommon thyroid gland carcinoma ▪ Predominance: biologically-female adults ▪ Derived from thyroid’s follicular epithelium ▫ Except medullary thyroid carcinoma → functional parafollicular C cells



TYPES Papillary thyroid ▪ Most common, least aggressive ▪ Multiple projections arise from follicular cells growing towards blood vessels, lymphatics; papillae = small projection/ outgrowth ▫ Lymphatic spread to cervical lymph nodes ▪ May be part of inherited syndrome (Cowden syndrome, Gardner syndrome) ▪ Light microscopy ▫ Cells with empty nuclei, AKA “Orphan Annie eyes”



Figure 15.5 The gross pathological appearance of an anaplastic thyroid carcinoma which has replaced an entire thyroid lobe.



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Figure 15.4 The cytological appearance of papillary thyroid carcinoma following fine needle aspiration. There are large cell clusters in a papillaroid configuration. The cell nuclei are of variable size.



Figure 15.6 The histological appearance of thyroid papillary carcinoma at high magnification demonstrating nuclear inclusion bodies and pale chromatin with a dark nuclear envelope giving the classic orphan Annie appearance.



Chapter 15 Endocrine Tumors



Figure 15.7 An ultrasound image of the left lobe of the thyroid demonstrating a papillary carcinoma. The tumor is well circumscribed and hypoechoic with visible microcalcifications. Follicular thyroid ▪ AKA follicular adenocarcinoma; second most common ▪ Follicular cell invasion of thyroid capsule → blood vessel invasion → hematogenous spread to bone, liver, brain, lungs ▫ Distant metastasis in some cases ▪ Well-circumscribed single nodules with colloid filled follicles; may be calcified, have central fibrosis ▪ May present with eosinophilic cells with granular cytoplasm; AKA Hürthle cells



Figure 15.9 The histological appearance of follicular thyroid carcinoma. The tumor cells form vague follicular structures and there is abundant central necrosis.



Medullary thyroid carcinoma ▪ Arises from functional parafollicular C cells; in upper ⅓ of gland ▫ Calcitonin secretion → breakdown → deposits in extracellular thyroid space → amyloid ▪ ⅓ familial, ⅓ sporadic, ⅓ associated with MEN 2A, 2B ▪ Germline RET mutations → abnormal receptor activation → cancer ▪ Light microscopy ▫ Spindle shaped cells; myloid deposits Anaplastic/undifferentiated carcinomas



Figure 15.8 The histological appearance of a spindled anaplastic thyroid carcinoma.



Figure 15.10 The histological appearance of medullary thyroid cancer. The nuclear chromatin displays a classic salt and pepper pattern.



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SIGNS & SYMPTOMS ▪ Large, solitary, painless, thyroid nodule (hard consistency, fixed) ▪ May impair thyroid hormone production → hypothyroidism ▫ Weight gain, fatigue, cold intolerance ▪ Mass effect ▫ Hoarseness, trouble swallowing



DIAGNOSIS DIAGNOSTIC IMAGING



Figure 15.11 The gross pathological appearance of medullary carcinoma of the thyroid gland. The tumor is well circumscribed occupying a single thyroid lobe with a fleshy cut surface.



CAUSES



▪ Gain-of-function mutations in growth factor signaling pathways ▫ Except medullary thyroid carcinoma



Ultrasound ▪ Thyroid ▫ Solid vs. cystic thyroid nodule (most cancers solid)



LAB RESULTS



▪ Thyroid hormone levels



Fine needle aspiration ▪ Confirm diagnosis (benign vs. malignant) Thyroid scan ▪ When fine needle aspiration indeterminate



RISK FACTORS Papillary thyroid ▪ Childhood ionizing radiation exposure: ionizing radiation → RET + BRAF protooncogene activation → cancer Follicular thyroid ▪ Iodine deficiency: RAS, PIK3CA protooncogene activation + PTEN tumor suppressor gene inactivation → cancer



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TREATMENT SURGERY



▪ Resection, adjuvant treatment



Chapter 2 Acyanotic Defects



NOTES



GONADAL DYSFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disturbance in gonadal development/ function due to gonadal disorder/ hypothalamic-gonadal axis dysfunction



CAUSES



▪ Impaired gonadal hormone production due to enzyme deficiency/receptor disturbance/ exogenous hormone use ▪ Hypogonadotropic hypogonadism (AKA central/secondary hypogonadism) ▫ Deficient gonadal hormone production due to decreased gonadotropin production ▫ Gonadotropins, gonadal hormone levels low ▪ Hypergonadotropic hypogonadism (AKA peripheral/primary hypogonadism) ▫ Deficient gonadal hormone production due to disease of gonads ▫ Gonadotropin levels high, gondal hormone levels low



RISK FACTORS



▪ Genetic (autosomal dominant disease), history (gestational diabetes) ▪ Environment (e.g. obesity, lack of physical exercise, steroid use)



COMPLICATIONS



▪ Most commonly leads to infertility



SIGNS & SYMPTOMS ▪ Individuals who are biologically male ▫ Primary sex characteristic dysfunction: small penis, testes; improper testicular descent; low sperm count ▫ Secondary sex characteristic dysfunction: lack of facial, body hair; low muscle mass; failure of voice mutation ▪ Individuals who are biologically female ▫ Primary sex characteristic dysfunction: amenorrhea (absence of menstruation), oligomenorrhea (irregular menstrual cycle) ▫ Secondary sex characteristic dysfunction: lack of breast development, pubic hair



DIAGNOSIS LAB RESULTS



▪ Blood tests ▫ Gonadotropic, gonadal hormone levels



OTHER DIAGNOSTICS



▪ Tanner scale ▫ Identify delayed development ▫ Development of primary, secondary sex characteristics divided into five stages based on pubic hair, testicular volume, breast development



TREATMENT OTHER INTERVENTIONS



▪ Hormone replacement therapy ▪ Infertility treatments



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5-ALPHA-REDUCTASE DEFICIENCY osms.it/5-alpha-reductase_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive sex-limited genetic mutation in SRD5A2 gene (encodes enzyme 5 alpha reductase) ▪ Defective/absent ▪ Affects only individuals who are biologically male ▪ Defective 5 alpha reductase → ↓ testosterone to dihydrotestosterone conversion → impaired secondary sexual characteristics development



COMPLICATIONS



DIAGNOSIS LAB RESULTS



▪ Genetic testing ▫ Karyotyping to ensure individual genetically male; confirm enzyme deficiency ▪ Normal serum testosterone level, ↓ dihydrotestosterone levels, ↑ testosterone to dihydrotestosterone ratio



OTHER DIAGNOSTICS



▪ Suspected in newborns with ambiguous genitalia



▪ Infertility; inflammation, infection of gonads due to malformation



SIGNS & SYMPTOMS Pre-puberty ▪ Male internal sex organs present, external genitalia with female appearance ▫ Phallus doesn’t fully elongate; resembles something between clitoris, penis ▫ Bifid scrotum: scrotum remains split ▫ Hypospadias: urethral opening remains on underside of penis ▫ Ambiguous genitalia: external genitalia does not look clearly male/female Puberty ▪ ↑ testosterone → despite no testosterone conversion, phallus, scrotum grow larger → male appearance, deepening of voice, muscle growth, development of facial, body hair



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TREATMENT MEDICATIONS



▪ Hormone replacement therapy ▫ Male/female sex hormones according to gender role adopted by individual



SURGERY



▪ Surgical procedures to help restore external genitalia to nonambiguous appearance



OTHER INTERVENTIONS



▪ Assisted reproduction techniques ▫ Internal genitalia do not produce ova, may produce sperm



Chapter 16 Gonadal Dysfunction



ANDROGEN INSENSITIVITY SYNDROME osms.it/androgen-insensitivity PATHOLOGY & CAUSES ▪ Genetic disorder of defective androgen receptor gene ▪ Person with XY genotype unresponsive to androgens ▪ Inherited in X-linked recessive pattern



TYPES



▪ Complete androgen insensitivity ▫ Completely nonfunctional receptor; cells do not respond to androgens at all ▪ Partial androgen insensitivity ▫ Some remaining function of androgen receptor; cells, tissues partially sensitive to androgens ▪ Mild androgen insensitivity ▫ Masculinization of external genitalia



CAUSES



▪ Defect in androgen receptor on external genitalia, genital ducts, testes itself



COMPLICATIONS



▪ Infertility (most cases) ▪ Risk of testicular cancer due to cryptorchidism in complete androgen insensitivity



SIGNS & SYMPTOMS Complete androgen insensitivity ▪ Cryptorchidism ▫ Without effects of androgens, testes fail to descend into scrotum, remain in abdomen/pelvis ▪ Ineffective spermatogenesis ▫ Epididymis, vas deferens, seminal vesicles do not develop normally



▪ Development of female secondary sex characteristics ▫ Excess testosterone converted into estrogen → breast growth, widening of hips, female fat distribution ▪ Failed development of internal female organs ▫ Testes still produce anti-Müllerian hormone → uterus, fallopian tubes do not develop, vagina ends in blind pouch → female appearance without menstrual cycles Partial androgen insensitivity ▪ Appearance of external genitalia, secondary sex characteristics varies widely Mild androgen insensitivity ▪ Masculinization of external genitalia, some female secondary sex characteristics



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Absence of uterus, ovaries; cryptorchidism



LAB RESULTS



▪ ↑ serum testosterone, dihydrotestosterone ▪ Genetic testing ▫ Karyotype; visualize sex chromosomes, ensure individual genetically male



OTHER DIAGNOSTICS



▪ Diagnosed in infants with cryptorchidism ▪ Can remain undiagnosed until puberty



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TREATMENT MEDICATIONS



▪ Hormone replacement therapy ▫ Male/female sex hormones according to gender role adopted by individual; testosterone/dihydrotestosterone if male, estrogen if female



SURGERY



▪ Surgical removal of testes (esp. in cryptorchidism) to reduce cancer risk ▪ External genitalia correction



DELAYED PUBERTY osms.it/delayed-puberty PATHOLOGY & CAUSES ▪ Onset of puberty after age 13 in individuals who are biologically female, after 14 in individuals who are biologically male



TYPES Primary/hypergonadotropic hypogonadism ▪ Dysfunction of gonads due to unresponsiveness to luteinizing hormone (LH), follicle-stimulating hormone (FSH)/lack of testosterone/estrogen, progesterone production in gonads → no negative feedback on hypothalamus → overproduction of LH, FSH ▪ Causes of acquired ▫ Radiation therapy, chemotherapy, trauma to gonads ▪ Causes of congenital ▫ Klinefelter syndrome: two X chromosomes in individuals who are biologically male → small testes, sterility ▫ Turner syndrome: X chromosome missing in individuals who are biologically female → dependence on hormonal treatment to develop secondary sex characteristics Secondary/ hypogonadotropic hypogonadism ▪ Hypothalamus/pituitary gland dysfunction; inability to produce gonadotropin-releasing hormone (GnRH)/LH, FSH; suppression



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from other hormones (e.g. prolactin, thyroid hormone) ▪ Causes of acquired ▫ Radiation therapy, chemotherapy, trauma to gonads, tumor of pituitary gland, hypothalamus ▪ Causes of congenital ▫ Kallmann syndrome, panhypopituitarism ▪ General causes ▫ Chronic illness (e.g. cystic fibrosis, celiac disease), excessive exercise, malnutrition/obesity, stress; affect hypothalamus, pituitary release of hormones Constitutional delay ▪ Temporary delay in puberty; doesn’t typically result in infertility ▪ Lack of GnRH, not pathologic → naturally slowed rate of maturation ▪ Onset of puberty occurs naturally, at later age; typically genetic component



COMPLICATIONS



▪ Permanent infertility if puberty never begins/fails to complete, sexual maturity never reached



SIGNS & SYMPTOMS ▪ Delayed primary, secondary sexual characteristics



Chapter 16 Gonadal Dysfunction



DIAGNOSIS LAB RESULTS



▪ Blood hormone levels ▫ Indicate type of hypogonadism; ↓ testosterone, estrogen in low gonad activity; ↓ FSH, LH in suppressed pituitary activity



OTHER DIAGNOSTICS



TREATMENT MEDICATIONS



▪ Hormone replacement therapy



OTHER INTERVENTIONS



▪ Constitutional delay can resolve on own with natural onset of puberty ▪ Infertility treatments



▪ Medical history ▫ Evaluate underlying medical conditions, family history for constitutional delay ▪ Tanner scale ▫ Estimates puberty development



KALLMANN SYNDROME osms.it/kallmann-syndrome PATHOLOGY & CAUSES ▪ Type of hypogonadotropic hypogonadism; delayed/absent puberty with impaired sense of smell (anosmia) ▪ Pituitary failure → ↓ sex hormones → hypogonadotropic hypogonadism → failure to start/complete puberty ▪ Defect in migration of neurons from olfactory placode ▫ Olfactory neurons: hyposmia/anosmia (reduced sense of smell) ▫ GnRH neurons: ↓ GnRH → ↓ LH, FSH



COMPLICATIONS



▪ Infertility, osteopenia, osteoporosis



SIGNS & SYMPTOMS



foot, teeth underdevelopment, cleft palate ▪ Neurological sensory, motor ▫ Hearing impairment, colour blindness, dyskinesias, cerebral ataxia



DIAGNOSIS LAB RESULTS



▪ Blood hormone levels ▫ ↓ GnRH, LH, FSH, sex hormones ▪ Genetic tests ▫ Gene mutation in FGFR1, PROKR2, PROK2, CHD7, FGF8; associated with Kallmann syndrome



OTHER DIAGNOSTICS ▪ Smell test, sperm count



▪ Underdevelopment of primary, secondary sex characteristics; anosmia; long arms in proportion to body (eunuchoid body); osteoporosis; kidney agenesis ▪ Skeletal ▫ Scoliosis, short middle finger, split hand/



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TREATMENT MEDICATIONS



▪ Hormone therapy ▫ Stimulate puberty, development of secondary sex characteristics



▪ Calcium, vitamin D ▫ Osteopenia



OTHER INTERVENTIONS ▪ Infertility treatments



POLYCYSTIC OVARY SYNDROME osms.it/polycystic-ovary PATHOLOGY & CAUSES ▪ Excessive androgen production by ovaries; primarily testosterone



CAUSES Hyperinsulinemia ▪ Aids LH overproduction ▪ Theca cells in ovary express insulin receptors → excess insulin induces growth, division of theca cells → ↑ LH receptors → hypothalamus ↑ rate of GnRH pulses → ↑ LH secretion Anterior pituitary produces excessive LH ▪ Theca cells produce excess amounts of androstenedione → converted into estrone by aromatase in adipose tissue → negative feedback signal → blocks anterior pituitary from releasing FSH, LH → no LH surge → no dominant follicle to break away from ovary → remains in ovary as cyst/ degenerates with other follicles → no ovulation Excessive adipose tissue ▪ Aromatase in adipose tissue converts androgens to estrogens → ↑ androgens



RISK FACTORS



▪ Genetic: autosomal dominant disease ▪ Obesity, lack of physical exercise ▪ History of gestational diabetes



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COMPLICATIONS



▪ Diabetes mellitus, hyperinsulinemia, infertility, increased risk of endometrial cancer



SIGNS & SYMPTOMS ▪ High levels of androstenedione → virilization ▫ Excessive hair growth on chin, upper lip, chest, back (hirsutism) ▫ Thinning of hair, from crown of head (male-pattern baldness) ▫ Acne on face, chest, back ▫ Lack of ovulation → oligomenorrhea, amenorrhea → infertility ▪ Insulin resistance ▫ Overweight/obese; dark, velvety patches in creases of neck, groin, underarms (acanthosis nigricans)



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Follicles on one/both ovaries, appear like small cysts



LAB RESULTS



▪ Blood tests ▫ ↑ LH to FSH ratio; ↑ androstenedione



Chapter 16 Gonadal Dysfunction



TREATMENT MEDICATIONS



▪ Oral contraceptives ▫ Regulate menstrual cycle ▪ Clomiphene citrate ▫ Induce ovulation ▪ Metformin ▫ Increase insulin sensitivity



Figure 16.1 An abdominal ultrasound scan demonstrating a polycystic ovary. The cysts are are represented by the well circumscribed hypoechoic areas within the ovary.



OTHER DIAGNOSTICS



▪ Rotterdam criteria (2 of 3) ▫ Lack of ovulation, excessive androgens, polycystic ovaries on ultrasound ▪ Oral glucose tolerance test (OGTT) ▫ Establish insulin resistance



SURGERY



▪ Ovarian drilling ▫ Puncturing cystic ovary; induces ovulation; can damage ovary, doesn’t resolve overall hormonal imbalance



OTHER INTERVENTIONS



▪ Incurable condition, treatment symptoms ▪ Weight loss, low glycemic index diet reduces insulin resistance, improves symptoms



PRECOCIOUS PUBERTY osms.it/precocious-puberty PATHOLOGY & CAUSES ▪ Onset of puberty at earlier age than average ▫ ≤ eight in individuals who are biologically female, ≤ nine in individuals who are biologically male



TYPES Central/gonadotropin-dependent precocious puberty ▪ Early maturation of hypothalamic-pituitarygonadal axis → early release of LH, FSH → ↑ sex hormones ▪ Cause ▫ Dysfunctional hypothalamus/pituitary gland: tumor releases GnRH/human



chorionic gonadotropin (hCG); infection; cyst; radiation damage to brain → impairs negative feedback system in hypothalamic-pituitary-gonadal axis ▫ Idiopathic precocious puberty: most common; normal variation; depends on weight, genetics Peripheral/gonadotropin-independent precocious puberty ▪ Abnormal overproduction of sex hormones by testes/ovaries ▪ Cause ▫ Ovarian/testicular cyst/tumor; genetic conditions (e.g. McCune–Albright syndrome); dysfunction of other glands (thyroid/adrenal gland); exogenous sex hormones from medications, creams



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SIGNS & SYMPTOMS ▪ Child starts progressing through Tanner scale before 95% of other children at same age ▪ Early sexual maturation



DIAGNOSIS



LAB RESULTS



▪ Gonadotropin hormone levels ▫ Distinguish gonadotropin-dependent/ independent causes



OTHER DIAGNOSTICS



▪ Physical exam ▫ Assess growth compared to age; Tanner scale



DIAGNOSTIC IMAGING MRI ▪ Structural abnormalities in brain Ultrasound ▪ Screening of gonads X-ray ▪ Estimates bone maturation



TREATMENT MEDICATION



▪ Hormone therapy ▫ GnRH analogues → suppress hypothalamic-pituitary-gonadal axis hormones, bind to GnRH receptor on pituitary gland → decrease release of LH, FSH → slow puberty



SURGERY



▪ Surgical removal of tumor/cyst from ovaries/ testicles



PREMATURE OVARIAN FAILURE osms.it/premature-ovarian-failure PATHOLOGY & CAUSES ▪ AKA primary ovarian insufficiency ▪ Loss of function of ovaries before age 40; not caused by menopause ▪ Follicles stop responding to pituitary LH, FSH → disrupted ovulation → ↓ estrogen, progesterone, androstenedione → amenorrhea, hypogonadotropism, hypoestrogenism ▪ Around half of biologically-female individuals maintain some intermittent ovarian function ▪ Usually no clear cause; associated with ▫ Acquired: chemotherapy, radiotherapy, autoimmune destruction ▫ Genetic: Turner syndrome, fragile X syndrome, BRCA1 mutations →



100 OSMOSIS.ORG



gonadal dysgenesis ▪ Two mechanisms ▫ No remaining follicles: ovary started off with few/rapid degeneration ▫ Follicles dysfunctional: hypergonadotropic hypogonadism; estrogen-low pituitary increases LH, FSH production



COMPLICATIONS



▪ Infertility, cardiovascular disease, osteoporosis, hypothyroidism, Addison’s disease



Chapter 16 Gonadal Dysfunction



SIGNS & SYMPTOMS ▪ Absence of ovulation; low levels of estrogen, progesterone ▪ Normal puberty with regular periods before disorder develops ▪ Infrequent menstrual periods → difficulty conceiving/infertility ▪ Lack of hormones: hot flashes, night sweats, vaginal dryness → dyspareunia (pain during sex) ▪ ↓ estrogen: cardiovascular disease, osteoporosis, decreased bone density ▪ Symptoms mimic natural menopause; some biologically-female individuals still able to get pregnant due to intermittent ovarian function



DIAGNOSIS



LAB RESULTS



▪ ↓ ovarian hormones (estrogen), ↑ LH, FSH ▪ If autoimmune cause suspected ▫ Test for steroid cell antibodies/ sulfoxythiocarbamate alkynes (STCAs) ▪ Genetic testing ▫ Karyotype, chromosomal abnormalities; evaluate for genetic disease



TREATMENT MEDICATIONS



▪ Hormone replacement therapy ▫ Estrogen, progesterone



OTHER INTERVENTIONS ▪ In-vitro fertilization ▫ Treat infertility



DIAGNOSTIC IMAGING Ultrasound ▪ Shrunken ovaries



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NOTES



NOTES



HYPERPARATHYROIDISM & HYPOPARATHYROIDISM



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ An imbalance of parathyroid hormone (PTH) due to overproduction or underproduction by the parathyroid gland resulting in impaired regulation of calcium and other electrolytes Hyperparathyroidism ▪ ↑ PTH → ↑ bone resorption and ↑ renal reabsorption of calcium → ↑ serum calcium levels → asymptomatic or symptomatic hypercalcemia Hypoparathyroidism ▪ ↓ PTH → ↓ serum calcium → symptomatic hypocalcemia



RISK FACTORS



▪ Hyperparathyroidism ▫ Genetic mutations, chronic kidney disease, ↓ vitamin D intake/absorption, hyperplasia of parathyroid glands ▪ Hypoparathyroidism ▫ Most commonly iatrogenic cause due to accidental removal or damage to parathyroid blood supply during thyroid surgery



COMPLICATIONS



▪ Hyperparathyroidism ▫ Osteoporosis, osteitis fibrosa cystica, nephrolithiasis, keratopathy, symptomatic hypercalcemia (e.g. hypertension, cardiac arrhythmias) ▪ Hypoparathyroidism ▫ Symptomatic hypercalcemia (e.g. respiratory paralysis, cardiac arrhythmias)



102 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS LAB RESULTS



▪ Measure serum PTH, calcium, phosphate, magnesium, 25-hydroxyvitamin D, urine calcium



OTHER DIAGNOSTICS ▪ Genetic testing



TREATMENT MEDICATIONS



▪ Hyperparathyroidism ▫ Vitamin D analogs, calcimimetics, bisphosphonates ▪ Hypoparathyroidism ▫ IV calcium gluconate (acute), vitamin D analogs, synthetic PTH, thiazide diuretics (↓ renal calcium excretion)



SURGERY



▪ Hyperparathyroidism ▫ Partial/complete parathyroidectomy; radiofrequency ablation



OTHER INTERVENTIONS



▪ Hyperparathyroidism ▫ Physical activity to ↓ bone resorption, maintain hydration to ↓ nephrolithiasis, vitamin D supplements ▪ Hypoparathyroidism ▫ Calcium, magnesium, and vitamin D supplements



HYPERPARATHYROIDISM



NOTES



osms.it/hyperparathyroidism PATHOLOGY & CAUSES TYPES Primary ▪ Parathyroid gland creates PTH independently of calcium levels, does not respond to normal feedback mechanisms Secondary ▪ Parathyroid gland hyperplasia, excess parathyroid hormone secreted in response to chronic hypocalcemia ▪ Impaired kidney function; kidneys do not filter phosphate properly into urine, make insufficient calcitriol ▫ AKA renal osteodystrophy (bone pain, fracture) ▪ Altered calcium, phosphate levels → increased parathyroid hormone levels → bone resorption Tertiary ▪ Develops in individuals with secondary hyperparathyroidism for many years, often due to hyperplasia of parathyroid glands ▪ Autonomous secretion of PTH separately from blood calcium levels ▫ Even if causes of secondary hyperparathyroidism (e.g. renal transplant) corrected, increased PTH persists



RISK FACTORS Primary ▪ Genetic mutations ▫ Multiple endocrine neoplasia (MEN) syndrome



COMPLICATIONS Primary ▪ Brown tumors, large bone cysts (due to high osteoclast activity)



SIGNS & SYMPTOMS ▪ “Stones, thrones, bones, groans, and psychiatric overtones”; see mnemonic Primary, tertiary ▪ Slower muscle contractions caused by less excitable neurons secondary to hypercalcemia Secondary ▪ Bone resorption/renal osteodystrophy; calcification of blood vessels, soft tissues



MNEMONIC



Signs and symptoms of hyperparathyroidism Stones: calcium-based kidney stones, gallstones Thrones: toilet; polyuria (frequent urination) from impaired sodium, water reabsorption Bones: pain from chronic hormone-driven demineralization Groans: constipation, muscle weakness Psychiatric overtones: depressed mood, confusion



OSMOSIS.ORG 103



DIAGNOSIS LAB RESULTS Primary ▪ High total serum calcium (hypercalcemia), low phosphate (hypophosphatemia), high PTH valve during diastole ▪ Hypercalciuria from excess calcium loss through urine, may cause dehydration ▪ Serum 25-hydroxyvitamin D ▫ Determine type Secondary ▪ Low calcium, high phosphate, low vitamin D Tertiary ▪ Normal-high calcium, high PTH, low vitamin D



Figure 17.1 An ultrasound of the neck demonstrating a large parathyroid adenoma situated posteriorly and to the right of the right thyroid lobe. The skin surface is at the top of the image.



TREATMENT MEDICATIONS Primary, tertiary ▪ Calcimimetics ▫ Drugs that imitate calcium by attaching to CaSR on parathyroid cells ▫ If surgery not an option Secondary ▪ Hyperphosphatemia ▫ Phosphate binders ▪ Vitamin D supplements ▫ Increase calcium absorption, reduce PTH synthesis ▪ Calcitriol, vitamin D analogs (doxercalciferol, paricalcitol) ▫ Suppress PTH levels ▪ Calcimimetics ▫ Modulate CaSR → increase sensitivity of serum calcium → decrease PTH levels Tertiary



SURGERY



▪ Remove abnormal parathyroid glands



104 OSMOSIS.ORG



Figure 17.2 A X-ray image of the forearm demonstrating a brown tumor of the distal radius in an individual with hyperparathyroidism.



Chapter 17 Hyperparathyroidism & Hypoparathyroidism



HYPOPARATHYROIDISM osms.it/hypoparathyroidism PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Underproduction of parathyroid hormone (PTH); hypo- = under/low ▪ No parathyroid hormone → ↓ bone resorption, ↓ renal calcium reabsorption, ↓ intestinal calcium reabsorption → hypocalcemia, hyperphosphatemia → ↑ cell excitability → tetany, paresthesias, seizures, arrhythmias



▪ Asymptomatic/life-threatening ▫ Degree, duration of hypocalcemia ▫ Muscular dysfunction → respiratory paralysis → death ▪ ECG changes ▫ Prolonged QT, ST ▫ Torsades des pointes ▫ Atrial fibrillation



CAUSES



Acute ▪ Muscular spasms/cramps → tetany → Chvostek, Trousseau signs ▪ Perioral numbness, paresthesias, seizures



Autoimmune disorders Magnesium deficiencies Latrogenic ▪ Most common ▪ Thyroid/parathyroid surgery/radiation Hereditary abnormalities ▪ DiGeorge syndrome (DGS) ▪ Autosomal dominant hypoparathyroidism ▪ Albright hereditary osteodystrophy (pseudohypoparathyroidism) ▫ Kidney resistance to PTH, increased PTH



Chronic ▪ Extrapyramidal movements → basal ganglia calcifications ▫ Dystonias, parkinsonism, athetosis, hemiballismus, oculogyric crisis ▪ Cataracts ▪ Dermatologic manifestations ▫ Dry, coarse skin; brittle nails; patchy alopecia



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Figure 17.3 Dry, brittle nails are a dermatologic manifestation of chronic hypoparathyroidism.



DIAGNOSIS LAB RESULTS



▪ Hypocalcemia, low serum PTH ▪ Hypercalciuria



OTHER DIAGNOSTICS



▪ Medical history of thyroid surgery/radiation



TREATMENT MEDICATIONS ▪ ▪ ▪ ▪



106 OSMOSIS.ORG



IV calcium gluconate (severe cases) Oral calcium (mild-moderate cases) Vitamin D supplementation Synthetic PTH



Chapter 2 Acyanotic Defects



NOTES



HYPERPITUITARISM & HYPOPITUITARISM



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders caused by excess/insufficient pituitary hormones, disruption in hypothalamic-pituitary axis function



CAUSES Hyperpituitarism ▪ Genetic inheritance ▪ Secreting tumors (intracranial, ectopic) Hypopituitarism ▪ Intracranial tumors, bleeding, infarction ▪ Neurosurgery, head trauma, infection ▪ Idiopathic



SIGNS & SYMPTOMS ▪ Disruption in growth, regulation; depends on affected hormones ▪ If pituitary adenoma, sequence of loss: “Go Look For The Adenoma” (see mnemonic)



MNEMONIC: Go Look For The Adenoma



Pituitary adenoma sequence of loss Growth hormone (GH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH)



DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI ▪ Intracranial, ectopic tumors; bleeding, infarction



LAB RESULTS



▪ Altered levels of pituitary, target tissue hormones



OTHER DIAGNOSTICS



▪ History, physical examination



TREATMENT MEDICATIONS Hyperpituitarism ▪ Somatostatin + dopamine agonists; GH receptor antagonists Hypopituitarism ▪ Hormone replacement (e.g. glucocorticoids, thyroid hormone)



SURGERY



▪ Surgical excision of tumor



OSMOSIS.ORG 107



ACROMEGALY osms.it/acromegaly PATHOLOGY & CAUSES ▪ GH hypersecretion in adulthood after epiphyseal closure → enlargement of extremities, face



CAUSES



▪ Pituitary adenoma produces excess GH ▪ Nonpituitary tumors (pancreatic, lung, adrenal gland) produce ectopic GH



COMPLICATIONS



▪ Glucose intolerance to Type II diabetes, high blood pressure, respiratory problems, carpal tunnel syndrome, heart/kidney failure



SIGNS & SYMPTOMS ▪ Soft tissue, bone swelling ▫ Hands, feet ▫ Skull: jaw protrusion, enlargement (macrognathia), increased spacing of teeth; forehead, brow protrusion ▫ Organomegaly: heart, kidneys; vocal cords → slow, deep voice ▪ Joint pain, headache, vision problems, thickened skin ▪ Excess sweating, hair growth, pigmentation



LAB RESULTS Blood tests ▪ Acromegaly ▫ ↑ insulin-like growth factor-1 (IGF-1) / somatomedin C ▪ Oral glucose tolerance test (OGTT) ▫ Hyperglycemia



TREATMENT MEDICATIONS



▪ Somatostatin agonists ▫ Stop GH production ▪ Dopamine agonists, alternative to somatostatin agonists ▫ For tumors that affect prolactin levels ▪ GH receptor antagonists ▫ Blocks GH binding to receptors



SURGERY



▪ Transsphenoidal tumor resection



OTHER INTERVENTIONS ▪ Tumor radiation



DIAGNOSIS DIAGNOSTIC IMAGING MRI of sella turcica with gadolinium ▪ Somatotroph adenoma; tumoral location CT scan of chest/abdomen ▪ Ectopic tumors



108 OSMOSIS.ORG



Figure 18.1 The clinical appearance of acromegaly. The facial features are coarse and mandibular overgrowth has lead to prognathism.



Chapter 18 Hyperpituitarism & Hypopituitarism



Figure 18.2 The appearance of the hands in the case of acromegaly. The acromegalic right hand is larger with expanded soft tissues and thickened, stubby fingers.



CONSTITUTIONAL GROWTH DELAY osms.it/constitutional-growth-delay PATHOLOGY & CAUSES ▪ Normal variation in rate of growth → temporary delay during early childhood, puberty ▪ Eventual adult height within normal range



CAUSES



▪ Alterations in hormones critical for growth, development ▪ GH axis: regulates bone, muscle growth ▪ ↓ GH → ↓ production of IGF-1/ somatomedin C (prevents cell death), ↑ cellular metabolism, cell division, differentiation throughout body ▪ Hypothalamic-pituitary-gonadal axis: regulates sexual maturation ▪ ↓ gonadotropin-releasing hormone (GnRH) → ↓ anterior pituitary production of gonadotropins (LH, FSH) → ↓ production of sex hormones by gonads (estrogen, progesterone in individuals who are biologically female, testosterone in individuals biologically male) → delayed development of sex organs, secondary sexual characteristics



RISK FACTORS



▪ Family history of delayed growth



COMPLICATIONS



▪ Psychosocial stress



SIGNS & SYMPTOMS ▪ Normal size at birth ▪ Short preadolescent stature ▪ Delayed pubertal development, skeletal age



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Delayed bone development



OTHER DIAGNOSTICS



▪ History, physical examination ▪ Height growth curve below, parallel to third percentile ▪ Delayed Tanner scale staging



OSMOSIS.ORG 109



TREATMENT OTHER INTERVENTIONS



▪ Provide reassurance regarding eventual normal growth, development



DIABETES INSIPIDUS (DI) osms.it/diabetes-insipidus PATHOLOGY & CAUSES ▪ Disorder of fluid balance characterized by defect in urine concentration → excretion of large volumes of dilute urine ▪ Diabetes = to pass through; insipidus = tasteless



TYPES Neurogenic (central) DI ▪ DI caused by absence/↓ secretion/ production of antidiuretic hormone (ADH) by posterior pituitary Nephrogenic DI ▪ Kidneys unresponsive to ADH secreted by posterior pituitary



▪ Damage of renal tubules from systemic disease (e.g. polycystic kidney disease, pyelonephritis, amyloidosis) ▪ Lithium toxicity ▫ Interferes with aquaporin function



SIGNS & SYMPTOMS ▪ Polyuria ▫ Neurogenic: urine amount varies depending on degree of ADH production/secretion ▫ Nephrogenic: daily output of > 3L in adults; > 2L/m2 in children ▪ Nocturia, polydipsia, dehydration, hypotension ▪ Neurogenic DI ▫ Lack of other pituitary hormones



CAUSES Neurogenic DI ▪ Idiopathic (most common) ▪ Damage to hypothalamus/pituitary/ supraoptico-hypophyseal tract (e.g. head trauma, pituitary adenoma), neurosurgery, infection (e.g. tuberculosis), infiltrative disease (e.g. Langerhans cell histiocytosis), hypoxic encephalopathy, ischemia ▪ Familial (familial neurohypophyseal DI) ▫ Autosomal dominant gene mutation ▪ Congenital (e.g. septo-optic dysplasia) Nephrogenic DI ▪ Hereditary ▫ Defect in genes encoding for ADH receptor/aquaporin function



110 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING Cranial MRI (neurogenic DI) ▪ Hyperintensities, pituitary stalk thickening identifies signs of hypothalamic/pituitary dysfunction



LAB RESULTS ▪ ▪ ▪ ▪



↓ ADH levels (neurogenic), urine osmolarity ↑ plasma osmolarity Hypernatremia Water deprivation test (ADH stimulation test): fluid deprivation → ADH (vasopressin) administered subcutaneously



Chapter 18 Hyperpituitarism & Hypopituitarism ▫ ↑ urine osmolality: confirms neurogenic DI ▫ Little/no ↑ urine osmolality: confirms nephrogenic DI



TREATMENT MEDICATIONS Neurogenic DI ▪ Desmopressin (dDAVP) (synthetic vasopressin) ▪ Chlorpropamide ▫ Enhances renal response to low levels of ADH



Neurogenic/nephrogenic DI ▪ Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. indomethacin) ▫ ↑ renal concentration of urine ▪ Thiazide diuretics (e.g. hydrochlorothiazide) + low sodium diet ▫ ↓ polyuria (↑ water permeability to collecting tubules)



OTHER INTERVENTIONS



▪ Fluid replacement ▪ Diet ▫ Low solute (low sodium, low protein)



GIGANTISM osms.it/gigantism PATHOLOGY & CAUSES ▪ GH hypersecretion during childhood → rapid, excessive linear growth



CAUSES ▪ ▪ ▪ ▪



Excessive secretion of GH, GHRH, IGF-1 Tumor in pituitary gland Tumors outside pituitary, secrete GH Hereditary ▫ Gene mutation (e.g. McCune Albright syndrome, multiple endocrine neoplasia Type I)



COMPLICATIONS



▪ Cardiovascular conditions: hypertension in children ▪ Bone conditions: osteoarthritis ▪ Diabetes mellitus: insulin resistance



SIGNS & SYMPTOMS



▪ Overgrowth of face, extremities ▪ Headaches ▪ Maxilla/mandible protrusion



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Pituitary tumors CT scan ▪ Tumors in other organs, might secrete GH/ GHRH X-ray ▪ Assess bones



LAB RESULTS Blood tests ▪ OGTT ▫ Hyperglycemia ▫ Elevated IGF-1



▪ Height significantly above standard deviations ▪ Obesity



OSMOSIS.ORG 111



TREATMENT MEDICATIONS



▪ Somatostatin agonists ▫ Shrink pituitary tumors, stop GH production ▪ Dopamine agonists ▫ If somatostatin agonists not effective ▫ Effective in tumors producing hyperprolactinemia ▪ Somatostatin + dopamine agonists ▪ GH receptor antagonists



SURGERY



▪ For small pituitary adenomas ▫ Transsphenoidal surgical approach



OTHER INTERVENTIONS



▪ Radiation (not recommended for children) ▫ Can produce panhypopituitarism (decreased secretion in most pituitary hormones) → learning disabilities, obesity Figure 18.3 The worlds tallest ever recorded man, Robert Wadlow, was diagnosed with from gigantism as a consequence of pituitary hyperplasia. He stood at 2.27m/8ft 11in and wore a size 37 shoe.



GROWTH HORMONE DEFICIENCY (GHD) osms.it/growth-hormone-deficiency PATHOLOGY & CAUSES ▪ Conditions caused by decreased production of GH (AKA somatotropin) ▪ Partial/complete, permanent/transient



112 OSMOSIS.ORG



CAUSES



▪ Hypothalamic/pituitary dysfunction ▫ Tumors (e.g. pituitary/parasellar adenomas); radiation; traumatic injury; autoimmune disease; genetic mutations (e.g. PROP1); congenital structural defects of brain (e.g. Prader–Willi, Turner syndrome); idiopathic



Chapter 18 Hyperpituitarism & Hypopituitarism



SIGNS & SYMPTOMS ▪ Newborns ▫ Hypoglycemia, micropenis, excessive jaundice ▪ Children ▫ Stunted growth/short stature, delayed puberty ▫ Nystagmus, hypoglycemia, retinal defects, midfacial defects (e.g. cleft lip) ▫ Severe cases: delayed basic motor skills (e.g. standing, walking) ▫ Moderately overweight (rare—severely obese) ▪ Adults ▫ Decreased muscle mass, decreased bone mineral density, high 5-alpha reductase, baldness, cardiac conditions ▫ Psychological issues (memory problems, social issues, depression)



▪ Serum IGF-1 ▫ More accurate assessment of GH secretion; not affected by external factors ▫ Less than standard gender-specific levels → confirms diagnosis ▪ Insulin tolerance test ▫ Regular insulin administered via intravenous (IV) → measure blood at 30 minute intervals ▫ Subnormal increase in serum GH confirms diagnosis



TREATMENT MEDICATIONS



▪ Daily injections with recombinant growth hormone (rGH) ▫ Childhood: GH daily injections; stature monitoring throughout growth period ▫ Adulthood: 25% treatment for children



DIAGNOSIS LAB RESULTS



▪ Serum GH levels < 1ng/mL ▫ Nonspecific test for GH deficiency: affected by circadian rhythms, food intake, stress



HYPERPITUITARISM osms.it/hyperpituitarism PATHOLOGY & CAUSES ▪ Disorders caused by pituitary hormones hypersecretion



CAUSES



▪ Pituitary adenoma (most common) ▪ Genetic mutation from single cell (monoclonal) → tumorigenesis → tumor secretes hormones ▫ Prolactin → prolactinoma ▫ ACTH → Cushing’s disease



▫ GH → acromegaly (occurs during adulthood after epiphyseal closure), gigantism (during childhood before epiphyseal closure)



SIGNS & SYMPTOMS ▪ Diaphoresis; visual field problems; headaches; lethargy; excessive hair growth; larger organs, extremities, facial components



OSMOSIS.ORG 113



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Sella turcica, pituitary glands



LAB RESULTS



▪ Elevated hormone levels in serum



TREATMENT MEDICATIONS



▪ Dopamine agonists: gonadal dysfunctions ▫ Inhibit prolactin secretion ▫ Inhibitors of tumoral cells division



SURGERY



▪ Total/partial removal of pituitary/tumor ▫ Endonasal transsphenoidal surgery (most common)



HYPERPROLACTINEMIA osms.it/hyperprolactinemia PATHOLOGY & CAUSES ▪ Disorder caused by high blood levels of pituitary hormone prolactin ▪ Prolactin: secreted by lactotroph cells in anterior segment of pituitary



CAUSES



▪ Prolactinoma/lactotroph adenoma (prolactin-secreting tumor) ▪ Pregnancy ▪ Damage to hypothalamic-pituitary stalk ▪ Disorders affecting hypothalamus ▪ Drugs, medication, heavy metal poisoning ▫ Inhibits dopamine production ▫ Dopamine receptor antagonists, synthesis inhibitors → pituitary overproduces prolactin ▪ Renal failure ▪ Primary hypothyroidism



SIGNS & SYMPTOMS ▪ Individuals who are biologically male ▫ Impaired genital activity (hypogonadism) → infertility, impotence ▫ Decreased libido



114 OSMOSIS.ORG



▫ Overdevelopment of mammary glands (gynecomastia) ▫ Spontaneous secretion, flow of breast milk (galactorrhea) ▪ Individuals who are biologically female ▫ Irregular menstrual cycles: sometimes complete lack of menstruation (amenorrhoea); no ovulation → infertility ▫ Galactorrhea ▫ Painful breasts ▪ Visual impairment, headaches when pituitary adenoma presses on optic nerve



DIAGNOSIS DIAGNOSTIC IMAGING Head MRI/CT scan ▪ Tumors/lesions in hypothalamic-pituitary area: if none + high serum levels: idiopathic hyperprolactinemia



LAB RESULTS



▪ High serum prolactin levels



OTHER DIAGNOSTICS



▪ Lower bone density ▪ Pregnancy/hypothyroidism



Chapter 18 Hyperpituitarism & Hypopituitarism



TREATMENT MEDICATIONS



SURGERY



▪ Surgical removal of tumor ▫ High rate recurrence



▪ Tumor: dopamine agonist (inhibit prolactin production, secretion) ▫ Bromocriptine/cabergoline



HYPOPITUITARISM osms.it/hypopituitarism PATHOLOGY & CAUSES ▪ Disorders caused by complete/partial lack of pituitary hormone production, secretion



CAUSES



▪ Tumors ▫ Pituitary adenomas → compression → intracranial pressure → destruction of pituitary ▫ Brain (e.g. metastatic cancer) ▫ Body ▪ Traumatic injury, shock, stroke → ischemia ▪ Vascular ▫ Hemorrhages (e.g. aneurysms, subarachnoid hemorrhage) ▪ Radiation ▪ Infections ▫ Brain (e.g. meningitis) ▫ Abnormal brain cells/substance infiltrations (e.g. hemochromatosis) ▫ Autoimmune disorders (e.g. autoimmune hypophysitis) ▪ Congenital (defect in transcription factors) ▫ PROP1 gene mutation → hormone deficiency (most common) ▫ Pituitary transcription factor 1 (PIT1) mutation → GH, prolactin, TSH deficiencies ▪ Hypothalamic dysfunction, decrease in releasing hormones



SIGNS & SYMPTOMS ▪ Occur when ≥ 75% of anterior pituitary nonfunctional ▪ Vary depending on hormone affected ▪ Sequence of loss: “Go Look For The Adenoma” (see mnemonic) ▪ If tumor present ▫ Pressure on optic chiasm → visual disturbances ▫ Increased intracranial pressure → headache



MNEMONIC: Go Look For The Adenoma



Pituitary adenoma sequence of loss Growth hormone (GH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH)



DIAGNOSIS LAB RESULTS



▪ Blood tests ▫ Serum thyroid levels (T3/T4) ▫ ACTH secretion (measure serum cortisol in the morning)



OSMOSIS.ORG 115



TREATMENT MEDICATIONS



▪ Hormone replacement ▫ ACTH deficiency: hydrocortisone ▫ TSH deficiency: levothyroxine



▫ FSH/LH deficiency: testosterone (for individuals who are biologically male); estrogen-progestin (for premenopausal individuals who are biologically female)



SURGERY



▪ Surgical excision of tumors



HYPOPROLACTINEMIA osms.it/hypoprolactinemia PATHOLOGY & CAUSES ▪ Low serum prolactin levels due to damaged lactotroph cells in anterior pituitary



CAUSES



▪ Sheehan’s syndrome ▫ Postpartum hemorrhage → hypotension, decreased circulation to pituitary, ischemia, damaged lactotroph cells ▪ Medications ▫ Dopamine, dopamine agonists; inhibit prolactin release ▪ Tumors ▫ Pressure on pituitary/hypothalamus → damage lactotroph cells



SIGNS & SYMPTOMS ▪ Individuals who are biologically female and breastfeeding ▫ Decreased lactation (agalactorrhea)



116 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Tumor confirmation



LAB RESULTS



▪ Low prolactin levels despite receiving thyrotropin-releasing hormone (TRH) ▫ Individuals who are biologically female: < 3µg/L ▫ Individuals who are biologically male: < 5µg/L



TREATMENT MEDICATIONS



▪ Dopamine antagonists ▫ Oppose dopamine in individuals who want to breastfeed



SURGERY



▪ Surgical removal of tumor



Chapter 18 Hyperpituitarism & Hypopituitarism



PITUITARY APOPLEXY osms.it/pituitary-apoplexy PATHOLOGY & CAUSES



DIAGNOSIS



▪ Pituitary function impaired due to hemorrhage into gland ▪ Hemorrhage → blood collects within pituitary interstitium → swelling → infarction, loss of pituitary function → compression of surrounding structures



DIAGNOSTIC IMAGING



RISK FACTORS



▪ ↓ pituitary hormone levels, target tissue hormones



▪ Intracranial tumors, head trauma, neurosurgery, Sheehan’s syndrome (postpartum pituitary necrosis)



COMPLICATIONS



▪ Hypopituitarism, neuronal damage



SIGNS & SYMPTOMS ▪ Meningeal stretching ▫ Severe headache ▪ Optic chiasm compression ▫ Diplopia, bitemporal hemianopia ▪ Parenchymal compression ▫ Mental status changes ▪ Clinical manifestations of hypopituitarism (e.g. ↓ ACTH → ↓ cortisol → hypoglycemia, hypotension, adrenal crisis)



CT scan/MRI ▪ Enlarged pituitary gland; hyperintense blood-filled center



LAB RESULTS



TREATMENT MEDICATIONS



▪ Hormone replacement ▫ Glucocorticoids (emergent), levothyroxine



SURGERY



▪ Surgical decompression ▪ Transphenoidal resection of pituitary gland



OSMOSIS.ORG 117



SHEEHAN'S SYNDROME osms.it/sheehans-syndrome PATHOLOGY & CAUSES



DIAGNOSIS



▪ AKA postpartum pituitary gland necrosis ▪ Destruction of lactotroph cells of anterior pituitary in setting of postpartum hemorrhage



DIAGNOSTIC IMAGING



CAUSES



LAB RESULTS



▪ Pituitary increases in size during gestation → metabolic activity of lactotrophs increase, blood supply does not → pituitary vulnerable to perfusion decrease → hypovolemia, hypotension, shock → pituitary infarction, necrosis



SIGNS & SYMPTOMS



MRI ▪ Pituitary ring sign (halo around empty sella)



▪ Pituitary hormone levels



OTHER DIAGNOSTICS ▪ Obstetric history



TREATMENT MEDICATIONS



▪ Glucocorticoid replacement (emergent) if adrenal insufficiency ▪ Ongoing hormone replacement as needed



▪ Pituitary dysfunction



SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH) osms.it/SIADH PATHOLOGY & CAUSES ▪ Inappropriate ADH secretion → ↓ water excretion ▫ ADH overproduced, secreted → highly concentrated urine, ↓ volume ▫ ↑ intake of fluids, ADH secretion → water retention → dilutes plasma sodium levels → hyponatremia



118 OSMOSIS.ORG



CAUSES



▪ Central nervous system (CNS) disorders enhance ADH production, release ▫ Trauma, stroke, hemorrhage, infection ▫ Mental illness, though carbamazepine effects ▪ Ectopic production of ADH ▫ Lung malignancies: e.g. small cell carcinoma



Chapter 18 Hyperpituitarism & Hypopituitarism ▫ Nonmalignant lung disorders: pneumonia, tuberculosis, cystic fibrosis (CF) ▪ Medications ▫ Anticonvulsants, opioids, sulfonylureas ▪ Injury/surgical removal of pituitary



SIGNS & SYMPTOMS ▪ Body weakness ▫ Fatigue, dizziness, confusion, nausea, lethargy; anorexia ▪ Muscle cramps ▫ Myoclonus,tremors ▪ Seizures



TREATMENT MEDICATIONS



▪ ADH receptor antagonist (e.g. tolvaptan)



OTHER INTERVENTIONS



▪ Water restriction ▫ < 800mL daily ▫ If SIADH associated with subarachnoid hemorrhage, fluid restriction not recommended ▪ IV hypertonic saline administration for severe cases, oral salt tablets, loop diuretics ▪ Urea administration ▫ Increases urine output



DIAGNOSIS LAB RESULTS



▪ Urinalysis ▫ Highly concentrated urine ▪ Serum tests ▫ Hyponatremia, low plasma osmolarity



OSMOSIS.ORG 119



NOTES



NOTES



HYPERTHYROIDISM & HYPOTHYROIDISM



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Imbalance in thyroid hormones triiodothyronine (T3), thyroxine (T4) → alterations in metabolism



CAUSES Hyperthyroidism ▪ Thyroid gland hyperfunction → overproduction of thyroid hormones ▫ Primary: dysfunction of thyroid gland ▫ Secondary: ↑ thyroid-stimulating hormone (TSH) secretion by pituitary gland Hypothyroidism ▪ Thyroid hormone deficiency ▫ Primary: dysfunction of thyroid gland ▫ Central (secondary): pituitary/ hypothalamic gland dysfunction → ↓ thyrotropin-releasing hormone (TRH)/ TSH



COMPLICATIONS



▪ Hyperthyroidism: thyroid storm ▪ Hypothyroidism: myxedema, cretinism (infants, young children)



SIGNS & SYMPTOMS ▪ Hyperthyroidism: hypermetabolic state, related to sympathetic nervous system stimulation ▪ Hypothyroidism: hypometabolic state



120 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING Radioiodine uptake scan (RAIU) ▪ Measures thyroid function ▫ Ability to absorb radioactive iodine (123I) Ultrasound ▪ Size of thyroid; characteristics of nodules/ cysts Color flow Doppler sonography (CFDS) ▪ Thyroid blood flow velocity, vascularity



LAB RESULTS



▪ Serum levels of TSH, total T4, free (unbound) T4, total T3, thyroid-stimulating immunoglobulins (TSI), TSH-receptor antibodies (TRAb)



TREATMENT MEDICATIONS Hyperthyroidism ▪ Antithyroid medication ▪ Beta blockers for symptomatic thyrotoxicosis Hypothyroidism ▪ Exogenous thyroid hormone replacement



SURGERY



▪ Hyperthyroidism ▫ Radioactive thyroid ablation ▫ Thyroidectomy



Chapter 19 Hyperthyroidism & Hypothyroidism



EUTHYROID SICK SYNDROME osms.it/euthyroid-sick-syndrome PATHOLOGY & CAUSES ▪ Older term; describes acquired, transient central hypothyroidism in severely sick ▫ Thought to be euthyroid despite ↓ T3 +/T4 concentrations ▫ Transient central hypothyroidism coincident with peripheral T3 metabolism/production abnormalities ▪ ↓ 5’-monodeiodinase activity → ↓ peripheral (skeletal muscle, liver, kidney) T4 → T3 conversion → ↓ T3 serum concentration ▪ ↑ 5’-monodeiodinase (D3) activity → ↑ conversion of T3 → rT3 → ↓ T3 serum concentration (↑ rT3, T2 breakdown products)



CAUSES



▪ Poor caloric intake ▪ High endogenous serum cortisol in setting of exogenous glucocorticoid therapy ▪ Circulating inhibitors of deiodinase activity (e.g. free/nonesterified fatty acids) ▪ Medications (e.g. amiodarone; propranolol, in high doses) ▫ Inhibit 5’-monodeiodinase activity ▪ Cytokines ▫ Tumor necrosis factor (TNF), interferonalpha (IFN-α), nuclear factor kappa-beta (NF-kB), interleukin 6 (IL-6) ▪ Impaired peripheral T4 uptake → ↓ T3 production



SIGNS & SYMPTOMS ▪ Similar to hypothyroidism, not attributable to critical illness ▫ Fatigue, cold intolerance, weight loss/ gain, constipation, muscle cramps, headache, hair loss/brittleness, menstrual irregularities



DIAGNOSIS LAB RESULTS



▪ Serum TSH (required for diagnosis) ▫ Detects TSH suppression



TREATMENT OTHER INTERVENTIONS



▪ Standard replacement therapy (e.g. levothyroxine) ▫ No benefit, unless diagnosis of preceding hypothyroidism/progression to myxedema coma



RISK FACTORS



▪ Severe illness, intensive care unit (ICU) hospitalization



COMPLICATIONS ▪ Myxedema coma



OSMOSIS.ORG 121



GRAVES' DISEASE osms.it/graves-disease PATHOLOGY & CAUSES ▪ Autoimmune disease; production of antibodies against TSH receptor ▪ Most common cause of hyperthyroidism (80%) ▪ Thyroid-stimulating immunoglobulin (TSI) antibody binds to TSH receptors, acts as analog



▫ Exophthalmos dries eyes → corneal ulcers; weakens muscles controlling eye, upper lid ▪ Infiltrative dermopathy ▫ Glycosaminoglycan builds up → pretibial myxedema → non-pitting edema ▪ Pretibial myxedema



RISK FACTORS



▪ Genetic; polymorphisms in CTLA4, PTPN22, HLA-DR3 allele ▪ Peak incidence occurs at 20–40 years old ▪ Individuals who are biologically female affected 10 times more often



COMPLICATIONS



▪ Congestive heart failure, osteoporosis ▪ Thyroid storm ▪ Autoimmune conditions ▫ Rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia, diabetes mellitus Type I ▪ Radioiodine treatment → hypothyroidism



SIGNS & SYMPTOMS ▪ Effects of TSI ▫ Thyroid hypertrophy, hyperplasia → diffuse goiter ▫ Increased synthesis, release of T3, T4 ▫ Follicular cells express molecules on surface, attract nearby T cells → T cells bind to follicular cells, infiltrate interstitium of thyroid tissue ▫ TSI stimulation of fibroblasts in eye orbit → increased production of glycosaminoglycans → local inflammation, swelling → exophthalmos, lid retraction



122 OSMOSIS.ORG



Figure 19.1 The clinical appearance of Graves’ disease. There is proptosis and lid retraction bilaterally.



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Radioiodine scans, measurements of iodine uptake ▫ Diffusely increased



LAB RESULTS



▪ ↓ TSH, ↑ T3, ↑ T4, ↑ TSI



TREATMENT MEDICATION



▪ Antithyroid medication ▫ Thioamides ▪ Beta-blockers



Chapter 19 Hyperthyroidism & Hypothyroidism



SURGERY



▪ Thyroidectomy ▪ Radioiodine radioisotope surgery ▫ Partially/completely destroy thyroid gland with radiation



OTHER INTERVENTIONS



▪ Ophthalmopathy ▫ Steroids, radiation and surgery



Figure 19.2 The histological appearance of scalloped colloid within a hyperplastic thyroid follicle; a classic sign of Graves’ disease.



Figure 19.3 The histological appearance of the thyroid gland in Graves’ disease. There are enlarged thyroid follicles lined by hyperplastic follicular epithelium. The epithelium demonstrates papillary infolding.



HYPERTHYROIDISM osms.it/hyperthyroidism PATHOLOGY & CAUSES ▪ Disorder caused by excessive amount of thyroid hormone produced by overactive thyroid gland ▪ ↑ thyroid hormone synthesis, secretion → thyrotoxicosis (↑ circulating thyroid hormones)



CAUSES



▪ Autoimmune ▫ Graves’ disease (most common cause) ▪ TSH-related disease ▫ TSH-secreting pituitary adenoma;



stimulation of TSH receptors due to excess hCG (e.g. trophoblastic tumors, hyperemesis gravidarum) ▪ Solitary autonomous adenoma ▪ Excessive iodine ingestion



RISK FACTORS ▪ More common in individuals who are biologically female ▪ Smoking, genetic inheritance (Graves’ disease)



COMPLICATIONS ▪ Thyroid storm



OSMOSIS.ORG 123



DIAGNOSIS



SIGNS & SYMPTOMS ▪ Thyroid ▫ Normal/enlarged, with/without palpable nodules (may be diffusely firm, tender) ▪ Cardiovascular ▫ Bounding, rapid pulse; hypertension; palpitations ▪ Respiratory ▫ Tachypnea, dyspnea on exertion ▪ Gastrointestinal (GI) ▫ ↑ appetite/↓ weight; hyperdefecation ▪ Integumentary ▫ Warm, flushed, moist skin; patchy hair loss; thyroid acropachy (digital clubbing); infiltrative dermopathy (pretibial myxedema) ▪ Musculoskeletal ▫ Osteoporosis (↑ bone resorption); skeletal muscle atrophy ▪ Neurological ▫ Heat intolerance, fine tremor, agitation, insomnia ▪ Reproductive ▫ Menstrual irregularities, ↓ libido, infertility ▪ Ocular changes (Graves’ disease) ▫ Wide, staring gaze; lid lag, exophthalmos



DIAGNOSTIC IMAGING RAIU ▪ ↑ 123I uptake confirms hyperthyroidism CFDS ▪ ↑ blood flow due to thyroid hyperactivity Ultrasound ▪ Benign/malignant nodules (e.g. microcalcifications, hypoechogenicity in malignant nodules)



LAB RESULTS



▪ ↓ TSH, ↑ free T4, total/free T3 ▫ Confirms hyperthyroidism with suppressed TSH ▪ ↑ TSH, free T4, total/free T3 ▫ Confirms TSH-induced hyperthyroidism ▪ ↑ TRAb/TSI



TREATMENT MEDICATIONS



▪ Antithyroid drugs



SURGERY



▪ Thyroidectomy



OTHER INTERVENTIONS ▪ Radioactive thyroid ablation



124 OSMOSIS.ORG



Chapter 19 Hyperthyroidism & Hypothyroidism



HYPOTHYROIDISM osms.it/hypothyroidism PATHOLOGY & CAUSES ▪ Hypometabolic state caused by underproduction of thyroid hormones T3, T4 ▪ ↓ availability of thyroid hormone → general slowing of thyroid hormone-induced cell metabolism ▪ Accumulation of matrix glycosaminoglycans in interstitial space → myxedema



TYPES Primary hypothyroidism (thyroid gland dysfunction) ▪ Iodine deficiency ▪ Autoimmune: Hashimoto’s thyroiditis ▫ Autoantibodies against thyroglobulin (Tg), thyroid peroxidase (TPO), TSH receptor → bound antibodies facilitate T-cell, complement-mediated immune destruction of thyroid cells; steric hindrance at TSH receptor ▪ Congenital ▫ Inborn errors of thyroid hormone metabolism ▫ Thyroid agenesis/hypoplasia ▪ Iatrogenic ▫ Treatment of hyperthyroidism, thyroid neoplasm (radiation, surgical) ▪ Medication-induced ▫ Overdose of antithyroid drugs (propylthiouracil, methimazole) ▫ Agents ↓ T4 absorption (cholestyramine, iron salts) ▫ Agents ↓ T4 → T3 conversion (amiodarone) ▫ Agents ↓ clearance of T4 (phenytoin, carbamazepine) ▫ Others: lithium carbonate, interferon alpha, IL-2, tyrosine kinase inhibitors (esp. sunitinib), P-aminosalicylic acid



Secondary, tertiary hypothyroidism (central hypothyroidism) ▪ Disorder of pituitary/hypothalamus/ hypothalamic-pituitary communication → ↓ TSH/TRH ▫ Hypopituitarism: surgical resection/ radiation for adenoma, trauma, postpartum pituitary necrosis (Sheehan’s syndrome), infiltrative disease ▫ Hypothalamic damage: radiation, granulomas, neoplasms



RISK FACTORS



▪ ↑ age ▪ More common in individuals who are biologically female



COMPLICATIONS



▪ Myxedema coma ▫ Common in older individuals who are biologically female with longstanding hypothyroidism; precipitated by acute event (e.g. trauma, infection, myocardial infarction) ▪ Dyslipoproteinemias ▪ Dilated cardiomyopathy; ↓ thyroid hormone → dysregulation of myocardial enzymes → ↓ myocardial contractility ▪ Anemia ▫ Hypoproliferative (normochromic, normocytic)/pernicious anemia (most common in chronic autoimmune thyroiditis) ▪ Hyperprolactinemia → galactorrhea ▪ ↓ clearance of drugs (e.g. antiepileptic, anticoagulant, opioids) in setting of hypothyroidism → ↑ accumulation of drugs → potential drug toxicity ▪ Congenital hypothyroidism ▫ Failure to thrive, intellectual disability



OSMOSIS.ORG 125



SIGNS & SYMPTOMS ▪ Fatigue, cold intolerance, constipation, muscle weakness, headache, weight gain, brittle hair/loss of eyebrow hair, menstrual irregularities, goiter (primary hypothyroidism) ▪ Neurologic manifestations ▫ Difficulty concentrating, poor memory, peripheral neuropathy, carpal tunnel syndrome, ↓ deep tendon reflexes ▪ Myxedema (nonpitting edema) ▫ Periorbital edema, tongue enlargement, puffy facies ▪ Myxedema coma ▫ Altered mental status, hypothermia, multi-organ failure, hypotension, bradycardia, hyponatremia, hypoglycemia, hypoventilation



Figure 19.4 Myxedema of the hands in an individual with hypothyroidism.



DIAGNOSIS LAB RESULTS



▪ Primary hypothyroidism ▫ ↑ TSH, ↓ free T4 ▪ Central hypothyroidism ▫ ↓ free T4, ↓/↔/↑ TSH ▪ Autoimmune autoantibody detection (Hashimoto’s thyroiditis) ▫ ↑ ↑ anti-TPO/Tg/TSH receptor antibodies



OTHER DIAGNOSTICS



▪ History, physical examination



TREATMENT MEDICATIONS



▪ Synthetic T4 (levothyroxine) replacement therapy



126 OSMOSIS.ORG



Figure 19.5 Pretibial myxedema in an individual with hypothyroidism.



Chapter 19 Hyperthyroidism & Hypothyroidism



THYROID STORM osms.it/thyroid-storm PATHOLOGY & CAUSES



DIAGNOSIS



▪ Severe, acute, life-threatening complication of hyperthyroidism



LAB RESULTS



CAUSES



OTHER DIAGNOSTICS



▪ Abrupt termination of hyperthyroidism therapy ▪ Complication of hypothyroid treatment ▪ Diabetic ketoacidosis ▪ Stressors (surgery, infection, trauma, childbirth) ▪ Increased sensitivity of tissues to thyroid hormone, catecholamines



COMPLICATIONS



▪ Myocardial infarction (MI), heart failure; coma, death



SIGNS & SYMPTOMS



▪ ↓ TSH, ↑ T3, ↑ T4



ECG ▪ Confirmation



TREATMENT MEDICATION



▪ Beta blockers ▪ Thyroid hormones reduction ▫ Thioamides, iodine preparations, glucocorticoids, bile acid sequestrants



OTHER INTERVENTIONS ▪ Plasmapheresis



▪ Exaggerated hyperthyroidism symptoms ▫ Heat intolerance → fever ▫ Hyperactivity, anxiety → agitation, confusion, seizures, coma ▫ Tachycardia → cardiac arrhythmias, high-output heart failure



OSMOSIS.ORG 127



TOXIC MULTINODULAR GOITER osms.it/toxic-multinodular-goiter PATHOLOGY & CAUSES ▪ Excess thyroid hormone production from multiple autonomous thyroid nodules, without stimulation of TSH ▪ Second most common cause of hyperthyroidism; AKA Plummer’s disease ▪ Starts as non-toxic multinodular goiter caused by chronic lack of dietary iodine ▫ Lack of iodine → low levels of thyroid hormones→ anterior pituitary releases TSH → thyroid hypertrophy, hyperplasia → some parts of thyroid gland more responsive to TSH than others → uneven growth → most responsive follicular cells grow quickly, develop into nodule → multiple nodules appear ▫ More follicular cells compensate for low thyroid hormone production → euthyroid state ▪ Non-toxic multinodular goiter becomes toxic when genetic mutation for TSH receptor occurs in one of dividing follicular cells → cell becomes constitutively active without TSH → overstimulation of thyroid to divide, produce thyroid hormone → toxic multinodular goiter



COMPLICATIONS ▪ Malignancy (rare)



SIGNS & SYMPTOMS ▪ Increased synthesis, release of T3, T4 → hyperthyroidism ▫ Increased basal metabolic rate, catabolism of proteins, carbohydrates, bone resorption ▫ Exacerbation of sympathetic nervous system ▫ Impairment of reproductive system



128 OSMOSIS.ORG



▪ Thyroid hypertrophy, hyperplasia → goiter ▫ Difficulty swallowing, airway obstruction ▫ Compression of recurrent laryngeal nerve → hoarse voice ▫ Superior vena cava syndrome → facial, arm swelling



Figure 19.6 The clinical appearance of a goiter.



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Radioiodine scans, measurements of iodine uptake ▫ Uneven (“hot” autonomous nodules)



LAB RESULTS



▪ ↓ TSH, ↑ T3, ↑ T4



TREATMENT MEDICATION



▪ Beta blockers ▪ Antithyroid medication ▫ Thioamides ▫ If radioiodine therapy, surgery not appropriate



Chapter 19 Hyperthyroidism & Hypothyroidism



SURGERY



▪ Thyroidectomy ▪ Radioiodine radioisotope surgery ▫ Partially/completely destroy thyroid nodules with radiation



OTHER INTERVENTIONS ▪ Inject ethanol into nodules



Figure 19.7 A CT scan of the head and neck in the sagittal plane demonstrating a massive goiter extending from the mandible to the suprasternal notch.



OSMOSIS.ORG 129



NOTES



NOTES



NEUROENDOCRINE TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Tumors arising from cells of neuroendocrine origin; most are functional with hormonesecreting capacity ▪ Can be sporadic; most associated with genetic syndromes



SIGNS & SYMPTOMS ▪ Mass effect ▪ Depends on secreted hormone



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Location; tumor, lymph node, metastasis (TNM) staging



130 OSMOSIS.ORG



LAB RESULTS



▪ Hormone level plasma measurement



OTHER DIAGNOSTICS



▪ History, physical examination ▪ Histopathological analysis, tumor grading



TREATMENT MEDICATIONS



▪ Chemotherapy; hormonal agonists, antagonists



SURGERY ▪ Resection



OTHER INTERVENTIONS ▪ Radiotherapy



Chapter 20 Neuroendocrine Tumors



CARCINOID SYNDROME osms.it/carcinoid-syndrome PATHOLOGY & CAUSES ▪ Signs, symptoms caused by tumor arising from neuroendocrine cells secreting serotonin ▪ ⅓ metastasize, ⅓ associated with secondary malignancy, ⅓ multiple tumors ▪ Most commonly arises from gastrointestinal (GI) tract; followed by lungs, liver, ovaries, thymus ▫ Most common small intestine malignancy ▫ Appendix most common GI tract site ▫ Liver most common site for metastasis; from ileal tumors



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Locate tumors



LAB RESULTS ▪ Niacin deficiency Urinalysis ▪ ↑ 5-hydroxyindoleacetic acid



SIGNS & SYMPTOMS ▪ Usually asymptomatic until liver metastasis; symptoms develop occasionally ▫ GI tract tumor → hormone secretion → enter into enterohepatic circulation → liver inactivates hormones → no symptoms ▫ Liver tumor → hormone secretion → released into circulation + liver dysfunction → symptoms ▪ Cutaneous flushing ▪ ↑ intestinal motility, diarrhea ▪ Collagen fiber thickening, fibrosis ▫ Heart valve dysfunction → tricuspid regurgitation, pulmonary stenosis (both right-sided) ▪ Bronchoconstriction, asthma, wheezing ▪ Pellagra (niacin/B3 deficiency) ▫ ↑ serotonin synthesis → ↓ tryptophan → ↓ niacin/B3 synthesis ▫ Dermatitis, diarrhea, dementia, death



Figure 20.1 The gross pathology a lung carcinoid tumor. The cut surface is firm and yellowish brown. The tumor has obstructed a nearby bronchus, leading to an obstructive pneumonia.



OSMOSIS.ORG 131



TREATMENT MEDICATIONS



▪ Somatostatin analogues ▪ Niacin supplementation ▪ Chemotherapy (if malignant)



SURGERY ▪ Resection



Figure 20.2 The histological appearance of a carcinoid tumorlet. The tumor cells form discrete nests.



MULTIPLE ENDOCRINE NEOPLASIA 1 (MEN1) osms.it/multiple-endocrine-neoplasia-1 PATHOLOGY & CAUSES ▪ Autosomal dominant disorder ▫ Characterization: predisposition for endocrine tumor development ▪ Tumors may be functional/non-functional (NF); benign/malignant; may affect one/ more tissues simultaneously



TYPES Parathyroid ▪ Most common Pancreas, duodenum ▪ Gastrinoma (ZES), insulinoma, glucagonoma, VIPoma Anterior pituitary adenoma ▪ Prolactinoma ▪ Other: corticotroph (ACTH) secreting, thyroid-stimulating hormone (TSH) secreting, growth hormone (GH) secreting, NF



132 OSMOSIS.ORG



Carcinoid ▪ Thymic, lung, gastric enterochromaffin-like tumor (NF) Adrenal cortical tumor ▪ NF



CAUSES



▪ Mutation of MEN1 gene located on chromosome 11 (11q13) ▫ Encodes protein menin (endocrine organ tumor suppressor) ▫ Menin function disruption/inactivation → clonal proliferation → somatic heterozygosity loss of remaining functional allele → endocrine neoplasia formation → primarily affects parathyroid, pituitary, pancreas (3Ps)



RISK FACTORS



▪ Mutant MEN1 inheritance



COMPLICATIONS



Chapter 20 Neuroendocrine Tumors ▪ Hyperparathyroidism: ↓ bone mineral density, nephrolithiasis ▪ Pituitary adenoma: mass effects (e.g. headache, diplopia, visual field defects), Cushing disease, acromegaly ▪ Gastrinoma: peptic ulcer disease, gastrointestinal bleeding ▪ Glucagonoma: necrolytic migratory erythema (NME) ▪ Metastasis, tumor recurrence



SIGNS & SYMPTOMS Clinical hormone imbalance, affected organ manifestations ▪ Hyperparathyroidism ▫ Hypercalcemia (e.g. muscle weakness, constipation) ▪ Pituitary adenoma ▫ Prolactinoma: menstrual irregularities, galactorrhea, ↓ libido, infertility ▫ ↑ GH: excessive bone, soft tissue growth; arthralgias ▫ ↑ ACTH: fat redistribution, plethoric facies, thin skin, striae ▫ ↑ TSH: hyperthyroidism (e.g. palpitations, tremulousness) ▪ Pancreatic tumors ▫ Glucose dysregulation (insulinomas, glucagonomas); watery diarrhea, hypokalemia, achlorhydria (WDHA) (VIPoma); steatorrhea (somatostatinoma), abdominal pain, gastroesophageal reflux (gastrinoma) ▪ Carcinoid tumors ▫ Dyspnea, wheezing (lung), nausea, vomiting, abdominal pain (gastrointestinal), clinical manifestations of Cushing’s syndrome (↑ ACTH from thymic tumor) Cutaneous manifestations ▪ Facial angiofibroma, lipoma, collagenoma



DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Identifies tumor, metastasis, organ structure



changes; TNM staging Upper GI endoscopy ▪ Identifies gastric, duodenal carcinoid tumors, peptic ulcers; allows biopsy Endoscopic ultrasound, somatostatin receptor scintigraphy ▪ Detects pancreatic neuroendocrine neoplasms (PanNETs)



LAB RESULTS Blood studies ▪ Parathyroid tumors ▫ ↑ basal serum calcium, ↑ serum PTH, hypercalciuria ▪ Anterior pituitary adenomas ▫ ↑ prolactin, ↑ ACTH, ↑ cortisol, ↑ GH ▪ PanNETs ▫ ↑ fasting gastrin, ↑ insulin, ↑ ↓ glucose, ↑ VIP



OTHER DIAGNOSTICS



▪ History, physical examination ▫ Occurrence of ≥ two primary MEN1 tumor types; identification of firstdegree relatives with similar findings ▪ MEN1 gene-mutation testing



TREATMENT MEDICATIONS



▪ Hyperparathyroidism ▫ Calcimimetic agents ▪ Prolactinoma ▫ Dopamine agonists ▪ Gastromas ▫ Proton pump inhibitors (PPIs) ▪ Glucagonomas, insulinomas, somatostatinoma, VIPoma ▫ Somatostatin analogue, antihyperglycemic agents ▪ Insulinoma ▫ Diazoxide



SURGERY



▪ Parathyroid tumor ▫ Parathyroidectomy, ethanol ablation



OSMOSIS.ORG 133



▪ Pituitary adenoma ▫ Gamma knife stereotactic radiosurgery, transsphenoidal surgical resection ▪ Glucagonoma, somatostatinoma, gastrinoma, insulinoma, VIPoma, carcinoid ▫ Tumor resection



OTHER INTERVENTIONS ▪ Correction of fluid, electrolyte, glucose, nutritional abnormalities ▪ Radiation therapy (e.g. pituitary adenoma)



MULTIPLE ENDOCRINE NEOPLASIA 2 (MEN2) osms.it/multiple-endocrine-neoplasia-2 PATHOLOGY & CAUSES ▪ Autosomal dominant disorder ▫ Characterization: predisposition for medullary thyroid carcinoma (MTC), pheochromocytoma, primary parathyroid hyperplasia



TYPES MEN 2A ▪ Most common type, AKA Sipple syndrome ▪ Variants ▫ Classic MEN2A with MTC, pheochromocytoma, primary hyperparathyroidism (milder than MEN1) (MEN2A with cutaneous lichen amyloidosis (CLA); MEN2A with Hirschsprung disease (HD)) ▫ Familial medullary thyroid carcinoma (FMTC) MEN 2B ▪ Variants ▫ MTC ▫ Pheochromocytoma ▫ Other features: mucosal neuromas (eyelid, lip, tongue), intestinal ganglioneuromas, marfanoid habitus, medullated corneal nerve fibers



CAUSES



▪ Defect in RET proto-oncogene located on



134 OSMOSIS.ORG



chromosome 10 (10q11.2) ▪ Encodes transmembrane tyrosine kinase receptor RET protein (integral to intracellular signalling that regulates cellular differentiation, proliferation) ▪ Mutation → RET activation → disulfidelinked RET dimerization → intracellular substrate phosphorylation → clinical syndromes



RISK FACTORS



▪ RET mutation presence



COMPLICATIONS



▪ MTC ▫ Hypercalcemia, cardiac arrhythmias, nephrolithiasis ▪ Parathyroid hyperplasia ▫ Hyperparathyroidism, nephrolithiasis, osteoporosis ▪ Pheochromocytoma ▫ Hypertension (therapy-resistant) ▪ HD ▫ Functional bowel obstruction, megacolon, enterocolitis ▪ Intestinal ganglioneuromas ▫ Bowel obstruction ▪ Metastasis



Chapter 20 Neuroendocrine Tumors



SIGNS & SYMPTOMS ▪ MTC/FMTC ▫ Palpable neck mass, cervical lymphadenopathy, facial flushing (peptide secretion by tumor), diarrhea (gastrointestinal fluid, electrolyte secretion from excess calcitonin); clinical Cushing’s syndrome manifestations (ectopic corticotropin (ACTH) production) ▪ Parathyroid hyperplasia ▫ Fatigue, muscle weakness, altered mental status, bone pain (↓ bone density), flank pain (nephrolithiasis), nausea, vomiting, thirst, frequent urination ▪ Pheochromocytoma ▫ Hypertension, paroxysms of palpitations, tachycardia, excessive sweating, facial flushing, tremors, anxiety (↑ catecholamines) ▪ HD ▫ Vomiting, abdominal distension, constipation ▪ CLA ▫ Scaly, papular, pigmented, lesions in either interscapular region/extensor surface extremities ▪ Intestinal ganglioneuromas ▫ Abdominal pain, gaseous distension ▪ Dysmorphic facies ▫ E.g. upper-eyelid margin thickening, eversion; nodules on tongue, vermilion border of lips



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Tumor identification, TNM staging Thyroid, neck ultrasound ▪ MTC ▫ Calcification presence



LAB RESULTS



▪ MTC ▫ ↑ carcinoembryonic antigen (CEA), ↑



serum calcitonin, pentagastrin/calcium stimulation test (↑ serum calcitonin) ▪ Parathyroid hyperplasia ▫ ↑ basal serum calcium, ↑ serum PTH, hypercalciuria ▪ Pheochromocytoma ▫ ↑ plasma fractionated metanephrines, ↑ 24-hour urine metanephrine



OTHER DIAGNOSTICS



▪ Medical history, family history, physical examination ▫ MEN 2A: ≥ two characteristic neoplasias in individual/close family members ▫ MEN 2B: mucosal neuromas of lips, tongue; marfanoid habitus; medullated corneal nerve fibers; gut ganglioneuromatosis; MTC ▫ FMTC ≥ four MTC cases in families without pheochromocytoma/ hyperparathyroidism ▪ Fine-needle aspiration (FNA) thyroid biopsy ▫ Histological analysis: MTC with large, pleomorphic, ↑ C cell number ▪ Rectal biopsy ▫ Absent ganglion cells (HD) ▪ Ophthalmic slit-lamp examination ▫ Detects thickened, medullated corneal nerve fibers ▪ Genetic RET mutation testing



TREATMENT MEDICATIONS ▪ Tyrosine kinase inhibitors ▪ Post-surgical hormone replacement ▪ Hyperparathyroidism ▫ Bisphosphonates/calcimimetics (cinacalcet) ▪ Cutaneous lichen amyloidosis ▫ Intralesional steroids, antihistamines, ultraviolet light/laser therapy



SURGERY



▪ Tumor resection (e.g. thyroidectomy, adrenalectomy, partial/cortex-sparing adrenalectomy) ▪ Lymphadenectomy



OSMOSIS.ORG 135



▪ HD ▫ Resect affected colon segment



NEUROBLASTOMA osms.it/neuroblastoma PATHOLOGY & CAUSES ▪ Neural crest cell tumor arising in adrenal gland/spinal cord ▪ Fetal development → oncogene, tumor suppressor gene mutation → adequate cellular differentiation failure → tumor formation ▪ Most common infant cancer; most occur in age < five; better prognosis ▪ Releases chemokines (esp. CXCL12) → stimulates cell growth, migration → metastasis ▪ Half metastasize to bone



▪ Abdominal mass Bone metastasis ▪ Pain, pathologic fractures ▪ Skull base fractures → battle, “racoon eyes” sign ▪ Myelosuppression → anemia, thrombocytopenia, leukopenia → fatigue, easy bruising, frequent infections



TYPES



▪ Three types: differentiation level



Undifferentiated ▪ Neural crest cells, AKA small blue round cells; contains nerve fibers, AKA neuropil Poorly differentiated ▪ Partially displays characteristics of differentiated, undifferentiated Differentiated ▪ Surrounded by myelin, AKA Schwannian stroma; better prognosis



SIGNS & SYMPTOMS ▪ Related to chemokine release; unspecific ▪ Fever; weight loss; sweating; fatigue Mass effect ▪ Horner syndrome → ptosis, miosis, anhidrosis ▪ Spinal cord compression syndromes → limb weakness, incontinence



136 OSMOSIS.ORG



Figure 20.3 The histological appearance of a neuroblastoma demonstrating Homer-Wright rosettes.



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Renal mass/mass adjacent to spinal nerve roots; confirm diagnosis



LAB RESULTS



▪ Catecholamine breakdown products: VMA, HMA



Complete blood count (CBC)



Chapter 20 Neuroendocrine Tumors



SURGERY



▪ Anemia, leukopenia



TREATMENT MEDICATIONS



▪ Localized ▫ Resection ▪ Metastatic ▫ Resection, bone marrow transplant



▪ Metastatic ▫ Chemotherapy



PANCREATIC NEUROENDOCRINE NEOPLASMS osms.it/pancreatic-ne-neoplasms PATHOLOGY & CAUSES ▪ AKA PanNETs ▫ Functional tumors arising from pancreatic neuroendocrine cells ▪ Unregulated hormone secretion → effect on target organs → hormone-related clinical syndrome



TYPES Insulinoma ▪ Rare functional tumor ▫ Arises from insulin producing pancreatic beta cells ▪ Most common functioning PanNET ▪ Usually benign, indolent, small (< 2cm/0.8in), solitary lesions; rarely malignant ▪ ↑ insulin secretion → hyperinsulinemia → ↓ hepatic gluconeogenesis → hyperinsulinemic hypoglycemia VIPoma ▪ Rare functional tumor ▫ Arises from pancreatic D-1 cells that produce vasoactive intestinal polypeptide (VIP) ▫ AKA Verner–Morrison syndrome/ pancreatic cholera syndrome ▪ Malignancy: 50% ▪ ↑ VIP secretion ▫ Cellular adenylate cyclase, cAMP



production by intestinal epithelial cells → secretion of fluid, sodium, chloride into intestinal lumen → high-volume secretory diarrhea Glucagonoma ▪ Rare functional tumor ▫ Arises from pancreatic glucagonproducing alpha cells ▪ Usually malignant ▪ Excessive glucagon ▫ ↑ liver’s catabolic action → ↑ amino acid oxidation, gluconeogenesis from amino acid substrates → glucagonoma syndrome (amino acid deficiency, ↑ blood glucose, glucose intolerance) ▫ Co-secretion of gastrin, VIP, serotonin, calcitonin → diarrhea Somatostatinoma ▪ Very rare somatostatin-secreting tumor ▫ Arises from pancreatic D-cells ▪ Commonly located within head of pancreas; may also arise from ampulla, periampullary region of duodenum; rarely in jejunum, liver, colon, rectum ▪ Usually malignant ▫ ↑ somatostatin → digestive organ inhibition → clinical syndrome



RISK FACTORS Insulinoma



OSMOSIS.ORG 137



▪ Multifocal insulinomas associated with MEN 1 VIPoma, glucagonoma ▪ Associated with MEN 1 Somatostatinoma ▪ Associated with MEN1, neurofibromatosis type 1 (NF1)



COMPLICATIONS Insulinoma ▪ Hypoglycemia, seizures, rarely metastasis Vipoma ▪ Dehydration, electrolyte imbalances, metastasis Glucagonoma ▪ NME, weight loss (secondary to hyponutrition) ▪ Diabetes, chronic diarrhea, venous thrombosis (deep vein thrombosis, pulmonary embolism) ▪ Neuropsychiatric complications (e.g. depression, psychosis, agitation, paranoid delusions) ▪ Metastasis Somatostatinoma ▪ Cholelithiasis, diabetes mellitus, metastasis



SIGNS & SYMPTOMS Insulinoma ▪ Whipple’s triad: hypoglycemia, hypoglycemia signs, intravenous (IV) glucose → symptom resolution ▫ Neuroglycopenic manifestations: visual disturbances, weakness, confusion ▫ Sympathetic/adrenergic manifestations: diaphoresis, tremors, palpitations, hunger VIPoma ▪ WDHA; stools tea-colored, odorless ▪ ↑ potassium secretion into large bowel → hypokalemia ▪ ↓ gastric acid secretion → hypochlorhydria ▪ ↑ glycogenolysis → hyperglycemia ▪ ↑ bone resorption → hypocalcemia



138 OSMOSIS.ORG



▪ ↑ vasodilation → flushing Glucagonoma ▪ Hyperglycemia, weight loss ▪ NME ▫ Erythematous, sometimes painful rash with papules/plaques on face, perineum, extremities; hair loss, nail dystrophy ▫ If mucous membranes affected: glossitis, angular cheilitis, stomatitis, blepharitis Somatostatinoma ▪ Classic syndrome ▫ ↓ cholecystokinin → colelithiasis ▫ ↓ pancreatic enzyme, ↓ intestinal lipid absorption → steatorrhea ▫ ↓ gastrin → hypochlorhydria ▫ ↓ insulin → diabetes mellitus ▪ Abdominal pain ▪ Weight loss



MNEMONIC: 6 Ds



Glucagonoma symptoms Dermatitis Diabetes Diarrhea Deep Venous Thrombosis Decreased Weight Depression



DIAGNOSIS DIAGNOSTIC IMAGING Endoscopic ultrasound ▪ Insulinoma, VIPoma, glucagonoma, somatostatinoma ▫ Detects small tumors, establishes local disease extent, allows for needle biopsy CT scan/MRI ▪ Insulinoma, VIPoma, glucagonoma, somatostatinoma ▫ Tumor localization, TNM staging CT scan ▪ VIPoma ▫ Homogeneous, well-circumscribed



Chapter 20 Neuroendocrine Tumors lesions; may have cystic regions ▪ Glucagonoma ▫ May appear solid/contain central lowattenuation areas ▪ Somatostatinoma ▫ Isodense; may be cystic MRI ▪ VIPoma, glucagonoma, somatostatinoma ▫ Low signal intensity on T1-weighted images, high signal intensity on T2weighted images



hyperchromasia, mitotic activity



TREATMENT MEDICATIONS Insulinoma ▪ Diazoxide: inhibits insulin release, enhances glycogenolysis VIPoma ▪ Somatostatin analogue



GLP-1 scintigraphy ▪ Insulinoma ▫ Identifies insulinoma via radiolabeled GLP-1 receptor imaging



Glucagonoma, somatostatinoma ▪ Somatostatin analogue ▪ Anti-hyperglycemic agents



Somatostatin receptor scintigraphy ▪ VIPoma, glucagonoma, somatostatinoma ▫ Detects metastases via radiolabeled form of somatostatin analog octreotide (Indium-111 [111-In]) pentetreotide



SURGERY



Functional PET imaging with 68-Ga DOTATATE ▪ Glucagonoma, somatostatinoma ▫ Detects small tumors



LAB RESULTS Insulinoma ▪ Overnight fasting plasma levels/72 hour fast test (inpatient) ▫ ↓↓ glucose, ↑ insulin, ↑ proinsulin, ↑ C-peptide VIPoma ▪ Hormonal assay: ↑ plasma VIP ▪ ↓ stool osmotic gap ( basal levels ▪ If other cause of hypergastrinemia ▫ Gastrin inhibition



OTHER DIAGNOSTICS ▪ MEN1 screening



142 OSMOSIS.ORG



MEDICATIONS



▪ Chemotherapy ▫ Metastatic disease



SURGERY ▪ Resection



OTHER INTERVENTIONS



▪ Proton pump inhibitors ▫ ↓ gastric acid ▪ Somatostatin analog ▫ ↓ gastrin levels; may slow tumor growth



Chapter 2 Acyanotic Defects



NOTES



THYROIDITIS GENERALLY, WHAT IS IT? DIAGNOSIS



PATHOLOGY & CAUSES ▪ Group of autoimmune disorders resulting in inflammation, destruction, and functional impairment of the thyroid gland



SIGNS & SYMPTOMS ▪ Hypothyroidism ▫ Weight gain despite reduced appetite, constipation ▫ Cold intolerance, fatigue, lethargy, weakness ▫ Brittle hair and nails, dry skin, hair loss (alopecia) ▫ Mental slowness (bradypsychia) ▫ Voice hoarseness → compression of recurrent laryngeal nerve ▫ Enlarged thyroid gland (goiter)



▪ Suspect based on clinical presentation



LAB RESULTS



▪ Serum antibody levels against thyroid components ▪ Thyroid biopsy via fine needle aspiration



TREATMENT MEDICATIONS



▪ Thyroid hormone replacement → levothyroxine



SURGERY



▪ Surgical removal if adjacent structures are affected



HASHIMOTO'S THYROIDITIS osms.it/hashimotos-thyroiditis PATHOLOGY & CAUSES ▪ Chronic autoimmune disorder leading to inflammation, gradual destruction and functional impairment of the thyroid gland resulting in hypothyroidism and increased risk of thyroid cancer ▪ Most common cause of hypothyroidism in areas where dietary iodine is sufficient ▪ Cause unclear; related to HLA-DR3 and HLA-DR5 genes; may occur in combination with Graves' disease; may be influenced by



environmental factors ▪ Hürthle cells ▫ Enlarged follicular cells with an eosinophilic, granular cytoplasm ▪ Gene mutation → B cell dysfunction → B cell thyroid invasion → B cell germinal centers established within thyroid → B cell activation and autoantibody production → NK cells signaled to destroy thyroid follicular cells + CD4+ cells produce inflammatory cytokines + CD8+ cells attack thyroid follicular cells → release of stored T3 and T4 → transient hyperthyroidism



OSMOSIS.ORG 143



→ burnout → hypothyroidism → compensatory increase in thyroidstimulating hormone (TSH), thyrotropinreleasing hormone (TRH) ▪ Chronic inflammation → connective tissue buildup → enlarged gland ▪ B cells have the potential to become malignant → B cell lymphoma of the thyroid ▫ Rare; usually in females over 70 with history of Hashimoto’s



SIGNS & SYMPTOMS Hypothyroidism ▪ Weight gain despite reduced appetite, constipation ▪ Brittle hair and nails, dry skin, hair loss (alopecia) ▪ Cold intolerance, fatigue, lethargy, weakness ▪ Mental slowness (bradypsychia) ▪ Enlarged, nodular thyroid gland (goiter) ▫ Non-tender, firm ▫ Voice hoarseness → compression of recurrent laryngeal nerve ▫ Stridor → tracheal compression ▪ Menstrual abnormalities, galactorrhea ▪ ↑ TRH → ↑ prolactin levels ▪ Myxedema ▫ Nonpitting edema caused by mucopolysaccharide deposition in upper skin layers ▫ Most common around tibial area, may also occur around eyes and feet ▪ Rapidly growing goiter suggests B cell lymphoma of the thyroid



▪ Perform fine needle aspiration (FNA) if B cell lymphoma of the thyroid suspected



TREATMENT MEDICATION



▪ Thyroid hormone replacement → levothyroxine



SURGERY



▪ Goiter affecting adjacent structures → surgical removal



Figure 21.1 The histological appearance of Hashimoto’s thyroiditis. The normal thyroid follicles are on the right. The lymphocytic infiltrate has replaced the normal thyroid tissue on the left.



DIAGNOSIS ▪ Suspect based on clinical presentation



LAB RESULTS



▪ ↓ T3 and T4 ▪ ↑ TSH and TRH ▪ Autoantibodies against thyroid peroxidase (anti-TPO) and against thyroglobulin (antiTG)



144 OSMOSIS.ORG



Figure 21.2 A low power image of Hashimoto’s thyroditis, showing the lymphoycytic infiltrate forming germinal centres.



Chapter 21 Thyroiditis



POSTPARTUM THYROIDITIS osms.it/postpartum-thyroiditis PATHOLOGY & CAUSES ▪ Autoimmune destruction of the thyroid gland occurring within one year after after parturition, resulting in transient thyroid dysfunction and thyroid hormone imbalance ▪ Related to normal fluctuations in maternal immune function in the setting of subclinical autoimmune thyroid disease ▪ Autoimmune-related thyroid inflammation (1–4 months postpartum) → damage to thyroid follicles and thyroglobulin → ↑ ↑ thyroxine (T4) and triiodothyronine (T3) release into the blood → hyperthyroidism (last 2–8 weeks) ▫ T4/T3 stores eventually used up + TSH-induced cessation of new thyroid hormone synthesis → transient hypothyroidism ▫ Resolution of inflammation → follicle regeneration → return to normal thyroid levels



RISK FACTORS



▪ Prior history of postpartum thyroiditis ▪ Pre-existing hypothyroidism (e.g. Hashimoto’s thyroiditis with remaining functional thyroid hormone) ▪ Type 1 diabetes mellitus ▪ Familial predisposition (possible inheritance pattern)



COMPLICATIONS



▪ Chronic hypothyroidism



SIGNS & SYMPTOMS ▪ Symptoms of hyper- and hypothyroidism are usually mild ▪ Hyperthyroid phase (↑ metabolic rate) ▫ Anxiety ▫ Heat intolerance ▫ Tachycardia, palpitations ▫ Tremor ▫ Fatigue ▫ Weight loss ▫ Diffuse, painless goiter ▪ Hypothyroid phase (↓ metabolic rate) ▫ Impaired concentration ▫ Cold intolerance ▫ Sluggishness ▫ Constipation ▫ Dry skin



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Radioactive iodine uptake ▫ Profoundly suppressed (test is contraindicated if breastfeeding)



LAB RESULTS



▪ Blood studies ▫ Hyperthyroid phase: ↑ T4, T3; ↓ TSH ▫ Hypothyroid phase: ↓ free T4, ↑ TSH ▫ ↑ antithyroid peroxidase antibodies ▪ Thyroid biopsy ▫ Lymphocytic thyroiditis - infiltration of lymphocytes, follicular destruction



OTHER DIAGNOSTICS



▪ History and physical examination



OSMOSIS.ORG 145



TREATMENT ▪ Mild symptoms require no treatment



MEDICATIONS



▪ Symptomatic hyperthyroidism: betablocker ▪ Symptomatic hypothyroidism: levothyroxine



RIEDEL'S THYROIDITIS osms.it/riedels-thyroiditis PATHOLOGY & CAUSES ▪ Rare autoimmune disorder leading to inflammation, fibrotic infiltration, gradual destruction, and functional impairment of the thyroid gland ▪ May be related to a systemic autoimmune fibrotic disease process ▪ Component of IgG4-related disease ▫ May also cause fibrosis of salivary glands, kidneys, pancreas and lungs ▪ IgG4 attacks thyroid follicular cells → T cells release inflammatory cytokines → abnormal fibroblast activation within thyroid stroma → stromal fibrosis replaces damaged follicles → gland enlarges and hardens → fibrosis spreads to neck structures (parathyroid glands, blood vessels, trachea, muscles, nerves)



SIGNS & SYMPTOMS ▪ Hardened, wood-like, fixed, painless and enlarged thyroid gland (goiter) ▪ Hypothyroidism ▫ Weight gain despite reduced appetite, constipation ▫ Brittle hair and nails, dry skin, hair loss (alopecia) ▫ Cold intolerance, fatigue, lethargy, weakness



146 OSMOSIS.ORG



▫ Mental slowness (bradypsychia) ▫ Bradycardia ▪ Other neck structures affected by compression ▫ Tracheal fibrosis → shortness of breath (dyspnea) ▫ Recurrent laryngeal nerve fibrosis → voice hoarseness ▫ Esophageal fibrosis → dysphagia ▫ Parathyroid gland fibrosis → hypocalcemia and tetany (hypoparathyroidism)



DIAGNOSIS ▪ Suspect based on clinical presentation



LAB RESULTS



▪ Autoantibodies against thyroid components (anti-TPO) ▪ ↓ T3 and T4 ▪ ↑ TSH and TRH ▪ Tissue biopsy ▫ Predominant fibrous tissue and collagen + lymphocyte infiltration



Chapter 21 Thyroiditis



TREATMENT MEDICATIONS



▪ Corticosteroids ▪ Tamoxifen may decrease goiter size ▪ Thyroid hormone replacement → levothyroxine



SURGERY



▪ Debulking or surgical removal if goiter affects adjacent structures



OSMOSIS.ORG 147



NOTES



NOTES



CHROMOSOMAL DELETION SYNDROMES



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Congenital syndromes: genetic deletions during parental gamete formation ▪ Mutation: permanent DNA change



TYPES Numerical ▪ Entire chromosome deletion (aneuploidy) Structural ▪ Structural change due to chromosome break → separated portion rearrangement ▫ Balanced rearrangement: without genetic material gain/loss; not associated with phenotypic anomaly ▫ Unbalanced rearrangement: with genetic material gain/loss; associated with phenotypic anomaly ▪ Deletion size: proportional to clinical severity



CAUSES



▪ Chromosomal breakage mechanism ▫ Endogenous: defect in DNA replication, transcription, recombination, repair ▫ Exogenous: radiation, chemical substances → DNA damage



RISK FACTORS



▪ Parental genetic defect



COMPLICATIONS



▪ Congenital heart defect; recurrent infection (e.g. urinary tract infections, otitis media); gastrointestinal abnormalities; severe constipation; impaired development; intellectual disability



148 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ Atypical facial features, short stature, noise sensitivity, additional organ defect-related signs/symptoms



DIAGNOSIS ▪ History, clinical examination



LAB RESULTS



▪ Genetic tests ▫ e.g. karyotyping, fluorescent in-situ hybridization (FISH)



TREATMENT OTHER INTERVENTIONS



▪ Early intervention education ▪ Physical, language, occupational therapy ▪ Associated condition treatment



Chapter 22 Chromosomal Deletion Syndromes



CRI DU CHAT SYNDROME osms.it/cri-du-chat PATHOLOGY & CAUSES ▪ Chromosomal deletion syndrome: physical, neurological congenital anomalies ▫ Caused by partial/total macrodeletion in short arm of chromosome 5 (5p-) ▫ AKA cat cry syndrome, 5p- syndrome, Lejeune’s syndrome ▫ Cri-du-chat: “cat’s cry” ▪ Inheritance pattern: mostly sporadic ▫ Paternal origin (most): sporadic chromosome breakage during male gamete formation ▫ Inherited Cri du chat syndrome (rare): parent with balanced translocation → child with unbalanced translocation (rearrangement with genetic material loss) in 5p ▪ Most due to terminal deletions



CAUSES



▪ Deletion ▫ 5p15.2: major clinical features (e.g. dysmorphism, intellectual impairment) ▫ 5p15.3: altered larynx anatomy, central nervous system (CNS) dysfunction → cat-like cry, high-pitched voice, speech delay ▪ CTNND2 gene loss: severe mental disability



RISK FACTORS



▪ Parental genetic defect ▪ Biologically-female individuals (more common)



COMPLICATIONS



gastrointestinal/genitourinary abnormalities



SIGNS & SYMPTOMS ▪ Cat-like cry, high-pitched voice: may resolve during infancy ▪ Poor feeding ▪ Facial features: microretrognathia (hypoplastic, posteriorly displaced mandible); round face; epicanthus (prominent eye folds); downslanting eyelids; hypertelorism (widely-spaced eyes); wide nasal bridge; low-set ears ▫ Physical signs become less prominent with age ▪ Body features: muscular hypotonia, short stature, short neck, small hands, single palmar crease, scoliosis, prenatal-growth deficiency, low birth weight ▪ Ocular: myopia, strabismus, cataracts ▪ Neurologic: noise sensitivity (hyperacusis); behavior alterations (e.g. aggression, hyperactivity, repetitive movement) ▪ Adulthood: small testes, premature hair graying (age ≥ 15), constipation ▫ Physical signs become less prominent with age



DIAGNOSIS LAB RESULTS



▪ Cytogenetic tests: FISH, karyotyping, chromosomal analysis ▪ Molecular genetics tests: heteroduplex analysis; single strand conformation analysis; whole genome sequencing; Southern, northern blotting



▪ Low birth weight; postnatal failure to thrive; microcephaly; developmental, mental disability; pneumonia; congenital heart defects; craniofacial dysmorphism; respiratory distress syndrome; hydrocephalus; chronic otitis media;



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TREATMENT OTHER INTERVENTIONS



▪ Early intervention education; physical, language, occupational therapy ▪ Associated condition treatment (e.g. heart defect repair)



Figure 22.1 The facial appearance of a child with Cri du chat syndrome.



WILLIAMS SYNDROME osms.it/williams-syndrome PATHOLOGY & CAUSES ▪ Chromosomal deletion syndrome: affects most organ systems ▫ AKA Williams–Beuren syndrome ▪ 26–28 genes involved ▪ Inheritance pattern: sporadic (mutation during gamete formation)



CAUSES



▪ Hemizygous microdeletion in long arm of chromosome 7 (7q11.23) ▫ Most chromosomal breaks in medial, centromeric duplicons (gene clusters organized in low-copy repeat blocks) ▪ May include elastin gene (ELN) deletion: involved in supravalvular aortic stenosis



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RISK FACTORS



▪ Parental genetic defect (e.g. Williams syndrome)



COMPLICATIONS



▪ Hypercalcemia/hypercalciuria; nephrocalcinosis; dysfunctional voiding; chronic kidney disease; urinary tract congenital anomalies; gastrointestinal conditions (e.g. chronic constipation, cholelithiasis); diabetes mellitus; diabetic nephropathy; progressive valvular stenosis; joint limitations; systemic arterial stenosis (esp. supravalvular aortic stenosis); hypothyroidism; type I Chiari malformation (cerebellar tonsils extend to foramen magnum); recurrent otitis media



Chapter 22 Chromosomal Deletion Syndromes



SIGNS & SYMPTOMS ▪ “Elfin”/pixie-like facies: flat nasal bridge, short upturned nose, long medial cleft, periorbital puffiness, full lips, wide mouth, broad forehead, medial eyebrow flare ▫ More distinctive with age ▪ Hoarse voice, high-tone sensorineural hearing loss, noise sensitivity (hyperacusis) ▪ Short stature ▪ Dental: small/abnormally shaped teeth, malocclusion ▪ Psychiatric: friendly, “cocktail party” personality; cognitive impairment; weak visuospatial/visuomotor skills; strong language skills; development delay; anxiety, phobias; obsessive-compulsive traits ▪ Neurologic: hyperreflexia; clonus; extrapyramidal signs (e.g. tremor, bradykinesia, dystonia); cerebellar signs (e.g. incoordination) ▪ Ocular: strabismus, amblyopia ▪ Gastrointestinal: constipation, gastroesophageal reflux, rectal prolapse ▪ Hypertension ▪ Hypercalcemia: irritability, ↓ appetite, constipation, hypotonia



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, echocardiogram ▪ Urinary tract abnormalities (e.g. bladder diverticula, renal aplasia) ▪ Cardiovascular: supravalvular aortic stenosis, “hourglass” aorta, left ventricular hypertrophy (occasionally)



LAB RESULTS



▪ Lab tests: altered thyroid function, hypercalcemia, hypercalciuria, ↑ serum creatinine ▪ Cytogenetic tests: FISH ▪ Comparative genomic hybridization



OTHER DIAGNOSTICS



▪ Audiologic tests: high-tone sensorineural hearing loss



TREATMENT OTHER INTERVENTIONS



▪ Early intervention education: physical, language, occupational therapy ▪ Associated condition treatment: e.g. aortic stenosis surgical repair, hypertension treatment



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NOTES



NOTES



CONNECTIVE TISSUE DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic disorders affecting synthesis of connective tissue components (e.g. fibrillin, collagen) ▪ Genetic mutation → dysfunctional protein (e.g. ↓ function fibrillin/collagen) → ↓ supportive function connective tissue → ↓ function of various organs, tissues ▪ Common disorders ▫ Marfan syndrome (fibrillin 1 mutation) ▫ Ehler–Danlos syndrome (various etiologies) ▫ Osteogenesis imperfecta (collagen Type I mutation) ▫ Alport syndrome (collagen Type IV mutation) ▪ Vary from dominant to recessive, range in severity



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SIGNS & SYMPTOMS ▪ May affect all organ systems containing connective tissue; esp. musculoskeletal, ocular, cardiovascular systems



DIAGNOSIS OTHER DIAGNOSTICS



▪ Standardized criteria ▪ Genetic testing (confirmation)



TREATMENT OTHER INTERVENTIONS ▪ Supportive due to the genetic basis of disease, not curable



Chapter 23 Connective Tissue Disorders



ALPORT SYNDROME osms.it/alport-syndrome PATHOLOGY & CAUSES ▪ Rare disorder caused by mutations in genes encoding for chains of Type IV collagen → abnormal basement membranes of kidney glomerulus, eye, cochlea ▫ AKA hereditary nephritis ▪ Mutation substitutes glycine with different amino acid → triple-helix unable to form → impaired basement membrane structure ▫ Glomerular basement membrane progressively hardens as abnormal Type IV collagen accumulates → thin glomerular basement membrane nephropathy ▫ Impaired ability of hair cells attached to basement membrane in organ of Corti (in cochlea) to generate nerve signals ▫ Thinning of lens capsule → disruption of lens shape → anterior lenticonus



TYPES X-linked ▪ COL4A5 on X-chromosome ▪ Presents early, most common form Autosomal recessive/dominant ▪ COL4A3, COL4A4 mutations Thin basement membrane nephropathy ▪ Mild mutations in COL4A3, COL4A5 ▪ Microscopic hematuria (sole symptom)



RISK FACTORS ▪ Family history



COMPLICATIONS ▪ End-stage renal disease, sensorineural hearing loss, changes in visual acuity, aortic aneurysms



SIGNS & SYMPTOMS ▪ Generally appear in early childhood/ adolescence ▪ Renal ▫ Progressive renal insufficiency, hypertension ▪ Eye ▫ Corneal abrasions, lens opacity, ocular pain ▪ Ear ▫ Initial high-frequency hearing loss → loss of normal speech



DIAGNOSIS LAB RESULTS Urinalysis ▪ Hematuria, proteinuria, ↑ creatinine



OTHER DIAGNOSTICS Clinical exam ▪ Renal failure with deafness, with no other apparent cause Ophthalmic examination ▪ Slit lamp examination of eye ▫ “Oil droplet” reflex ▪ Fundoscopy ▫ White/yellow granulations in retina (fleck retinopathy) Kidney/skin biopsy (confirmation) ▪ Immunohistochemistry (labelled antibody applied to biopsy, viewed on slide) ▫ Label usually identifies collagen alpha chains ▫ Misfolded collagen degraded; does not stain



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▪ Electron microscopy ▫ Early disease: thinning of glomerular basement membrane ▫ Later disease: glomerular basement membrane thin, thick, abnormal segments, split lamina densa (appears as woven basket) Gene testing ▪ Gene testing for COL4A genes ▫ Diagnostic procedure of choice due to noninvasive nature, accuracy



TREATMENT MEDICATIONS ▪ Renal ▫ Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers prevent progression to kidney failure, dialysis, kidney transplant



SURGERY ▪ Anterior lenticonus ▫ Replacement of lens



OTHER INTERVENTIONS ▪ Hearing loss may benefit from hearing aids



EHLERS–DANLOS SYNDROME (EDS) osms.it/ehlers-danlos_syndrome PATHOLOGY & CAUSES ▪ Defective collagen synthesis → group of rare connective tissue disorders → tissue fragility ▫ Single gene disorders ▫ Autosomal dominant/recessive ▫ 30 types of collagen may be affected ▫ 13 different Ehler–Danlos syndromes classified on distribution of tissue involvement



CAUSES ▪ Gene mutation (specific gene varies depending on type) → defective fibrous proteins/enzymes → ↑ elasticity of tissues, structure, ↓ strength of tissues ▪ Minor injuries → gaping defects → repair difficult due to low tensile strength



RISK FACTORS ▪ Family history



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COMPLICATIONS ▪ Colon, large artery, corneal rupture; retinal detachment, diaphragmatic hernias, premature arthritis; pregnancy complications (e.g. cervical insufficiency, premature rupture of membranes)



SIGNS & SYMPTOMS ▪ Skin ▫ Hyperextensive, fragile, vulnerable to trauma; easy bruising; atrophic scars ▪ Ligament laxity ▫ Hypermobile joints; joint dislocation predisposition (diagnosed by Beighton hypermobility scale); spinal malformations (e.g. scoliosis); osteochondrosis, arthritis; pain in muscles, joints ▪ Bones, joints ▫ Pes planus, pectus excavatum, high arched palate; islocations ▪ Cardiovascular



Chapter 23 Connective Tissue Disorders ▫ Spontaneous artery dissection; valvular disorders; arterial rupture; Raynaud’s phenomenon; impaired platelet aggregation ▪ Spontaneous organ rupture ▪ Cerebrovascular rupture



DIAGNOSIS OTHER DIAGNOSTICS ▪ Clinical exam ▫ Typical presentation (e.g. lens dislocation, cardiovascular incidents, hypermobility) ▫ Beighton score (evaluates hypermobility): nine criteria, four needed to establish hypermobility ▪ Ehler–Danlos specific genetic panel (confirmation) ▪ Skin biopsy



TREATMENT MEDICATIONS



▪ According to type ▫ Pain medication: nonsteroidal antiinflammatory drugs (NSAIDs) for arthralgia, myalgia



SURGERY



▪ According to type ▫ Joint surgery for severe arthritis



OTHER INTERVENTIONS



▪ According to type ▫ Education, counseling ▫ Physical therapy to prevent joint damage ▫ Casting/orthoses to stabilize joints ▫ Regular cardiovascular monitoring



Figure 23.1 Hypermobility at the wrist and metacarpophalangeal joints in an individual with Ehlers–Danlos syndrome.



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MARFAN SYNDROME osmosis.org/learn/marfan_syndrome PATHOLOGY & CAUSES ▪ Genetic disorder of defective connective tissue



CAUSES ▪ Fibrillin 1 structural protein dysfunction due to FBN1 gene mutation (locus 15q21) ▫ Autosomal dominant ▫ Compromised extracellular matrix (e.g. elastic fibers) ▫ Fibrillin loss → ↑ transforming growth factor beta (TGF-β) → ↓ vascular muscle, extracellular matrix → compromises strength, elasticity → Marfanoid appearance ▪ Skeleton, heart, blood vessels, eyes, lungs; most commonly affects aorta, ligaments, ciliary zonules supporting lens



▪ Hyperextensibility with inability to extend elbows 180º ▪ Scoliosis ▪ Pes excavatum, pigeon chest ▪ Arachnodactyly (long fingers) ▫ Thumb sign: thumb protrudes beyond ulnar margin when fist clenched ▫ Wrist sign: entire fingernail of fifth finger covered by thumb when wrapped around wrist ▪ Dolichocephaly ▫ Narrow skull



RISK FACTORS ▪ Family history



COMPLICATIONS ▪ Lens dislocation, aortic rupture, pneumothorax



SIGNS & SYMPTOMS ▪ Vary in severity, rarely present at birth (neonatal Marfan syndrome) Eyes ▪ Bilateral cranial, temporal dislocation of lens (ectopia lentis); highly specific ▪ Retinal detachment ▪ Downward slant of palpebral fissures Skeleton ▪ Tall, slim with long (↑ arm span to height ratio); slender limbs ▪ Narrow, arched palate



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Figure 23.2 An adolescent female with Marfan syndrome. She is taller than average and thin, with long arms and legs. Arachnodactyly is also seen. Heart ▪ Aortic root dilation, floppy valve syndrome (mitral valve), aortic dilation causes aortic valve insufficiency Lungs ▪ Blebs, bullae (dilated spaces filled with air predisposing to spontaneous pneumothorax)



Chapter 23 Connective Tissue Disorders Blood vessels ▪ Cystic medial necrosis of aorta, aortic incompetence, dissecting aortic aneurysms Skin ▪ Striae (stretch marks)



DIAGNOSIS OTHER DIAGNOSTICS ▪ History, physical exam ▫ Ghent nosology criteria: scale using major, minor indicators to establish Marfan diagnosis, max 20 points; includes family history, skeletal, vascular, ocular, pulmonary/skin symptoms (e.g. ectopic lens and aortic dissection) ▪ Genetic testing ▫ Confirmation of FBN1 mutation



TREATMENT MEDICATIONS ▪ Beta blockers (slow aortic dilation) ▪ Angiotensin receptor blockers (decrease TGF-β signalling, slow aortic dilation)



SURGERY ▪ Valve, lens replacement; aortic dissection repair



OTHER INTERVENTIONS



▪ Physiotherapy ▫ Restrict high-intensity exercise, scoliosis treatment ▪ Routine aortic, heart, ophthalmic screening



Figure 23.3 A contrast CT scan of the chest in the sagittal plane demonstrating aortic root dilation in an individual with Marfan syndrome.



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NOTES



NOTES



DNA REPLICATION & REPAIR DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of rare, inherited disorders; mutations in DNA maintenance, repair genes → spectrum of cancers (typically early-onset cancer diagnosis)



SIGNS & SYMPTOMS ▪ See individual conditions



DIAGNOSIS LAB RESULTS



▪ Genetic sequencing



OTHER DIAGNOSTICS ▪ Family history



TREATMENT OTHER INTERVENTIONS



▪ Adequate malignancy surveillance ▪ Minimize sun, radiation exposure



BLOOM SYNDROME osms.it/bloom-syndrome PATHOLOGY & CAUSES ▪ Rare autosomal recessive disease; extreme susceptibility to DNA damage, immune deficiency, cancer Pathogenesis ▪ Instability of DNA duplexes during recombination, repair, replication → DNA mutation → oncogenesis



CAUSES



▪ Mutation in BLM gene on chromosome 15q26.1 ▫ Encodes RecG helicase (AKA Bloom syndrome protein): helps maintain stability of DNA when duplexes



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unwound during recombination, repair, replication



RISK FACTORS



▪ Individuals of Ashkenazi Jewish descent



COMPLICATIONS



▪ Infertility (more common in individuals who are biologically male) ▪ Dehydration due to reflux, vomiting, diarrhea in infancy ▪ Immunodeficiency → secondary infection, early predisposition to cancer ▪ Limited intellectual ability ▪ Fetal intrauterine growth restriction



Chapter 24 DNA Replication & Repair Disorders



SIGNS & SYMPTOMS ▪ Microcephaly with proportionate small stature ▪ Sparse subcutaneous adipose tissue ▪ Integument: childhood rash (erythematous on nose, cheeks; worsens after sun exposure; persists 1–2 years); cafe-au-lait spots; hypopigmented skin lesions ▪ Facial anomalies



DIAGNOSIS LAB RESULTS



▪ Karyotype analysis ▪ Genetic testing (mutated BLM gene) ▪ ↓ immunoglobulins (IgM, IgA deficit > IgG), effector memory T-cells, memory B-cells



OTHER DIAGNOSTICS Physical examination ▪ Typical facies; body habitus; integument examination (erythematous rash, hyper/ hypopigmented lesions)



TREATMENT OTHER INTERVENTIONS ▪ No therapeutic options



Management ▪ Minimize radiation exposure (MRI/ ultrasound for diagnostic imaging); protect face from sun; IgG replacement for severe hypogammaglobulinemia; monitor fluid levels in infants Figure 24.1 A male child with Bloom syndrome. He has telangiectatic facial erythema, typical of the condition.



LI–FRAUMENI SYNDROME osms.it/li-fraumeni_syndrome PATHOLOGY & CAUSES ▪ Syndrome caused mutation of guardian of genome (TP53) → wide array of malignancies Pathogenesis ▪ Abnormal TP53 function → abnormal checkpoint inhibition, tumor suppression → damaged DNA cell proliferation → malignant transformation



▪ Abnormal TP53 function → dysregulated apoptosis signaling → proliferation of DNAdamaged cells → malignant transformation Diseases ▪ Sarcoma, leukemia, breast cancer, brain tumors (e.g. medulloblastomas, choroid plexus carcinomas), adrenocortical carcinoma



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CAUSES



▪ Autosomal dominant mutation on gene TP53, located on 17p3.1 chromosome (mostly missense mutations in exons 5, 8)



COMPLICATIONS



▪ Radiation-associated cancers



SIGNS & SYMPTOMS Sarcomas ▪ Growing, painless mass (arises with compression of surrounding structures) Osteosarcoma ▪ Localized pain for several months; soft tissue mass tender to palpation, commonly of long bones (e.g. femur, humerus) Breast cancer ▪ Breast mass (most common) Brain tumors ▪ Focal neurologic deficit Adrenocortical carcinomas ▪ Abdominal mass; hormone excess syndrome (e.g. Cushing, hyperaldosteronism, virilization, feminization)



DIAGNOSIS LAB RESULTS



▪ Genetic conformational testing ▪ ↑ hormonal levels in functional adrenocortical carcinoma, alkaline phosphatase in osteosarcoma setting



OTHER DIAGNOSTICS History ▪ Presence of malignancy ▪ Family history (diagnosis requires all three) ▫ Sarcoma diagnosed before age 45 ▫ First-degree relative with any cancer before age 45 ▫ First/second-degree relative with any cancer before age 45/sarcoma at any age



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TREATMENT SURGERY Resection ▪ Choroid plexus carcinoma (malignancyspecific therapy) Mastectomy + radiation therapy ▪ Breast cancer (malignancy-specific therapy)



OTHER INTERVENTIONS



▪ Management: surveillance of individuals, family members of diagnosed individuals ▫ Annual skin examination ▫ Noninvasive breast cancer screening at 18–20 years ▫ Regular diagnostic testing begins at 20–25 ▫ Colorectal cancer screening every 2–5 years, starting at 25 ▫ Whole body MRI recommended by American Association for Cancer Research ▪ Screening for ▫ Individuals with breast cancer < 31 years ▫ Individuals with adrenocortical carcinoma, regardless of age/family history ▫ Individuals with choroid plexus carcinoma ▫ Individuals with childhood sarcoma (except Ewing sarcoma)



Chapter 24 DNA Replication & Repair Disorders



XERODERMA PIGMENTOSUM osms.it/xeroderma-pigmentosum PATHOLOGY & CAUSES ▪ Rare autosomal recessive disease of nucleotide excision repair (NER) gene; extreme photosensitivity, early development of skin cancer ▪ Pathogenesis: UV light in setting of mutated NER gene → cross-linking of pyrimidine residues → inability for removal of covalently-linked pyrimidine residues → epithelial DNA mutation → ↑ oncogenesis risk



TREATMENT OTHER INTERVENTIONS



▪ No curative therapy ▪ Avoid sun ▪ Sunscreen, proper clothing (minimize photoreactivity, mitigate cancer risk) ▪ Basal, squamous cell cancer surveillance: annual skin examination



CAUSES



▪ Autosomal recessive mutation of NER gene on chromosome 9q22



COMPLICATIONS



▪ Basal, squamous cell carcinomas; melanoma ▪ Ocular: keratitis, opacification of cornea, iritis with synechiae formation, melanoma of choroid ▪ Neurologic abnormalities: primary neuronal degeneration ▪ Radiation complications: chromosome breakage → oncogenesis



SIGNS & SYMPTOMS ▪ Extreme photosensitivity to sunlight, abnormal pigmentation, xerosis (abnormal dryness of skin), telangiectasia, skin atrophy



Figure 24.2 A female child with xeroderma pigmentosum. There are numerous hyperkeratoses on the face as well as innumerable solar lentigines. Corneal scarring is also present.



DIAGNOSIS OTHER DIAGNOSTICS



▪ Clinical diagnosis: family history, photoreactivity history, physical examination (e.g. integument, ocular examination; xerosis, skin fragility, ocular complications)



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NOTES



NOTES



GENETIC MUTATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Permanent alterations of DNA sequence → clinically significant syndrome ▪ Germ cell mutations inherited ▪ Somatic cell mutations due to environmental factors (e.g. radiation) ▪ Physiologic, pathologic processes: evolution, immune system development, cancer Inheritance patterns ▪ Autosomal dominant: one genetic copy mutated ▪ Autosomal recessive: both genetic copies mutated ▪ X-linked (dominant/recessive): mutation in X chromosome; no transmission from father to son; individuals who are biologically male more frequently/severely affected ▪ Y-linked: mutation in Y chromosome; passed from father to son ▪ Codominant: two alleles affect same trait (e.g. ABO blood group) ▪ Mitochondrial: mutation in mitochondrial DNA; maternal inheritance



CAUSES Error during DNA replication ▪ Point mutation within coding sequences: substitution of single base; may occur as transition (e.g. purine → purine)/ transversion (e.g. purine → pyrimidine) ▫ Silent: codes same amino acid, no phenotypic change ▫ Missense: codes different amino acid, may cause phenotypic change (e.g. sickle cell anemia) ▫ Nonsense: early stop codon, produces nonfunctional protein, may cause



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▪



▪ ▪



▪ ▪



phenotypic change (e.g. adrenal gland hyperplasia) Point mutation within noncoding sequences: mutation of promoter/ enhancer sequences → reduced/abolished transcription Deletion: removal of bases Insertion: addition of bases ▫ Splice site mutation: altered splicing of mRNA ▫ Frameshift: shifted reading frame Trinucleotide-repeat mutation: ↑ trinucleotide repeats Disorders of imprinting: one gene copy silenced by methylation (e.g. Prader–Willis syndrome)



TYPES Mendelian disorder ▪ Single gene mutation, large effects Chromosomal disorder ▪ Numerical: insertion/deletion of entire chromosome (e.g. trisomies, aneuploidies) ▪ Structural: change in genetic sequence Complex multigenic disorder (polymorphism) ▪ Genes increase risk of disease, no gene capable of causing disease on own (e.g. hypertension, diabetes mellitus)



RISK FACTORS ▪ Parental genetic defect ▪ Exposure to radiation, carcinogens



COMPLICATIONS ▪ Spontaneous abortion; severe organ defects (e.g. tetralogy of Fallot, renal dysplasia); visual/hearing disturbances;



Chapter 25 Genetic Mutations growth deficiency; intellectual disability; cancer



SIGNS & SYMPTOMS ▪ Abnormal physical features ▪ Organ defect-related signs/symptoms



LAB RESULTS ▪ Altered blood tests, hormones, liver enzymes



OTHER DIAGNOSTICS ▪ History, physical examination ▪ Genetic tests



TREATMENT



DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan ▪ Evidence of organ defects (e.g. fibrous dysplasia, cardiac malformations)



SURGERY ▪ Surgical repair of significant defects



ALAGILLE SYNDROME (ALGS) osms.it/alagille-syndrome PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → liver, skeletal, ocular, cardiac, renal defects ▪ AKA arteriohepatic dysplasia, Alagille– Watson syndrome ▪ Variable penetrance; severity related to size of deletion ▪ Sometimes associated with somatic/ germline mosaicism ▪ Individuals susceptible to additional mutations



CAUSES ▪ Mutation/deletion related to notch signalling pathway (involved in angiogenesis, cell proliferation, differentiation) ▫ 95% involve JAG1 gene (chromosome 20p12) ▫ NOTCH2 gene (chromosome 1p.13); related to renal malformations ▪ Results in absence of intrahepatic bile ducts → ↑ risk of progressive liver disease → chronically elevated bilirubin, cholesterol



COMPLICATIONS ▪ ▪ ▪ ▪



Malabsorption Pancreatic insufficiency Abnormal vertebral segmentation Vascular anomalies (e.g. basilar artery aneurysm; ↑ risk of intracranial bleeding)



Liver ▪ Chronic cholestasis (95%), cirrhosis, liver failure Cardiac ▪ Peripheral pulmonary artery stenosis, tetralogy of Fallot Ocular ▪ Shallow anterior chamber, keratoconus, embryotoxon (prominent Schwalbe’s ring), Axenfeld anomaly (embryotoxon + attached iris strands), pigmentary retinopathy, cataracts Renal ▪ Dysplasia, renal tubular acidosis



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SIGNS & SYMPTOMS ▪ Intellectual disability, learning difficulties ▪ Hepatosplenomegaly Cholestasis ▪ Jaundice, pruritus, xanthomas (cholesterol deposits in skin) Facial features ▪ Triangular face, prominent forehead, hypertelorism (widely-spaced eyes), deepset eyes, upslanting eyelids, long nose with bulbous tip, large ears, prominent mandible, pointed chin; more prominent with age Growth deficiency ▪ Short stature



DIAGNOSIS DIAGNOSTIC IMAGING Spinal X-ray ▪ Butterfly-shaped vertebrae, hemivertebrae, spina bifida occulta



LAB RESULTS



▪ ↑ bilirubin (total, conjugated), ↑ liver enzymes, ↑ cholesterol ▪ Liver biopsy: intrahepatic bile duct paucity, portal inflammation



OTHER DIAGNOSTICS



▪ History, clinical examination ▪ Genetic tests



TREATMENT MEDICATIONS



▪ Choleretic agents: ursodeoxycholic acid + cholestyramine/rifampin/naltrexone



SURGERY ▪ Biliary diversion/liver transplantation ▪ Heart defect surgical repair



OTHER INTERVENTIONS ▪ Nutritional support



Abdominal ultrasound ▪ Kidneys: small, echogenic, presence of cysts, ureteropelvic obstruction



MCCUNE–ALBRIGHT SYNDROME osms.it/mccune-albright_syndrome PATHOLOGY & CAUSES ▪ Genetic disorder characterized by fibrous dysplasia (FD), endocrinopathy, unilateral café-au-lait skin spots ▪ Occurs most commonly in skull base/ proximal femur; most lesions appear < age 15 ▪ External beam radiotherapy: ↑ risk of malignant transformation ▪ More common among individuals who are biologically female



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▪ Post zygotic mutation in GNAS1 gene (20q.13.1-13.2) ▫ Encodes Gs alpha protein → G protein/ cAMP/adenylate cyclase signaling pathway ▪ Somatic mosaicism: some somatic cells mutated



COMPLICATIONS



▪ Pathologic fractures; osteosarcoma; osteomalacia; visual/hearing disturbances (due to nerve compression); severe pain; scoliosis; ovarian cysts; acromegaly,



Chapter 25 Genetic Mutations gigantism; Mazabraud syndrome (fibrous dysplasia + intra/juxtamuscular myxoma); liver disease; higher risk of thyroid, testicular, breast cancer



LAB RESULTS



SIGNS & SYMPTOMS



GH excess ▪ ↑ GH, ↑ prolactin



Clinical triad ▪ Bone fibrous dysplasia ▫ Limp, pain, dysmorphism ▪ Hyperfunctioning endocrinopathy ▫ Hyperthyroidism: change in appetite, insomnia, fatigue, palpitations ▫ Cushing’s syndrome: moon facies, plethora, hirsutism ▫ Growth hormone (GH) excess: enlarged facial/body features, excessive sweating, thickened skin ▫ Renal phosphate wasting: usually asymptomatic; weakness, pain, altered mental status ▫ Precocious puberty: early vaginal bleeding, breast development in individuals who are biologically female; early testicular/penile enlargement, scrotal rugae, body odor, pubic/axillary hair, sexual behaviour in individuals who are biologically male ▪ Café-au-lait skin spots ▫ Brown macules, irregular borders (“coast of Maine”); mostly on lower back, buttocks



DIAGNOSIS DIAGNOSTIC IMAGING X-ray, radionuclide bone scan ▪ Long bones: expansile, lytic lesions; endosteal scalloping (focal resorption of cortex inner layer), cortex thinning, “ground-glass” appearance of medulla; epiphysis usually spared ▫ Proximal femur: “shepherd’s crook” malformation ▪ Skull: sclerotic lesions, “ground-glass” appearance, cyst-like lesions



Hyperthyroidism ▪ ↓ thyroid stimulating hormone (TSH), ↑ triiodothyronine (T3)



Cushing’s syndrome ▪ ↑ 24-hour urinary free cortisol Renal phosphate wasting ▪ ↑ urinary phosphate, ↓ serum phosphate Precocious puberty ▪ ↑ testosterone/estradiol, ↓ luteinizing hormone (LH), ↓ follicle-stimulating hormone (FSH) Bone tissue biopsy ▪ Absence of lamelation pattern, “Chinese writing” pattern, areas of unmineralized osteoid



OTHER DIAGNOSTICS ▪ History, physical examination ▪ Genetic tests (e.g. polymerase chain reaction, next-generation sequencing)



TREATMENT MEDICATIONS ▪ Bisphosphonate treatment for pain management (no effect on disease progression) ▪ Medication for endocrine disorders (e.g. gonadotropin releasing hormone analogues, tamoxifen, thionamides)



SURGERY ▪ Surgical management of fibrous dysplasia (e.g. intramedullary devices, bone grafting)



OTHER INTERVENTIONS ▪ Physical exercise (e.g. cycling, swimming) ▫ ↑ bone support → ↓ fracture risk



Thyroid ultrasound ▪ Presence of cystic areas



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PRIMARY CILIARY DYSKINESIA osms.it/primary-ciliary-dyskinesia PATHOLOGY & CAUSES ▪ Congenital disease; defect in cilia motility → impaired mucociliary clearance, decreased fertility ▪ AKA immotile-cilia syndrome ▪ Affects cilia of respiratory tract, fallopian tubes, sperm flagella ▪ Inheritance pattern: autosomal recessive



CAUSES ▪ Defect in proteins of cilia structure → absent/altered motion (e.g. clockwise rotation) ▪ Genetic mutations ▫ DNAH5, DNAI1: encode axonemal outer dynein arms ▫ RSPH4A, RSPH9: encode radial spokes



COMPLICATIONS ▪ Chronic sinusitis; Kartagener’s syndrome (situs inversus, chronic sinusitis, and bronchiectasis); hydrocephalus; transposition of great vessels; epispadias; pectus excavatum; chronic secretory otitis media; conductive hearing loss



SIGNS & SYMPTOMS ▪ Recurrent upper/lower respiratory tract infections: chronic cough, mucopurulent sputum; symptoms increase during course of day ▪ Newborns: present with mild respiratory distress (tachypnea, mild hypoxemia) ▪ Bronchiectasis: crackles, wheezes ▫ Exacerbation: dark sputum, dyspnea, pleuritic pain ▪ Rhinosinusitis: runny nose, constant congestion, nasal polyps, altered sense of smell ▪ Fatigue, headaches



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▪ Infertility ▪ ↓ aerobic fitness



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan ▪ Pulmonary hyperinflation, peribronchial thickening, atelectasis, bronchiectasis; situs inversus



LAB RESULTS ▪ Reduced/absent nasal nitric oxide (also present in some cases of cystic fibrosis) Cell culture ▪ Inferior concha epithelium: tissue culture → cilia shed → emergence of new, immotile cilia → diagnosis confirmation



OTHER DIAGNOSTICS



▪ Spirometry: obstructive pattern ▪ Genetic tests



Ciliary motion, ultrastructure ▪ High speed video microscopy analysis (HSVA): live examination of respiratory epithelial cells; after air-liquid interface/ cooling → assessment of motion pattern, beat frequency ▪ Transmission electron microscopy (TEM): observation of ciliary ultrastructure defects



TREATMENT MEDICATIONS



▪ Bronchiectasis ▪ Antibiotics, airway hydration (e.g. nebulized hypertonic saline), mucolytic agents



Chronic rhinitis ▪ Nasal saline lavage + intranasal glucocorticoids



Chapter 25 Genetic Mutations



SURGERY Chronic rhinitis ▪ Polyp removal



OTHER INTERVENTIONS



▪ Smoking cessation ▪ Pneumococcus, influenza vaccination



Bronchiectasis ▪ Daily chest physiotherapy



TREACHER COLLINS SYNDROME osms.it/treacher-collins-syndrome PATHOLOGY & CAUSES ▪ Severe genetic disorder of craniofacial development ▪ AKA mandibulofacial dysostosis, Franceschetti–Zwahlen–Klein syndrome ▪ Inheritance pattern: autosomal dominant, variable penetrance; 60% spontaneous



CAUSES



▪ TCOF1 gene mutation (chromosome 5q32) → treacle protein (ribosome biogenesis regulator) insufficiency → neuroepithelial cell apoptosis → ↓ neural crest cells → first, second branchial arch anomalies → cranioskeletal hypoplasia ▪ Other genetic mutations: POLR1C (6q21.2), POLR1D (13q12.2); involved in ribosome biogenesis



COMPLICATIONS ▪ Perinatal death; bilateral conductive hearing loss; speech problems; airway compromise; feeding difficulties; visual loss; brachycephaly; choanal atresia; congenital heart defects; intellectual disability; renal malformation



SIGNS & SYMPTOMS ▪ Facial bone hypoplasia (esp. mandible, zygomatic bone): retrognathia, sunken cheeks ▪ Facial asymmetry ▪ Projection of scalp hair to lateral cheek ▪ Dental: high/arched/cleft palate; malocclusion, tooth agenesis, enamel opacities ▪ Ocular: downslanting eyelids, lower eyelid coloboma, paucity of eyelashes medial to notch, hypertelorism (widely spaced eyes) ▪ Malformation of external ear, external auditory canals, middle ear ossicles



DIAGNOSIS DIAGNOSTIC IMAGING Cranial X-ray, orthopantomogram, CT scan ▪ Facial bone hypoplasia, altered middle ear ossicles, external auditory canal stenosis



OTHER DIAGNOSTICS



▪ History, clinical examination ▪ Prenatal: amniocentesis, chorionic villus sampling



OSMOSIS.ORG 167



TREATMENT SURGERY



▪ Reconstructive surgery ▪ Tracheostomy (severe airway obstruction at birth) ▪ Glossopexy (tongue-lip adhesion) ▪ Corrective surgery for cleft lip/palate/ choanal atresia ▪ Gastrostomy tube placement



OTHER INTERVENTIONS ▪ Supportive treatments (e.g. hearing aid, speech therapy)



168 OSMOSIS.ORG



Figure 25.1 The face of a female child with Treacher Collins syndrome.



Chapter 2 Acyanotic Defects



NOTES



IMPRINTING DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic, epigenetic mutations/defects within imprinting controlling regions of genes ▪ Disruption of methylation of cytosine bases in CpG dinucleotides of DNA



RISK FACTORS



▪ Increased incidence in individuals conceived using assisted reproductive technology



SIGNS & SYMPTOMS ▪ Angelman syndrome ▫ Seizures, severe intellectual disability, jerky/tremulous limbs, characteristic facial appearance (e.g. large mouth, protruding tongue, prominent nose), excitability, impaired speech ▪ Beckwith–Wiedemann syndrome ▫ Premature birth, abdominal wall defects, embryonal tumors ▪ Prader–Willi syndrome ▫ Infancy: poor feeding, low muscle tone, weak cry, diminished reflexes ▫ Early childhood obesity, developmental delay, behavioral problems ▫ Dysmorphic facial features



DIAGNOSIS OTHER DIAGNOSTICS



▪ History, clinical examination ▪ Fluorescence in situ hybridization (FISH), genotyping, methylation DNA testing ▪ Methylation-sensitive multiplex ligation probe analysis (MS-MLPA)



TREATMENT MEDICATIONS



▪ Angelman syndrome: antiepileptic therapy ▪ Prader–Willi syndrome: thyroid, sex hormone replacement therapy



OTHER INTERVENTIONS



▪ Angelman syndrome: speech therapy ▪ Beckwith–Wiedemann syndrome: tumor surveillance, abdominal wall repair ▪ Prader–Willi syndrome: food restriction, vitamin D/calcium supplements



OSMOSIS.ORG 169



ANGELMAN SYNDROME osms.it/angelman-syndrome PATHOLOGY & CAUSES ▪ Genetic neurological disorder; severe developmental delay, intellectual disability, absence of speech, ataxia, dysmorphic features, unprovoked episodes of laughter



CAUSES



▪ Maternal 15q11-q13 deletion ▪ Loss of function of UBE3A ▪ Paternal uniparental disomy 15 (both copies of chromosome 15 from father)



SIGNS & SYMPTOMS ▪ Seizures, severe intellectual disability ▪ Ataxia, toe-walking, jerky/tremulous limbs ▪ Hypopigmentation, microcephaly, maxillary hypoplasia, large mouth, protruding tongue, prominent nose, wide-spaced teeth ▪ Inappropriate laughter (“happy puppet”), excitability, impaired speech



170 OSMOSIS.ORG



DIAGNOSIS OTHER DIAGNOSTICS



▪ FISH, genotyping, methylation DNA testing



TREATMENT MEDICATIONS



▪ Antiepileptic therapy for seizures



OTHER INTERVENTIONS



▪ Speech therapy; emphasis on nonverbal methods of communication



Chapter 26 Imprinting Disorders



BECKWITH–WIEDEMANN SYNDROME osms.it/beckwith-wiedemann_syndrome PATHOLOGY & CAUSES ▪ Pediatric overgrowth syndrome; visceromegaly, predisposition to tumors



CAUSES



▪ Error in imprinted gene expression in chromosome 11p15.5 region ▪ Usually sporadic, may be inherited in autosomal dominant fashion



SIGNS & SYMPTOMS Fetal macrosomia, premature birth Macroglossia Renal medullary hyperplasia Abdominal wall defects ▫ Omphalocele, umbilical hernia, diastasis recti ▪ Hypoglycemia due to islet cell hyperplasia ▪ Puberty, episeal fusion (early symptoms) ▪ Embryonal tumors (e.g. Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)



▪ ▪ ▪ ▪



DIAGNOSIS OTHER DIAGNOSTICS



▪ Clinical diagnosis ▪ MS-MLPA ▫ Detect majority of epigenetic, genetic etiologies



TREATMENT OTHER INTERVENTIONS



▪ Tumor surveillance with abdominal MRI/CT scan ▪ Abdominal wall repair for omphalocele ▪ Assess, treat airway insufficiency; feeding evaluation in presence of macroglossia ▪ Assess, treat hypoglycemia for neonates



OSMOSIS.ORG 171



PRADER–WILLI SYNDROME osms.it/prader-willi_syndrome PATHOLOGY & CAUSES ▪ Genetic multisystem disorder; weak muscle tone; delayed growth, development; behavioral abnormalities (e.g. insatiable hunger)



CAUSES



▪ Paternal 15q11-q13 deletion (maternal gene unchanged) ▪ Maternal uniparental disomy 15 (both copies of chromosome 15 from mother) ▪ Defects in imprinting center controlling chromosome 15 activity of genes ▪ Associated with dysregulation of hypothalamic-pituitary axis



COMPLICATIONS



▪ Sleep apnea (central/obstructive), scoliosis, osteoporosis, hypothyroidism, Type II diabetes



SIGNS & SYMPTOMS ▪ Infancy ▫ Poor feeding, low muscle tone, weak cry, diminished reflexes ▪ Overeating (hyperphagia), early childhood obesity ▪ Developmental delay ▫ Intellectual disability; delayed motor, language development ▪ Behavioral problems ▫ Inflexibility, obsessive-compulsive characteristics ▪ Low sex hormones in childhood, hypogenitalism/hypogonadism; cryptorchidism in individuals who are biologically male



172 OSMOSIS.ORG



▪ Dysmorphic facial features in childhood ▫ Almond-shaped eyes, narrow forehead, thin upper lip ▪ Small hands/feet, short stature



DIAGNOSIS OTHER DIAGNOSTICS



▪ History, clinical examination ▪ Fluorescence in situ hybridization (FISH), genotyping, methylation DNA testing



TREATMENT MEDICATIONS



▪ Human recombinant growth hormone therapy ▫ Decrease body weight/fat, increase muscle mass ▪ Address complications ▫ Thyroid, sex hormone replacement therapy



OTHER INTERVENTIONS



▪ Food restriction ▪ Address complications ▫ Vitamin D, calcium supplements



Chapter 2 Acyanotic Defects



NOTES



SEX CHROMOSOME DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders caused by numeric abnormalities (addition/loss)/structural damage of one/ both sex chromosomes (X, Y) ▪ Occur in approx. 1/448 live births ▪ Phenotypes less severe than autosomal defects due to X chromosome inactivation, low gene content of Y chromosome



SIGNS & SYMPTOMS ▪ Delay in puberty onset, absence of menstruation, ambiguous genitalia, infertility



DIAGNOSIS LAB RESULTS



▪ Prenatal fetus chromosomal analysis ▫ Amniocentesis, chorionic villi sampling of placenta



TREATMENT MEDICATIONS



▪ Hormone replacement therapy



OTHER INTERVENTIONS



▪ No corrective treatment available



KLINEFELTER'S SYNDROME osms.it/klinefelters-syndrome PATHOLOGY & CAUSES ▪ Extra copy of X chromosome in individuals who are biologically male due to sex chromosome nondisjunction during maternal/paternal meiotic division ▪ Most common ▫ 47, XXY karyotype ▪ Less common ▫ Greater/lesser numbers of X chromosome 48,XXXY, 49,XXXXY, 46,XY/4,XXY mosaicism karyotypes ▪ Greater number X chromosomes → greater phenotypic abnormalities ▪ Most common sex chromosome abnormality; occurs in approx. 1/1000 live



births ▪ Leads to primary hypogonadism, impaired cognitive development



COMPLICATIONS



▪ Increased risk for psychiatric disorders, autism ▪ Problems with social interactions ▪ Delayed speech, language competence



Predisposition to diseases ▪ May result in death ▪ Pulmonary ▫ Chronic bronchitis, emphysema ▪ Thromboembolic cancers ▫ Germ cell tumors, breast cancer



OSMOSIS.ORG 173



(morbidity much higher in individuals with Klinefelter), non-Hodgkin lymphoma ▪ Leg ulcers ▪ Diabetes mellitus



SIGNS & SYMPTOMS ▪ Newborns who are biologically male, phenotypically normal (e.g. with male external genitalia) ▪ Tall stature with decreased upper to lower extremity ratio due to decreased levels of testosterone, unsuppressed folliclestimulating hormone (FSH), luteinizing hormone (LH) ▪ Decreased testes size ▪ Increased levels of serum FSH, LH ▪ Variably decreased levels of serum testosterone → breast enlargement (increased risk of breast cancer); reduced facial, body hair; infertility



DIAGNOSIS LAB RESULTS



▪ Blood/urine test ▫ Abnormal hormone levels ▪ Karyotype analysis



OTHER DIAGNOSTICS



▪ Postnatally, observe signs of physical clinical manifestations ▫ Evaluation for infertility, enlarged breast tissue ▫ May present with cryptorchidism (undescended testes)



TREATMENT MEDICATIONS



▪ Testosterone replacement therapy; stimulate changes that typically occur during puberty (e.g. facial, body hair growth; increased muscle mass, penis size; improved bone density)



SURGERY



▪ Breast tissue removal



PSYCHOTHERAPY



▪ Psychological counseling



OTHER INTERVENTIONS



▪ Sex chromosome changes can’t be corrected ▪ Supportive therapy minimizes adverse effects, improves quality of life ▫ Speech therapy ▫ Fertility treatment



Figure 27.1 The body habitus of an individual with Klinefelter’s syndrome. The body type is rounded with prominent gynecomastia.



174 OSMOSIS.ORG



Chapter 27 Sex Chromosome Disorders



TURNER SYNDROME osms.it/turner-syndrome PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Completely/partially missing X chromosome in individuals who are biologically female ▫ Monosomy 45,X karyotype (most common) ▫ Mosaic X chromosome monosomy: 45,X/46,XX, 45,X/46,XY ▫ X chromosome abnormalities



▪ Newborns ▫ Congenital lymphedema (hands, feet), webbed neck, short fourth metacarpal ▪ Short stature, broad chest with widely spaced nipples, low hairline



COMPLICATIONS



DIAGNOSTIC IMAGING



▪ Primary hypogonadism ▪ Predisposition to several diseases, may result in death ▫ Cardiovascular: typically involves left outflow, coarctation of aorta (e.g. aortic valve abnormalities, elongated transverse aortic) ▫ Congenital renal anomalies: system, positional malformations ▪ Hearing loss, hypothyroidism, liver function abnormality incidences increase with age ▪ Low bone mineral density (BMD) ▫ Prone to fractures ▪ Ovarian insufficiency, infertility: premature oocyte death, degeneration of ovarian tissue ▪ Increased risk for learning disabilities, attention-deficit/hyperactivity disorder (ADHD)



DIAGNOSIS Fetal ultrasound ▪ Cardiac/renal abnormalities, short femur



LAB RESULTS



▪ Karyotype analysis



TREATMENT MEDICATIONS



▪ Growth hormone therapy ▫ Promote height and bone growth ▪ Estrogen therapy ▫ Promote breast, uterine development



OSMOSIS.ORG 175



NOTES



NOTES



TRINUCLEOTIDE REPEAT EXPANSION DISEASES



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of genetic diseases; mutations characterized by increased number of 3 base pair repeats ▫ C, G nucleotides: loci at which repeats expanded ▪ Mechanism of disease ▫ Loss-of-function: transcriptional silencing ▫ Toxic, gain-of-function: may occur at mRNA, translational level/protein structure level



RISK FACTORS



SIGNS & SYMPTOMS ▪ See individual diseases



DIAGNOSIS LAB RESULTS



▪ Genetic testing for number of repeats



OTHER DIAGNOSTICS



▪ Family history, physical examination (disease-specific, pathognomonic findings)



TREATMENT



▪ Family history



OTHER INTERVENTIONS



COMPLICATIONS



▪ Anticipation ▫ More severe, earlier-onset of disease as mutation passed down



▪ No curative treatment currently available ▪ Symptom management (hallmark of therapy)



FRAGILE X SYNDROME osms.it/fragile-x-syndrome PATHOLOGY & CAUSES ▪ Autosomal recessive, X-linked disease; intellectual disability, typical facies, macroorchidism



176 OSMOSIS.ORG



▪ Inherited defect in 5’ untranslated region (UTR) of familial mental retardation-1 (FMR1) gene → trinucleotide expansion → abnormal length → ↑ methylation → promoter region methylation → ↓ transcription of FMR1 gene → ↓ familial mental retardation protein (FMRP) synthesis → clinical phenotype



Chapter 28 Trinucleotide Repeat Expansion Diseases FMRP ▪ High concentration in testes, brain ▪ mRNA transport protein ▫ ↓ FMRP → ↓ transport of neuronal proteins from perinuclear space → dendritic spines → dysregulated synaptic function ▪ Translation regulator ▫ ↓ FMRP → via ↑ metabotropic glutamate receptor activity → ↑ translation of bound mRNA at synaptic junction → dysregulated synaptic activity → intellectual disability



CAUSES Trinucleotide (CGG) repeat expansion ▪ Trinucleotide (CGG) repeat expansion on 5’ UTR FMR1 gene at Xq27.3 locus ▫ 45–54: intermediate expansion repeat number ▫ 55–200: carrier/premutation individual repeat number ▫ 200–4,000: affected individual repeat number Inheritance ▪ Autosomal recessive (some caveats) ▪ Mutations occur/worsen during oogenesis, not spermatogenesis → abnormal autosomal recessive expression ▫ 20% of disease-genotype individuals who are biologically male: asymptomatic, carriers ▫ 30–50% of genotypically carrier individuals who are biologically female: symptomatic (preferential X-chromosome inactivation → inconsistent mutation expression → variable symptom presentation) ▪ Anticipation ▫ Genetic mutations continue through pedigree → ↑ length of expansion → ↑ severity of disease



RISK FACTORS



▪ Genotype-phenotype correlation ▫ Repeat size, methylation mosaicism: ↑ % cells with same expression/methylation amount → ↑ phenotype penetrance



COMPLICATIONS Behavioral features ▪ Autism, attention-deficit hyperactivity disorder (ADHD), anxiety disorders Seizures ▪ Simple/complex; occurs commonly in childhood, resolves in adulthood Fragile X tremor/ataxia ▪ Observed in carrier/premutation individuals ▪ Tremor/ataxia → parkinsonism ▫ Short-term memory loss, executive dysfunction (common) ▫ Individuals who are biologically female: ovarian insufficiency; early menopause (age ≤ 40) ▪ Pathogenesis ▫ Mild CGG repeat expansion → mild ↑ methylation (not including promoter region) → adequate transcription → RNA product → poor translation → abnormal protein → nuclear accumulation → aggregation of mRNAbinding protein → toxic effects to cell function → neurodegeneration



SIGNS & SYMPTOMS Impaired cognitive function ▪ Developmental delay: delayed attainment of language, motor milestones ▫ Delayed milestones: sit alone (10 months), walk (18 months), clear spoken words (20 months) ▪ Intellectual disability: IQ range of 20–60 Physical features ▪ Prominent in adulthood; more common in individuals who are biologically male ▪ Facies ▫ Prominent forehead, jaw; long, narrow face; large ears ▪ Macroorchidism ▪ Connective tissue ▫ Joint hyperlaxity, arched palate, flat feet, mitral valve prolapse (benign) ▪ Behavioral features ▫ Hyperactivity, inattention, gaze aversion, stereotypic movements (e.g. handflapping, unusual speech patterns)



OSMOSIS.ORG 177



TREATMENT MEDICATIONS



▪ Symptom-directed management



Behavioral features ▪ ADHD presentation ▫ < 5 years old: non-stimulant therapy (e.g. guanfacine, clonidine) ▫ > 5 year old: stimulant prescription (e.g. methylphenidate) Anxiety/mood disorders ▪ Selective serotonin reuptake inhibitors (SSRIs) Figure 28.1 A child with fragile X syndrome.



DIAGNOSIS LAB RESULTS DNA testing (obtained prenatally) ▪ Chorionic villus sampling (11–13 weeks of gestation) ▫ Degree of methylation variable in later development ▪ Amniocentesis (> 15 weeks of gestation) Complete prenatal screening ▪ DNA testing ▪ Fluorescent polymerase chain reaction (PCR) ▫ Identify degree of methylation ▪ AGG trinucleotide genotyping ▫ Determine risk in premutation/ carrier expansion individuals who are biologically female



OTHER DIAGNOSTICS History Physical examination ▪ Phenotypic characteristics on musculoskeletal, genitourinary examination ▪ Neurological ▫ Mental status (intellectual, behavioral deficits)



178 OSMOSIS.ORG



Seizures ▪ Anticonvulsants Premature ovarian insufficiency ▪ Estrogen replacement therapy



PSYCHOTHERAPY



▪ Symptom-directed management



Behavioral features ▪ Counseling, psychotherapy



OTHER INTERVENTIONS ▪ No curative therapy



Symptom-directed management ▪ Intellectual disability ▫ Speech/language therapy, early intervention, special education Prevention ▪ Genetic preconception counseling ▫ Preconception reproductive options (e.g. use of donor gametes from unaffected donor)



Chapter 28 Trinucleotide Repeat Expansion Diseases



HUNTINGTON'S DISEASE osms.it/huntingtons-disease PATHOLOGY & CAUSES ▪ Autosomal dominant, neurodegenerative disease; chorea, dementia ▫ Average age of onset is 40 ▪ Medium spiny striatal (GABAergic) neuronal cell death → dysregulation of basal ganglia circuitry → unchecked dopamine, glutamate-mediated basal ganglia activity → ↑ motor output → hyperkinetic movement ▪ Cortical cell death → cognitive impairment



CAUSES Trinucleotide repeat (CAG) expansion ▪ Trinucleotide repeat (CAG) expansion of first exon in huntingtin (HTT) gene on chromosome 4p16.3 ▫ Intermediate repeat number: 27–35 (rarely causes disease) ▫ Disease repeat number: 36–39 (incomplete penetrance) ▫ Disease repeat numbers: > 40 (complete penetrance ↑ repeat number → ↓ age of onset) ▪ Repeat CAG expansion in first exon of HTT → expansion of polyglutamine region at N terminus of HTT protein → gain-of-function ▪ Physiologic role of HTT protein unknown (high levels found in brain tissue) Possible pathophysiologic roles of HTT protein ▪ Aggregation of protein → cellular dysfunction ▫ Aggregation → uptake by neurons → neuronal death; akin to prionlike pathogenesis; most prominent aggregation (neuronal death) in caudate, putamen (AKA neostriatum) ▫ Aggregation → ↑ proteasomal, autophagic degradation pathways → dysregulated cell injury, death ▪ Transcriptional dysregulation



▫ Abnormal HTT protein → binding of various transcriptional regulators → ↓ mitochondrial oxidative stress protective genes → susceptibility of oxidative damage → neuronal death ▪ Altered levels of brain-derived neurotrophic factors Role of ras homolog enriched in striatum (Rhes) ▪ Avidly bind with mutant huntingtin ▪ Protein selectively expressed in striatum ▪ Rhes → mediates covalent attachment of small ubiquitin-like modifier (SUMO) to HTT → ↑ HTT aggregation → neurotoxicity Inheritance ▪ Autosomal dominant ▪ Anticipation ▫ Repeat expansion occurs during spermatogenesis → paternal transmission associated with early age of onset



COMPLICATIONS



▪ Depression → suicide ▪ Dysphagia → aspiration pneumonia (common cause of death)



SIGNS & SYMPTOMS ▪ Motor symptoms (movement inhibition; excessive, involuntary movements) ▫ Hypotonia with hyperreflexia (early symptom), chorea (e.g. face, head, neck, tongue, trunk, extremities), athetosis, dystonia, eye movement slows, gait abnormalities (unsteady, irregular → bradykinesia, rigidity in late disease) ▪ Psychiatric ▫ Apathy, irritability, depression, delusions, aggression, disinhibition, paranoia



OSMOSIS.ORG 179



▪ Cognitive ▫ Progressive dementia, inflexibility of thought; ↓ insight, concentration; memory loss ▪ Weight loss, cachexia



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Atrophy of head of caudate nuclei



LAB RESULTS



▪ Genetic testing for CAG repeat in HTT (> 36 repeats)



OTHER DIAGNOSTICS



▪ History ▪ Physical examination ▪ Neurological ▫ Motor, mental status examination



TREATMENT MEDICATIONS Chorea (symptomatic therapy) ▪ Presynaptic VMAT2 (vesicular monoamine transporter Type II) inhibitors: tetrabenazine/deutetrabenazine ▫ ↑ synaptic metabolism of dopamine → ↓ dopamine → ↓ basal ganglia output → ↓ hyperkinetic output ▫ May exacerbate parkinsonism symptoms ▫ As late symptom (e.g. chorea abates), periodic review of dosing recommended ▪ Neuroleptics: haloperidol/chlorpromazine ▫ Dopamine receptor antagonists → ↓ dopaminergic input → ↓ basal ganglia output → ↓ hyperkinetic output ▫ Similar parkinsonism side effects/ exacerbation of symptoms ▪ Psychosis: quetiapine (dopamine, serotonin antagonist properties)



PSYCHOTHERAPY ▪ Chorea (symptomatic therapy) ▫ Counseling, techniques to ↓ anxiety, stress



OTHER INTERVENTIONS



▪ No curative therapy ▫ Palliative, advance care planning ▪ Symptomatic therapy ▫ Chorea (severe cases): assistive equipment (e.g. helmets, padded reclining chairs, low beds) ▫ Dysphagia: thickened liquids ▫ Speech, language problems: physical therapy ▫ Gait impairment: hip protectors → ↓ hip fractures → ↓ morbidity



Figure 28.2 An MRI scan in the coronal plane of the head of an individual with Huntington’s disease. There is atrophy of both caudate nuclei which has led to hydrocephalus ex vacuo. There is also generalized cortical atrophy.



180 OSMOSIS.ORG



NOTES



NOTES



TRISOMIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



DIAGNOSIS



▪ Genetic disorders: trisomies (three copies of particular chromosome) → severe multiorgan defects (cardiac, gastrointestinal, genitourinary), debilitating dysmorphic features



DIAGNOSTIC IMAGING



CAUSES



LAB RESULTS



RISK FACTORS



OTHER DIAGNOSTICS



▪ Meiotic nondisjunction (most common, > 90%) ▪ Mutation (e.g. translocation) ▫ Mitotic nondisjunction → mosaicism



▪ Advanced maternal age



Ultrasound ▪ Prenatal diagnosis ▫ Nuchal translucency, organ defects



▪ Prenatal diagnosis ▫ Chorionic villus sampling, amniocentesis ▪ Postnatal diagnosis ▫ Karyotyping



▪ Postnatal diagnosis ▫ Clinical identification of dysmorphic features



COMPLICATIONS



▪ Widespread organ dysfunction



SIGNS & SYMPTOMS ▪ Depend on trisomy, affected organs



TREATMENT OTHER INTERVENTIONS ▪ Genetic counseling



DOWN SYNDROME osms.it/down-syndrome PATHOLOGY & CAUSES ▪ Autosomal trisomy of chromosome 21 ▪ Most common chromosomal abnormality in live births, cause of intellectual disability



▪ Range of dysmorphic features, congenital anomalies (e.g. congenital heart, otolaryngeal, gastrointestinal, hematologic, endocrine, urogenital defects)



CYTOGENETIC TYPES



▪ Meiotic nondisjunction in one parent (most common) → trisomy 21 (47 XY, +21)



OSMOSIS.ORG 181



▪ Chromosome 21 involved in Robertsonian translocation ▪ Trisomy 21 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +21) ▫ Duodenal atresia/stenosis, tracheoesophageal fistula, cervical spine instability, hematologic disorders



RISK FACTORS



▪ Advanced maternal age, previous child with trisomy 21, parental consanguinity



COMPLICATIONS



▪ Cardiac ▫ Valve disease (e.g. mitral valve prolapse) ▪ Developmental delay, intellectual disability (IQ: 20–75) ▪ Endocrine ▫ Hypothyroidism, obesity ▪ Gastrointestinal ▫ Delayed dental eruption, duodenal atresia, celiac disease ▪ Genitourinary ▫ Cryptorchidism, infertility (in individuals who are biologically male) ▪ Hematologic ▫ Anemia, ↑ risk of leukemia ▪ Musculoskeletal ▫ Atlantoaxial instability (↑ mobility of C2 in relation to C1); juvenile idiopathic arthritis, hip dislocation ▪ Neurologic/psychiatric ▫ Early onset dementia (by age 55), major depressive disorder, seizures ▪ Premature aging ▪ Respiratory ▫ Tracheal stenosis, obstructive apnea ▪ Sensory ▫ Congenital cataracts, hearing loss, frequent otitis media



SIGNS & SYMPTOMS ▪ Brushfield spots (small white/grayish spots on periphery of iris)



182 OSMOSIS.ORG



▪ Dysmorphic features ▫ Microcephaly, flat occiput, flattened face; epicanthal folds; flat nasal bridge; upward-slanting palpebral fissures; small nose/mouth; protuberant tongue; low-set/small ears; short neck, excessive nuchal skin; shortened extremities; big gap between first toe (hallux), others; single transverse palmar crease; short fifth finger with clinodactyly ▪ Gastrointestinal ▫ Vomiting, constipation, poor appetite, ↓ weight gain ▪ Neuromuscular ▫ Hypotonia, diastasis recti (abnormally large inter-recti distance) ▪ Pale, dry skin; fatigue ▪ Respiratory ▫ Dyspnea, wheezing



Figure 29.1 An eight-year-old boy with Down syndrome.



Chapter 29 Trisomies



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Prenatal diagnosis ▫ Nuchal translucency (weeks 11–14)



LAB RESULTS



▪ Chorionic villus sampling/amniocentesis ▪ Prenatal diagnosis ▫ ↓ pregnancy-associated plasma protein A (PAPP-A), unconjugated estriol (uE3), alpha-fetoprotein (AFP) ▫ ↑ serum beta human chorionic gonadotropin (β-hCG), inhibin A ▫ Quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping



OTHER DIAGNOSTICS



▪ Postnatal diagnosis ▫ Clinical identification of dysmorphic features



Figure 29.2 The feet of an individual with Down syndrome. There is a large space between the great and second toes.



TREATMENT OTHER INTERVENTIONS



▪ Prenatal genetic counseling ▪ Supportive management of affected body systems



EDWARDS SYNDROME osms.it/edwards-syndrome PATHOLOGY & CAUSES ▪ Autosomal trisomy of chromosome 18 ▪ Second most common autosomal trisomy in live births



CYTOGENETIC TYPES



▪ Meiotic nondisjunction in one parent (most common) ▫ Trisomy 18 (47 XY, +18) ▪ Translocation of chromosome 18 ▪ Trisomy 18 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +18)



RISK FACTORS



▪ Family history, more common in individuals who are biologically female (3:1), advanced maternal age



COMPLICATIONS



▪ ↑ risk of neoplasms (e.g. Wilms’ tumor, hepatoblastoma) ▪ Multi-organ abnormalities (e.g. cardiac septal defects, intestinal malrotation, Meckel’s diverticulum, neurological disorders, horseshoe kidney, hypotonia, pulmonary hypoplasia, cryptorchidism) ▪ Failure to thrive (FTT) ▪ Severe developmental, cognitive impairment



OSMOSIS.ORG 183



▪ ↓ life expectancy (< one year old); up to 50% die within first week



SIGNS & SYMPTOMS ▪ Dyspnea, hypotonia, wheezing, lack of appetite, severe mental disability, poor weight gain ▪ Dysmorphic features ▫ Clenched hand/overlapping fingers; microcephaly, prominent occiput; small mouth, low-set pointy ears; short sternum; ocular hypertelorism; abnormal retinal pigmentation; short nose with upturned nares; clubfeet, rocker bottom feet; scoliosis, narrow pelvis



DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound ▪ Postnatal diagnosis ▫ Presence of tumors Ultrasound ▪ Prenatal diagnosis ▫ Unchanged inhibin A; nuchal translucency (weeks 11–14)



LAB RESULTS



▪ Prenatal diagnosis ▫ Amniocentesis/chorionic villus sampling (CVS), ↓ PAPP-A, serum β-hCG, uE3, AFP, quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping



OTHER DIAGNOSTICS



▪ Prenatal ▫ Growth restriction: umbilical cord with two vessels; persistent clenched/ overlapping fingers; heart defects; cystic hygroma; polyhydramnios, oligohydramnios; intrauterine growth delay; omphalocele; hydrocephalus; agenesis of corpus callosum; Dandy– Walker abnormality; diaphragmatic hernia ▪ Postnatal ▫ Clinical identification: dysmorphic features



TREATMENT OTHER INTERVENTIONS



▪ Treat life-threatening/disabling conditions (e.g. infections, cardiac/gastrointestinal defects) ▪ Prenatal genetic counseling ▪ Psychosocial management



PATAU SYNDROME osms.it/patau-syndrome



▪ Autosomal trisomy of chromosome 13



▪ Trisomy 13 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +13)



CYTOGENETIC TYPES



RISK FACTORS



PATHOLOGY & CAUSES



▪ Meiotic nondisjunction in one parent ▫ Trisomy 13 (47 XY, +13) ▪ Translocation of chromosome 13



184 OSMOSIS.ORG



▪ Family history, advanced maternal age



Chapter 29 Trisomies



COMPLICATIONS



▪ Intrauterine growth restriction ▪ Multi-organ congenital anomalies (e.g. severe intellectual disability, capillary hemangioma, cardiac septal defects, cryptorchidism bicornuate uterus, intrauterine growth retardation, cerebral hypoplasia) ▪ High mortality ▫ Most fetuses die in utero/stillborn; neonates die shortly after birth (median survival is seven days)



OTHER DIAGNOSTICS



▪ Postnatal ▫ Clinical identification of dysmorphic features



SIGNS & SYMPTOMS ▪ Anophthalmia, microphthalmia, cyclopia, colobomas ▪ Holoprosencephaly (formation of single forebrain with single ventricle) ▪ Microcephaly, neural tube defects, deafness ▪ Cleft palate/lip, cutis aplasia, omphalocele, post-axial polydactyly, prominent heel (rocker-bottom feet), dextroposition, absent philtrum



Figure 29.3 An adolescent femal with Patau syndrome.



DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Unchanged inhibin A ▪ Nuchal translucency (weeks 11–14) ▫ Holoprosencephaly; ventriculomegaly; microcephaly; corpus callosum agenesis; cleft lip, palate; neural tube defects; omphalocele; single umbilical artery; radial aplasia; polydactyly



LAB RESULTS



▪ Prenatal diagnosis ▫ Amniocentesis/chorionic villus sampling (CVS): ↓ PAPP-A, serum β-hCG, uE3, AFP, quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping



Figure 29.4 An infant with a more severe case of Patau syndrome demonstrating cyclopia and a proboscis.



OSMOSIS.ORG 185



TREATMENT SURGERY



▪ Intensive treatment ▫ Surgical repair of cardiac defect, cleft lip/ palate



OTHER INTERVENTIONS



▪ Prenatal genetic counseling ▪ Noninterventional paradigm ▫ Palliative, supportive management



186 OSMOSIS.ORG



Chapter 2 Acyanotic Defects



NOTES



COMBINED B-CELL & T-CELL DEFICIENCIES



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of disorders characterized by impaired cellular, humoral immunity ▪ Diverse genetic causes ▪ Leads to immunodeficiency, increased susceptibility to recurrent, potentially fatal infections



SIGNS & SYMPTOMS ▪ Recurrent infections, chronic diarrhea, failure to thrive (FTT), skin rashes



DIAGNOSIS LAB RESULTS



▪ Low T lymphocyte, natural killer (NK) cell count ▪ Normal B lymphocyte count, low immunoglobulins ▪ Genetic testing to find defect



TREATMENT OTHER INTERVENTIONS



▪ Measures to prevent serious infections (e.g. antimicrobial prophylaxis, isolation)



Hematopoietic stem cell transplantation (HSCT) ▪ If HSCT fails ▫ Genetic therapy



ADENOSINE DEAMINASE DEFICIENCY osms.it/adenosine-deaminase-deficiency PATHOLOGY & CAUSES ▪ Absence of ADA → intracellular accumulation of metabolites (e.g. deoxyadenosine), toxic to lymphocytes (esp. T cells) ▪ Reduction of T, B lymphocytes, NK cell count → combined immunodeficiency ▪ Autosomal recessive pattern of inheritance



COMPLICATIONS



▪ Progresses to severe combined immunodeficiency (SCID)



SIGNS & SYMPTOMS ▪ Presents as SCID early in life ▪ Neurologic abnormalities (cognitive deficits, behavioral problems, gait abnormalities)



OSMOSIS.ORG 187



DIAGNOSIS



TREATMENT OTHER INTERVENTIONS



LAB RESULTS



▪ Measures to prevent infections, HSCT ▪ Gene therapy, enzyme replacement therapy (less effective)



▪ SCID ▫ Decreased ADA blood levels



OTHER DIAGNOSTICS ▪ Genetic testing



SEVERE COMBINED IMMUNODEFICIENCY (SCID) osms.it/SCID PATHOLOGY & CAUSES ▪ Rare genetic syndrome; disturbance in cellmediated, humoral immunity ▪ Combined defects in T, B lymphocyte development, function → severe immunodeficiency



CAUSES



▪ Underlying causes vary in different forms of SCID ▪ Cytokine receptor defects, adenosine deaminase (ADA) deficiency (most common) ▪ Cytokine receptor defects (50–60% of cases) ▫ Mutation in gene encoding common γ-chain subunit of interleukin (IL) receptors (IL-2 receptor gamma/IL-2Rγ) ▪ Impaired interleukin signaling required for survival, development, proliferation of lymphocytes (esp. T lymphocytes) ▪ Profound decrease in lymphocyte count (esp. T, NK-cells) ▪ B lymphocyte count can be normal, immunoglobulin synthesis defective due to lack of T helper cells



188 OSMOSIS.ORG



RISK FACTORS



▪ X-linked recessive pattern of inheritance, more common in individuals who are biologically male



COMPLICATIONS



▪ Susceptibility to recurrent, severe infections by wide range of microorganisms ▫ Candida albicans, Pneumocystis jiroveci, Pseudomonas, cytomegalovirus, varicella ▪ Without HSCT, death may occur within first year due to fatal infections



SIGNS & SYMPTOMS ▪ Recurrent infections ▪ Oral candidiasis presenting with prominent thrush ▪ Chronic diarrhea → malabsorption, failure to thrive ▪ Extensive rash ▪ Morbilliform rash due to reaction of maternal T cells against fetus → graft versus host disease (GVHD)



Chapter 30 Combined B-Cell & T-Cell Deficiencies



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Hypoplasia of lymphoid tissues ▫ Absence of thymic shadow; thymic hypoplasia



LAB RESULTS



▪ Complete blood count (CBC), manual differential ▫ Total lymphocyte count, ↓ T cell count, normal B cell count, ↓ immunoglobulin levels ▪ Polymerase chain reaction (PCR) ▫ Measure concentration of T cell receptor excision circles (TRECs); indicative of T cell maturation → decreased levels in SCID



▪ Genetic testing to find the specific defect ▪ Lymph node biopsy ▫ Hypoplasia of lymphoid tissues where lymphocytes develop ▫ Absence of germinal centers



TREATMENT OTHER INTERVENTIONS Prevention ▪ Isolation to prevent serious infections; “bubble baby disease” ▪ Avoidance of live vaccines ▪ Antimicrobial prophylaxis ▪ Immunoglobulin replacement therapy HSCT ▪ Curative therapy for most cases ▪ If HSCT fails ▫ Genetic therapy (less effective)



OSMOSIS.ORG 189



NOTES



NOTES



COMPLEMENT DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic diseases: a protein of the 30+ in complement system missing → abnormal inflammatory/immune response-prone individual



SIGNS & SYMPTOMS ▪ Recurrent bacterial infection (i.e. pneumonia, tonsillitis, otitis), especially encapsulated bacteria ▪ Rheumatologic/autoimmune disorders ▫ Can be systemic lupus erythematosus (SLE)-like (fever, rash, arthritis, glomerulonephritis)



DIAGNOSIS LAB RESULTS ▪ Screening based on recurrent infection/ autoimmune familial/individual history ▫ Genetic screening ▫ Total hemolytic complement (THC/ CH50) testing < 11% (measures individual serum’s ability to lyse sheep red blood cells (RBCs) coated with antiRBC rabbit antibody → activates serum complement proteins; AH50 alternative pathway evaluation test)



190 OSMOSIS.ORG



▪ Complement component serum levels ▫ Level ↓ correlates with specific protein deficiency ▫ Overactive pathway consumption → protein level ↓ (i.e. decreased C2/ C4 ↓ indicates classical pathway overactivation—as in C1 inhibitor deficiency)



TREATMENT MEDICATIONS



▪ Bacterial infection prevention: vaccination ▫ Meningococcal, pneumococcal, Haemophilus influenzae b (Hib) vaccines (conjugated vaccines preferred for Hib pneumococcal) ▪ Bacterial infection-suspicious symptoms → swift antibiotic management



Chapter 31 Complement Deficiencies



C1 ESTERASE INHIBITOR DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal dominant disorder: C1 inhibitor protein missing → clinical hereditary angioedema (HAE) syndrome ▪ C1 esterase inhibitor role: inhibits C1 protein cleavage in complement cascade ▫ C1 esterase inhibitor deficiency → overactive C1 cleavage → ↑ classical complement pathway activation → proinflammatory, ↑ immune responsive state → ↑ downstream anaphylatoxin production (C2a, C4a) ▪ C1 esterase inhibitor also mediates bradykinin production → hereditary angioedema (HAE) ▫ C1 esterase inhibitor absence → ↑ kallikrein, factor XII → unchecked bradykinin production → vasodilation → severe angioedema



SIGNS & SYMPTOMS Angioedema episodes ▪ Commonly last 24–72 hours, without urticaria/pruritis ▫ Frequent prodromal symptoms: fatigue, nausea, gastrointestinal (GI) symptoms, myalgias present ▫ Individuals may report stress (physical/ mental) as episode triggers Edematous episodes ▪ Nondependent areas, non-pitting ▫ Most common locations: upper respiratory/GI tract skin/mucosal tissue ▫ GI bowel edema → nonspecific GI distress symptoms (abdominal pain, colic) ▫ Laryngeal edema most feared → closed airway → asphyxiation



DIAGNOSIS LAB RESULTS



▪ Low C1 esterase inhibitor, C4 levels



OTHER DIAGNOSTICS History ▪ Recurrent, self-resolving angioedema episodes with/without colicky, abdominal pain ▪ No concurrent angiotensin-converting enzyme (ACE) inhibitors/nonsteroidal antiinflammatory drug (NSAIDs) use ▪ Positive angioedema family history Physical examination ▪ Nondependent (i.e. head/neck), non-pitting edema areas without urticaria/pruritis



TREATMENT MEDICATIONS



▪ Therapies: purified C1 inhibitor concentrate, kallikrein inhibitor, bradykinin-B2-receptor antagonist ▪ If above targeted therapy interventions unavailable → fresh frozen plasma ▪ Avoid angiotensin-converting-enzyme (ACE) inhibitors



SURGERY ▪ Acute episodes → intubation for airway management



OSMOSIS.ORG 191



C2 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive disorder: involves C2 protein absence in classical complement cascade ▫ Most common complement deficiency disorder ▫ Symptoms commonly present in early childhood ▪ Associated with IgG deficiency



SIGNS & SYMPTOMS ▪ Individuals sometimes present with SLElike symptoms ▫ Fever, rash, arthritis, glomerulonephritis ▪ ↑ infection risk from encapsulated bacteria ▫ Streptococcus pneumoniae, Haemophilus influenza type b, Neisseria meningitidis



DIAGNOSIS LAB RESULTS



▪ Recurrent SLE-like episodes: CH50 testing



OTHER DIAGNOSTICS ▪ Clinical/family recurrent, bacterial infection history



TREATMENT MEDICATIONS



▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ SLE-like episodes: corticosteroids, other immunosuppressants



C3 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive disorder: involving protein C3 (vital protein connecting three complement activation pathways— classical, alternative, lectin—to final, common pathway) ▫ Presents with severe infections shortly after birth ▫ Rarest complement deficiency disorder ▪ Cleavage product: C3b (major opsonin) ▫ Inability to effectively opsonize without C3b → antigen-antibody complex unable to be phagocytosed → excess immune complex formation, deposition



192 OSMOSIS.ORG



→ type III hypersensitivity reaction ▫ Inability to opsonize underlies frequently encountered sinopulmonary diseases (see bacterial infections below) ▪ Inability to form C5 convertase → deficient membrane attack complex (MAC) formation ▫ Inability to complete complement cascade underlies (primarily meningitisrelated) septic presentation ▪ Abnormal C3 protein levels → abnormal three complement pathway activation → abnormal pathway byproduct concentrations (i.e. anaphylatoxins C2a, C4a) → abnormal immune cell response to immune insult → abnormal neutrophil response → abscess formation



Chapter 31 Complement Deficiencies



SIGNS & SYMPTOMS ▪ Severe, recurrent encapsulated bacterial infections shortly after birth ▫ Particularly Streptococcus pneumoniae ▪ Children who survive severe infections develop problems secondary to immune complex deposition, reaction ▫ Especially membranoproliferative glomerulonephritis



TREATMENT MEDICATIONS



▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ Bacterial infection prophylaxis: vaccination ▫ Pneumococcal vaccination ▫ Meningococcal vaccination (for resulting dysfunctional C5–C9 MAC formation)



DIAGNOSIS LAB RESULTS ▪ Clinical/family history of recurrent, bacterial infections (especially Streptococcus pneumoniae) → CH50 testing



C5-C9 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES



DIAGNOSIS



▪ Autosomal recessive disorder group: involving any protein (C5–C9) involved in MAC formation (part of final, common complement pathway) ▪ MAC-forming inability: precludes ability to create osmotic gradient for cellular lysis



LAB RESULTS



SIGNS & SYMPTOMS



MEDICATIONS



▪ Frequent, recurrent bacterial infection ▫ Propensity for Neisseria gonorrhoeae, meningitidis infections (thin cell walls → especially complement destructionvulnerable)



▪ Clinical recurrent, bacterial infection history (especially Neisseria species) → CH50 testing



TREATMENT ▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ Severe bacterial infection mitigation: meningococcal vaccination



OSMOSIS.ORG 193



PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) osms.it/pnh PATHOLOGY & CAUSES ▪ Acquired genetic disorder: hematopoietic stem cells produce cells that lack cellmembrane protein CD55 (AKA decayaccelerating factor (DAF)) or CD59 that predispose cells to complement-mediated lysis ▫ Involved gene (on X chromosome) is phosphatidylinositol glycan complementation group A (PIGA) ▫ Biologically-male individuals in early 20s (most common) ▪ CD59: anchor protein for glycosylphosphatidylinositol (GPI), a marker of ‘self’ antigenicity on erythrocytes, leukocytes ▫ CD59 deficiency → cells sensitive to complement-mediated lysis → intravascular hemolysis ▫ Nocturnal: relative hypoventilation during sleep → slightly ↑ serum CO2 → slightly acidic serum pH → ↑ complement activity → ↑ nighttime hemolysis



COMPLICATIONS ▪ Potentially fatal venous (Budd–Chiari syndrome), arterial thrombosis ▪ Aplastic anemia, myelodysplasia, myelofibrosis, acute leukemia evolution



SIGNS & SYMPTOMS ▪ Episodic crises triggers include infection, dietary iron supplementation, menstruation ▪ Nocturnal hemoglobinuria (upon waking) ▪ Lumbar, abdominal, general musculoskeletal pain



194 OSMOSIS.ORG



▪ Splenomegaly may present in severe hemolysis setting ▪ Venous, arterial thrombosis



DIAGNOSIS LAB RESULTS ▪ Normochromic, normocytic anemia; pancytopenia; ↑ lactate dehydrogenase (LDH) tests Sugar water test ▪ Serum mixed in sucrose (isotonic solution, low ionic strength) → predisposes to complement-mediated lysis → CD55/59deficient cells hemolyze Acid hemolysis test (Ham test) ▪ Alternative complement cascade triggered in acidified serum conditions → CD55/59deficient cells hemolyze CD55/59 protein flow cytometry ▪ Most sensitive, specific test



TREATMENT MEDICATIONS ▪ Glucocorticoids (prednisone; typically poor response) ▪ Eculizumab: monoclonal antibody binds C5 cleavage → prevents MAC formation, complement-mediated cell lysis



SURGERY ▪ Bone marrow transplantation



Chapter 2 Acyanotic Defects



NOTES



HUMORAL & B-CELL DEFICIENCIES



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



DIAGNOSIS



▪ Ineffective B-cell function → impaired antibody production, cellular immunity intact → recurrent, severe upper/lower respiratory tract infections, encapsulated bacteria



LAB RESULTS



CAUSES



▪ Clinical presentation



▪ Familial/sporadic, specific mutations



SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Infections, recurrent fever, autoimmune diseases, allergic reactions, chronic diarrhea, hepatosplenomegaly, failure to thrive (FTT)



▪ Evaluate levels of immunoglobulins (Ig), specific antibodies, B-cells



OTHER DIAGNOSTICS



TREATMENT OTHER INTERVENTIONS ▪ Replacement of Ig



OSMOSIS.ORG 195



COMMON VARIABLE IMMUNODEFICIENCY osms.it/common-variable-immunodeficiency PATHOLOGY & CAUSES ▪ Immune disorder characterized by hypogammaglobulinemia ▫ IgG,IgM, IgA; inherited/sporadic ▪ Defect in B-cell differentiation → impaired lymphocyte activation, function



CAUSES



▪ Unclear ▪ Intrinsic defects in B-cells → antibody deficiency ▫ Impaired T-cell mediated activation ▫ Impaired differentiation into plasma cells → ↓ immunoglobulins ▪ Mutations in genes encoding B-cell activating factor (BAFF) cytokine receptor/ inducible costimulator (ICOS)



COMPLICATIONS



▪ Autoimmune disorders ▫ Rheumatoid arthritis, autoimmune hemolytic anemia (AHA) ▪ Lymphoid malignancy, gastric cancer ▪ Bronchiectasis secondary to recurrent infections ▪ Granulomatous infiltration ▪ Poor immune response to immunizations



SIGNS & SYMPTOMS ▪ Usually presents > two years old ▪ Variable presentation secondary to antibody deficiencies → recurrent infections (e.g. sinopulmonary pyogenic, meningoencephalitis)



196 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS



▪ Decreased serum IgG levels, marked decrease in IgM/IgA ▪ Lack of antibody immune response to protein antigens/immunization ▪ Genetic testing for mutations



OTHER DIAGNOSTICS



▪ > four years old ▪ History of recurrent infections, positive family history ▪ Physical examination ▫ Peripheral lymphadenopathy ▪ Exclusion of other causes of hypogammaglobulinemia (e.g. X-linked agammaglobulinemia)



TREATMENT MEDICATIONS



▪ Immunosuppressants to control autoimmune clinical features ▪ Antibiotics to treat chronic lung infections



OTHER INTERVENTIONS ▪ Ig replacement therapy



Chapter 32 Humoral & B-Cell Deficiencies



HYPER IGM SYNDROME osms.it/hyper-IgM-syndrome PATHOLOGY & CAUSES



DIAGNOSIS



▪ Immune disorder; elevated levels of IgM; low to absent IgG, IgA, IgE ▫ X-linked/autosomal recessive ▪ Defect in B-cell antibody class switching → defective lymphocyte activation, function ▪ Predisposition to certain infections ▪ IgM antibodies can react with blood cells → autoimmune hemolytic anemia, thrombocytopenia, neutropenia ▪ In elderly, proliferation of plasma cells producing IgM can infiltrate gastrointestinal (GI) tract mucosa



LAB RESULTS



CAUSES



MEDICATIONS



▪ Genetic defects ▫ Type 1 (most common): X-linked disease of CD40 ligand (CD40L) gene → affects T cell ability to stimulate, activate B cells ▫ Other subtypes: affect class switching, autosomal recessive diseases



SIGNS & SYMPTOMS ▪ Recurrent severe pyogenic/opportunistic infections early in life ▪ Related to cause of infection ▫ Fungi: Pneumocystis jiroveci → pneumonia ▫ Protozoa: Cryptosporidium → infects biliary tract → diarrhea, malabsorption ▫ Viruses: Cytomegalovirus (CMV) → viral pneumonia/hepatitis ▫ Encapsulated bacteria: Streptococcus pneumoniae → otitis media, sinusitis, bacterial pneumonia



▪ No serum IgA, IgE, extremely low IgG ▪ Normal/elevated IgM ▪ Flow cytometry/genetic test ▫ Confirm mutation in CD40L



OTHER DIAGNOSTICS



▪ History of recurrent infections, positive family history



TREATMENT ▪ Prophylactic treatment with trimethoprim/ sulfamethoxazole for Pneumocystis jiroveci



OTHER INTERVENTIONS



▪ Ig replacement therapy ▪ Individuals with persistent neutropenia may require granulocyte colony stimulating factor (G-CSF) ▪ Hematopoietic stem cell transplantation (HSCT) → bone marrow transplant (BMT)/ cord blood stem cell transplant



OSMOSIS.ORG 197



HYPERIMMUNOGLOBULIN E SYNDROME osms.it/hyper-IgE-syndrome PATHOLOGY & CAUSES ▪ Rare immunodeficiency; recurrent skin, respiratory infections, eczema, elevated serum IgE levels ▪ AKA Job syndrome ▪ Mostly sporadic



DIAGNOSIS LAB RESULTS



▪ Markedly elevated serum IgE levels



OTHER DIAGNOSTICS ▪ Clinical presentation



TYPES Autosomal dominant (AD-HIES) ▪ More common Autosomal recessive (AR-HIES) ▪ Increased risk of developing fatal complications, infections, malignancies, autoimmune disorders



SIGNS & SYMPTOMS ▪ Primary characteristics ▫ Newborn rash/eczema, first manifestation; impetigo, boils ▫ Recurrent staphylococcal skin abscesses, without typical signs of inflammation (“cold abscesses”) ▫ Recurrent respiratory infections → formation of lung cavities, pneumatoceles ▪ Ear, sinus infections; mucocutaneous candidiasis; facial, skeletal findings (e.g. hyperextensibility of joints, retained primary teeth, due to connective tissue, skeletal abnormalities); susceptibility to malignancies (esp. lymphomas), autoimmune diseases



198 OSMOSIS.ORG



TREATMENT MEDICATIONS



▪ Prophylactic administration of trimethoprim-sulfamethoxazole ▪ Limited use of steroids for eczema



SURGERY



▪ Incision, drainage for skin/lung abscesses



OTHER INTERVENTIONS



▪ Skin care, antisepsis (prevent infections); prompt treatment of skin, respiratory infections; control of pulmonary complications; moisturizing creams ▪ HSCT



Chapter 32 Humoral & B-Cell Deficiencies



IGG SUBCLASS DEFICIENCY osms.it/IgG-subclass-deficiency PATHOLOGY & CAUSES ▪ Decrease in serum concentration of ≥ one subclasses of IgG ▫ IgG1, IgG2, IgG3, IgG4 while total IgG concentration remains unchanged ▫ IgG1 accounts for 60–70% of total IgG; IgG1 deficiency presents with low total IgG ▫ IgG2/IgG3 deficiencies most common ▫ Low IgG4 alone insufficient evidence of antibody deficiency disorder ▪ IgG subclass deficiency ▫ Integral component of other primary immunodeficiency diseases (e.g. Wiskott–Aldrich syndrome) ▪ Individuals with IgG subclass deficiency have recurrent ear/sinus/lung infections ▪ In many children, deficiency resolves with age ▪ May develop into common variable immunodeficiency (CVID)



DIAGNOSIS LAB RESULTS ▪ ≥ one low IgG subclasses with normal total IgG ▪ History of recurrent sinopulmonary infections ▪ Inadequate response to vaccination



TREATMENT MEDICATIONS



▪ Antibiotic prophylaxis



OTHER INTERVENTIONS



▪ Treatment of conditions predisposing to recurrent infections (e.g. asthma) ▪ Immunization with conjugate vaccines ▪ Long-term Ig replacement therapy



SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Recurrent ear/sinus/pulmonary infections with encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae) ▪ Increased incidence of atopic disease, chronic airway disease, autoimmune disease (e.g. vasculitis)



OSMOSIS.ORG 199



ISOLATED PRIMARY IMMUNOGLOBULIN M DEFICIENCY osms.it/isolated-primary-IgM-deficiency PATHOLOGY & CAUSES ▪ Rare immune disorder; decreased IgM antibodies in bloodstream ▪ AKA selective IgM immunodeficiency (SIgMD) ▪ Unclear etiology ▫ Rapid degradation of B cells after being secreted ▫ B cells unable to mature, produce free IgM ▪ Associated with recurrent infections, allergic conditions, Bloom’s syndrome, celiac disease, systemic lupus erythematosus (SLE), malignancy



COMPLICATIONS



▪ Infections may progress to meningitis, sepsis



SIGNS & SYMPTOMS ▪ Start in infancy, vary widely ▫ May be asymptomatic; recurrent severe infection (e.g. sinusitis, diarrhea, skin infections); allergic reactions (e.g. atopic dermatitis)



200 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS



▪ Decreased levels of IgM antibodies



OTHER DIAGNOSTICS



▪ History of recurrent infections



TREATMENT MEDICATIONS



▪ Prophylactic antibiotics for severe recurrent infections ▪ Antibiotics to treat infections



Chapter 32 Humoral & B-Cell Deficiencies



SELECTIVE IMMUNOGLOBULIN A DEFICIENCY osms.it/selective-IgA-deficiency PATHOLOGY & CAUSES ▪ Most common primary immunodeficiency; isolated deficiency of IgA in blood, secretions ▪ IgA deficiency (primarily in mucosal surface secretions) → infections, GI disorders, autoimmune diseases, allergic reactions ▪ Unknown etiology; associated with several non-causative genetic alterations



RISK FACTORS ▪ Family history of IgA deficiency/CVID



SIGNS & SYMPTOMS ▪ May be asymptomatic; may present significant clinical problems (less common) ▪ Susceptibility to infections (e.g. sinopulmonary, ear infections) ▪ Autoimmune diseases ▫ Rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura ▪ GI disorders (e.g. diarrhea); Giardia lamblia infections ▪ Allergic disorders (e.g. asthma) ▪ Anaphylactic reactions to blood products



DIAGNOSIS LAB RESULTS



▪ Individual > four years old ▫ Undetectable levels of IgA



OTHER DIAGNOSTICS



▪ Clinical presentation ▪ Exclude other causes of hypogammaglobulinemia, IgA deficiency secondary to medications



TREATMENT MEDICATIONS



▪ Antibiotics to treat infections/long-term antibiotic prophylaxis to prevent them ▪ Anti-inflammatory drugs, steroids, monoclonal antibodies for autoimmune diseases ▪ Antihistamines, anti-inflammatory drugs, steroids for allergies



OSMOSIS.ORG 201



TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY osms.it/infant/hypogammaglobulinemia PATHOLOGY & CAUSES ▪ Temporary decrease in circulating Ig during first months of life ▫ Maternal IgG pass fetus through placenta in sixth month of pregnancy → maternal IgG slowly diminishes, disappears six months after birth ▫ By 3–6 months of age, healthy infants begin making IgG as maternal IgG levels fall ▫ If severe/prolonged beyond six months of age → THI ▪ More common in individuals who are biologically male (2:1) ▪ Most individuals with THI have adequate antibody responses to infections/ immunizations → usually not susceptible to infections ▪ Serum Ig levels should return by age four years, may persist for few more years ▪ Severe, life-threatening infections rare



SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Recurrent infections ▫ Upper respiratory, ear, sinus ▪ Atopic manifestations ▫ Asthma, eczema, food allergy ▪ GI difficulties



202 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS



▪ IgG level < two standard deviations below age-appropriate mean, with/without diminished levels of other serum Ig, on at least two occasions ▪ Ig must normalize during childhood/rarely during adolescence



OTHER DIAGNOSTICS



▪ Diagnosis of exclusion; other permanent forms of hypogammaglobulinemia must be excluded first



TREATMENT MEDICATIONS



▪ Antibiotics ▫ If persistent infections occur



OTHER INTERVENTIONS



▪ Immunoglobulin replacement therapy if infections severe/persistent



Chapter 32 Humoral & B-Cell Deficiencies



WISKOTT–ALDRICH SYNDROME osms.it/wiskott-aldrich_syndrome PATHOLOGY & CAUSES ▪ Rare syndrome; classic triad of microthrombocytopenia, eczema, recurrent pyogenic infections ▪ AKA eczema-thrombocytopeniaimmunodeficiency syndrome ▪ X-linked recessive inheritance pattern; can also result from spontaneous DNA mutation affecting hematopoietic cells ▪ Most commonly presents in individuals who are male, > two years old ▪ Progressive loss of T lymphocytes in peripheral blood, lymph nodes → impairment of T-cell mediated, humoral immunity



CAUSES



▪ Mutation in Wiskott–Aldrich syndrome protein (WASP) gene at Xp11.23 ▫ Encodes for hematopoietic cellular proteins involved in cytoskeletal architecture



COMPLICATIONS



▪ Increased risk of infections, bleeding, autoimmune disease, malignancy



SIGNS & SYMPTOMS ▪ Thrombocytopenia → petechiae, bruising, epistaxis, severe bleeding ▪ Eczema, atopic symptoms ▪ Recurrent sinopulmonary/opportunistic infections caused by ▫ Encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) ▫ Fungi (e.g. Pneumocystis jirovecii, Candida albicans) ▫ Viruses (e.g. molluscum contagiosum, varicella zoster, cytomegalovirus)



DIAGNOSIS LAB RESULTS



Low to normal IgG, IgM High IgA, IgE Decreased number, function of T cells Peripheral blood smear ▫ Fewer, smaller platelets secondary to cytoskeletal remodeling ▪ Genomic DNA sequencing ▪ Flow-cytometry ▫ Screening test, determine presence of WASP



▪ ▪ ▪ ▪



OTHER DIAGNOSTICS



▪ History of bleeding, recurrent infections, eczema ▪ Clinical presentation, positive family history



TREATMENT MEDICATIONS



▪ Prophylactic antimicrobials ▪ IVIG for recurrent infections



SURGERY



▪ Splenectomy for severely low platelets



OTHER INTERVENTIONS



▪ Platelet transfusions for severely low platelets ▪ Blood transfusions for severe bleeding ▪ HSCT ▫ Potentially curative



OSMOSIS.ORG 203



X-LINKED AGAMMAGLOBULINEMIA osms.it/x-linked_agammaglobulinemia PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Immunodeficiency disorder; severe hypogammaglobulinemia, deficiency of all classes of antibodies → increased susceptibility to infection ▪ AKA Bruton’s disease ▪ Familial/sporadic mutation in BTK gene on X-chromosome → X-linked recessive genetic condition ▫ Manifests as disease in individuals who are biologically male ▫ Individuals who are biologically female only carriers ▪ Ineffective Bruton’s tyrosine kinase (BTK) enzyme → B-lymphocyte precursors fail to mature into B lymphocytes, plasma cells → differentiation stops at pre-B cell stage → absence of B-cells in circulation → deficiencies of all Ig → high risk of developing infections ▫ Bacterial (e.g. acute/chronic pharyngitis, sinusitis, otitis media, bronchitis, pneumonia), viral (e.g. enteroviruses, polio, coxsackievirus), protozoal intestinal parasitosis (e.g. giardia lamblia) ▪ T-cell mediated immunity remains intact; some viral, fungal, protozoal infections still cleared



▪ Newborns typically asymptomatic; after six months transplacentally-delivered Ig no longer present → prone to develop infections ▪ Infections frequently occur at mucous membranes, can also involve bloodstream, spread to internal organs, bones, joints, brain (e.g. otitis media, pharyngitis, bronchitis) ▪ Small/absent tonsils, lymph nodes



DIAGNOSIS LAB RESULTS



▪ Serum Ig levels ▫ All Ig markedly reduced/absent ▪ Number of B-cells in peripheral blood ▫ Nearly absent (most characteristic finding)



OTHER INTERVENTIONS



▪ Clinical presentation ▫ Any child with recurrent/severe bacterial infections ▪ Genetic testing ▫ Absence of BTK protein/presence of BTK mutation



TREATMENT OTHER INTERVENTIONS



▪ Lifelong IVIG can be given to replace missing Ig ▪ Complete, prompt treatment of infections ▪ Avoid live viral vaccines (e.g. polio vaccine)



204 OSMOSIS.ORG



Chapter 2 Acyanotic Defects



NOTES



HYPERSENSITIVITY REACTIONS: MULTIPLE MECHANISMS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Hypersensitivity (intolerance): undesirable reactions produced by immune system (e.g. allergies, autoimmunity) ▪ Range from minor (e.g. swelling, itching) to tissue-damaging, fatal ▪ Multiple mechanisms indicates the presence of two or more of the four types of hypersensitivity reaction ▫ Type I: allergy, acute hypersensitivity ▫ Type II: antibody-dependent cytotoxicity ▫ Type III: immune complex disease ▫ Type IV: delayed type hypersensitivity/ cell-mediated immune memory response ▫ Tissue specific antibody response: autoimmune disease/organ rejection Common Hypersensitivity reactions with multiple mechanisms ▪ Hypersensitivity pneumonitis ▪ Transplant rejection ▪ Latex allergy (I+IV) ▪ Sjögren syndrome ▪ Autoimmune hepatitis Autoimmune polyendocrine syndrome (APS1, APS2) ▪ Autoimmune adrenalitis ▪ Systemic autoimmune disease



SIGNS & SYMPTOMS ▪ Non-specific flu-like symptoms (e.g. fever, chills, malaise, cough, joint pains) ▪ Multiple mechanisms varies by location; see individual disorders



DIAGNOSIS LAB RESULTS



▪ Acute (Type I) hypersensitivity ▫ Spirometry/pulmonary function, skin tests (exposure to specific allergens provokes skin reaction), radioallergosorbent tests (quantify allergen specific IgE levels) ▪ Type II–IV hypersensitivity ▫ Identify organ/cell component specific antibodies



Biopsy (Type II–IV hypersensitivity) ▪ Immune cell infiltration of organ ▪ Compromise of normal organ anatomy



TREATMENT MEDICATIONS Acute (Type I) hypersensitivity ▪ General ▫ Withdraw offending agent, H1 receptor blockers ▪ Anaphylaxis ▫ Hypertension: epinephrine, intravenous fluids, vasopressors (e.g. dopamine) ▫ Bronchoconstriction: nebulized B2 agonists (e.g. salbutamol) ▫ Late-phase reaction, corticosteroids Type II–IV hypersensitivity ▪ Immunosuppression



SURGERY Type II–IV hypersensitivity ▪ Irreversible organ damage/rejection → transplant of new organ



OSMOSIS.ORG 205



OTHER INTERVENTIONS Type II–IV hypersensitivity ▪ Support organ function



HYPERSENSITIVITY PNEUMONITIS osms.it/hypersensitivity-pneumonitis PATHOLOGY & CAUSES ▪ AKA (extrinsic) allergic alveolitis ▪ Reaction to antigens usually 1–5 micrometers in size; fungal, bacterial, mycobacterial, animal, chemical sources ▫ Type III (antibody complex mediated) and IV hypersensitivity (delayed cellmediated) ▫ Inhaled antigen → forms haptens → inflammation of alveoli, small distal airways within lung ▫ Histological changes: inflammation of bronchi, peribronchiolar tissue; diffuse interstitial inflammatory infiltrate; poorly defined granulomas, associated giant cells within lung interstitium/alveoli ▫ Long-standing disease → pulmonary fibrosis, emphysematous changes → ↓ lung capacity, alveolar gas exchange → hypoxemia ▪ > 200 common causative agents identified, often given eponymous names (e.g. farmer’s lung, bird fancier’s lung, etc.)



RISK FACTORS



▪ Farming, ventilation, water-related exposure; poultry, bird handling; veterinary work, animal handling; grain, flour processing; grain dust; mold contamination; milling, construction; plastic manufacturing; painting; electronics industry, other chemical industries; textile workers



206 OSMOSIS.ORG



SIGNS & SYMPTOMS Acute ▪ Fever, chills, malaise, cough, chest tightness, dyspnea, rash, headache ▪ Resolves 12 hours to several days after cessation of exposure Sub-acute ▪ Productive cough, dyspnea, fatigue, anorexia, weight loss, pleurisy, mild hypoxemia ▪ Lesser severity, longer duration ▪ Resolves weeks to months after cessation of exposure Chronic ▪ Insidious onset cough, progressive dyspnea, fatigue, weight loss, clubbing, tachypnea, respiratory distress, inspiratory crackles (lower lung fields) ▪ Emphysematous component ▪ May have irreversible component, even if antigen removed



DIAGNOSIS DIAGNOSTIC IMAGING Bronchoscopy/bronchoalveolar lavage ▪ Marked lymphocytosis; ↑ IgG, IgA, IgM Chest X-ray ▪ Subacute hypersensitivity ▫ Micronodular/reticular opacification in middle to lower lung zones ▪ Chronic hypersensitivity ▫ Progressive fibrotic changes, loss of lung volume (esp. upper lobes)



Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms High-resolution chest CT scan ▪ Subacute hypersensitivity ▫ Diffuse micronodules, ground-glass opacification, focal air trapping/ emphysematous changes, mild fibrosis ▪ Chronic hypersensitivity ▫ Interstitial inflammation, alveolar destruction, dense fibrosis, features of emphysema (centrilobular nodules), ground glass opacification, subpleural honeycombing



Figure 33.1 A high resolution CT scan in the axial plane of an individual with hypersensitivity pneumonitis. There are multiple centrilobular ground glass nodules and anterior subpleural reticulation.



LAB RESULTS



▪ Lung biopsy ▫ Loose, poorly-defined noncaseating granulomas in vicinity of small airways ▫ Focal fibrotic changes ▪ Immunoassay ▫ Detect antibodies against specific antigens ▫ Chemical labels accumulate in response to specific antigen-antibody reactions/ enzymes bind to specific markers → catalyze color-changing reaction ▫ Known antigens: identify specific antibodies in blood sample



OTHER DIAGNOSTICS Diagnostic criteria: acute hypersensitivity ▪ Definite hypersensitivity pneumonitis: 2 and 3, plus one other ▪ Probable disease: 1, 2A, 3 ▪ Subclinical disease: 1, 3A ▪ Previous sensitization: 1 only 1. Known exposure ▪ History of exposure ▪ Aerobiological/microbiological investigation of environment → confirmed exposure ▪ Specific IgG antibodies against identified antigen 2. Compatible clinical, radiographic, physiologic evidence ▪ Respiratory signs: crackles, weight loss, cough, breathlessness, fever, wheezing fatigue, esp. hours after exposure ▪ Radiographic: reticular, nodular, ground glass pattern ▪ Lung function: spirometry (restrictive, obstructive, mixed); diffusion capacity for carbon monoxide (reduced, altered gas exchange) 3. Bronchoalveolar lavage ▪ Lymphocytosis ▪ Positive specific immune response to antigen 4. Inhalation challenge testing ▪ Worsening clinical condition after exposure to environment ▪ Worsening clinical condition after exposure to specific antigen in hospital setting 5. Histopathology ▪ Poorly formed noncaseating granulomas ▪ Mononuclear cell infiltrate Lung function ▪ Subacute ▫ Restrictive pattern ▪ Chronic ▫ Restrictive pattern, hypoxemia at rest, desaturates with exercise, ↓ carbon monoxide diffusion capacity



OSMOSIS.ORG 207



TREATMENT MEDICATIONS



▪ Glucocorticoids ▫ Subacute, chronic hypersensitivity ▪ Immunosuppression ▫ Refractory disease



SURGERY



▪ Lung transplant ▫ Advanced chronic lung disease



OTHER INTERVENTIONS



▪ Identify allergen, reduce/eliminate exposure → disease generally self-limiting (if acute) ▪ Occupational measures ▫ Reduce antigenic burden, moisture control, ventilation, personal protective devices (respirator masks)



Figure 33.2 A section of the lung of an individual with hypersensitivity pneumonitis. The alveolar septa are thickened and contain numerous lymphocytes.



TRANSPLANT REJECTION osms.it/transplant-rejection PATHOLOGY & CAUSES ▪ Transplanted tissue rejected (attacked) by new host’s immune system → destruction of transplanted tissue Timescale of rejection ▪ Hyperacute rejection ▫ Minutes after transplant ▫ Initiated by humoral immunity ▫ If tissue left implanted → systemic inflammatory response syndrome ▫ Often caused by preexisting anti-human leukocyte antibodies (HLA) ▪ Acute rejection ▫ Highest risk window one week to three months after transplant ▫ Mediated by cellular immunity ▫ Occurs in nearly all transplants if recipient inadequately immunosuppressed



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▫ Highly vascularised tissue (e.g. kidney, liver) esp. vulnerable ▫ Can be treated prior to organ failure; multiple episodes → chronic rejection ▪ Chronic rejection ▫ Months to years after transplantation ▫ Fibrosis of blood vessels → long term loss of function in transplanted organs Multiple divisions of immune system involved in rejection ▪ Innate immunity → attraction, activation of phagocytes ▪ Humoral immunity → activation of B cells → antibody secretion ▪ Adaptive response → cellular immunity → killer T cells induce apoptosis Cellular markers influencing rejection ▪ Blood group, major histocompatibility (MHC) antigens ▫ Most intense graft rejection reactions



Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms (hyperacute rejection) occur due to differences between donor, recipient ABO blood-groups, MHC antigens ▫ Blood-group antigens expressed on red blood, epithelial, endothelial cells → donor, recipient must be ABO compatible ▫ Minor blood group exposure (e.g. Kell antigen) following allogeneic blood transfusion/trauma during pregnancy may also prime recipient’s humoral immunity against future transplants ▫ MHC compatibility assessed via molecular assay using sequencespecific primers (“tissue typing”) → determination of which HLA alleles expressed by donor, recipient



STAGING



▪ Of acute graft rejection



Sensitization ▪ Recipient antigen-reactive lymphocytes proliferate in response to alloantigens on graft ▪ Dendritic cells migrate to peripheral lymphoid tissue → present donor’s “self” peptides to recipient’s lymphocytes → presentation of antigen to T cells (helper, killer subclasses), B cells → specific immunity directed at donor self peptides/



▫ Presence of preformed antibodies to HLA alloantigens must be evaluated to reduce risk of rejection ▪ Minor histocompatibility locus ▫ Short variable proteins, 9–12 amino acids in length, bound to MHC class I, II proteins ▫ Provoke less vigorous immune response, may still lead to slow graft rejection ▫ Potential for graft rejection even if ABO, MHC antigens match ▪ Donor cell debris ▫ Damage-associated molecular patterns by pattern recognition receptors (e.g. toll-like receptors on phagocytes) → further secretion of proinflammatory cytokines, phagocyte chemotaxis



donor major histocompatibility complex/ both ▪ CD4+ (T helper), CD8+ (T killer) T cells recognize alloantigen (major, minor histocompatibility complex) on foreign graft cells → proliferation ▫ Direct presentation: donor MHC directly recognised as foreign ▫ Indirect presentation: donor peptides residing in cleft of recipient MHC recognised ▪ T helper (Th) cells activate when they interact with antigen presenting cells



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(APCs) that express appropriate antigenicligand/MHC-molecule complex, provide costimulatory signal ▫ Dendritic cells found in most tissue, express high levels of class II MHC → activated dendritic cells mediate direct presentation in grafts/draining lymph nodes ▫ APCs of host origin migrate into grafts, endocytose foreign alloantigens → indirect presentation of alloantigen ▫ Langerhans, endothelial cells present alloantigen to recipient’s immune system Effector phase ▪ Influx of immune cells into graft ▪ Most common rejection mechanism: cell mediated immunity ▪ Less common: antibody-mediated complement lysis, antibody-dependent cellmediated cytotoxicity ▪ Th cell cytokines play central role → Th1 cells secrete interleukin (IL) 2, interferon (IFN) gamma → T cell proliferation, delayed type hypersensitivity response, IgG synthesis by B cells → complement activation ▪ Cytokines → increased expression of MHC class I, II; IFN, tumor necrosis factor (TNF) ▪ Elevated levels of IL-4, 5, 13, 17 → B-cell activation, eosinophil accumulation within grafts ▪ Antibody-mediated rejection ▫ Antibodies directed against donor HLA molecules/endothelial antigens ▫ Dependent on T cell maintenance of alloreactive B cells → antibody production → activation of complement, deposition of C4d among cells lining graft capillaries



TYPES Autograft ▪ Transplant of “self” tissue; surplus tissue that can regenerate/tissue moved from one site to another (e.g. skin, ligament grafts) Isograft ▪ Transplant of tissue between two genetic identical members of same species (e.g.



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transplant between two identical twins) Allograft ▪ Transfer of tissue between genetically non-identical members of same species; non-identical grafts recognised by immune system, destroyed Xenograft ▪ Transplant from one member of species to another (e.g. porcine heart valve transplant)



SIGNS & SYMPTOMS ▪ Fever, chills, dizziness, nausea, malaise, night sweats ▪ Specific to transplanted organ: failure of associated organ



DIAGNOSIS LAB RESULTS Tissue biopsy ▪ T cell infiltration, accompanied by eosinophils, plasma cells, neutrophils ▪ Structural compromise of tissue anatomy ▪ Blood vessel injury



Figure 33.3 A biopsy from a transplanted lung showing a prominent perivascular lymphocytic infiltrate, consistent with rejection. There are numerous background macrophages and eosinophils.



Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms



TREATMENT MEDICATIONS Generalized immunosuppression ▪ Mitotic inhibitors (antiproliferatives) ▫ Suppression of B, T cell proliferation; antimetabolites, DNA alkylating agents, fungal metabolites (also suppress T-cell cytokine expression) ▪ Corticosteroids ▫ Anti-inflammatory, potent immunosuppressives at higher doses Specific immunosuppression ▪ Targeted to specific antigens ▪ Monoclonal antibodies ▫ Soluble ligands, bind specific cellsurface molecules → can be used to deplete recipient of particular cell population/block specific steps in cellular signalling ▫ Modern monoclonal antibodies carry toxins (e.g. diphtheria) → target cell internalizes toxin → cell death ▫ Cellular markers expressed only by activated T cells kill cell lines activated after transplant ▫ Cytokines targeted as well; neutralized cytokine no longer stimulates target (e.g. costimulatory signals needed to activate T-helper cells)



SURGERY



▪ Removal of transplanted tissue (hyperacute rejection) ▪ Bone marrow transplant (acute rejection) ▫ Recipient bone marrow replaced with donor marrow; risk of graft vs host disease ▪ New transplant (chronic rejection)



OTHER INTERVENTIONS



▪ Prevent rejection ▫ Total lymphoid irradiation; X-rays eliminate lymphocytes prior to transplant (e.g. bone marrow transplantation)



For acute rejection ▪ Extensive immunosuppressive regimens: corticosteroids, calcineurin inhibitors, antiproliferatives, mTOR inhibitors ▪ Antibody-based treatment ▫ Monoclonal anti-IL-2R alpha receptor antibodies (e.g. basiliximab), polyclonal anti-T cell antibodies (e.g. antithymocyte globulin, antilymphocyte globulin), monoclonal anti-CD20 antibodies (e.g. rituximab)



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NOTES



NOTES



PHAGOCYTE DEFICIENCIES



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited immunodeficiency disorders: mutations in genes that code immune-cell functioning ▪ Impaired immune function: recurrent, often severe, life-threatening infections



SIGNS & SYMPTOMS ▪ Recurrent infection history



DIAGNOSIS



LAB RESULTS ▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Genetic testing



TREATMENT MEDICATIONS ▪ Infection prophylaxis/treatment



OTHER INTERVENTIONS ▪ Hematopoietic cell transplantation



▪ Characteristic findings upon physical examination



CHEDIAK–HIGASHI SYNDROME osms.it/chediak-higashi_syndrome PATHOLOGY & CAUSES ▪ Rare, inherited immunodeficiency disorder; impaired leukocyte lysosomal granules function in phagocytes, NK cells → recurrent pyogenic infections ▪ Autosomal recessive; lysosomal trafficking regulator gene CHS1/LYST defect ▫ Trafficking: protein movement within cell ▪ Genetic mutation → impaired trafficking → absent/partially functioning CHS1/LYST protein → large, abnormal intracellular granules → decreased phagocytosis → infections primarily affect skin, mucous



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membranes, respiratory tract ▪ Accelerated disease phase: profound lymphohistiocytic organ infiltration, worsening immunodeficiency



RISK FACTORS



▪ Parental consanguinity



COMPLICATIONS ▪ Related to impaired intracellular trafficking ▫ Oculocutaneous albinism (reduced skin, eye pigment) ▫ Neurologic abnormalities ▫ Coagulation defects



Chapter 34 Phagocyte Deficiencies ▫ Hemophagocytic lymphohistiocytosis (disorder resembles lymphoma) ▫ If bone marrow transplant unsuccessful → childhood death from infection usually occurs



SIGNS & SYMPTOMS ▪ Presents in infancy: frequent/severe bacterial, viral, fungal infections ▪ Neurological: nystagmus, ataxia, peripheral neuropathy, seizures, Parkinsonian-like features may develop ▪ Coagulation defect presents as easy bruising ▪ Photosensitivity ▪ Hair has silvery tint



DIAGNOSIS LAB RESULTS



▪ Microscopic hair examination: pigmentation clumping ▪ CBC: neutropenia ▪ Peripheral blood smear analysis: giant intracellular granules ▪ Bone marrow aspiration: large inclusion bodies in precursor cells ▪ Genetic testing



TREATMENT MEDICATIONS ▪ Prophylactic antibiotics ▪ Prompt, aggressive infection treatment



OTHER INTERVENTIONS ▪ Hematopoietic cell transplant; cord blood transplant ▫ Does not address debilitating neurological manifestations/albinism



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CHRONIC GRANULOMATOUS DISEASE (CGD) osms.it/chronic-granulomatous-disease PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Rare immune-system disorder; affects neutrophils, monocytes, macrophages → serious, life-threatening infections (bacterial/fungal), granuloma formation ▫ X-linked: CYBB encoded ▫ Autosomal recessive form common with consanguinity—CYBA encoded ▫ De novo mutations also occur ▪ Mutations: genes encoding for phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes lysosomal reactive oxygen species ▪ Impaired NADPH → phagocytes unable to effectively phagocytize, destroy certain microbes → ↑ infection susceptibility; especially catalase-positive bacteria/fungi



▪ History of disorder-characteristic recurrent infections, granulomatous lesions ▪ Fever, leukocytosis, lymphadenopathy, abnormal wound healing, diarrhea, chronic disease anemia, growth failure (children)



Host immune system response ▪ Recruiting additional phagocytes, activating T cells ▪ Immune cells collect around microbe → granulomas form ▪ Childhood/adulthood diagnosis (underlying mutation-dependent) Frequent infection sites ▪ Lung, skin, lymph nodes, liver Common infections ▪ Pneumonia, bacteremia, fungemia, impetigo, cellulitis, granulomatous lesions (skin, organs), gingivitis, gastroenteritis, otitis Inflammation manifestations ▪ Esophageal/urethral strictures, colitis, cystitis, interstitial pneumonitis, dermatosis



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DIAGNOSIS LAB TESTS



▪ ↑ inflammation markers: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) ▪ Immune stimulation → hypergammaglobulinemia ▪ Neutrophil function tests: e.g. dihydrorhodamine (DHR) 123 test measure neutrophils ability to produce oxidative burst ▪ Genetic testing



TREATMENT MEDICATIONS ▪ Antimicrobial prophylaxis using combination of therapies ▫ Antibacterial: TMP/SMX ▫ Antifungal: itraconazole ▫ Immunomodulatory: interferon-gamma ▪ Aggressive acute infection treatment ▪ Inflammatory manifestations: oral glucocorticoids ▪ Avoid live bacterial vaccines



OTHER INTERVENTIONS ▪ Hematopoietic cell transplantation: curative if successful



Chapter 34 Phagocyte Deficiencies



LEUKOCYTE ADHESION DEFICIENCY (LAD) osms.it/leukocyte-adhesion-deficiency PATHOLOGY & CAUSES ▪ Rare, inherited immunodeficiency disorders; mutations in genes encoding leukocyte adhesion molecules → impaired leukocyte function, deficient immunological response (foreign antigens), ↓ inflammatory response to injury ▫ Autosomal recessive inheritance ▪ Leukocyte adhesion cascade initiated in response to infection/injury ▫ Involves adhesion molecule-activation on vascular endothelial cells which bind to glycoproteins on leukocyte surface ▪ Stepwise adhesion, activation process ▫ Capture: temporary leukocyte to endothelial cell tethering ▫ Rolling: leukocyte rolls along endothelial cells (weak, reversible initial adherence) ▫ Slow rolling: endothelial cell ligands interact with leukocyte selectins → slow movement along vessel wall ▫ Firm adhesion: leukocyte integrins bind to endothelial intercellular adhesion molecules (ICAMs) → leukocyte stops (arrest) on endothelial surface ▫ Transmigration: leukocyte movement between endothelial cells, into interstitium/infected tissue



TYPES



▪ Categorization: specific genetic defects ▪ LAD I: integrin beta-2 gene mutation (ITGB2) encoding CD18 subunit → CD18 requires activation before endothelial ligand adhesion can occur ▫ Integrins: glycoproteins that mediate firm adhesion, transmigration along endothelium (via endothelial cell counter-receptors) ▫ LAD I defect prevents leukocyte bloodstream → interstitium migration



▪ LAD II: guanosine diphosphate (GDP)fucose transporter gene (SLC35C1) mutation → absent ligands for selectins ▫ Selectins: endothelial, leukocyte adhesion glycoproteins that mediate margination, leukocyte rolling (slows velocity → allows endothelial ligand adhesion) ▫ Fucose (monosaccharide; cellular glycans, glycolipids component) metabolism defect → absent fucosylated endothelial ligands for selectins ▪ LAD III: mutations in CalDAG-GEF1, kindlin-3; FERMT3 genes → defects all beta integrins (e.g. 1, 2, 3) activation ▫ Integrin glycoproteins remain inactivated, unable to adhere to endothelial ligands ▫ Beta-3 defect impairs platelet aggregation → severe bleeding tendency ▫ Also involves natural killer (NK) cell activity impairment



COMPLICATIONS ▪ Specific mutation dependent ▫ Poor wound healing ▫ Bleeding tendencies (may involve neonatal cerebral hemorrhage, gastrointestinal tract bleeding) ▫ Developmental delay ▫ Decreased lifespan (e.g. infection)



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SIGNS & SYMPTOMS



DIAGNOSIS ▪ High index of suspicion at birth with delayed umbilical cord separation, leukocytosis, along with additional findings ▫ LAD I: recurrent soft tissue infections ▫ LAD II: psychomotor impairment, Bombay blood group presence ▫ LAD III: bleeding complications from birth



LAB RESULTS



▪ White blood cell count with differential: elevated leukocyte count ▫ Leukocytes unable to leave bloodstream → persistent leukophilia (basal) + ↑↑ during infection (especially neutrophils) ▪ Flow cytometry ▫ LAD I: CD18, alpha subunit molecules (CD11a, CD11b, CD11c) absence



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▫ LAD-II: SLeX expression (CD15a) absence ▪ LAD-II: genetic testing confirms defect of gene that encodes for guanosine diphosphate (GDP)-fucose transporter ▪ LAD III: impaired integrin activation



TREATMENT MEDICATIONS



▪ Antibiotics: mild–moderate infections



OTHER INTERVENTIONS



▪ Control periodontitis: scrupulous oral hygiene, dental care ▪ Bacterial infection treatment: mitigate severity ▪ Fucose supplementation (LAD II) ▪ Hematopoietic cell transplantation



NOTES



NOTES



T–CELL DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Impaired function of T lymphocytes due to thymic hypoplasia → deficiency of cell-mediated immunity → high risk of infections ▪ Two main causes of thymic hypoplasia ▫ DiGeorge syndrome (DGS)/22q11.2 deletion syndrome ▫ Ataxia-telangiectasia (AT) syndrome (see Chapter 84 in Volume 1) ▪ Inherited, due to genetic defects ▪ Associated with other congenital abnormalities



SIGNS & SYMPTOMS ▪ Recurrent infections; usually viral ▪ Depend on cause of thymic hypoplasia



DIAGNOSIS LAB RESULTS Blood tests ▪ T cell numbers, function ▪ Calcium levels ▫ Hypocalcemia → DGS, eucalcemia → AT



OTHER DIAGNOSTICS



▪ Genetic testing ▫ Identify genetic defect



TREATMENT MEDICATIONS



▪ Management of symptoms ▫ Antibiotic therapy/prophylaxis for infections



SURGERY



▪ Thymus transplantation



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DIGEORGE SYNDROME (DGS) osms.it/digeorge-syndrome PATHOLOGY & CAUSES ▪ AKA 22q11.2 deletion syndrome ▪ Genetic condition; q11.2 portion of DNA on chromosome 22 deleted → deletion of TBX gene on chromosome 22 → impaired development of pharyngeal pouches 3, 4 → hypoplasia of thymus, inferior parathyroid gland ▫ Deficiency in mature T cells, adaptive immune response: complete thymic aplasia can be fatal in first year of life ▫ Parathyroid hypoplasia → low levels of parathyroid hormone → hypocalcemia ▪ 22q11.2 region encodes genes that affect other organs/tissues → congenital cardiac defects; facial, developmental abnormalities; behavioral, mental health conditions



SIGNS & SYMPTOMS ▪ Characteristic facial appearance: long face, small teeth, broad nose ▪ Developmental abnormalities (e.g. cleft palate) ▪ Cardiac defects (e.g. truncus arteriosus, tetralogy of Fallot) ▪ Thymus gland abnormalities → underdevelopment of cellular immune system → susceptibility to recurrent sinopulmonary infections/severe combined immunodeficiency (SCID) ▪ Learning difficulties/mental health conditions (e.g. schizophrenia) ▪ Hypoparathyroidism → hypocalcemia → seizures, tetany, osteoporosis



DIAGNOSIS LAB RESULTS Blood tests ▪ Reduced T cell number, function ▪ Hypocalcemia ▪ Low levels of parathyroid hormone



OTHER DIAGNOSTICS ▪ Genetic testing



TREATMENT MEDICATIONS



▪ Management of symptoms ▫ Antibiotics for infections



SURGERY



▪ Thymus transplantation



OTHER INTERVENTIONS



▪ Vitamin D, calcium supplements for hypocalcemia



Figure 35.1 A child with DiGeorge syndrome.



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NOTES



NOTES



TYPE I HYPERSENSITIVITY REACTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Exaggerated immune reaction mediated by IgE antibodies (atopy) triggered by harmless antigen (allergens) Sensitization phase ▪ Allergen → antigen presenting cells (APCs) → B-cell, Th2 cells assist in IgE production → bind via Fc region to mast cells → mast cells sensitized Re-exposure/effector phase ▪ Cytotropic/IgE receptor binding; allergens bind to Fab region of IgE on sensitized cells → activates mediator release ▪ Early phase reactions (within minutes) ▫ Primarily mast cell-release of preformed mediators (e.g. histamine, proteases, chemotactants); causes vasodilation, capillary leak, increased secretions, bronchial smooth muscle contraction ▪ Late phase reactions (8–12 hours) ▫ Mediators require synthesis (e.g. interleukins 4, 5, 10; leukotrienes); increases early downstream effects, prolongs inflammatory response Common Type I hypersensitivity reactions ▪ Ingested allergens ▫ Foods, dander, bee stings, mold, drugs/ medications, pollen ▪ Other allergens ▫ Latex, lotions, soaps, penicillin ▪ Atopic eczema ▪ Allergic urticaria ▪ Allergic rhinitis (Hay fever) ▪ Allergic asthma ▪ Anaphylaxis ▪ Eosinophilic esophagitis



CAUSES



▪ Causes of hyper/overactive re-exposure/ effector phase unclear; environmental exposure (esp. in early childhood), genetic factors ▪ “Atopic march”: multiple atopic (IgEmediated) diseases occur over lifetime



SIGNS & SYMPTOMS ▪ Range from mild, local (e.g. urticaria, rhinorrhea, itching) to life-threatening anaphylactic reaction (e.g. cardiac arrhythmia, shock, bronchospasm, laryngeal obstruction)



DIAGNOSIS LAB RESULTS



▪ Skin allergen testing, variable sensitivities ▪ Eosinophilia



OTHER DIAGNOSTICS



▪ History of symptoms, frequency, triggers



TREATMENT MEDICATIONS



▪ Symptom-based ▫ Antihistamines (e.g. H1 blockers), corticosteroids, epinephrine



OTHER INTERVENTIONS



▪ Hypo/de-sensitization ▫ Escalating doses of allergen subcutaneously injected over course of years; variable effectiveness, more severe reactions less responsive



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ACUTE RHINITIS osms.it/acute-rhinitis PATHOLOGY & CAUSES ▪ IgE-mediated immune response upon re-exposure of airborne allergens to eyes, nose ▪ AKA hay fever ▪ Local mast cells of eye, nose mucosa degranulate, release immediate mediators (e.g. histamine)



CAUSES ▪ Hay, pollen (seasonal due to flowering plants), dust, animal hair, mold spores



SIGNS & SYMPTOMS ▪ Due to increased fluid in eyes, nasal cavity ▫ Conjunctival injection, eyelid edema; sneezing; rhinorrhea, nasal obstruction; edematous bluish-red nasal turbinates



DIAGNOSIS LAB RESULTS



▪ Skin allergen tests ▫ Subdermal introduction of defined amount of allergen to volar surface of forearm; observe for “wheal-and-flare” reaction at specific site



OTHER DIAGNOSTICS



▪ Clinical presentation ▫ History of symptoms, frequency, triggering events



TREATMENT MEDICATIONS



▪ Oral antihistamine (e.g. H1 blockers) ▪ Nasal corticosteroids



OTHER INTERVENTIONS



▪ Nasal irrigation ▪ Environmental control (to avoid antigen) ▪ When severe, hypo/desensitization to allergen



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Chapter 36 Type I Hypersensitivity Reactions



ANAPHYLAXIS osms.it/anaphylaxis PATHOLOGY & CAUSES ▪ Generalized, life-threatening allergic response ▪ Systemic release of large quantities of immune mediators; symptoms most severe at site of greatest mediator concentration Immune mediators ▪ Histamine (ubiquitous systemic concentration) ▫ Vasodilator, immune system modulator ▫ H1 receptor → tachycardia, pruritus, rhinorrhea, bronchospasm ▫ H2 receptor → flushing, hypotension ▪ Tryptase (high skin concentration) ▫ Activate complement, coagulation pathways, kallikrein–kinin systems ▫ Angioedema, hypotension, disseminated intravascular coagulation (DIC) ▪ Leukotriene C4, prostaglandin D2 (in high lung concentration) ▫ Bronchoconstriction, increased mucus secretion



CAUSES



▪ Drugs (e.g. beta-lactam antibiotics, insulin) ▪ Foods (e.g. nuts, eggs, seafood) ▪ Proteins (e.g. blood transfusions, tetanus antitoxin) ▪ Latex



SIGNS & SYMPTOMS ▪ Generalized, mild-moderate ▫ Flushing, feeling of doom, tachycardia, urticaria, incontinence ▪ Generalized, severe ▫ Syncope, shock, hypoxia, cardiorespiratory collapse



DIAGNOSIS OTHER DIAGNOSTICS



▪ Clinical presentation ▫ Symptoms indicate allergic reaction



TREATMENT MEDICATIONS



▪ Immediate, necessary ▫ Epinephrine intravenously (IV) (1:10,000)/intramuscularly (IM) (1:1,000), repeat every 30 minutes with potential epinephrine infusion after bolus(es) ▪ Adjunct therapy ▫ H1, H2 receptor blockers, IV corticosteroids ▪ IV fluids, O2 supplementation ▪ Critical care ▫ Intubation, vasopressors if necessary



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FOOD ALLERGY osms.it/food-allergy PATHOLOGY & CAUSES ▪ Adverse food reaction; immune response to ingested antigens ▪ Distinct from non-immunologic adverse food reactions ▫ Enzyme deficiency (e.g. lactase), toxin ingestions (e.g. staphylococcal toxin), intolerance (e.g. caffeine)



TYPES IgE-mediated ▪ Rapid onset (minutes to couple hours after ingestion); immune mediator release from tissue mast cells, circulating basophils; common allergens include peanuts, soy, milk, wheat, fish Non-IgE mediated ▪ Symptoms subacute to chronic in nature; leukocytosis; local, lymphocytic destruction of gastrointestinal (GI) tissue; celiac disease, food protein-induced enterocolitis syndrome (FPIES) Mixed IgE/non-IgE-mediated ▪ Variable immune response, acute responses involving IgE-mediation, others favoring leukocytes (e.g. eosinophils, lymphocytes); atopic dermatitis, eosinophilic esophagitis, eosinophilic gastroenteritis



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SIGNS & SYMPTOMS ▪ Dermatologic (e.g. pruritus, erythema, urticaria), GI (e.g. nausea, vomiting, abdominal pain, diarrhea), anaphylactic (e.g.cardiac/respiratory reactions) ▪ Non-IgE-mediated food allergies ▫ Nonspecific, subacute/chronic GI symptoms; distinct dermatologic vesicular, papular eruptions; dermatitis herpetiformis in celiac disease



DIAGNOSIS LAB RESULTS



▪ Skin allergen testing



OTHER DIAGNOSTICS ▪ Food elimination trials



TREATMENT MEDICATIONS



▪ Antihistamines ▫ May be of little value unless urticaria, angioedema present



OTHER INTERVENTIONS



▪ Elimination of offending food from diet; mild disease may remit with time



NOTES



NOTES



TYPE II HYPERSENSITIVITY REACTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Antibody-mediated hypersensitivity reactions; tissue-specific, broad spectrum of disease manifestations ▪ Disorder due to self-reactive B cells that produce antibodies (e.g. IgM, IgG) that bind antigens on host cells, form antigenantibody complex at tissue site ▫ Defective central tolerance → autoantibodies against self/intrinsic antigens ▫ Embedded outside/extrinsic antigens into normal cell surface alter cell antigenicity Common Type II hypersensitivity reactions ▪ Hemolytic disease of the newborn ▪ Autoimmune hemolytic anemia ▪ Immune thrombocytopenic purpura ▪ Bullous pemphigoid ▪ Pemphigus vulgaris ▪ Rheumatic fever ▪ Goodpasture syndrome ▪ Guillain–Barré syndrome ▪ Graves’ disease ▪ Myasthenia gravis ▪ Pernicious anemia



TYPES



▪ Four pathologic mechanisms



Activation of complement system ▪ IgM/IgG antibody binds fixed antigen on cell → C1 binds Fc portion of IgM/IgG → classical pathway C2–C9 cleavage/ activation → C3a–C5a anaphylatoxin production ▫ Chemoattract promote degranulation of neutrophils, basophils, mast cells



(granules of lysosomal contents of leukocytes fuse, degrade target cell → cell death; mast cell degranulation contents include histamine → promote further immune cell response) ▫ Promote macrophage, monocytes pro-inflammatory cytokine release; interleukin (IL1), 6 (e.g. Goodpasture’s syndrome, antibodies against Type IV collagen in lung, kidney) ▪ Membrane attack complex (MAC) formation (C5b–C9) → insertion into, disruption of cell membrane → impaired osmotic gradient → cell lysis (e.g. ABO mismatch in transfusion reaction, hyperacute transplantation reaction) Opsonization, phagocytosis ▪ Antigen-opsonin C3b/IgG complex circulate ▫ To spleen → fixed macrophages recognize IgG-bound antigens → phagocytosis ▫ To liver → Kupffer cells recognize C3b-bound antigens → phagocytosis (Autoimmune hemolytic anemia (AIHA), ABO, Rh-hemolytic disease of newborn) Antibody-dependent cell-mediated cytotoxicity (ADCC) ▪ Natural killer cells bind Fc portion of antibody-antigen complex → release perforins, granzymes, granulysin → apoptotic cell death Antibody-mediated cellular dysfunction (only non-cytotoxic mechanism) ▪ Physical presence of antibody at receptor binding site impairs physiologic function ▫ Activate: thyroid hormone receptor in Graves’ disease ▫ Inhibit: acetylcholine receptor in Myasthenia gravis (MG)



OSMOSIS.ORG 223



SIGNS & SYMPTOMS ▪ Acute hemolytic transfusion reactions ▫ Fevers, chills; nausea/vomiting; flank, chest pain; dyspnea ▪ Autoimmune hemolytic anemia ▫ Fatigue, jaundice, hepatosplenomegaly (HSM) ▪ Bullous pemphigoid ▫ Abdominal, groin, extremity blistering ▪ Erythroblastosis fetalis ▫ Kernicterus, death in fetus ▪ Goodpasture syndrome ▫ Dyspnea, hemoptysis, hematuria ▪ Graves’ disease ▫ Tremor, insomnia, irritability, weight loss, tachycardia ▪ Guillain–Barre syndrome ▫ Ascending paralysis ▪ Idiopathic thrombocytopenic purpura ▫ Petechiae, skin ecchymoses ▪ Myasthenia gravis ▫ Weakness, ptosis, diplopia, dysphagia ▪ Pemphigus vulgaris ▫ Blistering of oral mucosa ▪ Pernicious anemia ▫ Fatigue, glossitis, B12 deficiency sequelae ▪ Rheumatic fever ▫ Migratory polyarthritis, fever, +/- cardiac involvement



224 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS



▪ Coombs testing ▫ Direct: detects Fc region of bound antibodies on red blood cells (RBCs) (e.g. ABO incompatibility) ▫ Indirect: detects circulating serum antibodies against known antigen (e.g. anti-D) ▪ RBC antigen testing ▪ Immunohistochemistry (IHC) ▪ Diffuse radioactive iodine (RAI) uptake



OTHER DIAGNOSTICS ▪ Clinical presentation of disease-specific symptoms



TREATMENT MEDICATIONS



▪ Corticosteroids ▪ Severe reactions may require plasmapheresis/immunosuppressants



Chapter 37 Type II Hypersensitivity Reactions



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NOTES



NOTES



TYPE III HYPERSENSITIVITY REACTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Hypersensitivity reaction mediated by immune complexes ▫ Antibodies (IgG) binding to soluble antigens → antigens not bound to cell surfaces ▪ Formation of immune complexes → complement activation (esp. C3a, C4a, C5a) ▫ Anaphylatoxins → increase vascular permeability → edema ▫ Chemokins → recruitment of phagocytes, neutrophils, mast cells → degranulation of lysosomal enzymes, reactive oxygen species → inflammation, tissue necrosis (fibrinoid necrosis) ▫ May also elicit systemic inflammation ▪ Common sites of immune complex accumulation ▫ Blood vessel walls → vasculitis ▫ Kidneys → glomerulonephritis ▫ Joints → arthritis ▪ If triggered by single exposure to antigen, resolves after catabolism of immune complexes → acute serum sickness ▪ If repeated/prolonged exposure → chronic serum sickness ▫ Systemic erythematosus lupus (SLE), polyarteritis nodosa, poststreptococcal glomerulonephritis, reactive arthritis Common Type III hypersensitivity reactions ▪ Henoch–Schönlein purpura ▪ Hypersensitivity vasculitis ▪ Reactive arthritis ▪ Farmer’s lung ▪ Post-streptococcal glomerulonephritis ▪ Serum sickness ▪ Arthus reaction



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▪ Systemic lupus erythematosus ▪ Subacute bacterial endocarditis ▪ Rheumatoid arthritis



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪



Fever, fatigue, weight loss Skin: rash, urticaria Kidney: proteinuria Joints: arthralgias Mucosa: ulcers Serosa: pleuritis, pericarditis



DIAGNOSIS LAB RESULTS



▪ Antibody testing ▪ Histopathology to observe fibrinoid necrosis ▫ Necrosis of vessel wall with infiltration of neutrophils, eosinophils, complement, plasma proteins; staining pattern reminiscent of fibrin



Figure 38.1 A vessel displaying fibrinoid necrosis in Churg–Strauss syndrome, which is a type III hypersensitivity reaction.



Chapter 38 Type III Hypersensitivity Reactions ▪ Immunofluorescence microscopy to visualize immune complexes ▪ Complement levels in blood ▫ Track disease progression



TREATMENT MEDICATIONS



▪ SLE ▫ Administration of anti-inflammatory, corticosteroids, cytotoxic medications to decrease inflammatory activity



SERUM SICKNESS osms.it/serum-sickness PATHOLOGY & CAUSES ▪ Systemic Type III hypersensitivity reaction against foreign antibodies in serum ▪ Exposure to foreign serum → triggers B cells to become plasma cells, produce IgG antibodies against foreign antibodies → immune complexes formed, deposited in basement membrane → complement activation, immune cells recruitment → lysosomal enzymes, reactive oxygen species, cytokines produced → local, systemic inflammatory response ▪ Initial exposure ▫ 4–10 days to develop reaction ▪ Second exposure ▫ Faster, more potent reaction ▪ Resolves after withdrawal of culprit agent



CAUSES



▪ Medications (e.g. cefaclor, anti-seizure medications); infections (e.g., hepatitis B); vaccines



SIGNS & SYMPTOMS ▪ Allergy-like response ▪ Present within 1–2 weeks if initial exposure, 12–36 hours if second exposure ▫ General malaise, erythema, itching, arthralgia ▪ Fever > 38.5°C/101.3°F, rash, lymphadenopathy, polyarthritis, proteinuria



DIAGNOSIS LAB RESULTS



▪ Complete blood count (CBC) ▫ Neutropenia, increase in lymphocytes ▪ Elevation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) ▪ Urinalysis ▫ Mild proteinuria (50%)



OTHER DIAGNOSTICS



▪ Clinical presentation; suspected when allergy-like symptoms present after administration of potential responsible agent (e.g. antivenom serum after bitten by snake) ▪ Testing to exclude infections (e.g. hepatitis B)



TREATMENT MEDICATIONS



▪ Relieve symptoms with antihistamines, analgesics ▪ Glucocorticoids for individuals with severe clinical features (e.g. very high fever, severe arthritis, extensive rashes)



OTHER INTERVENTIONS



▪ Discontinue, avoid offending agent



OSMOSIS.ORG 227



NOTES



NOTES



TYPE IV HYPERSENSITIVITY REACTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Delayed, T cell-mediated (antibodyindependent) hypersensitivity reaction ▪ 24–72 hour delayed nature due to stepwise sensitization-response progression ▫ Antigen presentation by antigen presenting cells (APCs) → naive T-cells recognition → T-cells, macrophages migration, response Role of CD4+ (helper) T cells, macrophages ▪ CD4+ (helper) T cells ▫ APC displays antigen on MHC II receptor → naive CD4+ T cell binds MHC II via T cell receptor, CD4 coreceptor → T cell expresses CD28 → binds APC B7 → cobinding stimulates APC cytokine secretion ▫ Interleukin (IL) 12 produced → TH1 cell maturation → TH1 secrete IL-2, IFN𝛄 → proliferation of TH1 response, macrophage recruitment, activation ▫ IL-6, TGF-beta produced → TH17 cell maturation → TH17 secrete IL-17 → recruit neutrophils ▪ Macrophages ▫ Secrete TNF-alpha, IL-1, IL-6 → promote inflammation, leaky endothelium → edema, fever; secrete lysosomal enzymes, complement, and reactive oxygen species (ROS) → tissue damage ▪ Pathophysiology in inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA) Role of CD8+ (AKA cytotoxic, effector, killer) T cells ▪ Altered host cell MHC I signal → CD8+ T cell receptor → activate CD8+ T cells



228 OSMOSIS.ORG



▪ Secrete perforins, granzymes → create membrane pores, induce cellular apoptosis ▪ Pathophysiology in Type I diabetes mellitus (DM), against islet cells; Hashimoto’s thyroiditis, against epithelial cells; immune response to some tumor cells Common Type IV hypersensitivity reactions ▪ Allergic contact dermatitis ▪ Mantoux test ▪ Diabetes mellitus type I ▪ Hashimoto’s thyroiditis ▪ Multiple sclerosis ▪ Coeliac disease ▪ Giant-cell arteritis ▪ Postorgasmic illness syndrome ▪ Reactive arthritis ▪ GVHD ▫ Transfusion-associated graft versus host disease



TYPES Contact hypersensitivity ▪ Molecules covalently alter major histocompatibility complex (MHC) I receptors to neo-self antigens; nickel, urushiol (poison ivy molecule) Chronic, delayed hypersensitivity ▪ Agents unusually resistant to elimination by immune system; tuberculosis (TB), leprosy, silicosis, sarcoidosis



COMPLICATIONS



▪ Granuloma formation in chronic, delayedtype hypersensitivity reactions ▪ Due to hyperactive macrophages, surrounding inflammatory reaction “walls off” offending agent (e.g. sarcoidosis, tuberculosis, silicosis)



Chapter 39 Type IV Hypersensitivity Reactions



SIGNS & SYMPTOMS ▪ Local inflammatory reaction → erythema, warmth, edema, fever ▪ Sequelae of organ-specific cell destruction ▫ Islet cell destruction in pancreas → insulin-deficient (e.g. lethargy, seizure, coma) ▪ Chronic inflammation → granuloma formation → organ failure



DIAGNOSIS OTHER DIAGNOSTICS



▪ Exposure history of molecule/agent at site of symptoms ▪ Contact hypersensitivity ▫ Patch test (adhesive-mounted patches with miniscule amounts of allergen imbued in tape) ▫ Evaluate in 48–96 hours for local skin reaction



▪ Tuberculosis ▫ Tuberculin skin test (TST)/purified protein derivative (PPD) test ▫ Intradermal injection of tuberculin protein → pre-sensitized T-cells react to antigen → measure induration size at 48–72 hours ▫ Positive test (induration size) inversely related to TB exposure risk of individual



TREATMENT MEDICATIONS ▪ Corticosteroids for inflammatory control ▫ Systemic for severe, generalized reactions; otherwise, site-specific (e.g. topical for contact dermatitis; inhaled for hypersensitivity pneumonitis)



GRAFT-VERSUS-HOST DISEASE (GvHD) osms.it/graft-versus-host-disease PATHOLOGY & CAUSES ▪ Type of transplant rejection caused by immunocompetent, donor T cells reacting against recipient MHC I “foreign” antigens ▫ Variable time course of symptoms ▫ Common targets: skin, liver, intestine epithelial tissue ▪ Donor CD4+ T cell → recognize recipient MHC II as foreign → activated donor CD4+ T cells → cytokine release → recipient macrophage, CD4+ recruitment → exacerbate cytokine response ▫ Tumor necrosis factor (TNF) alpha: possible cause of “metabolic wasting”



▪ Donor CD8+ T cell → recognize recipient MHC I as foreign → activated CD8+ T cells → Fas, perforin-mediated cytotoxicity ▫ Majority of tissue destruction occurs via CD8+ T cells ▪ Similar graft-versus leukemia reaction (GvL) beneficial in individuals with leukemia due to ability to help eliminate recipient’s hematopoietic cancer cell line



RISK FACTORS



▪ Liver, bone marrow transplants (rich in lymphocytes) ▪ T cell immunodeficient individuals, newborns



OSMOSIS.ORG 229



SIGNS & SYMPTOMS ▪ Metabolic wasting/failure to thrive, maculopapular rash, jaundice, bloody diarrhea, hepatosplenomegaly



DIAGNOSIS LAB RESULTS



▪ Histological analysis of easily biopsied tissue in individual with history of transplantation ▫ Liver, skin, gastrointestinal (GI) tract; most helpful in chronic, indolent disease



OTHER DIAGNOSTICS



▪ Clinical presentation ▫ Constellation of symptoms



TREATMENT MEDICATIONS



▪ Prophylaxis (e.g. cyclosporine, methotrexate) ▪ Site-directed corticosteroids ▫ Topical for primary skin manifestation; non-absorbable (e.g. budesonide, beclomethasone) for GI involvement



Figure 39.1 A CT scan in the coronal plane of the abdomen of an individual with graftversus-host disease. The gastrointestinal tract, including the stomach and small bowel, is grossly edematous.



OTHER INTERVENTIONS Prevention ▪ Proper donor, recipient human leukocyte antigen (HLA), MHC, minor histocompatibility (MiHA) matching; irradiation of transfused blood products Figure 39.1 A colonic biopsy taken from an individual with graft-versus-host disease. There is florid cryptitis (neutrophils infiltrating the crypt wall) and apoptotic debris at the crypt bases.



230 OSMOSIS.ORG



NOTES



NOTES



AMINO ACID METABOLISM DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited disorders of amino acid metabolism, transportation, excretion ▪ Impaired enzymes → reactant accumulation → toxicity ▪ Inherited autosomal/X-linked recessive



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS LAB RESULTS



▪ Amino acids levels in blood, urine



CAUSES



▪ Gene mutation



TREATMENT



RISK FACTORS



▪ Infants with central nervous system (CNS) disorders most commonly affected



OTHER INTERVENTIONS ▪ Modified diet



ALKAPTONURIA osms.it/alkaptonuria PATHOLOGY & CAUSES ▪ Inherited autosomal recessive disorder of tyrosine, phenylalanine metabolism with build-up of degradation product (homogentisic acid) in connective tissues ▪ Homogentisic acid transforms into polymer → deposition of polymer into collagen fibers of connective tissues (e.g. cartilage) → ochronosis



CAUSES



▪ Mutation of homogentisic oxidase gene (HDG) → deficit of homogentisate oxidase → ↑ homogentisic acid



COMPLICATIONS



▪ Coronary artery disease ▪ Arthritis ▪ Renal stones



SIGNS & SYMPTOMS ▪ Usually asymptomatic in childhood/ adolescence ▪ In infants, urine in diapers darkens due to oxidation of homogentisic acid; “black nappies” ▪ Bluish pigmentation of sclera, ear, etc. ▪ Pain in spine, hip, knee joints



OSMOSIS.ORG 231



DIAGNOSIS DIAGNOSTIC IMAGING Radiology ▪ Calcification of multiple intervertebral discs



LAB RESULTS



▪ Dark brown/black color of urine on prolonged air exposition ▪ Chromatography ▫ ↑ homogentisic acid



TREATMENT MEDICATIONS



▪ Herbicide nitisinone → inhibits enzyme which converts tyrosine to homogentisic acid → ↓ homogentisic acid



OTHER INTERVENTIONS



▪ Tyrosine, phenylalanine restriction → ↓ homogentisic acid excretion



Figure 40.2 Alkaptonuria leads to the accumulation of homogentisic acid giving the clinical appearance known as ochronosis.



232 OSMOSIS.ORG



Figure 40.1 An X-ray image demonstrating calcification of the intervertebral discs in an individual with ochronosis.



Chapter 40 Amino Acid Metabolism Disorders



CYSTINURIA osms.it/cystinuria PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; high levels of cystine in urine → kidney, ureter, bladder stones



CAUSES



▪ Mutation of SLC3A1, SLC7A9 gene → defect of intestinal, renal amino acid transporter affecting positively charged amino acids (e.g. cysteine, arginine, ornithine)



COMPLICATIONS



▪ Hydronephrosis, pyelonephritis, frequent urinary tract infections (UTIs)



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Flank pain, hematuria



DIAGNOSIS LAB RESULTS



▪ Sodium cyanide-nitroprusside test ▫ Determination of cystine concentration ▪ Urinalysis ▫ Pathognomonic hexagonal crystals ▪ Stone analysis



TREATMENT MEDICATIONS



▪ Chelation therapy with penicillamine ▫ Forming soluble disulfide complex



OTHER INTERVENTIONS



▪ Sufficient hydration; urine alkalization ▪ Protein, sodium restriction ▪ Formed stones ▫ Renal: extracorporeal shock wave lithotripsy (ESWL) ▫ Ureteric: intracorporeal lithotripsy ▫ Bladder: cystolitholapaxy



HARTNUP DISEASE osms.it/hartnup-disease PATHOLOGY & CAUSES ▪ Inherited autosomal recessive metabolic disorder affecting neutral amino acids (esp. tryptophan)



CAUSES



▪ Intestinal, renal deficiency of neutral amino acid transporters → ↓ absorption from



intestines, ↓ reabsorption from kidneys → less amino acids available to build proteins



COMPLICATIONS



▪ Drop of tryptophan to niacin conversion → decrease of nicotinamide, NAD+ → pellagra-like symptomatology ▪ Hyper/hypopigmentation in repeated sunlight exposure



OSMOSIS.ORG 233



SIGNS & SYMPTOMS Pellagra-like symptoms Photosensitivity Diarrhea Nervous system symptoms (e.g. ataxia, tremor, headaches; intellectual disability, mental abnormalities) ▪ Ocular manifestations (e.g. nystagmus, double vision) ▪ ▪ ▪ ▪



DIAGNOSIS LAB RESULTS



▪ Urine chromatography ▫ Increased levels of neutral amino acids (e.g. aminoaciduria)



TREATMENT OTHER INTERVENTIONS



▪ High-protein diet, nicotinic acid supplements, sunlight protection



HOMOCYSTINURIA osms.it/homocystinuria PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; high levels of homocysteine in blood, urine due to impaired methionine metabolism



TYPES



▪ Type I ▫ Deficiency of cystathionine synthase ▪ Type II ▫ Deficiency of methionine synthase ▪ Type III ▫ Cystathionine synthase impairment → decreased affinity for pyridoxal phosphate



COMPLICATIONS



▪ Increased risk for thrombotic strokes



SIGNS & SYMPTOMS ▪ Ocular anomalies (e.g. myopia, ectopia lentis) ▪ Marfan-like presentation ▪ Intellectual disability ▪ Cardiovascular defects ▪ Osteoporosis



234 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Large-vessel/lacunar stroke



LAB RESULTS



▪ Blood, urine quantitative test for homocystinuria ▪ Cyanide nitroprusside test ▫ Urine screening test for amino acids containing sulfur ▪ Measurement of cystathionine synthase activity in cultured fibroblasts



TREATMENT OTHER INTERVENTIONS



▪ Vitamin B6, B12, folate acid supplements in cystathionine synthase deficiency ▪ Methionine in methionine synthase deficiency ▪ Cysteine, high doses of vitamin B6 in decreased affinity of cystathionine synthase for pyridoxal phosphate



Chapter 40 Amino Acid Metabolism Disorders



MAPLE SYRUP URINE DISEASE osms.it/maple-syrup-urine-disease PATHOLOGY & CAUSES ▪ Disease caused by impaired metabolism of branched amino acids (e.g. isoleucine, leucine, valine); AKA branched-chain ketoaciduria ▪ Autosomal recessive inheritance ▪ Impaired metabolism → accumulation of byproducts with toxicity in brain, other organs



TYPES



DIAGNOSIS LAB RESULTS



▪ Plasma amino acid test ▫ Alloisoleucine detection ▪ Prenatal diagnostic by measuring enzyme activity in cultured amniocytes



OTHER DIAGNOSTICS



▪ Genetic testing ▫ BCKDHA, BCKDHB, DBT ▪ Physical examination, newborn screening



Classic MSUD ▪ Most common; occurs soon after birth Non-classic MSUD ▪ Later onset, less severe symptoms



CAUSES



▪ Mutation of genes BCKDHA, BCKDHB, DBT → dysfunction of enzyme complex



COMPLICATIONS



TREATMENT SURGERY



▪ Liver transplant



OTHER INTERVENTIONS



▪ Regular metabolism check ▪ Regulation of isoleucine, leucine, valine intake



▪ Possible permanent brain damage ▪ Fatal if not treated in first five months



SIGNS & SYMPTOMS ▪ Sweet (maple syrup-like) smelling urine Classic MSUD ▪ Healthy-looking infants at birth, quick deterioration; feeding difficulties, failure to thrive (FTT), vomiting, seizures Non-classic MSUD ▪ Vomiting, diarrhea, rapid neurological decline, ataxia, seizures, coma



OSMOSIS.ORG 235



ORNITHINE TRANSCARBAMYLASE DEFICIENCY osms.it/OTC-deficiency PATHOLOGY & CAUSES



DIAGNOSIS



▪ X-linked disorder affecting ornithine transcarbamylase enzyme ▪ Disorder of urea cycle → accumulation nitrogen in form of ammonia ▪ Defect of ornithine transcarbamylase enzyme → carbamoyl phosphate accumulation → conversion of carbamoyl phosphate into orotic acid ▪ Presents often in neonatal form, may present later



LAB RESULTS



RISK FACTORS



▪ Ornithine transcarbamylase only expresses in liver; liver biopsy needed to confirm diagnosis ▪ Newborn screening



▪ Individuals who are biologically male fully affected due to X-recessive transmission ▪ Individuals who are biologically female usually asymptomatic



SIGNS & SYMPTOMS ▪ Neonatal form ▫ Lethargy, irritability, poor feeding, seizures, impaired thermoregulation; hyperventilation → respiratory alkalosis; cerebral edema, possible progression into coma, death ▪ Later presentation ▫ Headaches, nausea, vomiting, psychiatry disorders



236 OSMOSIS.ORG



▪ Plasma, urine amino acid analysis ▫ Elevated arterial/venous ammonia (hallmark finding), orotic acid, glutamine ▫ Decreased blood urea nitrogen (BUN), citrulline concentrations ▪ Urine organic acid analysis ▫ Orotic acid in urine



OTHER DIAGNOSTICS



TREATMENT SURGERY



▪ Liver transplant



OTHER INTERVENTIONS



▪ Low-protein diet ▪ Nitrogen scavenging agents ▫ Sodium benzoate, arginine



Chapter 40 Amino Acid Metabolism Disorders



PHENYLKETONURIA osms.it/phenylketonuria PATHOLOGY & CAUSES



DIAGNOSIS



▪ Genetic disorder characterized by high levels of phenylalanine ▪ Autosomal recessive inheritance



LAB RESULTS



CAUSES



Chromatography/tandem mass spectrometry ▪ ↑ phenylalanine



▪ PAH gene mutation → hepatic phenylalanine hydroxylase deficiency → defect in metabolism of phenylalanine → activation of alternative pathways → accumulation of phenylalanine, byproducts ▪ Mutation of HPABH4 genes → impairment in synthesis, recycling of tetrahydrobiopterin cofactor (BH4) → impaired function of phenylalanine hydroxylase enzyme



COMPLICATIONS



▪ If untreated ▫ Severe intellectual disability ▪ Seizures ▪ Increased risk of anxiety, inattention, depression, other neuropsychiatric disorders ▪ Phenylalanine embryopathy ▫ Inappropriate diet during pregnancy in individuals with phenylketonuria → elevated levels of phenylalanine concentration in serum → teratogenic effects of phenylalanine passing placenta → newborn with microcephaly, mental disorders, congenital heart defects



SIGNS & SYMPTOMS ▪ Skin, hair pigmentation disorders (lack of melanin pigment) ▪ Eczema ▪ Musty odor



Cranial magnetic resonance spectrometry ▪ Brain phenylalanine levels



Guthrie test ▪ Formerly used; replaced with tandem mass spectrometry Ferric chloride urine test ▪ Rarely used; results may be negative in first months of life



OTHER DIAGNOSTICS ▪ Newborn screening



Figure 40.3 The heelprick test is performed on all newborn babies and screens for phenylketonuria.



TREATMENT MEDICATIONS ▪ Sapropterin



OTHER INTERVENTIONS



▪ Lifelong low-phenylalanine diet with tyrosine supplements ▪ Avoid artificial sweeteners containing phenylalanine (e.g. aspartame)



OSMOSIS.ORG 237



NOTES



NOTES



CARBOHYDRATE METABOLISM DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited disorders of carbohydrate metabolism (fructose, glucose, galactose) ▪ Determined by exposure to external triggers (e.g. dietary factors) ▪ Disruption in certain metabolic pathways → accumulation of byproducts → systemic alterations, organ failures



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS LAB RESULTS



▪ Enzymatic dosage



OTHER DIAGNOSTICS ▪ Genetic testing



TREATMENT OTHER INTERVENTIONS ▪ Avoid triggers



ESSENTIAL FRUCTOSURIA osms.it/essential-fructosuria PATHOLOGY & CAUSES ▪ Benign disease; impaired fructose metabolism → increased excretion in urine



CAUSES



▪ Autosomal recessive mutation in fructokinase, AKA ketohexokinase (KHK) ▫ First enzyme in fructose metabolism ▪ Intake of fructose-rich food/fructose-related sugar (e.g. sucrose, sorbitol) → increase of fructose in blood → excretion of fructose in urine



SIGNS & SYMPTOMS ▪ Asymptomatic



238 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS



▪ Positivity for reducing substances in urine



TREATMENT OTHER INTERVENTIONS ▪ No treatment necessary



Chapter 41 Carbohydrate Metabolism Disorders



GALACTOSEMIA osms.it/galactosemia PATHOLOGY & CAUSES ▪ Disease characterized by altered metabolism of galactose



CAUSES



▪ Autosomal recessive disorder



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



FTT Vomiting, diarrhea with lactation Jaundice, hepatomegaly Cataract Intellectual disability, lethargy, speech disorder, altered muscle coordination (ataxia)



Three possible mutations ▪ Galactose-1-phosphate uridyl transferase (GALT) deficiency (most common) ▫ Accumulation of galactose-1-phosphate + alternative metabolic pathway activation → accumulation of galactose metabolites (galactitol, galactonate) ▪ Galactokinase deficiency (uncommon) ▫ Less severe, often asymptomatic ▪ Uridine diphosphate (UDP) galactose-4epimerase deficiency (uncommon)



LAB RESULTS



COMPLICATIONS



OTHER INTERVENTIONS



▪ Metabolites accumulate in ▫ Eyes: increasing osmotic pressure → water attraction → opacification of lens (cataract) ▫ Liver: fatty alteration, cirrhosis ▫ Brain: cell damage, edema, gliosis ▫ Kidney: prevent amino acid reabsorption → aminoaciduria ▪ Altered neutrophil activity → increased risk of sepsis from E.coli ▪ Gonadal failure, hemolysis, coagulopathy



DIAGNOSIS ▪ Routinely screened in newborns ▫ Dosage of enzymes involved in galactose metabolism



TREATMENT ▪ Elimination of galactose from diet



OSMOSIS.ORG 239



HEREDITARY FRUCTOSE INTOLERANCE osms.it/hereditary-fructose-intolerance PATHOLOGY & CAUSES ▪ Disease characterized by alteration of fructose metabolism



CAUSES



▪ Autosomal recessive mutation in liver aldolase (aldolase B) ▪ Aldolase B deficiency → fructose 1-phosphate buildup → ▫ Local fructose toxicity → liver cell death ▫ Hypoglycemia ▫ Adenosine triphosphate (ATP), phosphate depletion → inhibition of protein synthesis → hepatic, renal damage



SIGNS & SYMPTOMS ▪ Avoidance of foods containing fructose (e.g. fruit, juice) ▪ Acute ingestion of fructose/compounds which contain fructose (e.g. sucrose, sorbitol) → nausea, vomiting; restlessness; pallor; sweating, trembling; lethargy, apathy; convulsions; coma ▪ Repeated ingestion of fructose → failure to thrive (FTT); liver disease (e.g. jaundice, hepatomegaly); kidney disease



240 OSMOSIS.ORG



DIAGNOSIS OTHER DIAGNOSTICS



▪ Nutritional history, clinical presentation ▪ Genetic testing



TREATMENT OTHER INTERVENTIONS



▪ Elimination of fructose from diet



Chapter 2 Acyanotic Defects



NOTES



CHEMICAL & DRUG TOXICITY



GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Variety of disorders caused by excessive exposure to harmful substances ▪ Adverse effects of exposure ▫ Direct damage to DNA, disruption of metabolic processes, organ dysfunction ▪ Excessive exposure to offending agent ▫ Intentional/unintentional, acute/chronic



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS ▪ See individual disorders



TREATMENT MEDICATIONS



▪ Administer available antidote



OTHER INTERVENTIONS



▪ Removal of offending agent ▪ Address comorbidities, complications



ACUTE RADIATION SYNDROME (ARS) osms.it/acute-radiation-syndrome PATHOLOGY & CAUSES ▪ Group of organ system toxicities caused by excessive exposure to ionizing radiation of whole body/significant part of body ▪ Ionizing radiation ▫ Composed of particles, short electromagnetic waves with potential to damage biological tissues; displaces electrons from orbits → creates unstable atoms → ionization occurs as free electrons collide with other atoms ▫ Causes damage to tissues by direct impact on DNA, proteins, cell membrane lipids, generating free radicals; rapidly dividing cells most vulnerable due to



DNA damage; mutagenic, carcinogenic, teratogenic effects Types of ionizing radiation ▪ X-rays, gamma rays ▫ Medical, industrial, military applications (e.g. medical imaging, radiosurgery) ▪ Alpha particles ▫ Unable to penetrate skin, harmful if ingested/inhaled (e.g. plutonium-236, uranium-238) ▪ Beta particles ▫ Penetrate subcutaneous tissues, also harmful if ingested/inhaled (e.g. strontium-90, cesium-137)



OSMOSIS.ORG 241



Measurement ▪ Radiation dose: measured in grays (Gy) ▫ Amount of energy deposited into mass of tissue; 1Gy = 1 joule of absorbed energy per kilogram of biological matter ▪ Effective dose: measured in sieverts (Sv) ▫ Type of radiation + variable tissue sensitivity; adjusts relative biologic effect of different radiation types on different tissues (e.g. 1Gy of alpha radiation more dangerous than 1Gy of gamma radiation) ▪ Nuclear medicine procedures: mSv; 1mSv = 1mGy ▪ Typical threshold dose for whole-body/ significant partial-body irradiation ▫ ≥ 1Gy delivered at relatively high dose rate



STAGING



Four organ-system toxicities ▪ Neurovascular/cerebrovascular ▫ Caused by localized central nervous system (CNS) changes ▪ Gastrointestinal (GI) ▫ Caused by loss of intestinal crypt cells, breakdown of mucosal barrier, loss of epithelium ▪ Hematopoietic ▫ Caused by impairment of mitotically active hematopoietic precursors ▪ Cutaneous ▫ Caused by damage to epidermis, dermis, hair follicles, subcutaneous tissues



▪ Malnutrition, cognitive impairment, hemorrhage, permanent skin/hair loss, malignancies, infertility, congenital malformations, radiation pneumonitis, multiorgan failure, high mortality



RISK FACTORS



▪ Occupational exposure (e.g. medical imaging technicians) ▫ Especially with insufficient shielding ▪ Injurious incident (e.g. nuclear power plant, transportation, overtreatment during medical therapy) ▪ Detonation of nuclear bomb/radiological dispersal device (dirty bomb) ▪ ↑ dose, rate of dose; ↓ distance from radiation source, type of radiation ▪ Individuals < 12 years , > 60 more sensitive to radiation



242 OSMOSIS.ORG



▪ Prodromal ▫ 0–2 days post-exposure; fever, tachycardia, nausea, vomiting, headache, fatigue ▪ Latent phase ▫ 2–20 days post-exposure; partial functionality ▪ Manifest illness ▫ 21–60 days post-exposure; progression to organ-system syndromes ▪ Recovery/death ▫ Death may occur days after exposure to high amounts of radiation/ weeks, months after low exposure; death inevitable if doses > 10–12Gy



COMPLICATIONS



SIGNS & SYMPTOMS ▪ Neurovascular/cerebrovascular ▫ Meningeal inflammation, cerebral edema → ↑ intracranial pressure, hemorrhage ▪ GI ▫ Abdominal cramping, pain; loose stools, vomiting → fluid, electrolyte imbalance; bleeding → anemia; bowel ulceration, necrosis, perforation ▪ Hematopoietic ▫ Pancytopenia; bone marrow hypoplasia, aplasia ▪ Cutaneous ▫ Erythema; edema; dry, moist desquamation; ulceration (subcutaneous tissue, muscle, bone); blisters, bullae



Chapter 42 Chemical & Drug Toxicity



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ GI ▫ Segmental inflammation, bowel thickening, fibrosis, bowel obstruction ▪ Neurovascular/cerebrovascular ▫ Cranial edema, swelling



LAB RESULTS



▪ Serial complete blood counts (CBCs) ▫ Demonstrate changes in bone marrow function ▪ Peripheral blood sample ▫ Cytogenetic biodosimetry analyzes chromosomal aberrations in lymphocytes; correlation with radiation dose



OTHER DIAGNOSTICS



▪ Geiger counter/alpha-radiation detection device ▫ Determines degree of contamination ▪ Medical Treatment Protocols for Radiation Accident Victims (METREPOL) ▫ During first 48 hours



TREATMENT MEDICATIONS



▪ Nonradioactive potassium iodide (KI) ▫ Take within first hours of exposure; inhibits corporation of radioactive isotopes of iodine into thyroid gland ▪ External decontamination ▫ Wounds, body orifices



▪ Internal decontamination ▫ Minimize absorption, maximize excretion ▫ Chelating agents: diethylene-triaminepentaacetic acid (DTPA) ▫ Oral ferric hexacyanoferrate (Prussian blue): traps radioactive materials in intestines → prevents reabsorption ▪ Sodium bicarbonate ▫ ↓ risk of renal tubular necrosis ▪ Pain management ▪ Anxiolytics Organ-based management ▪ Hematopoietic: cytokine therapy (e.g. granulocyte colony-stimulating factor); recombinant human erythropoietin, antimicrobials ▪ GI: antiemetics (e.g. selective 5HT3 receptor antagonists), antidiarrheals



SURGERY Organ-based management ▪ Hematopoietic: stem cell transplant



OTHER INTERVENTIONS



▪ Address injuries (e.g. fractures, burns) ▪ Fluid, electrolyte replacement ▪ Lung lavage, mechanical ventilation



Organ-based management ▪ Hematopoietic: blood products ▪ Neurovascular: address increased intracranial pressure; comfort care (outcome likely fatal with neurovascular syndrome) ▪ Cutaneous: debridement, wound care



OSMOSIS.ORG 243



244 OSMOSIS.ORG



Chapter 42 Chemical & Drug Toxicity



ARSENIC POISONING osms.it/arsenic-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure (acute/chronic) to arsenic → disruption of metabolic processes ▫ Naturally-occurring metalloid element, organic/inorganic compounds (organic— relatively low toxicity, inorganic—high toxicity) ▫ Present in soil, groundwater in certain areas; in gaseous state (arsine); tasteless, odorless ▪ Arsenic taken up by red blood cells → distributed to all body tissues, penetrates blood-brain barrier → interacts with intracellular compounds ▫ Interferes with metabolic processes (e.g. binds to sulfhydryl groups → impairs enzymatic reactions, interferes with cellular respiration) ▫ Concentrates in keratin-rich tissues (e.g. skin, hair, nails) ▫ Excreted in urine



RISK FACTORS



▪ Ingestion ▫ Contaminated groundwater: natural leaching from soil/agricultural, industrial pollution ▫ Foods (e.g. rice) grown in water containing arsenic ▫ Certain Asian homeopathic compounds ▪ Inhalation ▫ Arsenic-containing gas/dust from melting, refining, coal-fired power plants ▪ Occupational exposure ▫ Glass manufacturing, metallurgy, mining, semiconductor manufacturing (e.g. gallium arsenide), pressure-treated wood products using chromated copper arsenate (CCA) ▪ Potential toxicity when administered therapeutically (e.g. arsenic trioxide for leukemia)



COMPLICATIONS



▪ Skin pigmentation, structural changes → squamous cell carcinoma ▪ Fluid, electrolyte imbalance, shock → common cause of death ▪ Blocks cardiac potassium channels → conduction disturbances ▪ Respiratory distress syndrome ▪ Hepatotoxicity ▪ Intravascular hemolysis → renal failure ▪ Peripheral vascular disease, gangrene (“black foot”) ▪ Encephalopathy ▪ Bone marrow depression, pancytopenia ▪ Malignancies ▫ Lung, liver, kidney bladder, colon; basal/ squamous cell carcinoma ▪ Crosses placenta → ↑ risk for spontaneous abortions, stillbirths, preterm births



SIGNS & SYMPTOMS ▪ GI ▫ Abdominal cramping, nausea, vomiting, hematemesis, diarrhea ▪ Cardiovascular ▫ Tachycardia, hypotension ▫ Conduction disturbances: QT prolongation, ventricular dysrhythmias (e.g. torsades de pointes) ▪ Neurological ▫ Peripheral neuropathy (“stocking-glove” distribution), diminished vibratory sensation, decreased deep tendon reflexes, delirium, seizures ▪ Skin ▫ Plantar/palmar hyper/hypopigmentation, “raindrop on dusty road” pigmentation, hyperkeratosis, Mees lines on nails (transverse leukonychia) ▪ Breath ▫ Garlic odor



OSMOSIS.ORG 245



OTHER DIAGNOSTICS



▪ History of exposure, physical examination ▪ Analysis of hair/fingernails ▫ Degree of chronic exposure



ECG ▪ Dysrhythmias



TREATMENT MEDICATIONS Figure 42.1 Mee’s lines appear on the nails after an episode of acute arsenic poisoning.



DIAGNOSIS LAB RESULTS ▪ 24-hour urinary arsenic excretion ▫ Methylated metabolites of inorganic arsenical compounds ▪ ↑ LFTs, hyperbilirubinemia ▪ CBC: anemia, leukopenia, thrombocytopenia ▪ ↑ blood urea nitrogen (BUN), creatinine



▪ Chelation therapy ▫ Dimercaprol, AKA British anti-Lewisite (BAL); meso-2,3-dimercaptosuccinic acid (DMSA)



OTHER INTERVENTIONS



▪ Chronic exposure ▫ Remove source, protective equipment for occupational exposure ▪ Fluid, electrolyte administration, correction of imbalances



CYANIDE POISONING osms.it/cyanide-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure to cyanide → arrest of cellular respiration, death ▫ Highly toxic chemical compound ▫ Contains carbon triple-bonded to nitrogen—cyano group (C≡N) ▫ Organic, inorganic, salt, liquid forms ▫ Hydrogen cyanide: distinctive odor of bitter almonds ▫ Cyanogenic compounds found in some fruit seeds (e.g. apricots, peaches) ▫ Seed capsule broken, exposed to



246 OSMOSIS.ORG



intestinal beta-glucosidase → cyanide formed ▫ Also produced by certain bacteria, fungi, algae ▫ Sodium nitroprusside: contains five cyanide groups ▪ Rapidly absorbed into body via all routes → 60% bound to protein → metabolized in liver → thiocyanate → eliminated via urine, lungs ▪ Toxic effect ▫ Blocks mitochondrial electron transport → halts aerobic cellular respiration → cellular hypoxia → metabolic switch to



Chapter 42 Chemical & Drug Toxicity anaerobic pathway → lactic acidosis



RISK FACTORS



▪ Industrial exposure ▫ Metal industries (e.g. extraction, plating), plastics, textiles ▪ Inhalation of smoke from burning synthetic materials ▪ Pediatric risk ▫ Consumption of acetonitrile-containing false fingernail remover ▪ High rate of sodium nitroprusside administration ▪ Rare cases of poisoning from peach, apricot, chokecherry pits



COMPLICATIONS



▪ Lactic acidosis, hypoxia → cardiac failure → death



SIGNS & SYMPTOMS ▪ Respiratory ▫ Hyperpnea, apnea, pulmonary edema; musty almond odor ▪ Cardiovascular ▫ Hypertension (early), tachycardia, dysrhythmias, asystole ▪ Neurological ▫ Altered level of consciousness, seizures, coma ▪ Mucocutaneous ▫ Flushing (cherry-red), cyanosis ▪ Constitutional ▫ Headache ▪ Exposure to small amounts → weakness, nausea, lacrimation, rhinorrhea



DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪



Urine cyanide, thiocyanate level ↓ oxygen saturation Arterial blood gas (ABG): lactic acidemia Bright red appearance of blood



OTHER DIAGNOSTICS ECG ▪ Dysrhythmias



TREATMENT OTHER INTERVENTIONS



▪ Remove source of exposure ▪ Supplemental oxygen ▪ Hydroxocobalamin (vitamin B12a ) ▫ Cyanokit: each hydroxocobalamin molecule binds with one cyanide ion → forms vitamin B12 → excreted in urine ▪ Cyanide antidote kit ▫ Amyl nitrate, sodium nitrate, sodium thiosulfate ▫ Nitrates form methemoglobin ▫ Sodium thiosulfate converts cyanide to thiocyanate → excretion in urine



OSMOSIS.ORG 247



ETHYLENE GLYCOL POISONING osms.it/ethylene-glycol-poisoning PATHOLOGY & CAUSES ▪ Ingestion of ethylene glycol → accumulation of toxic metabolites, metabolic acidosis, cellular dysfunction, organ damage ▪ Found in antifreeze, deicing solution, brake fluid, engine coolant, etc. ▪ Metabolism of ethylene glycol → generation of toxic metabolites ▫ Ingestion → absorbed rapidly from GI system → metabolized in liver by alcohol dehydrogenase → converted into glycolaldehyde → aldehyde dehydrogenase converts glycolaldehyde to glycolic acid (later converted into oxalic acid) → metabolic acidosis ▫ Concurrent ingestion of ethanol delays generation of toxic metabolites



STAGING Stage I ▪ Neurologic (30 minutes–12 hours postexposure) ▫ Osmolal gap: direct effect of ethylene glycol ▫ Mimics inebriation (e.g. stupor, euphoria, vomiting) ▫ More severe CNS effects as ethylene glycol metabolized (e.g. nystagmus, seizures) Stage II ▪ Cardiopulmonary (12–24 hours postexposure) ▫ Toxic metabolite accumulation → metabolic acidosis, oxalate crystals in heart, lungs, vasculature ▫ Pulmonary edema → dyspnea; Kussmaul respirations (due to metabolic acidosis) ▫ Impaired cardiac function (e.g. heart failure, circulatory collapse)



248 OSMOSIS.ORG



▫ CNS derangements (e.g. cerebral edema) ▫ Death likely Stage III ▪ Renal (24–72 hours post-exposure) ▫ Renal accumulation of calcium oxalate in kidneys + direct effects of toxic metabolites → acute tubular necrosis, renal failure



RISK FACTORS



▪ Ingestion of products containing ethylene glycol (unintentional/intentional)



COMPLICATIONS



▪ Metabolic acidosis ▪ Hypocalcemia, calcium oxalate crystalluria, renal failure ▪ Hypomagnesemia (cofactor for metabolism of glycolic acid) ▪ Cerebral edema, seizures, coma, death



SIGNS & SYMPTOMS ▪ Dizziness, headache, lethargy, slurred speech, nausea/vomiting, tachycardia, tachypnea, hyperpnea



DIAGNOSIS LAB RESULTS



▪ Urinalysis: calcium oxalate crystals; hematuria; blood, protein casts ▪ ↑ osmolal gap (soon after ingestion) → marker for ethylene glycol ▪ ↑ anion gap metabolic acidosis (later) → marker for toxic metabolites ▪ Hypocalcemia ▪ ↑ BUN, creatinine ▪ Serum ethylene glycol ▪ CBC: leukocytosis



Chapter 42 Chemical & Drug Toxicity



OTHER DIAGNOSTICS



▪ History of exposure, physical examination



ECG ▪ Dysrhythmias secondary to hypocalcemia



TREATMENT MEDICATIONS



▪ Fomepizole: inhibits alcohol dehydrogenase ▪ Ethanol: competitive inhibitor of alcohol dehydrogenase



Address acute complications ▪ Fluids, sodium bicarbonate: metabolic acidosis



▪ Benzodiazepines: seizures ▪ Calcium gluconate: hypocalcemia ▪ Magnesium sulfate: hypomagnesemia



OTHER INTERVENTIONS



▪ Gastric aspiration ▫ Within 60 minutes of ingestion ▪ IV isotonic fluids → facilitate urinary excretion of metabolites ▪ Respiratory support ▪ Hemodialysis ▫ Significant metabolic acidosis, renal failure, hemodynamic instability



FETAL ALCOHOL SYNDROME (FAS) osms.it/fetal-alcohol-syndrome PATHOLOGY & CAUSES ▪ Prenatal exposure to alcohol → dysmorphic craniofacial features, growth deficits, neurobehavioral impairment, CNS dysfunction ▪ Embryo, early fetus have underdeveloped hepatic enzymes needed for ethanol metabolism → ↓ ethanol metabolism → ↑ ethanol concentration → teratogenic effects ▪ Degree of alcohol-related teratogenesis influenced by stage of development, dosage, duration of exposure ▫ Vulnerability continues throughout all three trimesters, all organ systems at risk



RISK FACTORS



▪ Maternal alcohol consumption ▫ No safe amount of alcohol consumption during pregnancy ▪ Low socioeconomic status ▪ Poor psychological indicators ▪ Sibling diagnosed with FAS



COMPLICATIONS



▪ Cardiac ▫ Atrial/ventricular septal defect ▪ Musculoskeletal ▫ Flexion contractures, scoliosis ▪ Auditory ▫ Conductive/neurosensory hearing loss ▪ Ophthalmologic ▫ Optic nerve hypoplasia, strabismus ▪ Renal ▫ Aplastic/dysplastic/hypoplastic kidneys, horseshoe kidney ▪ Mental health disorders ▫ Attention-deficit/hyperactivity disorder, mood impairment ▪ Neurological ▫ Seizure disorder ▪ Intellectual, cognitive deficits ▪ Developmental delay



OSMOSIS.ORG 249



SIGNS & SYMPTOMS ▪ Sentinel dysmorphic features ▪ Growth restriction (intrauterine/postnatal) ▪ Functional, behavioral issues ▫ Poor impulse control, poor judgment, attention problems, hyperactivity; deficits in learning, speech, memory



TREATMENT OTHER INTERVENTIONS



▪ Early intervention ▫ Occupational, speech, behavioral therapy; specialized education; parenting training



DIAGNOSIS OTHER DIAGNOSTICS



▪ Documentation of maternal alcohol consumption



Four features required ▪ Two of three sentinel craniofacial anomalies ▫ Short palpebral fissures ▫ Smooth philtrum ▫ Thin vermilion border of upper lip ▪ Pre/postnatal growth deficiencies ▫ Height/weight ≤ 10th percentile (racially/ ethnically-appropriate standard growth curve) ▪ Deficient brain growth, abnormal morphogenesis, abnormal neurophysiology, including ≥ one ▫ Head circumference ≤ 10th percentile ▫ Structural brain anomalies visualized through imaging ▫ Recurrent nonfebrile seizures (other causes of seizures ruled out) ▪ Neurobehavioral impairment ▫ Children ≥ three years old: cognitive/ behavioral impairment ▫ Children < three years old: developmental delay



250 OSMOSIS.ORG



Figure 42.2 The face of a baby diagnosed with fetal alcohol syndrome. There is a smooth philtrum, a thin upper lip and small eye openings.



Chapter 42 Chemical & Drug Toxicity



FETAL HYDANTOIN SYNDROME osms.it/fetal-hydantoin-syndrome PATHOLOGY & CAUSES ▪ Prenatal exposure to phenytoin/metabolites → spectrum of congenital anomalies, growth deficiencies ▪ Teratogenic mechanism unclear; may be related to phenytoin-associated impairment of folate absorption



RISK FACTORS



▪ Prenatal exposure to phenytoin/ metabolites; no safe amount of phenytoin during pregnancy



▪



▪



▪ ▪



(bowed upper lip; broad alveolar ridge; cleft lip, palate) Limbs ▫ Stiff, tapered fingers; digit, nail hypoplasia; hip dislocation Mild/moderate growth deficiencies ▫ Prenatal onset, continues through postnatal life Mild/moderate mental deficiencies Short neck, umbilical/inguinal hernia, pilonidal sinus, low-set hairline



DIAGNOSIS OTHER DIAGNOSTICS



COMPLICATIONS



▪ Microcephaly, congenital heart defects, growth deficiency, systemic abnormalities (e.g. nervous, renal, GI systems)



SIGNS & SYMPTOMS ▪ Craniofacial anomalies ▫ Wide anterior fontanel; ocular hypertelorism, epicanthal folds; nasal (short; flat, broad nasal bridge); mouth



▪ History of maternal ingestion of phenytoin during pregnancy, physical examination



TREATMENT OTHER INTERVENTIONS



▪ Early intervention ▫ Occupational, speech, behavioral therapy; specialized education



MERCURY POISONING osms.it/mercury-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure to mercury → neurotoxicity, widespread interruption of cellular processes, teratogenesis ▪ Naturally occurring metal found in various forms in environment ▫ Organic, inorganic, methylmercury (MeHg)



Sources ▪ Medical preservative (thiomersal) ▪ Thermometers (phased out) ▪ Dental amalgam ▪ Dietary: inorganic mercury from industrial waste → transformed to methylmercury by soil, marine organisms → bio-amplified in tissues of predatory fish (e.g. tuna) ▪ Household items (e.g. fluorescent bulbs,



OSMOSIS.ORG 251



batteries, paint) ▪ Fungicides, pesticides ▪ Some homeopathic folk remedies Properties ▪ Lipid soluble; easily crosses cellular membranes ▫ Disrupts cellular physiology by binding to functional groups (e.g. sulfhydryl, carboxyl, phosphoryl) ▫ Crosses blood-brain barrier → neurotoxic effects (impairs synthesis of proteins, nucleic acids; disrupts neurotransmitter synthesis, uptake) ▫ Crosses placenta → concentrates in fetus → teratogenic effects ▪ High affinity for sulfhydryl groups in red blood cells (RBCs) → distributed throughout body ▪ Other organ toxicities ▫ Concentrates in kidneys → oxidative damage; pulmonary, GI ▪ Eliminated in feces, urine



RISK FACTORS



▪ Occupational (e.g. dentists, hygienists, miners, ceramic workers, taxidermy)



COMPLICATIONS



▪ Minamata disease ▫ Neurotoxicity caused by severe methylmercury poisoning ▪ Renal, respiratory failure; hemorrhagic colitis; fetal anomalies, death



SIGNS & SYMPTOMS ▪ Acute exposure ▫ Cough, dyspnea, circulatory collapse, vomiting, bloody diarrhea ▪ Chronic inhalation exposure (classic triad) ▫ Tremor (e.g. intentional tremor, tetanus mercurialis)



252 OSMOSIS.ORG



▫ Neuropsychiatric problems (e.g. fatigue, memory loss, mental instability) ▫ Gingivostomatitis ▪ Chronic ingestion exposure ▫ Nervous system: tremor, headache, dysarthria, paresthesia, irritability, psychosis ▫ Cardiovascular: hypo/hypertension ▫ Hematologic: cytopenias ▫ Ocular: conjunctivitis; corneal opacities, ulcers



DIAGNOSIS LAB RESULTS



▪ Mercury, anemia in urine/blood; leukocytosis ▪ Renal tubular damage ▫ N-acetyl-beta-D-glucosaminidase (NAG), albuminuria, epithelial cell casts, oliguria



TREATMENT MEDICATIONS



▪ Chelation therapy: oral DMSA, intravenous (IV) dimercaprol (contraindicated with methylmercury, may shift mercury to brain)



OTHER INTERVENTIONS ▪ Remove source of exposure; IV fluids, electrolytes; respiratory support



Chapter 42 Chemical & Drug Toxicity



PARACETAMOL TOXICITY osms.it/paracetamol-toxicity PATHOLOGY & CAUSES ▪ Excessive ingestion of paracetamol (acetaminophen) → fulminant hepatic failure, coma, death ▪ Acetaminophen metabolization in liver ▫ 90% conjugated via glucuronic acid → nontoxic compounds → excreted in urine ▫ 2% excreted unchanged in urine ▫ Remainder metabolized by cytochrome P450 system → toxic intermediary N-acetyl-p-benzoquinone imine (NAPQI) conjugated by hepatic glutathione → further metabolized → excreted in urine ▫ Glutathione rapidly depleted in acute overdose → accumulation NAPQI → binds to cellular proteins → hepatic necrosis



STAGING Stage I ▪ 0–24 hours post-ingestion; nonspecific indications of toxicity Stage II ▪ 24–72 hours post-ingestion; onset of hepatotoxicity, deterioration of renal function Stage III ▪ 72–96 hours post-ingestion; fulminant hepatic failure Stage IV ▪ hepatic recovery; regeneration of liver if individual survives Stage III



RISK FACTORS



▪ Acute overdose of acetaminophen (intentional/unintentional) ▪ Chronic ingestion of supratherapeutic doses



▪



▪ ▪ ▪



▫ Multiple acetaminophen-containing products, acetaminophen Concomitant ingestion of certain drugs ▫ Hepatic enzyme inducers (e.g. CYP2E1 inducers isoniazid, rifampin, phenobarbital), drugs that deplete glutathione (e.g. zidovudine, trimethoprim-sulfamethoxazole) Decreased hepatic glucuronidation capacity (e.g. chronic alcohol use) Existing hepatic disease (e.g. alcoholic liver disease, hepatitis) Genetic ▫ Gilbert syndrome (inherited deficiency in glucuronidation), cytochrome P450 polymorphisms



COMPLICATIONS



▪ Liver failure; death related to liver, multiorgan failure



SIGNS & SYMPTOMS ▪ May be asymptomatic/demonstrate nonspecific findings (e.g. nausea, vomiting, malaise) ▪ Progressive liver damage ▫ Right upper quadrant (RUQ) pain, jaundice, hypoglycemia, coagulopathy, hepatic encephalopathy, impaired renal function, metabolic acidosis



DIAGNOSIS LAB RESULTS



▪ Urinalysis: renal damage ▪ Serial blood draws for serum acetaminophen concentration ▫ Plot on the Rumack–Matthew nomogram if time of ingestion known ▪ LFTs ▫ ↑ transaminases: AST, ALT



OSMOSIS.ORG 253



▫ ↑ bilirubin, lipase ▪ Metabolic panel ▫ ↑ BUN, creatinine, ammonia; ↓ glucose ▪ Coagulation ▫ ↓ prothrombin time, INR ▪ ABG ▫ ↓ pH; anion gap



OTHER DIAGNOSTICS



SURGERY



▪ Liver transplant



OTHER INTERVENTIONS



▪ Activated charcoal: adjunctive treatment for GI decontamination ▪ Address complications ▫ Hemodialysis: renal failure ▫ Fresh frozen plasma: coagulopathy



▪ History of acetaminophen use, physical examination (liver toxicity)



TREATMENT MEDICATIONS



▪ Acetylcysteine: most effective if administered within eight hours of ingestion; replenishes glutathione, detoxifies NAPQI



SEROTONIN SYNDROME osms.it/serotonin-syndrome PATHOLOGY & CAUSES ▪ Potentially life-threatening disorder ▫ Excessive presence of serotonin (5-hydroxytryptamine/5-HT), overactivation of central serotonin receptors → clinical manifestations related to mental status, neuromuscular excitation, autonomic excitation ▪ May be caused by therapeutic use of single serotonergic drug, overdose, drug interactions between ≥ two drugs 5HT increase ▪ ↑ serotonin synthesis ▫ Phentermine, L-tryptophan ▪ ↑ serotonin release ▫ Amphetamines/amphetamine derivatives; dopamine agonists ▪ ↑ activation of serotonergic receptors ▫ Certain antidepressants (buspirone); triptans; prokinetic agents (e.g.



254 OSMOSIS.ORG



metoclopramide); ergot alkaloid derivatives; lithium ▪ ↓ serotonin reuptake ▫ Selective serotonin reuptake inhibitors (SSRIs); serotonin noradrenergic reuptake inhibitors (SNRIs); tricyclic antidepressants (TCAs); 5HT3, receptor antagonists; certain opiates (e.g. methadone, tramadol), drug abuse (e.g. ecstasy); Saint John’s wort ▪ ↓ serotonin metabolism ▫ Monoamine oxidase inhibitors (MAOIs); triptans ▪ ↓ activity of certain CYP450 enzymes ▫ Dextromethorphan



RISK FACTORS



▪ Therapeutic use of serotonergic drug ▪ Polypharmacy (increases likelihood of drug interaction)



Chapter 42 Chemical & Drug Toxicity



COMPLICATIONS



▪ Ventricular dysrhythmias ▪ Rhabdomyolysis, myoglobinuria (due to hyperthermia) → renal failure ▪ Metabolic acidosis ▪ Acute respiratory distress syndrome



SIGNS & SYMPTOMS ▪ Neuromuscular excitation ▫ Hyperreflexia, tremors, clonus, muscle rigidity, bilateral Babinski sign ▪ Autonomic nervous system hyperactivity ▫ Vomiting, diarrhea, hypertension, tachycardia, dysrhythmias, tachypnea diaphoresis, hyperthermia, mydriasis ▪ Altered mental status ▫ Anxiety, agitation, confusion



TREATMENT MEDICATIONS



▪ Antidote (if supportive measures insufficient) ▫ Cyproheptadine (H1, 5-HT2 antagonist effects) ▪ Benzodiazepines, short-acting antihypertensives ▫ Address symptomatology



OTHER INTERVENTIONS



▪ Discontinue serotonergic drug ▪ Cooling measures, IV fluids, supplemental oxygen ▫ Address symptomatology



DIAGNOSIS LAB RESULTS



▪ ↑ white blood cell count, creatine phosphokinase; ↓ serum bicarbonate



OTHER DIAGNOSTICS Hunter Serotonin Toxicity Criteria ▪ History of taking serotonergic agent + any one of following clinical features ▫ Spontaneous clonus ▫ Inducible clonus + agitation/diaphoresis ▫ Ocular clonus + agitation/diaphoresis ▫ Tremor + hyperreflexia ▫ Hypertonia + temperature > 38°C/100°F + ocular/inducible clonus



OSMOSIS.ORG 255



NOTES



NOTES



DYSLIPIDEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic disorders: abnormal lipid levels, with ↑ cardiovascular, other disease risk ▪ Lipids: water-insoluble organic molecules contribute to normal metabolic process ▫ Building blocks for cell membranes ▫ Energy source ▫ Fat-soluble vitamin absorption (needed) ▫ Key molecule components (e.g. steroids, prostaglandins, bile acid) ▫ Fat storage ▪ Lipoproteins: triacylglycerol (TAG), cholesterol, phospholipids, apolipoproteins ▪ Classified according physicochemical characteristics ▫ Lipid density, the apolipoproteins types contained (↓ density → ↑ lipid relative to protein) ▪ Lipoprotein types: chylomicrons, very low-density lipoprotein (VLDL), lowdensity lipoprotein (LDL), and high-density lipoprotein (HDL) ▪ Optimal lipid levels ▫ Total cholesterol: 75–169mg/dL (ages ≤ 20 years); 100–199mg/dL (ages > 21 years) ▫ LDL: < 70mg/dL (cardiovascular disease/ very high risk individuals), < 100mg/dL (individuals with multiple cardiovascular disease risk-factors), < 130mg/dL (low cardiovascular disease risk individuals) ▫ HDL: > 40mg/dL ▫ Triglycerides: < 150mg/dL



TYPES



▪ Types organized by Fredrickson classification



Type I ▪ ↑ triglycerides > 99th percentile; ↑



256 OSMOSIS.ORG



chylomicron level Type IIa ▪ Total cholesterol level > 90th percentile; ↑ LDL level; familial hypercholesterolemia Type IIb ▪ Total cholesterol/triglyceride level > 90th percentile; ↑ LDL, VLDL levels; combined hyperlipoproteinemia Type III ▪ Total cholesterol, triglyceride levels > 90th percentile; ↑ VLDL remnants, chylomicron levels; familial dysbetalipoproteinemia Type IV ▪ Total cholesterol level > 90th percentile, triglyceride level > 90th percentile likely; ↑ VLDL, low HDL level; endogenous hyperlipidemia Type V ▪ Triglyceride level > 99th percentile; ↑ VLDL, chylomicron levels; familial hypertriglyceridemia



RISK FACTORS



▪ Western diet (e.g. ↑ refined carbohydrate, ↑ calorie, ↑ dietary fat levels) ▪ Physical inactivity ▪ Risk ↑ with age ▪ Genetic/epigenetic influence



COMPLICATIONS



▪ Atherosclerosis → cardiovascular, cerebrovascular disease; pancreatitis, cholelithiasis (some cases)



Chapter 43 Dyslipidemia



SIGNS & SYMPTOMS ▪ Asymptomatic until atherosclerosis progresses, produces complications ▪ Abdominal adiposity ▫ Dyslipidemia correlation ▪ Lipid-related skin eruptions (e.g. xanthomas) ▪ Corneal arcus ▫ Lipid deposition in peripheral cornea ▪ Clinical presentation suggests lipid-related vascular disease



DIAGNOSIS



OTHER DIAGNOSTICS



▪ Pooled risk calculation: lipid levels + variables (age, sex, blood pressure, blood glucose level, smoking status)



TREATMENT MEDICATIONS



▪ Hyperlipidemia ▪ Low, moderate, high statin therapy based on risk ▪ Non-statin therapy (bile acid sequestrants, fibrates)



OTHER INTERVENTIONS



▪ Risk reduction (hyperlipidemia)



LAB RESULTS



▪ Genetic testing as indicated



Blood studies ▪ Lipid profile



ABETALIPOPROTEINEMIA osms.it/abetalipoproteinemia PATHOLOGY & CAUSES ▪ Rare autosomal-recessive disorder ▫ MTTP gene mutation in encoding microsomal triglyceride transfer protein (MTP) ▫ AKA Bassen–Kornzweig disease ▪ MTP: required for hepatic, intestinal assembly of apolipoprotein B (apo B), lipids → ↓ serum apo B-containing lipoproteins (e.g. chylomicrons, LDL, VLDL) → impaired fat-soluble vitamin (A, D, E, K) transport ▫ Vitamin E most susceptible to deficiency ▫ Normally transported from small intestine to liver by chylomicrons, delivered to peripheral tissues via VLDLs



COMPLICATIONS ▪ Malabsorption, failure to thrive; retinal degeneration, ophthalmoplegia; peripheral neuropathy; cerebellar dysfunction (Friedreich-type spinocerebellar ataxia)



SIGNS & SYMPTOMS ▪ Impaired fat absorption ▫ Initially presents (infancy) with gastrointestinal symptoms ▫ e.g. poor feeding/weight gain, failure to thrive, gastrointestinal problems (e.g. nausea, abdominal distension, steatorrhea) ▪ Neurological (related to vitamin E malabsorption) ▫ ↓ deep tendon reflexes, progressive ataxia, dysarthria, neuropathy, lowerextremity spasticity



OSMOSIS.ORG 257



▪ Ocular (related to vitamin A malabsorption) ▫ Vision impairment, retinitis pigmentosa; strabismus, nystagmus, ophthalmoplegia (eye muscle paralysis)



DIAGNOSIS LAB RESULTS



▪ ↓ ↓ triglycerides ▪ ↓ ↓ total cholesterol ▪ Lipoprotein electrophoresis → abetalipoproteinemia ▪ Peripheral blood-smear analysis → ↑ ↑ acanthocytes (red blood cell (RBC) with spiked membranes); normocytic anemia ▪ ↓ ↓ alpha-tocopherol, gamma-tocopherol (vitamin E) ▪ ↑ transaminases (present hepatic steatosis)



OTHER DIAGNOSTICS



▪ Sensory nerve conduction studies ▫ Reduced nerve action potential amplitude; normal conduction velocity



TREATMENT OTHER INTERVENTIONS



▪ Address neurological symptoms ▫ Vitamin E ▪ Address gastrointestinal symptoms ▫ Reduced fat-intake ▪ Supplement fat-soluble vitamins ▫ A, D, K



258 OSMOSIS.ORG



Figure 43.1 Accumulation of lipids in the enterocytes of an individual with abetalipoproteinemia leads to a clear appearance.



Chapter 43 Dyslipidemia



FAMILIAL HYPERCHOLESTEROLEMIA osms.it/familial-hypercholesterolemia PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → ↑ ↑ low density lipoprotein cholesterol (LDL-C) levels → early-onset atherosclerotic disease ▫ Caused by receptor-mediated LDL-C catabolism-encoding gene mutation ▫ Individuals often still experience ↑ LDL-C levels despite ↑ lipid-lowering therapy ▫ LDL receptor mutation classes involve altered receptor synthesis/function ▪ LDL-mediated atherscelerotic plaque formation ▫ Abnormal lipid metabolism → hyperlipidemia (LDL; especially those containing B-100 apolipoproteins) → subendothelial LDL retention → LDL oxidation → ↑ LDL by macrophages → foam cell formation → cytokine, growth factor release from foam cells → smooth muscle cell migration from vascular media to intima, fibrous cap formation, chronic inflammation → atherosclerotic plaque → cardiovascular, cerebrovascular, other sequelae potential



COMPLICATIONS ▪ Coronary artery calcification ▪ alvular cholesterol deposits → aortic stenosis ▪ Accelerated athersclerotic placque formation → myocardial infarction → sudden cardiac death ▫ Homozygous FH: possible sudden cardiac death before age 20



SIGNS & SYMPTOMS ▪ Evidence of atherosclerotic cardiovascular disease (e.g. angina) ▪ Evidence of aortic stenosis, left ventricular outflow obstruction (e.g. exertional dyspnea) ▪ Xanthoma presence (usually before age 10) ▫ Tendon xanthomas: Achilles tendon (commonly) ▫ Cutaneous xanthomas: planar xanthomas on palms, soles of hands/ feet (may be painful)



TYPES Heterozygous FH ▪ LDL-C ≥ 160mg/dL (children); ≥ 190mg/dL adults (one first-degree relative diagnosed with premature coronary artery disease/ similar LDL-C levels) ▪ Positive genetic testing for LDL-C receptor defect Homozygous FH ▪ LDL-C ≥ 400mg/dL, (one/both parents clinically diagnosed with FH) ▪ Positive genetic testing for LDL-C receptor defect



Figure 43.2 Numerous tendinous xanthomata on the hand of an individual with familial hypercholesterolemia.



OSMOSIS.ORG 259



▪ Xanthelasmas: soft, yellow, cholesterolfilled plaques (usually appear on eyelid’s medial aspect) ▪ Corneal arcus: white/grey ring around cornea



DIAGNOSIS ▪ Positive family history ▪ Characteristic findings upon physical examination



LAB RESULTS



▪ Genetic testing ▪ ↑ total cholesterol, LDL-C (LDL > 90th percentile for age/sex) ▪ Normal/↓ HCL-C



TREATMENT MEDICATIONS Figure 43.3 Xanthelasmata around the eyes of an individual with familial hypercholesterolemia.



▪ High-intensity statin therapy ▪ Cholesterol-absorption inhibitors ▫ Monotherapy or in conjunction with statin therapy ▪ PCSK9 inhibitor/monoclonal antibodies ▫ Binds to PCSK9 → inhibits hepatic LDL receptor-binding → ↑ LDL receptors available to clear LDL → ↓ LDL-C levels



HYPERLIPIDEMIA osms.it/hyperlipidemia PATHOLOGY & CAUSES ▪ ↑ serum total cholesterol, LDL-C ▪ Lipids enter circulation via exogenous pathway via gut/endogenous pathway (hepatic synthesis) → lipoproteins transport circulating lipids to various tissues



CAUSES



▪ Primary: genetic abnormalities (e.g. familial hypercholesterolemia), defective apoprotein B (familial) ▪ Secondary: Cushing syndrome, excessive alcohol intake, uncontrolled diabetes mellitus, chronic kidney/liver disease, certain drugs (glucocorticoids, beta blockers, thiazide diuretics, HIV



260 OSMOSIS.ORG



antiretroviral regimens, oral estrogen replacement)



RISK FACTORS



▪ Genetic predisposition ▪ Diet/other lifestyle factors (e.g. physical inactivity, high-fat diet) ▪ Pregnancy temporarily increases serum cholesterol ▪ Biologically-male > biologically-female individuals (premenopausal)



COMPLICATIONS



▪ Cardiovascular disease (e.g. angina, myocardial infarction) ▪ Cerebrovascular disease (e.g. stroke)



Chapter 43 Dyslipidemia ▪ Peripheral vascular disease ▪ Cholelithiasis ▪ Pancreatitis (triglycerides > 500mg/dL)



SIGNS & SYMPTOMS ▪ Cardiovascular/cerebrovascular disease evidence ▪ Xanthomas: cutaneous/found/along tendon sheaths (tendinous xanthoma) ▪ Corneal arcus



DIAGNOSIS ▪ Physical examination → presence of risk factors/cardiovascular disease symptoms ▪ History of cardiovascular diseasecharacteristic symptoms



LAB RESULTS



▪ Fasting lipid profile: ↑ total cholesterol, ↑ triglycerides, ↑ LDL, ↓ HDL



TREATMENT ▪ Address secondary hyperlipidemia causes



MEDICATIONS ▪ Statin therapy



OTHER INTERVENTIONS



▪ Non-statin therapy ▫ E.g. fibrates, fish oil supplements containing eicosapentaenoic acid/ docosahexaenoic acid concentrate; nicotinic acid (not as monotherapy) Figure 43.4 Blood drawn from an individual with hyperlipidemia.



OSMOSIS.ORG 261



HYPERTRIGLYCERIDEMIA osms.it/hypertriglyceridemia PATHOLOGY & CAUSES ▪ Elevated serum triglyceride levels



CAUSES Primary: genetic mutation (primary) ▪ Familial hypertriglyceridemia ▪ Familial combined hyperlipidemia ▪ Chylomicronemia ▪ Dysbetalipoproteinemia (APOE mutations) ▪ Lipoprotein lipase deficiency ▪ Apolipoprotein C-II deficiency (APOC2 mutations) ▪ Apolipoprotein A-V variants (APOA5 mutations) Secondary: consequence of disease states ▪ Diabetes (especially poor glycemic control) ▪ Obesity ▪ ↑ refined carbohydrate diet ▪ Nephrotic syndrome ▪ Chronic renal failure ▪ Hypothyroidism ▪ Pregnancy (temporarily increased serum triglycerides) ▫ Certain drugs (glucocorticoids, beta blockers, thiazide diuretics, HIV antiretroviral regimens, retinoids, oral estrogen replacement)



RISK FACTORS ▪ Influence of diet/other lifestyle factors (e.g. physical inactivity, ↑ fat diet) ▪ Genetic predisposition



COMPLICATIONS



▪ ↑ atherosclerotic plaque formation risk → cardiovascular, cerebrovascular events ▪ Pancreatitis (serum triglycerides > 1000mg/ dL)



262 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ Clinical atherosclerosis manifestations ▫ May not be evident until complications develop ▪ Xanthomas, xanthelasmas ▫ Usually associated with hereditary forms ▪ Lipemia retinalis: creamy appearance within retinal blood vessels ▫ May be seen with severe hypertriglyceridemia



DIAGNOSIS ▪ Physical examination → presence of risk factors/cardiovascular disease symptoms ▪ History of cardiovascular disease symptoms



LAB RESULTS



▪ Fasting lipid profile: ↑ triglycerides ▫ Normal: 886mg/dL



TREATMENT ▪ Address secondary causes



MEDICATIONS ▪ Statin therapy



OTHER INTERVENTIONS



▪ Non-statin therapy ▫ E.g. fibrates, fish oil supplements containing eicosapentaenoic acid/ docosahexaenoic acid concentrate; nicotinic acid (not as monotherapy)



NOTES



NOTES



FAT SOLUBLE VITAMINS DEFICIENCY



GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Insufficient plasma concentrations of fat soluble vitamins required for normal metabolic processes



RISK FACTORS ▪ Reduced intake, impaired absorption, increased elimination



DIAGNOSIS ▪ See individual disorders



TREATMENT OTHER INTERVENTIONS ▪ Increased dietary intake; supplementation



SIGNS & SYMPTOMS ▪ See individual disorders



VITAMIN D DEFICIENCY osms.it/vit-d-deficiency PATHOLOGY & CAUSES ▪ Body’s metabolic needs not met as there is insufficient 25-hydroxyvitamin D ▪ Liver, kidneys hydroxylate physiologically inert vitamin D ▫ Precursor molecule (7-dehydrocholesterol) exposed to ultraviolet light/dietary vitamin D → D3/D2 released into blood → first hydroxylation in liver → second hydroxylation in kidneys → metabolically active calcitriol (1,25-dihydroxyvitamin D) ▪ Insufficient vitamin D → ↓ intestinal absorption of calcium → ↓ serum calcium → ↑ serum PTH → ↑ intestinal calcium absorption + ↑ osteoclastic activity,



calcium resorption from bones + ↑ renal conservation of calcium → normalization of serum calcium



CAUSES ▪ Insufficient dietary, supplementary intake ▪ Increased need, but insufficient intake ▫ Pregnancy, lactation ▪ Obesity, vitamin D sequestration in adipose tissue ▪ Impaired absorption ▫ Small bowel disease; bariatric surgery; gastrectomy; pathology of hepatobiliary tree, pancreas; abetalipoproteinemia ▪ Decreased synthesis in skin ▫ Insufficient sun exposure; dark skin



OSMOSIS.ORG 263



(large amounts of melanin in epidermal layer); excessive sunscreen ▪ Impaired liver, kidney hydroxylation ▫ Cirrhosis, renal failure ▪ Altered vitamin D metabolism from drugs ▫ Phenobarbital, phenytoin, rifampin, isoniazid, carbamazepine, ketoconazole Genetic mutations ▪ 1-alpha-hydroxylase deficiency: mutations in CYP27B1; previously called vitamin D-dependent rickets type 1A ▪ 25-hydroxylase deficiency: mutations in CYP2R1; previously called vitamin D-dependent rickets type 1B ▪ Hereditary resistance to vitamin D: mutations in VDR (vitamin D receptor gene); previously called vitamin D-dependent rickets type 2



RISK FACTORS ▪ Risk increases with age ▪ Gastrointestinal tract, liver, kidney conditions ▪ Medications that interfere with vitamin D metabolism ▪ Decreased ultraviolet light exposure ▫ Cold climate/high latitudes, institutionalization/incarceration Perinatal factors (↓ neonatal vitamin D stores) ▪ Exclusively breastfed infants ▫ Maternal vitamin D status dictates amount vitamin D in milk ▪ Premature birth ▫ Low stores of vitamin D ▪ Low maternal vitamin D during gestation



COMPLICATIONS ▪ Related to accompanying hypocalcemia ▫ Osteoporosis ▫ Increased risk of fractures ▫ Osteomalacia ▫ Ricketts (children) ▫ Secondary hyperparathyroidism



264 OSMOSIS.ORG



SIGNS & SYMPTOMS SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



Mild deficiency may be asymptomatic Decreased bone density, osteoporosis Fractures Dental enamel hypoplasia Severe deficiency ▫ Hypocalcemia-related osteomalacia symptoms ▫ Bone tenderness/pain ▫ Muscle weakness, cramping, numbness/ tingling, positive Trousseau sign, Chvostek’s sign ▫ Bone malformations: difficulty ambulating, waddling gait



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ High-stress areas ▫ Fractures; vertebral compression fractures ▪ Radiolucent bands (indicate pseudofractures) ▪ Codfish vertebrae ▫ Biconcave vertebral discs ▪ Children ▫ Epiphyseal plate widening; osteopenic/ malformed long bone shafts, pathological fractures Dual-energy X-ray absorptiometry (DEXA) ▪ Decreased bone density



LAB RESULTS ▪ Decreased serum 25-hydroxyvitamin D (calcidiol) level ▪ Elevated alkaline phosphatase (bone turnover marker) ▪ Decreased serum calcium ▪ Increased parathyroid hormone (PTH)



Chapter 44 Fat Soluble Vitamin Deficiency



TREATMENT OTHER INTERVENTIONS ▪ Vitamin D3 supplementation ▫ Dietary: fish, egg yolk, fortified foods



▫ Supplementation ▫ Ultraviolet light/natural sunlight exposure ▪ Increase calcium intake



VITAMIN K DEFICIENCY osms.it/vit-k-deficiency PATHOLOGY & CAUSES ▪ Body’s metabolic needs not met; insufficient vitamin K ▫ Coagulation function ▫ Bone biology ▫ Vascular biology ▪ Dietary vitamin K1 (phylloquinone) → bile salts make fat soluble vitamin soluble → incorporated into gastrointestinal tract’s micelles → absorbed by small intestine → integrated into chylomicrons → transported to portal circulation → liver uses to synthesize coagulation factors, other essential proteins



TYPES Infancy: vitamin K-deficiency bleeding (VKDB) ▪ Early-onset VKDB: occurs within first 24 hours of life; caused by immature liver function, low stores of vitamin K at birth, sterile gut, exclusive breastfeeding (breastmilk low in vitamin K), medications present in maternal circulation interfering with vitamin K (anticonvulsants, warfarin) ▪ Classic VKDB: occurs between 1–4 weeks; prevented by vitamin K1 prophylaxis at birth ▪ Late-onset VKDB: occurs between 3 weeks–8 months; associated with lack of vitamin K1 prophylaxis at birth, exclusive breastfeeding (breastmilk low in vitamin K)



▫ Diseases of small intestines, liver, gallbladder, pancreas



RISK FACTORS Infants ▪ No vitamin K1 prophylaxis at birth ▪ Immature liver uses vitamin K inefficiently ▪ Low vitamin K stores ▪ Sterile gut ▪ Maternal ingestion of coumarin-like anticoagulants/some anticonvulsants/ antibiotics during gestation ▪ Antibiotic administration (destroys developing gut flora) Adults ▪ Prolonged diarrhea ▪ Use of broad-spectrum antibiotics, low intake of vitamin K ▪ TPN administration without added vitamin K



COMPLICATIONS ▪ Most common ▫ Bleeding, ranging from mild (mucocutaneous) to severe (intracranial hemorrhage most common in late onset VKDB) ▪ Impaired bone mineralization ▪ Vascular calcium deposits



Later childhood, adulthood ▪ Fat absorption and vitamin K metabolism disorders



OSMOSIS.ORG 265



SIGNS & SYMPTOMS ▪ Low bone density signs Impaired coagulation ▪ Mucocutaneous bleeding: gingival, nasal, easy bruising ▪ Gastrointestinal bleeding: melena ▪ Genitourinary bleeding: hematuria ▪ Neonatal bleeding: umbilical stump/ circumcision site ▪ Intracranial hemorrhage: vomiting, seizures



DIAGNOSIS DIAGNOSTIC IMAGING DEXA ▪ Low bone mineralization



266 OSMOSIS.ORG



LAB RESULTS ▪ Coagulation studies ▪ Prolonged prothrombin time (PT), partial thromboplastin time (PTT), International Normalized Ratio (INR) ▪ Elevated serum undercarboxylated proteins (proteins induced by vitamin K absence)



TREATMENT OTHER INTERVENTIONS ▪ Administer Vitamin K ▫ Subcutaneous phytonadione ▪ ↑ dietary vitamin K ▫ Liver, green leafy vegetables (broccoli, spinach, kale)



NOTES



NOTES



GLYCOGEN STORAGE DISEASES (GSD)



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Metabolism disorders → pathological intracellular accumulation of glycogen/ metabolic products ▪ AKA dextrinoses/glycogenoses ▪ Impaired glycogen metabolism → cells without energy between meals → cell dysfunction, death ▪ Tissues most dependent on carbohydrates most affected ▫ Liver, heart muscle, brain, skeletal muscle



CAUSES ▪ Enzyme deficiency in glycogen synthesis/ breakdown ▪ Genetic, environmental factors



COMPLICATIONS



▪ Rhabdomyolysis; cardiomyopathy; atrioventricular block (AV) block; renal failure (myoglobin from dead muscle cells impairs renal function); lactic acidosis due to energy being generated from triglycerides, protein; hyperuricemia, gout (lactic, uric acid excreted via same renal transport mechanism)



DIAGNOSIS LAB RESULTS



▪ Cell count, hormones, metabolites



Muscle/liver biopsy ▪ With periodic acid-Schiff stain ▪ Detects glycogen



OTHER DIAGNOSTICS ▪ Genetic testing



Fasting test for clinical orientation ▪ Hypoglycemia



TREATMENT OTHER INTERVENTIONS



▪ Corrective diet ▪ Symptomatic therapy (cell growth factors) ▪ Enzyme replacement therapy for symptom relief



SIGNS & SYMPTOMS ▪ Symptomatic at birth/early adulthood ▪ Hypoglycemia, hyperlipidemia (compensatory mechanism for hypoglycemia), fatigue, hypotonia (floppy baby), hepato/splenomegaly, hypoglycemia → seizures, metabolic acidosis → hyperventilation, vomiting



OSMOSIS.ORG 267



GLYCOGEN STORAGE DISEASE TYPE I (GSD I) osms.it/GSD-I PATHOLOGY & CAUSES ▪ AKA von Gierke disease ▪ Pathological intracellular accumulation of glucose-6-phosphate (G6P) due to impaired glycogenolysis, gluconeogenesis ▪ Final product of both mechanisms: G6P ▪ Most common glycogen storage disease



TYPES GSD Ia ▪ Mutation of G6PC gene GSD Ib ▪ Mutation of G6PT1 gene GSD Ic ▪ Mutation of SLC17A3 gene



CAUSES



▪ G6P deficiency → G6P trapped inside cell (too polar to pass through cell membrane) → severe hypoglycemia ▪ Autosomal recessive mutations



COMPLICATIONS



▪ Hepatomegaly; kidney enlargement; atherosclerosis due to hyperlipidemia; growth, development disorders; gout, kidney damage due to hyperuricemia



SIGNS & SYMPTOMS Fasting hypoglycemia ▪ Blood glucose level regulation impaired (esp. between meals) → low insulin → high cortisol, glucagon Metabolic acidosis ▪ Lactate cannot convert into pyruvate due to



268 OSMOSIS.ORG



accumulation of G6P (lactate + pyruvate → G6P via gluconeogenesis) → compensatory hyperventilation, vomiting Hypertriglyceridemia ▪ Compensate for chronically low insulin Hyperuricemia ▪ Excess G6P in pentose phosphate pathway → high blood concentrations of uric acid → competes with other organic acids (e.g. lactic acid) for excretion in kidneys



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Enlarged liver, kidneys



LAB RESULTS Liver biopsy with periodic acid-Schiff stain ▪ Glycogen detection



OTHER DIAGNOSTICS ▪ Genetic testing



Fasting test ▪ Hypoglycemia, doesn’t respond to glucagon injection



TREATMENT OTHER INTERVENTIONS



▪ Diet consisting of frequent meals high in carbohydrates ▪ Regulation of metabolic complications



Chapter 45 Glycogen Storage Diseases



GLYCOGEN STORAGE DISEASE TYPE II (GSD II) osms.it/GSD-II PATHOLOGY & CAUSES



DIAGNOSIS



▪ AKA Pompe disease ▪ Pathological accumulation of glycogen in lysosome ▪ Mainly affects skeletal muscles, heart; also liver, nervous system



DIAGNOSTIC IMAGING



TYPES



▪ ↑ creatine kinase, lactic dehydrogenase, alanine transaminase, aspartate transaminase



Early/infantile onset ▪ Few months after birth, typically 4–8; progression much faster Late onset ▪ > two years; as late as 50–60



CAUSES



▪ Autosomal recessive disease caused by mutation on chromosome 17 ▪ Acid alpha-glucosidase deficiency → glycogen cannot break down, accumulates in lysosome → lysosome bursts → glycogen, lysosomal enzymes leak into cytoplasm → cell dysfunction, death



X-ray ▪ Cardiomegaly



LAB RESULTS



Muscle biopsy ▪ Glycogen detection



OTHER DIAGNOSTICS ECG ▪ Arrhythmia, cardiomyopathy



TREATMENT OTHER INTERVENTIONS



▪ Enzyme replacement therapy



COMPLICATIONS



▪ Rhabdomyolysis, completely impaired motor function, respiratory/heart failure, development disorders



SIGNS & SYMPTOMS ▪ Progressive muscle weakness, respiratory insufficiency due to weakened diaphragm function, arrhythmia, cardiomegaly, cardiomyopathy, hepatomegaly, hypotonia, recurrent chest infections



OSMOSIS.ORG 269



GLYCOGEN STORAGE DISEASE TYPE III (GSD III) osms.it/GSD-III PATHOLOGY & CAUSES ▪ AKA Cori’s disease, Forbes disease, limit dextrinosis ▪ Intracellular pathological accumulation of incompletely broken down glycogen → buildup of dextrins (intermediate products of glycogen breakdown) → osmotic pressure of cell increases → pulls water in, damages cell ▪ Affects liver, skeletal muscles, heart



TYPES GSD IIIa ▪ Liver, muscles GSD IIIb ▪ Liver GSD IIIc ▪ Liver, muscles



CAUSES



▪ Autosomal recessive disease ▪ Deficiency of glycogen debranching enzyme (GDE): amylo-alpha-1,6glucosidase, 4-alpha-glucanotransferase



COMPLICATIONS



▪ Hepatosplenomegaly, cardiomegaly, developmental disorders, liver failure



SIGNS & SYMPTOMS ▪ Hypoglycemia, hypotonia, arrhythmia, cardiomyopathy, rhabdomyolysis, musclerelated symptoms (later in life), may resemble GSD I



270 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Hepatosplenomegaly



LAB RESULTS Liver/muscle biopsy with periodic acid-Schiff stain ▪ Glycogen detection



OTHER DIAGNOSTICS ▪ Genetic analysis



TREATMENT OTHER INTERVENTIONS ▪ High glucose, protein diet



Chapter 45 Glycogen Storage Diseases



GLYCOGEN STORAGE DISEASE TYPE IV (GSD IV) osms.it/GSD-IV PATHOLOGY & CAUSES ▪ AKA Andersen’s disease ▪ Intracellular accumulation of abnormally formed glycogen ▪ Improper glycogen synthesis → buildup of polyglucosan bodies (unbranched long chains of glucose) → precipitation of polyglucosan bodies → foreign body reactions, increased osmotic pressure → cell damage



CAUSES



▪ Autosomal recessive mutation of GBE1 gene on chromosome 3 ▪ Deficiency of 1,4-alpha-glucan branching enzyme (GBE)



SIGNS & SYMPTOMS ▪ Fatal perinatal neuromuscular ▫ Fetal hydrops, hydramnion; hypotonia; reduced infant mobility; cardiomyopathy present at birth; death approx. one month after birth ▪ Childhood neuromuscular ▫ Variable intensity, life expectancy; manifests in childhood; myopathy, cardiomegaly ▪ Progressive hepatic ▫ Failure to thrive (FTT); liver cirrhosis; portal hypertension; ascites; death few months after birth ▪ Non-progressive hepatic ▫ Similar to progressive hepatic type, symptoms less intense; cirrhosis not present; can live into adulthood ▪ Congenital muscular ▫ Manifests shortly after birth; cardiomegaly; life expectancy few months



DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Fetal hydrops, hydramnion ECG ▪ Heart abnormalities



LAB RESULTS Liver/muscle biopsy with periodic acid-Schiff stain ▪ Glycogen detection



OTHER DIAGNOSTICS ▪ Genetic analysis



Echocardiography ▪ Heart abnormalities



TREATMENT OTHER INTERVENTIONS



▪ Only symptomatic treatment available



OSMOSIS.ORG 271



GLYCOGEN STORAGE DISEASE TYPE V (GSD V) osms.it/GSD-V PATHOLOGY & CAUSES ▪ AKA McArdle’s disease ▪ Intracellular pathological accumulation of glycogen in muscle tissue ▪ Cannot release glucose-1-phosphate → ↓ glycolysis, cell energy status, Na+/K+ ATPase function → osmotic cell imbalance → cell damage ▪ Affects only muscle tissue



TYPES Early onset ▪ More severe symptoms, progression Adult onset ▪ Less severe symptoms, progression



CAUSES



▪ Autosomal recessive disease ▪ Deficiency of myophosphorylase (musclespecific isoform of glycogen phosphorylase)



COMPLICATIONS



▪ Renal failure due to myoglobinuria from rhabdomyolysis ▪ Muscle contractures due to fibrosis caused by extensive damage



SIGNS & SYMPTOMS ▪ Exercise intolerance, fatigue, rhabdomyolysis, muscle fibrosis ▪ ‘’Second wind’’ phenomenon: shift in metabolism during exercise → sudden burst of energy, despite being out of breath



272 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS Muscle biopsy ▪ With periodic acid-Schiff stain ▪ Glycogen detection



OTHER DIAGNOSTICS ▪ Genetic analysis



TREATMENT OTHER INTERVENTIONS



▪ Only symptomatic treatment available



Chapter 45 Glycogen Storage Diseases



OSMOSIS.ORG 273



NOTES



NOTES



HYPERVITAMINOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Toxic effects due to increased ingestion/ storage of vitamins, most often fat soluble vitamins (vitamins A, D, E, K) ▫ Fat-soluble vitamins stored in fatty tissues, liver; remain in body for longer periods of time than water-soluble vitamins



RISK FACTORS



DIAGNOSIS ▪ See individual disorders



TREATMENT OTHER INTERVENTIONS



▪ Discontinue consumption of vitamin supplements/food containing high levels of vitamins



▪ Increased ingestion of vitamin supplements/food containing high levels of vitamins



EXCESS VITAMIN A osms.it/excess-vitamin-a PATHOLOGY & CAUSES ▪ Condition caused by excessive amounts of vitamin A in body ▪ Acute toxicity ▫ Occurs in adults when > 200,000mcg (> 660,000IU) consumed in single dose ▫ Occurs in infants < six months when > 6,000mcg (> 20,000IU) consumed < one month ▪ Chronic toxicity ▫ Long-term ingestion of high doses of vitamin A



CAUSES



▪ Most likely by increased ingestion of synthetic “preformed” vitamin A, approximately 10 times the Recommended



274 OSMOSIS.ORG



Dietary Allowance (RDA) ▫ Proforms of vitamin A (e.g. carotenoids) generally not toxic ▪ Teratogenic effects ▫ Effects on fetus during first trimester of pregnancy



SIGNS & SYMPTOMS ▪ May compromise bone metabolism, health ▪ Acute toxicity ▫ Nausea, vomiting, blurry vision ▫ In extremely high doses: drowsiness, vomiting ▪ Chronic toxicity ▫ Ataxia, hair loss, bone/muscle pains, vision changes, liver damage, dry skin,



Chapter 46 Hypervitaminosis nausea, headache, hepatomegaly, increased risk of osteoporotic fractures ▪ Teratogenic effects ▫ Can cause spontaneous fetal death, facial/cardiac malformations (e.g. microcephaly)



DIAGNOSIS DIAGNOSTIC IMAGING Bone X-rays ▪ Weakness/damage



▪ Liver function tests (LFTs): mild elevation of liver enzymes ▫ Liver biopsy: enlarged hepatocytes, increased fibrosis in chronic hypervitaminosis A



TREATMENT OTHER INTERVENTIONS



▪ Discontinue consumption of vitamin A supplements/foods containing high levels of vitamin A, esp. containing natural vitamin A (e.g. kidney, liver, egg yolks)



LAB RESULTS



▪ Most vitamin A stored in liver, circulating concentrations not always accurate indicator



EXCESS VITAMIN D osms.it/excess-vitamin-d PATHOLOGY & CAUSES ▪ Toxicity caused by excessive amounts of vitamin D ▫ Vitamin D increases circulating levels of calcium ▫ Most often caused by excessive intake ▪ Maximum tolerable intake 100mg for children > nine years old, adults, pregnant/ lactating individuals; lower for younger children ▪ Main consequence is hypercalcemia



SIGNS & SYMPTOMS ▪ Acute intoxication (often due to hypercalcemia) ▫ Confusion, excessive thirst, nausea, vomiting



▪ Chronic intoxication ▫ Bone demineralization, pain; nephrocalcinosis; kidney damage



DIAGNOSIS LAB RESULTS



▪ Serum concentration of 25(OH)D > 150ng/ mL (374nmol/L)



TREATMENT OTHER INTERVENTIONS



▪ Discontinue consumption of vitamin D supplements; restrict dietary intake of calcium, dairy products (milk, cheese, yogurt), almonds



OSMOSIS.ORG 275



NOTES



NOTES



MALNUTRITION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Supply/demand imbalance of nutrients, energy required for growth, maintenance, function ▪ Disease spectrum ▫ Kwashiorkor: inadequate protein intake with adequate total caloric intake ▫ Marasmus: inadequate protein, caloric intake ▪ Malnutrition impairs immune function → ↑ infection likelihood → ↑ nutritional demand → further malnutrition ▫ Malnutrition → atrophy of lymph glands, tonsils, thymus → impaired cellular immunity, delayed hypersensitivity loss ▫ Protein insufficiency → ↓ immunoglobulins, ↓ complement → impaired phagocytosis ▫ Acute-phase immune response loss → typical infection signs loss (leukocytosis, fever) ▪ Refeeding syndrome ▫ Metabolic disturbance: excessivelyrapid nutrition reintroduction to severely malnourished individual ▫ Rapid nutrient reintroduction → glycogen, fat, protein synthesis → serum potassium, magnesium, phosphorus consumption → mineral imbalance → cardiac, pulmonary, neurological sequelae (cardiac arrhythmias, cardiac failure, confusion, convulsions, coma)



SIGNS & SYMPTOMS ▪ Kwashiorkor ▫ Bilateral pitting edema, distended abdomen, hair thinning, skin/hair depigmentation, dermatitis



276 OSMOSIS.ORG



▪ Marasmus ▫ Emaciated appearance (“wizened” facies), severe muscle wasting, subcutaneous-fat loss



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infection workup: respiratory distress



LAB RESULTS



▪ Hypoglycemia ▪ Anemia (normochromic-normocytic or hypochromic-microcytic/macrocytic) ▪ Electrolyte levels (calcium, phosphate, magnesium, serum albumin, urea) → various deficiencies



Infection workup ▪ Blood culture ▪ Common endemic infection tests (e.g. HIV, malaria, parasites)



OTHER DIAGNOSTICS Anthropometry ▪ Body weight < 62.36% expected body weight for age ▪ Weight-for-height Z-score < -3 standard deviations → severe wasting ▪ Mean upper-arm circumference < 11.5cm/4.53in → severe wasting



Chapter 47 Malnutrition



TREATMENT World Health Organisation (WHO) 10 steps for severe malnutrition management ▪ Treat/prevent hypoglycemia (blood glucose < 3mmol/L) ▫ Prevention: urgent small frequent feeds ▫ Treatment: dextrose water ▪ Treat/prevent hypothermia (rectal/oral temperature < 35.5°C/95.9°F) ▪ Treat/prevent dehydration ▫ Prevention: oral rehydration (sunken eyes, no urine passed for 12 hours, thirst) ▫ Treatment: intravenous fluid infusion (lethargy/consciousness loss) ▪ Correct electrolyte imbalances ▫ Total-body sodium excess (likely in severe malnourishment) avoid high sodium solutions, feeds ▫ Specialized refeeding milk feeds contain



▪



▪



▪



▪



▪ ▪



necessary electrolytes Treat infection ▫ Broad-spectrum antibiotics ▫ In endemic regions: children < one year of age, assume presence of parasitic infection → mebendazole Correct micronutrient deficiencies ▫ Supplements: multivitamin, vitamin A, potassium, magnesium, iron, folic acid, zinc, copper Start cautious feeding ▫ WHO recommended starter formula “F-75” Achieve catch-up growth ▫ WHO recommended catch-up formula “F-100” ▫ Reintroduce normal meals Provide sensory stimulation, emotional support Prepare for discharge, post-recovery follow-up



KWASHIORKOR osms.it/kwashiorkor PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Sufficient calorie intake, severely inadequate protein intake ▪ AKA “the sickness the baby gets when the new baby comes” ▫ Older children in food-scarce environments weaned off breast milk → carbohydrate rich diet ▪ Characterization ▫ Inadequate adaptation; insufficient dietary nutrient intake ▫ Extreme protein deficiency → ↓ liver protein synthesis → osmotic imbalance → edema, abdominal distension ▫ ↓ lymphatic function → ↓ fluid recovery, low lipid absorption → further abdominal distension



▪ Bilateral pitting edema, distended abdomen (rarely ascites; typically weak abdominal musculature, hepatomegaly) ▪ Hepatomegaly (with fatty infiltration) ▪ Muscle wasting ▪ Integumentary change (thinning hair, skin/ hair depigmentation, dermatitis) ▪ Irritability, listless affect



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infection workup: respiratory distress



OSMOSIS.ORG 277



LAB RESULTS



▪ Hypoglycemia ▪ ↓ blood lipids ▪ Hypoalbuminemia, hypoproteinemia (transferrin, essential amino acids, lipoprotein) ▪ Anemia (normochromic-normocytic/ hypochromic microcytic/macrocytic) ▪ Electrolyte depletion → hypocalcemia, hypophosphatemia, hypomagnesemia, hypokalemia



Infection workup ▪ Blood culture ▪ Common endemic infection tests (e.g. HIV, malaria, parasites)



OTHER DIAGNOSTICS Anthropometry ▪ Body weight < 62.36% expected body weight for age ▪ Weight-for-height Z-score < -3 standard deviations → severe wasting ▪ Mean upper arm circumference < 11.5cm/4.53in → severe wasting



TREATMENT MEDICATIONS



▪ Prophylactic antibiotics ▫ Malnutrition-induced immunodeficiency compensation



OTHER INTERVENTIONS



▪ Correct glycemic, electrolyte, hydration abnormalities ▪ Protein refeeding, gradually ↑ protein amount ▫ Excessively-rapid protein refeeding → protein catabolism → urea accumulation → may overwhelm already-impaired liver → liver failure



278 OSMOSIS.ORG



Figure 47.1 A child with kwoshiorkor.



Chapter 47 Malnutrition



MARASMUS osms.it/marasmus PATHOLOGY & CAUSES ▪ Severe malnutrition: inadequate calorie/ protein intake ▪ Insufficient energy balance → evolving adaptation ▫ ↓ intake, ↑ loss (e.g. emesis, diarrhea, burns), ↑ energy expenditure → negative energy balance ▫ Negative energy balance adaptations: ↓ physical activity, lethargy, ↓ basal metabolic rate, growth retardation, weight loss



SIGNS & SYMPTOMS ▪ Emaciated appearance (“wizened” facial appearance), head (compared to body) appears disproportionately large ▪ Severe muscle wasting → redundant skin folds ▪ Subcutaneous fat loss ▪ Irritability, weakness, lethargy



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infection workup: respiratory distress



Infection workup ▪ Blood culture ▪ Common endemic infection tests (e.g. HIV, malaria, parasites)



OTHER DIAGNOSTICS Anthropometry ▪ Body weight < 62.36% expected body weight for age ▪ Weight-for-height Z-score < -3 standard deviations → severe wasting ▪ Mean upper arm circumference < 11.5cm/4.53in → severe wasting



TREATMENT MEDICATIONS



▪ Prophylactic antibiotics ▫ Malnutrition-induced immunodeficiency compensation



OTHER INTERVENTIONS



▪ Correct glycemic, electrolyte, hydration abnormalities ▪ Protein refeeding, gradually ↑ protein amount ▫ Excessively-rapid protein refeeding → protein catabolism → urea accumulation → may overwhelm already impaired liver → liver failure



LAB RESULTS



Hypotension Hypothermia Hypoglycemia Anemia (normochromic-normocytic/ hypochromic microcytic/macrocytic) ▪ Hyponatremia +/- non-specific electrolyte imbalances ▪ ▪ ▪ ▪



OSMOSIS.ORG 279



NOTES



NOTES



MINERAL DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inadequate dietary minerals (vital for normal health/function) ▪ Minerals ▫ 5% of average diet



CAUSES



▪ Poor diet/required mineral absorption ▪ Macrominerals ▫ Calcium, phosphorus, potassium, sulfur, sodium, chloride, magnesium ▫ Adults > 100mg/day/< 1% of total body weight required ▪ Trace minerals/elements ▫ Iron, zinc, copper, manganese, iodine, fluoride, cobalt, selenium ▫ Adults 1–100mg/day/ 12 years old: 150μg/day ▫ Pregnant, lactating: 250μg/day



CAUSES Malnutrition ▪ Body does not create iodine; diet only source ▪ High deficiency rates ▫ Europe, Africa, Asia ▪ Low deficiency rates ▫ Industrialized countries (most water, salt, bread iodized)



RISK FACTORS



▪ Pregnant/nursing, children, vegan/glutenfree individuals



SIGNS & SYMPTOMS Goiter ▪ Thyroid enlarges because ↑ TSH ▫ Compensation strategy: decreased thyroid hormone production → goiter formation ▪ Low iodine levels → ↓ T4, T3 production → ↑ thyroid stimulating hormone (TSH) attempts restoration of T4, T3 production → TSH stimulates thyroid growth



▪ Often, goiter diffuse initially; eventually may develop nodules (can enlarge, calcify over time) ▪ If large → choking, difficulty swallowing/ breathing Hypothyroidism ▪ ↓ thyroid hormone levels (iodine necessary for production) ▪ Fatigue, constipation, weight gain, muscle weakness Pregnancy ▪ Miscarriages, premature delivery, fetal congenital abnormalities ▪ Child’s physical growth, mental development decrease Cretinism ▪ Infants, children: untreated iodine deficiency → cretinism (permanent intellectual disability, developmental deficiency)



DIAGNOSIS LAB RESULTS



▪ Iodine concentration in urine; site of ~90% ingested iodine, good site for current iodine nutrition measurement ▫ Mild iodine deficiency: 50–99μg/day ▫ Moderate deficiency: 20–49μg/day ▫ Severe deficiency: < 20μg/day



OTHER DIAGNOSTICS ▪ Thyroid size measurements (reflect iodine nutrition over extended periods)



OSMOSIS.ORG 281



TREATMENT OTHER INTERVENTIONS



▪ Iodine supplementation, iodine enriched foods ▫ Dairy: cheese, milk, yogurt ▫ Meat/alternatives: shellfish, saltwater fish, eggs



ZINC DEFICIENCY osms.it/zinc-deficiency PATHOLOGY & CAUSES ▪ Insufficient zinc intake ▪ Recommended doses ▫ Oral intake: 4–15mg/day ▫ Dietary intake: 8mg/day (children), 11mg/day (biologically male), 9mg/day (biologically female)



CAUSES



▪ Malnutrition ▪ Malabsorption diseases (chronic inflammatory bowel disease) ▫ Poor zinc absorption; absorbed in small intestine ▪ Prolonged breastfeeding ▫ Individual’s breast milk contains low zinc levels, infant exclusively breastfed ▪ Acrodermatitis enteropathica ▫ Autosomal, recessive, inherited intestinal zinc absorption (partial) defect



SIGNS & SYMPTOMS ▪ Skin, nails, hair ▫ Skin lesions, acne, eczema, alopecia, compromised wound healing ▪ Immune dysfunction → respiratory, gastrointestinal infections ▪ Delayed growth/development ▪ Impaired vision, smell, taste ▪ Delayed sexual maturation ▪ Appetite loss



DIAGNOSIS LAB RESULTS ▪ Measure zinc biomarkers ▫ Red blood cell linoleic acid to dihomo-ylinolenic acid (LA:DLGA) ratios



TREATMENT OTHER INTERVENTIONS



▪ Zinc supplementation, zinc enriched foods ▫ Fortified cereals, whole grains, nuts, meats (oysters, beef, lamb)



282 OSMOSIS.ORG



NOTES



NOTES



MITOCHONDRIAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Impaired mitochondrial activity → disorder



CAUSES



▪ Nuclear, mitochondrial DNA mutations



SIGNS & SYMPTOMS ▪ Muscle weakness, visual/hearing problems, neurological signs/symptoms, heart, kidney, respiratory disorders



DIAGNOSIS DIAGNOSTIC IMAGING



LAB RESULTS



▪ Molecular genetic testing ▫ Southern blot (deletions/duplications) ▫ Sequencing ▫ Polymerase chain reaction (PCR) ▪ Serum tests ▪ ↑ levels metabolites made by shunt pathways



TREATMENT MEDICATION



▪ Enzyme stimulation



OTHER INTERVENTIONS ▪ Supplementation ▪ Diet



MRI ▪ Brain lesions



MITOCHONDRIAL MYOPATHY osms.it/mitochondrial-myopathy PATHOLOGY & CAUSES ▪ Mitochondrial disorders ▫ Inability to produce ATP ▪ Muscles and brain: require high levels of ATP ▫ Only muscles: myopathy ▫ Muscles, brain: encephalomyopathy ▪ Variable clinical phenotypes with myopathy as main/minor feature; phenotypes can overlap



Isolated myopathy ▪ Nuclear DNA mutations ▫ Respiratory chain defects, coenzyme Q10 deficiency ▪ Rarely caused by mtDNA mutations Chronic progressive external ophthalmoplegia, Kearns–Sayre syndrome ▪ Autosomal dominant/autosomal recessive/ maternal inheritance ▪ Nuclear DNA, mtDNA mutations can cause same clinical presentation



OSMOSIS.ORG 283



Encephalomyopathy ▪ Infants, children Myopathy with diseases of multiple systems ▪ Barth’s syndrome ▫ X-linked inheritance; TAZ gene mutation; associated with cardiomyopathy, muscle weakness, neutropenia ▪ Myoclonic epilepsy with ragged red fibers (MERRF) ▫ mtDNA mutation → maternally inherited ▪ Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) ▫ mtDNA mutation → maternally inherited



CAUSES



▪ Nuclear/mitochondrial DNA (mtDNA) mutation



RISK FACTORS



▪ Mitochondrial DNA maternally inherited; only biological females can pass mutations to children



SIGNS & SYMPTOMS Isolated myopathy ▪ Fatigue, myalgia, chronic progressive extraocular ophthalmoplegia (CPEO), progressive extraocular muscles paresis, bilateral ptosis Kearns–Sayre syndrome ▪ Chronic progressive extraocular ophthalmoplegia ▪ Retinal pigment degeneration ▪ Onset < 20 years old Encephalomyopathy in infants, children ▪ Hypotonia, respiratory muscle weakness, poor feeding, seizures Barth’s syndrome ▪ Underdeveloped, weak muscles; delayed growth; MERRF ▪ Myoclonus (visible muscle spasms) ▪ Neurological defects ▪ Usually begins after normal early development



284 OSMOSIS.ORG



MELAS ▪ Stroke-like episodes ▪ Lactic acidosis ▪ Hearing, weight loss



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Lesion within deep gray matter in both hemispheres, cerebrum/cerebellum atrophy, lesions similar to stroke



LAB RESULTS



▪ Serum ▫ ↑ lactate and pyruvate, ↑ alanine, ↑ creatine kinase ▪ Urine analysis ▫ Tests for organic acids (↑ Krebs cycle intermediates) ▫ Myoglobinuria (in isolated myopathy) ▪ Muscle biopsy ▫ Mitochondrial buildup in subsarcolemmal area of affected muscle → ragged red fibers ▪ Histochemical studies ▫ Gomori trichrome stain: ragged red fibers ▫ Succinate dehydrogenase: ragged blue fibers ▪ Biochemical analysis ▫ ↓ respiratory chain complex function



OTHER DIAGNOSTICS Electromyography (EMG) ▪ Short-lasting, polyphasic motor unit potentials



Chapter 49 Mitochondrial Disease



TREATMENT OTHER INTERVENTIONS



▪ Aerobic exercises ▪ Coenzyme Q10, L-carnitine, creatine supplementation ▪ MELAS ▫ Intravenous arginine hydrochloride with saline, fluids with dextrose ▪ Avoid ▫ Valproic acid, tetracyclines, barbiturates, chloramphenicol, aminoglycosides, metmorfin



PYRUVATE DEHYDROGENASE DEFICIENCY osms.it/PDH-deficiency PATHOLOGY & CAUSES ▪ X-linked disease characterized by abnormal pyruvate metabolism



CAUSES



▪ E1 alpha gene mutation ▫ Pyruvate dehydrogenase E1 alpha subunit deficiency → ↓ production of acetyl-coenzyme A (CoA) → limited citrate production → citric acid cycle (Krebs cycle) impairment ▪ Impaired Krebs cycle ▫ Energy production disorder; brain needs energy from Krebs cycle → neurological symptoms ▫ Pyruvate accumulation → transformation to lactate, alanine → lactate buildup → lactic acidosis → metabolic symptoms ▪ Residual activity of enzyme determines clinical presentation ▫ Severe deficiency → congenital brain malformations



▫ Moderate deficiency → neurological symptoms onset in infancy/later childhood



COMPLICATIONS



▪ Intellectual disability, microcephaly, blindness ▪ Leigh syndrome ▫ Gray matter degeneration, capillary proliferation, focal necrosis



SIGNS & SYMPTOMS ▪ Metabolic disorders ▫ Lethargy, poor feeding, mental/ psychomotor delay ▪ Neurological symptoms ▫ Ataxia, hypotonia, progressive encephalopathy, abnormal eye movements, seizures, dystonia ▪ Acidosis respiratory symptoms ▫ Dyspnea, Cheyne–Stokes breathing, respiratory failure



OSMOSIS.ORG 285



DIAGNOSIS DIAGNOSTIC IMAGING Magnetic resonance spectroscopy ▪ ↑ lactate levels MRI ▪ Cerebral atrophy ▪ Corpus callosum absence ▪ Medullary pyramids absence



LAB RESULTS



▪ Pyruvic acid test ▫ ↑ lactate, pyruvate levels in blood, cerebrospinal fluid ▪ Serum, urine analysis ▫ ↑ alanine in serum, urine



286 OSMOSIS.ORG



TREATMENT OTHER INTERVENTIONS



▪ Thiamine, carnitine, lipoic acid cofactor supplementation ▪ Ketogenic diet ▫ Controls lactic acidosis ▪ Dichloroacetate ▫ Stimulation of pyruvate dehydrogenase



NOTES



NOTES



MUCOPOLYSACCHARIDOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic disorder: dysfunction of lysosomal enzymes involved in glycosaminoglycans (GAG) breakdown ▪ Lysosomal storage disease ▪ Impaired glycosaminoglycans metabolism → GAGs (heparan, dermatan, keratan, chondroitin sulfate) accumulation within lysosomes → damage of cells, tissues, organs ▫ Heparan (in nervous tissue): decline of neurological function ▫ Keratan (in skeletal system): skeletal abnormalities ▫ Dermatan (in skin, lungs, heart valves): skin changes, mitral valve damage, lung diseases



▪ Residual enzyme activity determines life expectancy MPS VI: Maroteaux–Lamy syndrome ▪ Dermatan, chondroitin sulfate accumulation ▪ Mild to severe forms MPS VII: Sly syndrome ▪ Heparan, dermatan, chondroitin sulfate accumulation ▪ Mild to severe forms MPS IX: Natowicz syndrome (rarest type) ▪ Hyaluronidase deficit → hyaluronan accumulation



CAUSES



▪ Inherited autosomal recessive, except for MPS II (X-linked)



TYPES



COMPLICATIONS



MPS I: Hurler syndrome ▪ Attenuated MPS I ▪ Severe MPS I ▫ Associated with progressive intellectual disability, earlier onset



▪ ▪ ▪ ▪ ▪ ▪ ▪



MPS II: Hunter syndrome ▪ Mild to severe forms MPS III: Sanfilippo syndrome ▪ Four forms: A, B, C, D ▪ Early life clinical presentation ▪ Lack of appropriate enzymes → accumulation heparan sulfate → neurological damage → adolescent death MPS IV: Morquio syndrome ▪ Two forms: A, B ▪ Keratan, chondroitin sulfate accumulation



Hearing, vision loss Skeletal abnormalities, limited movement Valve dysfunction Recurrent respiratory infections Joint stiffness Behavioral problems, intellectual disability C1-C2 subluxation → cord compression → central apnea ▪ Hydrocephalus



SIGNS & SYMPTOMS MPS III: Sanfilippo syndrome ▪ Three stages ▫ Mental, motor skills delays (usually between ages two–six) ▫ Sleep disorders, hyperactivity with aggressiveness, dementia ▫ Inability to walk until age of ten



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▪ Visual, hearing problems; CNS degeneration; intellectual disability; excessive hair growth MPS IV: Morquio syndrome ▪ Skeletal abnormalities, joint stiffness, blurry cornea, common ear infections, hearing loss, breathing difficulties ▪ Severe forms: life expectancy of four decades ▪ Mild forms: life expectancy up to seven decades MPS VI: Maroteaux–Lamy syndrome ▪ Large head, tongue; rough facial features; corneal cloudiness; heart, hearing problems; short growth; progressive, limiting skeletal disorders; spinal cord damage from spinal stenosis ▪ Mild form: slower progression MPS VII: Sly syndrome ▪ Hydrops fetalis; skeletal, soft tissue abnormalities MPS IX: Natowicz syndrome ▪ Pain, swelling nodular masses of soft tissue around joints



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Maroteaux–Lamy: spinal canal stenosis, cord compression X-ray ▪ Sanfilippo syndrome: dysostosis multiplex ▪ Morquio syndrome: dysostosis multiplex, vertebra flattening, pectus carinatum, odontoid dysplasia ▪ Sly syndrome: flared ribs, pectus carinatum



LAB RESULTS



▪ Prenatal diagnosis: enzyme activity measurement in amniotic cells ▪ Enzyme test: ↓ activity



288 OSMOSIS.ORG



Urine analysis ▪ ↑ glycosaminoglycans ▫ Sanfilippo syndrome: ↑ heparan sulfate ▫ Morquio syndrome: ↑ keratan sulfate ▫ Maroteaux-Lamy syndrome: ↑ dermatan sulfate ▫ Sly syndrome: ↑ dermatan, heparan sulfate



TREATMENT OTHER INTERVENTIONS ▪ ▪ ▪ ▪ ▪ ▪



No definitive cure Enzyme replacement therapy Hematopoietic bone marrow transplant Home exercises Gene therapy in development Treat associated complications



Chapter 50 Mucopolysaccharidosis



HUNTER SYNDROME osms.it/hunter-syndrome PATHOLOGY & CAUSES ▪ X-linked disorder ▫ Impaired metabolism of glycosaminoglycans (GAG) → heparan, dermatan sulfate accumulation



TYPES MPS II A (severe form) ▪ Affects children in early life MPS II B (mild form) ▪ Symptoms later in life; life expectancy up to seventy years



CAUSES



▪ Mutation of IDS gene → enzyme iduronate2-sulfatase dysfunction → ineffective breakdown of GAG in lysosomes → accumulation; cell, tissue, organ damage



COMPLICATIONS MPS II A ▪ Carpal tunnel syndrome ▪ Airway obstruction ▪ Heart problems ▫ Heart valve leaflet dysfunction; thickening of the myocardium → coronary blood vessel compression ▪ Intellectual disability ▪ Seizures MPS II B ▪ Valvular heart disease, hydrocephalus



SIGNS & SYMPTOMS ▪ Death due to heart and lung problems ▪ Lack of blurry cornea differentiates Hunter syndrome from Hurler syndrome



MPS II A ▪ Early life ▫ Rough facial features (enlarged head, flat bridge of nose, bulging forehead) ▫ Skeletal abnormalities, stiff joints, limited movement ▫ Intellectual disability ▫ Skin (ivory colored lesions) ▪ Later life ▫ Progressive neurological decline ▫ Hydrocephalus ▫ Seizures MPS II B ▪ Later onset: milder symptoms ▪ Rough facial features ▪ Rigid joints ▪ Hearing, pulmonary disorders



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Skeletal abnormalities CT scan/MRI ▪ Cord compression level, odontoid hypoplasia assessment



LAB RESULTS



▪ Prenatal diagnosis ▫ ↓ enzyme activity in amniocytes ▪ Enzyme-linked immunosorbent assay (ELISA) ▫ ↑ heparan, dermatan sulfate in blood, urine ▪ Enzyme activity test on leucocytes/ fibroblasts ▫ ↓ activity ▪ Bone marrow cells histology ▫ Alder–Reilly granulations



OSMOSIS.ORG 289



OTHER DIAGNOSTICS



▪ Physical examination ▫ Characteristic findings



ECG, pulmonary testing ▪ Determination of functions



TREATMENT OTHER INTERVENTIONS ▪ No definitive cure ▪ Address complications ▪ Recombinant human iduronate sulfatase ▫ dursulfase; enzyme replacement therapy ▪ Hematopoietic bone marrow transplant



HURLER SYNDROME (MPS I) osms.it/hurler-syndrome PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; glycosaminoglycans buildup ▪ Alpha-L iduronidase deficiency → heparan sulfate accumulation in lysosomes → cell, tissue, organ damage



TYPES Attenuated form ▪ Better prognosis ▪ Presentation: age two–adolescence ▪ Life expectancy: twenties–middle age Severe form ▪ Presentation: within first two years ▪ Life expectancy: about 10 years



CAUSES



▪ IDUA gene mutation



COMPLICATIONS



▪ Carpal tunnel syndrome ▪ Heart valve abnormalities → heart failure ▪ Thick secretions → frequent sinopulmonary infections ▪ Enlargement of tonsils, adenoids → airway obstruction → sleep apnea ▪ Vision, hearing loss



290 OSMOSIS.ORG



▪ C1-C2 subluxation → spinal cord compression → central apnea ▪ Hydrocephalus



SIGNS & SYMPTOMS ▪ Developmental delays; in severe form, progressive intellectual disability ▪ Attenuated form; normal intelligence ▪ Rough facial features ▫ Enlarged head, nose, cheeks, lips, tongue ▪ Repeated ear, respiratory infections ▪ Retinal degeneration, corneal blurriness ▪ Hepatosplenomegaly ▪ Hernias (umbilical, inguinal) ▪ Rib, hip, pelvis, vertebral abnormalities ▪ Stiff joints, claw-like hands ▪ Long bones thicken ▪ Thickened skin, short neck



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Enlargement of skull, frontal bulging ▪ Lumbar, thoracic vertebral hypoplasia ▪ Pelvis hypoplasia, small femoral heads ▪ Metacarpals narrow proximally, widen distally



Chapter 50 Mucopolysaccharidosis



LAB RESULTS ▪ Enzyme activity in fibroblasts ▫ ↓alpha-L iduronidase ▪ ↑ heparan sulfate



OTHER DIAGNOSTICS



▪ Physical examination ▫ Characteristic findings



TREATMENT SURGERY



▪ Hand, foot abnormalities



Figure 50.1 An X-ray image of the head of an infant with Hurler syndrome, showing a J-shaped sella turcica.



OTHER INTERVENTIONS ▪ No definitive cure ▪ Address complications ▪ Recombinant human alpha-L-iduronidase ▫ Laronidase (replaces missing enzyme) ▪ Bone marrow transplant



Figure 50.2 X-ray image of the hands of an infant with Hurler syndrome. The metacarpals are pointed at the proximal ends.



OSMOSIS.ORG 291



NOTES



NOTES



PURINE & PYRIMIDINE METABOLISM DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Enzymatic disorders in biochemical pathways crucial for biosynthesis of nucleobases → impaired nucleotide formation ▫ Adenosine triphosphate (ATP), guanosine monophosphate (GMP) ▪ Inherited conditions



SIGNS & SYMPTOMS ▪ Disease-specific ▪ Lesch–Nyhan syndrome ▫ Kidney stones, hematuria, urinary tract infections (UTIs), arthritis, tophi ▫ Spasticity, chorea, hyperactive reflexes, grimacing, dystonia ▫ Intellectual impairment, developmental delay, self mutilation, lack of speech, compulsions ▪ Orotic aciduria ▫ Glossitis, growth failure, developmental delay, intellectual disability, congenital malformation, immunodeficiency



292 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS ▪ No activity in one enzyme, excess in one metabolite



OTHER DIAGNOSTICS



▪ Clinical evaluation, genetic testing



TREATMENT MEDICATIONS



▪ Lesch–Nyhan syndrome ▫ Xanthine oxidase inhibitors, benzodiazepines, baclofen, gabapentin, neuroleptics



OTHER INTERVENTIONS



▪ Lesch–Nyhan syndrome ▫ Lithotripsy, protecting devices ▪ Orotic aciduria ▫ Pyrimidine replacement therapy



Chapter 51 Purine & Pyrimidine Metabolism Disorders



LESCH–NYHAN SYNDROME osms.it/lesch-nyhan_syndrome PATHOLOGY & CAUSES ▪ Rare disease; excess of uric acid



CAUSES



▪ Behavioural, cognitive ▫ Intellectual impairment, developmental delay, self-mutilation (e.g. finger, lip biting), lack of speech, compulsions (e.g. spitting)



▪ X-linked recessive mutation in HPRT gene → lack of enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) ▪ Decreased HGPRT activity, recycling of cell waste products → increased transformation of cell waste products into uric acid → increased uric acid



LAB RESULTS



COMPLICATIONS



OTHER DIAGNOSTICS



▪ Uric acid precipitation in urine → urate stones in kidney, ureter, bladder → renal failure ▪ Uric acid deposition in joints → gout-like arthritis (AKA juvenile gout) ▪ Central nervous system (CNS) alterations, may be due to ▫ Uric acid accumulation → oxidative damages ▫ Decreased nucleotide production → decreased dopamine production → lesions in striatal dopaminergic pathways ▪ Insufficient vitamin B12 → megaloblastic anemia



SIGNS & SYMPTOMS



DIAGNOSIS ▪ HGPRT activity in blood, other tissues ▪ Increased urate-to-creatinine ratio in urine ▪ Hyperuricosuria, hyperuricemia



▪ Clinical evaluation, genetic testing



TREATMENT MEDICATIONS ▪ Xanthine oxidase inhibitors to reduce production of uric acid ▪ Benzodiazepines, baclofen for neurological issues ▪ Benzodiazepines, gabapentin, neuroleptics for behavioural issues



OTHER INTERVENTIONS



▪ Lithotripsy for kidney stones ▪ Protecting devices for behavioural issues



▪ Uric acid hyperproduction ▫ Urate precipitation in urinary tract: “orange sand” deposits in diapers of infants; kidney stones → hematuria, UTIs ▫ Arthritis, tophi ▪ Neuromuscular ▫ Spasticity, chorea, hyperactive reflexes, grimacing, dystonia



OSMOSIS.ORG 293



OROTIC ACIDURIA osms.it/orotic-aciduria PATHOLOGY & CAUSES ▪ Extremely rare disease; alteration in pyrimidine synthesis → excessive excretion of orotic acid (intermediate metabolite) in urine



CAUSES



▪ Autosomal recessive disease ▪ Defect in activity of uridine monophosphate synthetase (UMPS) → decreased UTP production and increased dihydroorotate accumulation ▫ Type 1: both enzymes affected; orotidine monophosphate decarboxylase (OMP-decarboxylase), orotate phosphoribosyltransferase (OPRT) ▫ Type 2: only OMP-decarboxylase affected



COMPLICATIONS



▪ Decreased production of pyrimidin, cofactors needed for erythropoiesis → megaloblastic anemia unresponsive to vitamin B12 supplementation, folic acid



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪



294 OSMOSIS.ORG



Glossitis Growth failure Developmental delay Intellectual disability Congenital malformation Immunodeficiency



DIAGNOSIS LAB RESULTS



▪ Anemia ▪ Orotic acid dosage in urine



OTHER DIAGNOSTICS ▪ Clinical evaluation



TREATMENT OTHER INTERVENTIONS



▪ Pyrimidine replacement therapy ▫ Uridine monophosphate



NOTES



NOTES



SPHINGOLIPIDOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Lysosomal storage diseases ▪ Metabolic disorders characterized by dysfunctional metabolism of sphingolipids ▪ Sphingolipids accumulate within various tissues’ cell lysosomes → affected organ damage ▪ Causes genetic defects → lysosomal enzyme deficiency ▪ Inheritance mode autosomal recessive, except in Fabry disease (X-linked recessive)



SIGNS & SYMPTOMS ▪ Vary depending on organs affected, sphingolipid storage extent



DIAGNOSIS ▪ Clinical presentation, family history ▪ Enzymatic assays ▪ Mutation analysis



TREATMENT ▪ Enzyme replacement therapy ▪ Gene therapy



FABRY DISEASE osms.it/fabry-disease PATHOLOGY & CAUSES ▪ Lysosomal enzyme alpha galactosidase A (a-GAL A) deficiency ▪ → Accumulation of a sphingolipid, called glycoglobotriaosylceramide (Gb3/ceramide trihexoside), within lysosomes ▪ Gb3 most commonly deposits in vessels, ganglions, kidneys, heart ▪ X-linked recessive inheritance pattern



COMPLICATIONS



SIGNS & SYMPTOMS ▪ Early presentation ▫ Acroparesthesias (severe peripheral neuropathic pain in extremities) ▫ Angiokeratomas (painless red to blue papules with hyperkeratosis), Telangiectasias (dilated vessels) presenting on the skin ▫ Gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting) ▫ Corneal opacities



▪ Affected organ dysfunction, vascular occlusions, infarctions



OSMOSIS.ORG 295



▪ Later symptoms ▫ Progressive renal failure, cardiovascular disease, heat/cold intolerance, hypohidrosis (decreased sweat production), hearing loss



DIAGNOSIS LAB RESULTS



▪ Enzymatic assay for alpha galactosidase ▪ Genetic testing



TREATMENT OTHER INTERVENTIONS Figure 52.1 Numerous angiokeratomas on the skin of an individual with Fabry disease.



▪ Symptom management (e.g., analgesics) ▪ Enzyme replacement therapy ▪ Gene therapy



GAUCHER'S DISEASE osms.it/gauchers-disease PATHOLOGY & CAUSES ▪ Most common lysosomal storage disease ▪ Lysosomal enzyme glucocerebrosidase deficiency ▪ → Accumulation of sphingolipid glucocerebroside in cellular lysosomes, particularly macrophages resembling crumpled tissue paper (AKA Gaucher cells) ▪ Glucocerebroside also deposits in liver, spleen, bone marrow, bones, kidneys, lungs, central nervous system (CNS) ▪ Autosomal recessive pattern of inheritance



TYPES



▪ Three types based upon CNS involvement ▫ Type I: absence of CNS involvement ▫ Type II: acute neuronopathic form ▫ Type III: subacute or chronic neuronopathic form



296 OSMOSIS.ORG



COMPLICATIONS



▪ Thrombocytopenia, anemia, bone disease, neurological deficits



SIGNS & SYMPTOMS ▪ Hepatosplenomegaly ▪ Pancytopenia, due to bone marrow infiltration with Gaucher cells, hypersplenism, leads to ▫ Easy bruising (thrombocytopenia) ▫ Fatigue (anemia) ▪ Bone disease (e.g., osteoporosis, aseptic necrosis of various bones); most commonly affects the femur ▪ Neurological complications (e.g. seizures, hypotonia, cognitive/olfactory abnormalities) present only in types II, III



Chapter 52 Sphingolidosis



DIAGNOSIS LAB RESULTS ▪ Enzymatic assay to confirm glucocerebrosidase deficiency ▪ Genetic testing ▫ Prenatal diagnosis available



TREATMENT OTHER INTERVENTIONS



▪ Enzyme replacement therapy



Figure 52.2 A section of bone marrow demonstrating numerous crinkled paper macrophages, or Gaucher cells, in an individual with Gaucher’s disease.



KRABBE DISEASE osms.it/krabbe-disease PATHOLOGY & CAUSES ▪ AKA globoid cell leukodystrophy ▪ Lysosomal enzyme galactocerebrosidase deficiency ▪ Lipids galactocerebroside and psychosine buildup → ▫ Globoid cell formation (multinucleated macrophages) ▫ Oligodendrocyte destruction → demyelination ▪ Autosomal recessive inheritance pattern ▪ Progressive damage to nervous system → fatal



SIGNS & SYMPTOMS ▪ Usually present within first six months of life ▪ Peripheral motor, sensory neuropathy, loss of sensation, muscle atrophy in extremities



▪ Central nervous system dysfunction ▫ Irritability, developmental delay, spasticity, optic atrophy, seizures, weakness



DIAGNOSIS LAB RESULTS



▪ Enzymatic assay to measure galactocerebrosidase activity in leukocytes ▪ Microscopy shows demyelination, characteristic globoid cells (i.e, multinucleated macrophages containing ↑periodic acid-Schiff (PAS) positive materials) ▪ Genetic testing



TREATMENT OTHER INTERVENTIONS



▪ Affective therapy not yet available ▪ Hematopoietic stem cell transplantation is beneficial, especially in early onset of symptoms



OSMOSIS.ORG 297



METACHROMATIC LEUKODYSTROPHY osms.it/metachromatic-leukodystrophy PATHOLOGY & CAUSES ▪ Lysosomal enzyme arylsulfatase A (ARSA) deficiency → ↑ cerebroside sulfate storage in various tissues, progressive demyelination ▪ Metachromatic leukodystrophy (MLD) also caused by saposine deficiency (i.e. protein that normally stimulates ARSA) ▪ Autosomal recessive inheritance pattern



COMPLICATIONS



▪ Central, peripheral nervous system dysfunction, paralysis, coma ▪ If untreated, fatal in 5–6 years



SIGNS & SYMPTOMS ▪ Usually develops in late infancy, but can also present later in life ▪ Infantile onset ▫ Gait difficulties ▫ Developmental delay



▫ Muscle tone, strength abnormalities ▫ Ataxia ▫ Peripheral neuropathy ▫ Progressive vision loss ▪ Late onset ▫ Behavioral difficulties ▫ Psychiatric disorder ▫ Dementia



DIAGNOSIS LAB RESULTS



▪ Enzymatic assay for ARSA ▪ Sulfatides measurement in urine to confirm diagnosis ▪ Genetic testing



TREATMENT OTHER INTERVENTIONS



▪ Hematopoietic stem cell transplantation ▪ Gene therapy ▪ Enzyme replacement



NIEMANN–PICK DISEASE osms.it/niemann-pick_disease PATHOLOGY & CAUSES ▪ Group of disorders caused by defects in sphingomyelin storage ▪ Types A, B are characterized by enzyme acid sphingomyelinase deficiency → sphingomyelin accumulation in macrophage lysosomes in various tissues



298 OSMOSIS.ORG



▪ Type C is characterized by impaired cellular processing, low-density lipoprotein (LDL)cholesterol transport ▪ Autosomal recessive inheritance pattern



Chapter 52 Sphingolidosis



COMPLICATIONS



▪ Progressive neurodegeneration, developmental delay, interstitial lung disease



SIGNS & SYMPTOMS ▪ Hepatosplenomegaly, hypersplenism → thrombocytopenia ▪ Various neurologic deficits ▫ Ataxia, dysarthria, dysphagia, dystonia ▪ Developmental delay ▪ Interstitial lung disease, recurrent respiratory infections ▪ Lipid abnormalities ▪ Dementia/depression/bipolar disease/ schizophrenia (in adults) ▪ Macular cherry red spot seen on fundoscopy examination ▫ Fovea appears bright red compared to rest of retina where lipids are accumulated



TREATMENT ▪ No treatment proven to modify onset/ progression of disease



MEDICACTIONS



▪ Miglustat (glycosphingolipids biosynthesis inhibitor) may be beneficial for type C



OTHER INTERVENTIONS



▪ Physical/occupational therapy, nutritional assessments



DIAGNOSIS LAB RESULTS



▪ Types A, B ▫ Enzymatic assay for sphingomyelinase ▪ Type C ▫ Impaired response to LDL-cholesterol in cultured fibroblasts ▪ Histology shows large lipid laden macrophages in reticuloendothelial system (AKA foam cells) ▪ Genetic testing



Figure 52.3 Numerous lipid-laden macrophages in the spleen of an individual with Niemann–Pick disease.



OSMOSIS.ORG 299



TAY–SACHS DISEASE osms.it/tay-sachs_disease PATHOLOGY & CAUSES ▪ Hexosaminidase A deficiency → glycolipid GM2 ganglioside buildup in neuronal lysosomes ▪ Autosomal recessive inheritance pattern



TREATMENT OTHER INTERVENTIONS



▪ Symptom reduction/infection prevention



COMPLICATIONS



▪ Progressive neurodegeneration ▪ Mental/physical ability deterioration ▪ Death at ages 2–5, primarily → pneumonia



SIGNS & SYMPTOMS ▪ Typically presents at 2–6 months of age ▪ Progressive motor skill loss with hyperreflexia, hypotonia ▪ Physical ability deterioration ▫ Blindness, deafness, dysphagia, dysarthria ▪ Milder symptoms in late onset Tay–Sachs disease ▪ Cherry red spot macula sign a characteristic finding on fundoscopy



DIAGNOSIS LAB RESULTS



▪ Enzymatic assay for hexosaminidase A ▪ Genetic testing



300 OSMOSIS.ORG



Figure 52.4 A cherry red spot on the retina of an individual with Tay–Sachs disease.



NOTES



NOTES



WATER SOLUBLE VITAMINS DEFICIENCY



GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Vitamin: micronutrient that participates in essential cellular function



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS



CAUSES ▪ Insufficient water-soluble vitamin intake → ↑ demand, malabsorption, loss → insufficient for body’s metabolic needs



COMPLICATIONS ▪ Chronic water-soluble vitamin deficiency → specific clinical disorders



OTHER DIAGNOSTICS ▪ History, clinical presentation



TREATMENT OTHER INTERVENTIONS ▪ ↑ dietary intake ▪ Synthetic formulation supplementation ▪ Address complications



FOLATE (VITAMIN B9) DEFICIENCY osms.it/folate-(vitamin-b9)-deficiency PATHOLOGY & CAUSES ▪ Insufficient folate (pteroylglutamic acid) for body’s metabolic needs ▪ Body cannot synthesize, normally maintains low stores ▪ Folate must be obtained in diet; lack for several weeks → deficiency ▪ Folate deficiency → impaired DNA synthesis during erythropoiesis (cell cycle S-phase delay) → uncoordinated cytoplasm, nuclei maturation in erythroblasts (nuclear-cytoplasmic asynchrony) → ineffective hematopoiesis



→ ↑ erythroid apoptosis + abnormally large erythrocytes (macrocytosis) → defective cells with fragile membranes → ↓ red blood cell (RBC) lifespan → anemia Sources of folate ▪ Present naturally in plant (especially dark green leafy vegetables), animal products (especially liver) ▪ Folic acid available in dietary supplements, fortified foods (e.g. cereals) Recommended dietary allowances (RDAs) ▪ Folate RDAs listed as micrograms of dietary folate equivalents (DFEs), reflect



OSMOSIS.ORG 301



▪ ▪ ▪ ▪



higher bioavailability in food vs. supplement Child 9–13: 300mcg DFE 14+: 400mcg DFE Pregnancy: 600mcg Lactation: 500mcg



RISK FACTORS Insufficient diet ▪ Alcohol abuse ▫ Impairs folate absorption, metabolism; accelerates breakdown ▪ Chronic systemic disease; mental illness; advanced age ▪ Food insecurity ▪ Self-imposed dietary restrictions (e.g. vegan) ▪ ↓ vitamin C (cofactor for folate metabolism) Adequate diet but increased requirements ▪ Pregnancy, lactation, malignancy ▪ Disease state with ↑ cellular turnover (e.g. chronic hemolysis, exfoliative skin disease) Malabsorption ▪ E.g. celiac disease, inflammatory bowel disease, gastric surgery, achlorhydria Metabolic interference from medication ▪ E.g. methotrexate (folate antagonist), phenytoin, trimethoprim Hereditary forms ▪ Hereditary folate malabsorption (HFM) ▫ Loss-of-function mutation of PFCT gene encoding for proton-coupled folate transporter (rare, autosomal recessive disorder) ▪ Infantile cerebral folate deficiency ▫ Autoantibody against folate receptor in choroid plexus → prevents folate transport across blood-brain barrier



COMPLICATIONS ▪ Megaloblastic anemia ▪ Insufficient folate during gestation → ↑ neural tube defect risk ▪ Developmental delay, neurological disorders (child)



302 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ Megaloblastic anemia ▫ Hypoxemia, tissue hypoxia → fatigue, activity intolerance, pallor, ↑ heart rate ▪ ↑ hemolysis → jaundice ▪ Atrophic glossitis, angular stomatitis, anorexia, nausea, diarrhea ▪ Hereditary folate malabsorption ▫ Manifests at age 1–3 months ▫ Failure to thrive, neurologic deterioration, megaloblastic anemia ▪ Infantile cerebral folate deficiency ▫ Manifests at age 4–6 months ▫ Irritability, ↓ sensorineural hearing, seizure, developmental delay, sleep disturbance → visual disturbance/loss



DIAGNOSIS LAB RESULTS ▪ ↓ RBC count; ↓ reticulocyte count; evidence of megaloblastic anemia (↑ mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)) ▪ Macrocytosis, anisocytosis, poikilocytosis, hypersegmented neutrophils ▪ ↑ hemolysis markers ▫ ↓ indirect bilirubin, ↓ lactate dehydrogenase, ↓ haptoglobin ▪ ↓ serum folate ▪ Hypercellular bone marrow ▪ Infantile cerebral folate deficiency ▫ Cerebrospinal fluid (CSF) assay shows ↓ 5-methyltetrahydrofolate ▫ Serum, RBC folate normal



TREATMENT OTHER INTERVENTIONS ▪ Address complications (e.g. neurologic manifestation) ▪ ↑ dietary folate intake ▪ Folic acid supplementation (synthetic formulation)



Chapter 53 Water Soluble Vitamins Deficiency



NIACIN (VITAMIN B3) DEFICIENCY osms.it/niacin-(vitamin-b3)-deficiency PATHOLOGY & CAUSES ▪ Insufficient niacin (nicotinic acid, nicotinamide) for body’s metabolic needs ▫ Niacin obtained in diet ▫ Liver converts tryptophan to niacin (60g tryptophan = 1mg niacin) ▪ Active forms ▫ Nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP+) ▪ Moderate/↑ doses of niacin supplement → ↓ total/low-density lipoprotein (LDL) cholesterol Sources of niacin ▪ Present in plant, animal products (e.g. dairy products, meat, grain (↓ corn), legumes, seeds) ▪ Dietary supplement; enriched grain, cereal, milk



Metabolic defects ▪ E.g. carcinoid syndrome → impaired tryptophan metabolism Accelerated niacin depletion ▪ Prolonged isoniazid use → ↓ pyridoxal phosphate (active form of vitamin B6) → ↑ tryptophan synthesis Tryptophan-to-niacin conversion nhibited by medication ▪ E.g. phenobarbital, chloramphenicol, pyrazinamide



COMPLICATIONS ▪ Pellagra



RDAs ▪ Children 9–13: 12mg ▪ 19+ male: 16mg; 19+ female: 14mg ▪ Pregnancy: 18mg ▪ Lactation: 14mg



RISK FACTORS Insufficient niacin/tryptophan intake ▪ Alcohol abuse ▪ Self-imposed dietary restrictions ▪ Chronic systemic disease; mental illness; advanced age ▪ Food insecurity ▪ Corn-based diet (unless corn treated with alkali, e.g. tortillas) Malabsorption ▪ E.g. bariatric surgery, malabsorptive disease states ▪ Hartnup disorder: defective tryptophan absorption



Figure 53.1 A desqauamating rash on the skin of an individual who presented with diarrhea and confusion. The diagnosis was confirmed as pellagra.



OSMOSIS.ORG 303



SIGNS & SYMPTOMS ▪ Dermatitis ▫ Photosensitive, pigmented ▪ Diarrhea ▫ Potentially also vomiting ▪ Dementia ▫ Potentially also anxiety, disorientation ▪ Death ▫ Untreated pellagra potentially fatal



DIAGNOSIS LAB RESULTS ▪ ↓ N-methylnicotinamide (niacin metabolism product)



TREATMENT OTHER INTERVENTIONS ▪ Niacin supplementation ▪ ↑ dietary niacin/tryptophan ▪ Address complications



VITAMIN B12 DEFICIENCY osms.it/vitamin-b12-deficiency PATHOLOGY & CAUSES ▪ Insufficient B12 for body’s metabolic needs ▪ Active cobalamin (coenzyme) forms: methylcobalamin, 5-deoxyadenosylcobalamin ▪ Dietary cobalamin in food protein → gastric hydrochloric acid, protease-free cobalamin → cobalamin + intrinsic factor complex → distal ileum absorption ▪ Cobalamin essential for metabolic reactions involving hematopoiesis; protein, DNA, RNA, myelin synthesis; gastrointestinal tract mucosa maintenance ▫ Methylcobalamin: methionine synthase (folate-dependent enzyme) cofactor → methionine synthase catalyzes homocysteine remethylation to form methionine (essential amino acid for tissue growth/repair; hormone, protein, purine, pyrimidine synthesis) ▫ 5-deoxyadenosylcobalamin: L-methylmalonyl-coenzyme A conversion to succinyl CoA → enters citric acid cycle → lipid, protein energy production ▪ Impaired DNA synthesis during erythropoiesis (e.g. cell cycle S-phase delay) → uncoordinated cytoplasm,



304 OSMOSIS.ORG



nuclei maturation in erythroblasts (nuclear-cytoplasmic asynchrony) → ineffective hematopoiesis → ↑ erythroid apoptosis, abnormally large erythrocytes (macrocytosis) → defective cells with fragile membranes → ↓ RBC lifespan → anemia Sources of cobalamin ▪ Animal products (meat, egg, dairy) ▪ Supplements, enriched food RDAs ▪ Child 9–13: 1.8mcg ▪ 14+: 2.4mcg



RISK FACTORS Insufficient intrinsic factor ▪ Pernicious anemia ▫ Autoimmune condition destroys parietal cells → ↓ intrinsic factor production → cobalamin not absorbed ▪ Gastrectomy, bariatric surgery ▪ Gastric atrophy Malabsorption ▪ Achlorhydria (acid promotes gastric mucosa absorption) ▫ ↑ age → ↑ risk ▫ ↓ acid due to medication (e.g. antacid,



Chapter 53 Water Soluble Vitamins Deficiency H2 receptor blocker, proton pump inhibitor) ▫ Ileal resection, disease (e.g. celiac disease) Insufficient diet ▪ Alcohol abuse ▪ Chronic systemic disease, mental illness, advanced age ▪ Food insecurity ▪ Self-imposed dietary restrictions (e.g. vegan) Adequate diet but increased requirements ▪ Pregnancy, lactation, malignancies ▪ Disease states with ↑ cellular turnover (e.g. chronic hemolysis, exfoliative skin disease) Medication interfering with absorption ▪ E.g. Metformin, cycloserine, isoniazid, neomycin Fish tapeworm Diphyllobothrium latum infestation ▪ Competes for absorption in ileum Imerslund–Gräsbeck syndrome ( juvenile megaloblastic anemia) ▪ Autosomal recessive disorder ▪ Vitamin B12-intrinsic factor receptor defect cblD inborn error of cobalamin metabolism ▪ MMADHC gene mutation → MMADHC protein defect (cobalamin transporter)



COMPLICATIONS ▪ Macrocytic anemia ▪ Neurodegenerative disorder



▪ ↑ hemolysis → jaundice ▪ ↓ gastrointestinal tract mucosa integrity → atrophic glossitis, angular stomatitis, anorexia, nausea, diarrhea ▪ Impaired myelin production → cognitive impairment, paresthesias, impaired proprioception, gait disturbance, slowed cognition



DIAGNOSIS LAB RESULTS Blood study ▪ ↓ cobalamin ▪ CBC ▫ ↓ RBC count; ↓ reticulocyte count; megaloblastic anemia (↑ MCV, ↓ MCH) ▪ Blood smear analysis ▫ Macrocytosis, oval macrocytes; anisocytosis; poikilocytosis; hypersegmented neutrophils ▪ ↑ hemolysis markers ▫ Elevated indirect bilirubin, lactate dehydrogenase, ↓ haptoglobin Hypercellular bone marrow



TREATMENT OTHER INTERVENTIONS ▪ ↑ dietary cobalamin ▪ Supplementation (cyanocobalamin) ▫ Pernicious anemia → parenteral cobalamin ▪ Address complications



SIGNS & SYMPTOMS ▪ High body stores → 1–2 years insufficient intake → symptoms (adult/child) ▪ B12-deficient mothers → infant cobalamin deficiency sequelae at age 6–18 months ▪ Megaloblastic anemia ▫ Hypoxemia, tissue hypoxia → fatigue, activity intolerance, pallor, ↑ heart rate



OSMOSIS.ORG 305



VITAMIN C DEFICIENCY osms.it/vitamin-c-deficiency PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Insufficient vitamin C for body’s metabolic needs ▪ Body cannot synthesize, must obtain in diet ▪ Active form: L-ascorbic acid



▪ ↓/no intake → symptoms within one month ▪ Mucocutaneous signs ▫ Spongy gums → loose teeth ▫ Capillary fragility → petechiae, ecchymoses, perifollicular hemorrhage, subperiosteal hemorrhage ▫ Hair structure changes → corkscrew hair ▪ Inability to maintain bone matrix ▫ Arthralgias, bone structure changes ▪ Anemia ▫ Fatigue, malaise ▪ Impaired wound healing



RDA ▪ 9–13 years old: 45mg ▪ 14–18 years old: 75 mg (biologically-male); 65mg (biologically-female) ▪ 19+ years old: 90 mg (biologically-male); 75mg (biologically-female) ▪ Pregnancy: 85mg ▪ Lactation: 120mg ▪ Smokers: ↑ 35mg/day



RISK FACTORS Insufficient diet ▪ Food insecurity ▪ Self-imposed dietary restrictions ▪ Chronic systemic disease, mental illness, advanced age ▪ Feeding infants evaporated/boiled cow’s milk ↑ oxidative stress ▪ Smoking, secondhand smoke



COMPLICATIONS ▪ Scurvy, related sequelae (e.g. periodontal disease; bone, joint disorders) ▪ Impaired wound healing ▪ Weakened immune system ▪ Depression ▪ Microcytic anemia



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DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Sclerotic, lucent metaphyseal bands, soft tissue edema



TREATMENT OTHER INTERVENTIONS ▪ ↑ dietary/supplementation vitamin C ▫ Present in many fruits, vegetables (especially citrus, tomatoes, broccoli, bell peppers, potatoes) ▫ Supplements, enriched grains ▪ Address complications



Chapter 53 Water Soluble Vitamins Deficiency



Figure 53.2 An X-ray of the leg of a child with scurvy. There is a dense zone of provisional calcification at the epiphysis, known as a Frankel line, with underlying radiolucency known as a Trümmerfeld zone.



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NOTES



NOTES



ADENOVIRIDAE



ADENOVIRUS osms.it/adenovirus PATHOLOGY & CAUSES ▪ Seven subgroups, 52 serotypes ▪ Directly invades human epithelial cells (several organs) → multiple cytopathic effects, usually within 2–7 days postinfection ▪ Responsible for variety of upper, lower respiratory tract; gastrointestinal; genitourinary infections ▪ Common clinical syndromes ▫ Upper respiratory disease, pharyngoconjunctival fever, coryza, pneumonia, gastroenteritis, hepatitis, hemorrhagic cystitis, interstitial nephritis, epidemic keratoconjunctivitis Genetic material ▪ Double-stranded DNA virus Taxonomy ▪ Adenoviridae family Morphology ▪ Non-enveloped icosahedral nucleocapsid ▪ Unique ▫ Fiber-like projections (hemagglutinins) protrude from capsid’s 12 vertices Transmission ▪ Aerosol droplets ▪ Fecal-oral route ▪ Neonates ▫ Infected cervical secretion exposure ▪ Solid organ transplant



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▪ Fomite contact ▫ Survives on environmental surfaces for long periods; inactivated by heat, formaldehyde, bleach



RISK FACTORS



▪ Close living space (e.g. military barracks, daycare centers) ▪ Summer camps (especially with swimming pools/lakes) ▪ Healthcare facilities ▪ Immunocompromised status (especially cell-mediated immunity deficiency)



COMPLICATIONS



▪ Secondary bacterial infection; meningoencephalitis; myocarditis; disseminated intravascular coagulation; myositis, rhabdomyolysis; hypogammaglobulinemia ▪ Disseminated adenovirus infection ▫ Affects multiple organs, immunocompromised individuals especially; high mortality rate



SIGNS & SYMPTOMS ▪ Varies with clinical syndrome ▪ Upper respiratory ▫ Sore throat, nasal congestion, rhinorrhea, dry cough, hoarseness, inflamed tonsils, cervical lymphadenopathy; wheezes/rhonchi on auscultation



Chapter 54 Adenoviridae ▪ Ocular ▫ Conjunctivitis, preauricular, lymphadenopathy ▪ Gastrointestinal ▫ Nausea, vomiting, diarrhea ▪ Systemic ▫ Fever, malaise, headache, myalgia



DIAGNOSIS ▪ History, physical examination ▫ Characteristic findings ▫ Diagnostic test choice based on clinical presentation



DIAGNOSTIC IMAGING Chest X-ray ▪ May show diffuse bilateral pulmonary mononuclear cell infiltration, hyaline membranes, necrosis



LAB RESULTS Microbe identification ▪ Viral culture (e.g. nasopharyngeal swabs, blood, urine, sputum) ▪ Viral assay (e.g. adenovirus-specific enzyme immunoassay (EIA)/ immunofluorescence assay) ▪ Nucleotide amplification test (NAT) ▪ Polymerase chain reaction (PCR)



Serology ▪ Antigen/complement fixation assays ▪ Hemagglutination inhibition/neutralizing antibodies ▪ Restriction endonuclease (RE) analysis Tissue biopsy ▪ Eosinophilic inclusions (early stage) ▪ Basophilic inclusion surrounded by clear intranuclear inclusion Electron microscopy ▪ Icosahedral virions forming intranuclear paracrystalline aggregates



TREATMENT ▪ Usually self-limiting disease



MEDICATIONS Pharmacotherapy ▪ Immunocompromised/severe infection individuals ▫ Antivirals, immunoglobulin (IVIG) Prevention ▪ Infection control measures ▪ Live oral enteric-coated vaccine used for military recruits only



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NOTES



NOTES



AEROBIC RODS MICROBE OVERVIEW ▪ Gram-positive, rod-shaped, aerobes/ facultative anaerobes



BACILLUS ANTHRACIS (ANTHRAX) osms.it/bacillus-anthracis PATHOLOGY & CAUSES ▪ Etiologic agent of anthrax; nonmotile, nonhemolytic; potential biological weapon ▪ Endospore-forming (centrally located) ▫ Highly adaptable to extreme environmental conditions ▪ Surrounded by protein capsule (composed of poly-D-gamma-glutamic acid) ▫ Prevents phagocytosis



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▪ Transmission (4 Is) ▫ Ingestion ▫ Inhalation ▫ skin Invasion ▫ direct Injection ▪ Anthrax toxin composed of three proteins ▫ Protective antigen (PA): essential for binding, entry to cell ▫ Lethal factor (LF): alteration of signaling pathways → cell death; ↑



Chapter 55 Aerobic Rods proinflammatory cytokines production → inflammation ▫ Edema factor (EF): ↑ cyclic adenosine monophosphate (cAMP) → disordered water, electrolyte balance → edema



RISK FACTORS



▪ Occupational ▫ People who work with animals/ animal products (e.g. veterinarians, livestock producers, butchers); possible bioterrorism (e.g. military personnel); laboratory professionals ▪ Injecting drug users (e.g. heroin contaminated with anthrax spores)



COMPLICATIONS



▪ Hemorrhagic meningitis, mediastinitis; pleural effusion; pneumonia; shock



SIGNS & SYMPTOMS ▪ Respiratory infection ▫ Prodromal phase: flu-like symptoms (e.g. fever, malaise, myalgia), hemoptysis, dyspnea, nausea, chest pain ▫ Fulminant phase: severe dyspnea, hypoxemia, cyanosis, shock, coma ▪ Gastrointestinal (GI) infection ▫ Severe abdominal pain; nausea; vomiting; ascites; ulcerations → GI hemorrhage ▪ Cutaneous infection ▫ Painless, pruritic papule → enlarges, forms central black-colored necrotic ulceration → black eschar ▫ Surrounding edema ▫ Regional lymphadenopathy, lymphadenitis



Figure 55.1 A lesion on the neck caused by Bacillus anthracis.



DIAGNOSIS LAB RESULTS



▪ Identify microbe ▫ Gram stain, culture, direct fluorescent antibody (DFA), polymerase chain reaction (PCR)



OTHER DIAGNOSTICS



▪ History, physical examination



TREATMENT MEDICATIONS ▪ Antibiotics



OTHER INTERVENTIONS



▪ Vaccine (people at high risk of exposure, post-exposure prophylaxis)



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BACILLUS CEREUS (FOOD POISONING) osms.it/bacillus-cereus PATHOLOGY & CAUSES ▪ Common foodborne pathogen; also associated with contaminated medical equipment (e.g. ventilators, dialysis machines), opportunistic infections ▪ Endospore-forming (centrally located) ▫ Highly adaptable to extreme environmental conditions ▪ Motile, catalase positive, beta-hemolytic ▪ Can be transient component of GI microflora Pathogenesis of food poisoning ▪ Production of enterotoxins ▫ Diarrheal toxin (thermolabile) → ↑ cAMP → disordered function of ion pumps → ↑ efflux of ions, water from infected enterocytes → diarrhea ▫ Emetic toxin, cereulide (thermostable) → ↑ afferent vagus nerve stimulation → nausea, vomiting ▪ Two types of food poisoning ▫ Diarrheal syndrome (meat, vegetables, sauces) → toxicoinfection → ingestion of bacteria, production of toxins in digestive tract ▫ Emetic syndrome (rice) → alimentary intoxication → direct ingestion of toxin



RISK FACTORS



▪ Consumption of improperly cooked food



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SIGNS & SYMPTOMS ▪ Abdominal cramps, diarrhea, nausea, vomiting



DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪



Stool/contaminated food sample Gram stain Culture (blood agar) PCR



TREATMENT OTHER INTERVENTIONS ▪ Intravenous (IV) fluid, electrolyte replacement



Chapter 55 Aerobic Rods



CORYNEBACTERIUM DIPHTHERIAE (DIPHTHERIA) osms.it/corynebacterium-diphtheriae PATHOLOGY & CAUSES ▪ Infectious agent of diphtheria ▪ Rods with widening at polar regions forming club-like shape ▪ Characteristic “Chinese-letter” arrangement ▪ Nonmotile, non-spore-forming ▪ Stain ▫ Albert’s/Ponder’s; metachromatic granules (e.g. Babes–Ernst, volutin) ▪ Culture ▫ Löffler's medium ▪ Differentiation ▫ Hoyle’s tellurite agar ▪ Types of infection ▫ Respiratory (pharyngeal), cutaneous



RISK FACTORS



▪ Absent/incomplete immunization ▪ Immunocompromised individuals ▪ Citizens, migrants, returning travellers from endemic areas (e.g. African, Asian, South American countries)



COMPLICATIONS



▪ Myocarditis, nerve damage (e.g. demyelinating polyneuropathy, paralysis), renal failure, suffocation (due to pseudomembrane aspiration)



Pathophysiology ▪ Diphtheria toxin → composed of two subunits ▫ A: active, catalytic ▫ B: binding; composed of R (receptor), T (translocation) domains ▪ Bacteria binds to host cell using R domain → endocytosis → acidification inside endosome → T domain transfers to endosomal membrane → translocation of A subunit to cytosol ▪ Subunit A inactivates elongation factor EF2 → inhibition of protein synthesis → cell death ▪ Toxin expression regulated by level of iron ▫ ↑ Fe → ↓ production of toxin ▫ ↓ Fe → ↑ production of toxin Figure 55.2 A pharyngeal pseudomembrane in a child with diphtheria.



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SIGNS & SYMPTOMS ▪ Respiratory infection ▫ Sore throat; malaise; low-grade fever; dysphagia; thick, grey, isolated necrotic tissue → pseudomembrane; massive swelling of tonsils, cervical lymph nodes → “bull neck”; stridor ▪ Cutaneous infection ▫ Lesions, pain, rash, tenderness, erythema, ulceration



DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪



Gram stain Culture Elek test (differentiation of toxigenic strains) PCR



OTHER DIAGNOSTICS



▪ History, physical examination



TREATMENT MEDICATIONS



▪ Diphtheria antitoxin ▪ Antibiotic



OTHER INTERVENTIONS



▪ Prophylaxis ▫ Young children: diphtheria-tetanusacellular pertussis (DTaP) vaccine ▫ Adolescents/adults: tetanus-diphtheria (Td)/tetanus-diphtheria-pertussis (Tdap) vaccine



314 OSMOSIS.ORG



Figure 55.3 An ulcerating skin lesion on the leg caused by cutaneous diphtheria.



Chapter 55 Aerobic Rods



LISTERIA MONOCYTOGENES osms.it/listeria-monocytogenes PATHOLOGY & CAUSES ▪ Facultative intracellular bacteria, anaerobe; beta-hemolytic ▪ Capable of growing at refrigeration temperatures (0–4°C/32–39.2°F) ▪ Motile ▫ ≤ 30°C/32°F (flagella); body temperature (comet tail structures, polymerized host cells actin) ▪ Foodborne pathogen, common cause of bacterial neonatal meningitis Pathophysiology ▪ Listeria enters host cell via zipper mechanism → bacterial protein internalin binds onto cell membrane protein cadherin → releases listeriolysin O → disruption of vacuolar membrane → invasion of cytosol → actin assembling-inducing protein → polymerisation of cytoskeleton → bacteria gains motility → rapid movement through cytosol, between cells



RISK FACTORS



▪ Mild febrile gastroenteritis ▫ Immunocompetent individuals, ingestion of contaminated food (e.g. raw meat, unpasteurized dairy, seafood) ▪ Cutaneous infection ▫ Direct inoculation of skin (e.g. veterinarians, farmers handling infected animals) ▪ Invasive listeriosis ▫ Immunocompromised individuals, age (neonates, elderly), pregnancy



COMPLICATIONS ▪ Immunodeficient, elderly individuals ▫ Sepsis, meningitis, encephalitis, pneumonia, corneal ulcer



▪ Pregnant individuals ▫ Neonatal meningitis, granulomatosis infantiseptica, miscarriage, stillbirth, premature delivery with chorioamnionitis



SIGNS & SYMPTOMS ▪ Previously healthy individuals ▫ Fever, headache, diarrhea, vomiting, nausea, pustular skin lesions ▪ Individuals with weakened immune system ▫ Stiff neck, confusion, convulsions, loss of balance, cranial nerve palsies ▪ Pregnant individuals ▫ Nonspecific flu-like illness ▪ Newborns ▫ Low birth weight, irritability, fever, poor feeding, circulatory/respiratory insufficiency, pyogranulomatous lesions



DIAGNOSIS LAB RESULTS



▪ Culture ▫ Blood, cerebrospinal fluid (CSF); cervix, amniotic fluid in pregnant individuals; meconium, gastric aspirate, infected tissues (e.g. skin granulomatous lesions) in newborns



OTHER DIAGNOSTICS



▪ History, physical examination



TREATMENT MEDICATIONS



▪ Antibiotics (e.g. ampicillin, penicillin G, gentamicin)



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NOTES



NOTES



ANAEROBIC RODS MICROBE OVERVIEW ▪ Rod-shaped (bacilli) bacteria, grampositive, strict anaerobes



CLOSTRIDIUM BOTULINUM (BOTULISM) osms.it/clostridium-botulinum PATHOLOGY & CAUSES ▪ Ubiquitous presence (esp. soil, water); spore-forming; catalase negative, superoxide dismutase positive, subterminal endospore ▪ Fermentation ▫ Carbohydrates ▪ Obligate anaerobe, can tolerate small amounts of oxygen due to superoxide



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dismutase ▪ Potential bioterrorism weapon ▪ Absorption of toxin into bloodstream → spreads to nervous system → binds to presynaptic receptors → endocytosis → cleavage of SNAP-25 protein → lack of acetylcholine with impaired transduction Virulence factors ▪ Seven distinct types of neurotoxins (A–G) ▫ Type A: most potent



Chapter 56 Anaerobic Rods ▪ Heat-resistant ▫ Toxins enduring temperature of 100ºC/212°F for several hours ▪ H-antigen from flagelle Culture ▪ Chopped meat, glucose, starch medium for isolation; egg yolk agar incubation in anaerobic conditions Disease ▪ Causes disease characterized by muscle weakness, nervous system impairment ▪ Infant botulism ▫ Spores ingestion → germination in gastrointestinal (GI) tract → toxin produced in vivo ▪ Foodborne ▫ Ingestion of botulinum toxincontaminated food ▫ Average incubation period is 12–36 hours ▪ Wound botulism ▫ Wound infection with spores → toxin produced in vivo ▫ Average incubation period is 10 days ▪ Adult intestinal toxemia botulism ▫ Colonization of intestines with toxins production ▪ Iatrogenic botulism ▫ Complication of therapeutic use of botulinum neurotoxins ▪ Enteric infectious botulism ▫ C. botulinum colonizes adult GI tract



RISK FACTORS



▪ Infant botulism ▫ Honey consumption in first year of life; ingestion of dust/soil containing C. botulinum spores ▪ Foodborne botulism ▫ Home-canned, improperly preserved food; smoked fish ▪ Wound botulism ▫ IV/subcutaneous drug usage; crush injuries ▪ Enteric infectious botulism ▫ Achlorhydria/other GI diseases → colonization



COMPLICATIONS



▪ Sudden infant death syndrome (SIDS), seizures, ileus, death



SIGNS & SYMPTOMS ▪ General symptoms precede muscle weakness ▫ Abdominal pain, nausea, vomiting, lack of fever (wound botulism only type with fever) ▪ Cranial nerve impairment ▫ Dilated pupil, ptosis; double vision (due to disconjugate eye movement); ophthalmoplegia; dry mouth, difficulty swallowing; loss of facial expressions ▪ Progressive symmetrical muscle weakness descending from head ▫ Hypotonia, hyporeflexia; floppiness in infants ▫ Respiratory muscles: breathing difficulties ▪ Hyperactivation of autonomic system ▫ ↓ salivation, lacrimation, orthostatic hypotension, obstipation, urine retention



DIAGNOSIS LAB RESULTS



▪ Toxin detection/bacteria isolation



Enzyme-linked immunosorbent assay (ELISA), mass spectroscopy, polymerase chain reaction (PCR) ▪ Isolation of C. botulinum from feces, vomitus, food



OTHER DIAGNOSTICS



▪ History, physical examination



Electromyogram (EMG) ▪ Short-lasting motor unit potentials with small amplitude



OSMOSIS.ORG 317



TREATMENT MEDICATIONS



▪ IV botulinum immunoglobulin/heptavalent botulinum antitoxin ▫ Manage infection ▪ Antibiotics ▫ Manage secondary infection ▪ Cholinesterase inhibitors



OTHER INTERVENTIONS



▪ Manage infection ▫ Debridement, irrigation of wound ▫ Colon cleansing (enema, cathartics) ▪ Nasogastric tube (feeding), Foley catheter (urinary retention), intubation/mechanical ventilation



Prevention ▪ Pentavalent-botulinum-toxoid (PBT) vaccine ▫ Five dose vaccination with booster dose once per year



CLOSTRIDIUM DIFFICILE (PSEUDOMEMBRANOUS COLITIS) osms.it/clostridium-difficile PATHOLOGY & CAUSES ▪ Ubiquitously present, can be part of “normal” flora; subterminal endospore; motile ▪ Intestinal microbiota disturbance → infection, colonization of gut → produces A, B toxins → binds to receptors on intestinal wall → internalization → fusion with lysosome → toxins exit endosome → damage of cytoskeleton → cell apoptosis → inflammatory response with accumulation of inflammatory cells, fibrin, dead cells → formation of membrane-like structure (pseudomembrane) Virulence factors ▪ Enterotoxin A (TcdA), cytotoxin B (TcdB), H-antigen from flagelle Culture ▪ Agar with cycloserine, cefoxitin, fructose ▪ C. difficile-associated colitis combined with formation of pseudomembranous plaques Transmission ▪ Fecal-oral route by ingestion of spores



318 OSMOSIS.ORG



RISK FACTORS



▪ Antibiotic exposure ▫ Disturbance of intestinal microbiota ▪ Previous hospitalization ▫ ↑ risk for infection ▪ Children with neutropenia ▫ More prone to common bacterial infections requiring antibiotics → disturbance of intestinal microbiota ▪ Gastric acid suppression, > 65 years, comorbidities



COMPLICATIONS



▪ Multiple relapses, dehydration (due to excessive diarrhea)



GI complications ▪ Toxic megacolon (due to inflammation damaging muscularis propria, underlying neurons); ileus; colon perforation; intussusception; pneumatosis; ascites; sepsis Extraintestinal complications ▪ Splenic abscess; osteomyelitis



Chapter 56 Anaerobic Rods



SIGNS & SYMPTOMS ▪ Watery diarrhea (most common) with mucus/blood ▪ Abdominal distension, cramps ▪ Malaise ▪ Fever



DIAGNOSIS DIAGNOSTIC IMAGING Sigmoidoscopy/colonoscopy ▪ Visualization of plaques



LAB RESULTS



SURGERY



▪ Colectomy ▫ In persons with acute abdomen, refractory colitis, fulminant colitis



OTHER INTERVENTIONS



▪ End previous antibiotic use ▪ Second relapse: pulse therapy ▪ Recurrent: biological therapies ▫ Fecal microbiota transplant: transplantation of microbiota from healthy individual ▪ Electrolytes, fluids replacement; appropriate nutrition ▪ Prevention of hospital-acquired infection ▫ Infection control protocol, antibiotic stewardship



WBCs ▪ ↑ white blood cells Stool analysis ▪ Presence of blood/mucus ▪ Stool culture ▪ Enzyme immunoassay test ▫ Detection of glutamate dehydrogenase antigen ▪ Toxin detection ▫ Enzyme immunoassay, real-time PCR ▪ Cell culture cytotoxicity assay ▪ Biomarkers ▫ Differentiation between colonization, actual disease; ↑ fecal cytokines, CXCL5, phosphorylated p38



Figure 56.1 The gross pathological appearance of the colonic mucosa in psuedomembranous colitis.



TREATMENT MEDICATIONS



▪ Mild disease: oral metronidazole ▪ Severe disease: oral vancomycin ▪ Complications: combination of oral vancomycin, IV metronidazole ▪ Second relapse: oral vancomycin tapered ▪ Recurrent: probiotics



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CLOSTRIDIUM PERFRINGENS osms.it/clostridium-perfringens PATHOLOGY & CAUSES ▪ Ubiquitous in nature, also part of human microbiota; subterminal endospore; nonmotile Virulence factors ▪ Divided into subtypes A–E ▪ Produces 12 toxins ▪ Alpha ▫ Enzyme lecithinase splits lecithin → ↑ vascular permeability → cell destruction ▫ Responsible for gas gangrene, hemolysis ▪ Beta ▫ Formation of selective pores → ↑ permeability with cell destruction ▫ Responsible for enteritis necroticans; deactivated by trypsin ▪ Epsilon ▫ Pores form on cells → destruction ▪ Iota ▫ AB toxin: enzyme (A), binding (B) domain ▫ Destruction of cells through affection of cytoskeleton Culture ▪ Growth on tryptose sulfite cycloserine agar Clostridial gas gangrene ▪ Saprophytic anaerobic bacteria → clostridial gas gangrene due to tissue infection/food poisoning through ingestion ▪ Disease characterized by necrosis, gangrene due to infection of skin, deep tissues ▪ Bacteria produces gas → characteristic crepitation sound during palpitation ▪ Divided into ▫ Traumatic: wound → spore inoculation → bacteria growth in appropriate anaerobic conditions → production of toxins → destruction of fibroblasts,



320 OSMOSIS.ORG



blood cells, muscle cells → necrosis of muscles, subcutaneous fat with blood vessels thrombosis ▫ Postoperative: after interventions on intestinal system ▫ Spontaneous: due to immune system weakness/intestinal diseases Food poisoning ▪ Begins 6–24 hours after ingestion ▪ Infection of food with spores → food standing temperature 30–50ºC/86–122°F → development of vegetative form → ingestion of infected food → toxin production → ↓ glucose absorption, ↑ water, sodium, chloride secretion → damage of intestinal epithelium Enteritis necroticans ▪ Inflammation of jejunum, ileum; type of food poisoning in persons who lack trypsin



RISK FACTORS



▪ Gas gangrene: begins 1–4 days after infection ▫ Traumatic: injury during war/natural disaster; car crash ▫ Postoperative: GI/biliary surgery; septic abortion ▫ Spontaneous: colorectal adenocarcinoma; neutropenic states (e.g. AIDS, chemotherapy); intestinal diseases ▪ Food poisoning: improper food-handling ▪ Enteritis necroticans: improper nutrition (e.g. too many sweet potatoes); trypsin inhibitors → ascariasis



COMPLICATIONS



▪ Disseminated intravascular coagulation; hemodynamic shock, hypotension, renal failure; systemic hemolysis; peritonitis; sepsis; death



Chapter 56 Anaerobic Rods



DIAGNOSIS



SIGNS & SYMPTOMS Gas gangrene ▪ Two types ▫ Cellulitis: infection of necrotic skin; crepitation sounds ▫ Clostridial myonecrosis: infection, destruction of muscles, adjacent tissue ▪ Paleness, serosanguineous exudate, pain, swelling, tenderness at injury site → color changes to bronze → purple bullae with green/black discoloration due to necrosis ▪ Characteristic sweet odor ▪ ↑ heart rate with low-grade fever Food poisoning ▪ If only toxins ingested ▫ Asymptomatic/diarrhea ▪ If vegetative form ingested ▫ Watery diarrhea without blood/mucus; abdominal cramps, last > 24 hours Enteritis necroticans ▪ Abdominal cramps; diarrhea; vomiting; meteorism (excessive gas production in intestines); blood in stool; fever



DIAGNOSTIC IMAGING X-ray ▪ Gas gangrene: detection of gas in softtissue ▪ Enteritis necroticans: small bowel dilatation with presence of gas



LAB RESULTS



▪ Gas gangrene: molecular methods for detection of alpha toxins; ELISA, PCR ▪ Food poisoning: detection of toxins in feces; PCR



Biopsy ▪ Gas gangrene: necrosis of myocytes, connective tissue with small number of neutrophils



OTHER DIAGNOSTICS



▪ Gas gangrene: physical examination; characteristic discoloration, odor, crepitation sound



TREATMENT MEDICATIONS



▪ Gas gangrene: antimicrobial therapy (combination of penicillin G, clindamycin) ▪ Enteritis necroticans: penicillin G/ metronidazole; destruction of bacteria



SURGERY



Figure 56.2 An individual with gas gangrene of the right leg. The causative agent is Clostridium perfringens.



▪ Gas gangrene: removal of dead tissue; hyperbaric oxygen (augments neutrophil, ↓ clostridial exotoxin, spore production); amputation ▪ Enteritis necroticans: resection of necrotic intestinal parts



OTHER INTERVENTIONS



▪ Food poisoning: oral/IV rehydration



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CLOSTRIDIUM TETANI (TETANUS) osms.it/clostridium-tetani PATHOLOGY & CAUSES ▪ Ubiquitously present in soil; resistant to chemical/heat disinfection; terminally present endospore; motile ▪ Anaerobic rod causes nervous system disorder (i.e. tetanus) ▪ Injury → infection with spores → development of vegetative form in appropriate anaerobic conditions → production of exotoxins (tetanospasmin) → blood/lymphatic transmission → spread to neurons through neuromuscular junction → retrograde transport to spinal cord → endocytosis into inhibitory Renshaw cell interneurons → exotoxins protease activity cleaves SNARE proteins → block of glycine, gamma-aminobutyric acid (GABA) neurotransmitter-filled vesicles release at neuromuscular junction → overactivation of muscles → muscle spasms Virulence factors ▪ Two toxins: tetanolysin (relatively unknown function); tetanospasmin (responsible for clinical presentation of tetanus) ▪ H-antigen from flagelle Culture ▪ Oxygen-reduced blood agar with anaerobic incubation



TYPES



▪ Four types of tetanus ▫ Generalized: affects whole musculature, from head downwards ▫ Localized: affects only area near injury ▫ Cephalic: cranial nerves affected due to head/neck injury ▫ Neonatal: tetanus occurring in neonates via infection of umbilical stump



322 OSMOSIS.ORG



RISK FACTORS



▪ Deep puncture wounds with/without splinters, crush injuries, middle ear infections, frostbites, burns ▪ IV/subcutaneous drug abuse ▪ Infected diabetic wounds ▪ Septic abortion ▪ Umbilical stump infection via contaminated instruments, hands, cultural practices (e.g. application of cow dung, ghee) ▪ Lack of vaccination/immunization



COMPLICATIONS



▪ Cardiac arrest ▫ Due to ↑ catecholamine levels, brainstem damage ▪ Palsies of phrenic, laryngeal nerves due to toxic effect ▪ Respiratory muscles ▫ Apnea ▪ Vertebral fractures/intramuscular bleeding (due to opisthotonus)



SIGNS & SYMPTOMS Generalized ▪ Masseter muscle spasm → trismus/“lockjaw” → severe generalized muscle contractions ▫ Risus sardonicus: characteristic sarcastic-like facial expression due to facial muscles contraction ▫ Opisthotonus: arched back due to contraction of back muscles ▪ Abdominal respiratory muscles, diaphragm: breathing arrest Localized ▪ Weakness, pain of muscles/extremites in proximity of injury ▪ Stiffness of affected muscles occurring in following days, lasting up to few months ▪ May progress into generalized form



Chapter 56 Anaerobic Rods Cephalic ▪ Palsy of facial nerve ▪ Difficulty swallowing ▪ Weakness of extraocular muscles Neonatal ▪ Sucking difficulty in first days of life ▪ Generalization, opisthotonus may occur Sympathetic overactivity ▪ ↑ heart rate, arrhythmias ▪ Agitation, diaphoresis ▪ ↑/↓ blood pressure ▪ Fever ▫ Due to overactivity/superinfection



TREATMENT MEDICATIONS



▪ Human tetanus immunoglobulin (TIG)/ intravenous immunoglobulins (IVIG) ▫ Neutralization of toxin ▪ Antibiotics ▫ Penicillin, cephalosporins, tetracyclines, metronidazole, vancomycin ▪ Benzodiazepines ▫ Muscle relaxation, sedation ▪ Muscle relaxants ▫ Pancuronium/vecuronium ▪ Labetalol ▫ Autonomic hyperactivity management



OTHER INTERVENTIONS



Figure 56.3 This body posture is known as opisthotonus and is caused by the Clostridium tetani toxin.



▪ Active immunization with tetanus/ diphtheria toxoid (Td) ▪ Respiratory support if needed ▪ Prevention ▫ Primary: vaccination at two months of life, with booster doses at 4, 6, 12–18 months, 4–6, 11–12 years (booster doses every ten years later); passive immunization in immunocompromised ▫ Secondary: vaccination, antitoxin after injury ▫ Tertiary: vaccination, antitoxin after tetanus presentation



DIAGNOSIS OTHER DIAGNOSTICS



▪ History, physical investigation ▪ Spatula test ▫ Touching oropharynx with spatula causes reflex biting due to masseter spasm



EMG ▪ Loss/shortening of silent interval between action potentials with continuous discharge from motor units



OSMOSIS.ORG 323



324 OSMOSIS.ORG



NOTES



NOTES



ARENAVIRIDAE MICROBE OVERVIEW Taxonomy ▪ Zoonotic virus family ▫ Associated with hemorrhagic fevers, meningoencephalitis ▪ Comprises > 20 viruses ▪ Groups ▫ Old World viruses (e.g. lymphocytic choriomeningitis virus, Lassa, Lujo) ▫ New World viruses (e.g. Junin, Machupo) Morphology ▪ Single-stranded RNA virus ▪ Ribosomes produce sand-like granular appearance under electron microscopy ▫ Latin: arena = sand ▪ Shape varies: pleomorphic–spherical



▪ Enveloped in lipid membrane with glycoprotein spikes ▫ Lipids in membrane → inactivation susceptibility by organic solvents/ detergents ▫ Also inactivated by temperatures > 55°C/131°F, ↑ ↓ pH, UV light, gamma irradiation Transmission ▪ Reservoir ▫ Rodents shed virus in urine, feces, saliva, nasal secretion ▪ Transmission ▫ Ingestion, direct contact, aerosolizedparticle inhalation → entry into cell by GP1 glycoprotein attachment to cellular receptors → systemic dissemination



LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCMV) osms.it/LCMV PATHOLOGY & CAUSES ▪ Arenavirus ▫ Causes febrile illness with central nervous system (CNS) involvement, congenital infection ▪ Reservoir ▫ Mice (M. musculus/M. domesticus); occasional human disease outbreak related to pet hamster/guinea pig ▪ Transmission ▫ Ingestion, aerosolized-particle



inhalation, transplacentally (infected mother → fetus) ▪ Post-transmission → 7–14 days incubation → replication in lungs → hematogenous dissemination → strong neurotropism (infects meninges, choroid plexus, ventricular ependyma)



RISK FACTORS



▪ Infected rodent contact; dwelling/working in rodent habitats ▪ ↑ risk in substandard housing (e.g. mobile homes, inner-city housing), barns/



OSMOSIS.ORG 325



outbuildings ▪ Peak incidence: autumn, winter



COMPLICATIONS



▪ Encephalitis, aseptic meningitis ▪ Transplacental infection: spontaneous abortion, neonatal neurologic deficits, chorioretinitis, seizures, periventricular calcifications, hydrocephalus, microcephaly ▪ Rarely: orchitis, parotitis, myocarditis



SIGNS & SYMPTOMS ▪ May be asymptomatic/mild flu-like symptoms ▪ Prodrome: headache (retro-orbital), nausea, vomiting ▪ Meningitis: fever, rigors, malaise, myalgia, arthralgia anorexia, photophobia ▪ Encephalitis: focal seizures, cranial nerve palsies, papilledema



326 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS ▪ Cerebrospinal fluid (CSF) ▫ ↑ lymphocytes, ↑ protein, ↓ glucose, negative Gram stain Microbe identification ▪ Viral culture, polymerase chain reaction (PCR) Serology ▪ ↑ antibody titer (IgM, IgG)



TREATMENT OTHER INTERVENTIONS Prevention ▪ Rodent control



NOTES



NOTES



BUNYAVIRUSES MICROBE OVERVIEW ▪ Bunyaviruses: RNA virus order ▪ AKA Bunyavirales Genetic material ▪ Negative-sense, single-stranded RNA ▪ Tripartite genome ▫ Large (L) segment (encodes RNApolymerase); medium (M) segment (encodes surface glycoproteins); small (S) segment (encodes nucleocapsid proteins)



Morphology ▪ Enveloped (outer lipid membrane) ▪ Spherical ▪ Size: 90–100nm Replication ▪ Host cytoplasm replication Transmission ▪ Vector-borne, person-to-person, contact with reservoir (species-dependent) ▪ Reservoirs: arthropods, mammals (especially rodents



Figure 58.1 Families of the Bunyavirus order and associated clinical syndromes.



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HANTAVIRUS osms.it/hantavirus PATHOLOGY & CAUSES ▪ Single-stranded RNA virus genus → causes severe renal/pulmonary disease ▪ AKA Orthohantavirus ▪ Hantaviridae family ▪ Reservoir ▫ Rodents (mice, voles, shrews, rats) ▪ Incubation period ▫ 9–33 days ▪ Tissue tropism ▫ Lymphoid organ, heart, lung, kidney vascular endothelium ▪ Hantavirus inhalation → lung phagocytosis → transport to lymph nodes → hantavirus enters epithelial cells using beta-3 integrins → ↑ vascular permeability → dissemination ▪ Immune response ▫ CD4+/CD8+ cytotoxic T cells, dendritic cells ▪ High-prevalence regions ▫ China, Russia, Europe Associated clinical syndromes ▪ Hemorrhagic fever + renal syndrome (“Old World” AKA Asia, Europe)



328 OSMOSIS.ORG



▪ ↑ vascular permeability → ↓ blood pressure → kidney endothelial dysfunction ▪ Hantavirus cardiopulmonary/pulmonary syndrome (“New World” AKA North, South America) ▪ ↑ vascular permeability → non-cardiogenic pulmonary edema



CAUSES



▪ Rodents (urine/feces/saliva particle inhalation); person-to-person (rare)



RISK FACTORS ▪ ▪ ▪ ▪



Rural indoor spaces (e.g. barns) Wild rodent exposure Smoking → Puumala virus infection risk ↑ risk among biological males



COMPLICATIONS



▪ Cardiogenic shock, pulmonary edema, arrhythmia, renal insufficiency, acute kidney injury (AKI), coagulopathy, disseminated intravascular dissemination (DIC), hemorrhage; high mortality rate



Chapter 58 Bunyaviruses



SIGNS & SYMPTOMS



Urinalysis ▪ Renal syndrome: proteinuria, hematuria



Pulmonary syndrome ▪ Systemic ▫ Fever, chills, myalgia, headaches, weakness ▪ Nausea, vomiting, diarrhea, abdominal pain, cough, oliguria ▪ Sometimes conjunctivitis, flushing, petechiae



Tissue biopsy ▪ Kidneys: edema, perirenal hemorrhage, tubular destruction ▪ Lungs: edema, mononuclear cell infiltrates, tracheal/pleural fluid, hyaline deposits ▪ Lymphoid organs: mononuclear cell infiltrates



Hemorrhagic fever + renal syndrome ▪ Fever, hypotension, malaise, headache, diffuse hemorrhage (e.g. petechiae, melena, ecchymoses), abdominal/loin pain, nausea/ vomiting, oliguria



TREATMENT



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Lungs: bilateral pulmonary infiltrates, pleural effusion Abdominal ultrasound ▪ Kidneys: ↑ size, perirenal fluid



LAB RESULTS



MEDICATIONS



▪ Renal syndrome antivirals ▫ Nucleoside analogue



OTHER INTERVENTIONS



▪ ICU monitoring, mechanical ventilation ▪ Severe cases ▫ Extracorporeal membrane oxygenation (ECMO), dialysis, platelet transfusion



Prevention ▪ Potential rodent nesting site removal (e.g. debris, garbage) ▪ Closed spaces ventilation ▪ Avoid rodent contact



▪ Reverse-transcriptase polymerase chain reaction (RT-PCR)



Tests ▪ Diagnostic triad: thrombocytopenia, ↑ immunoblasts (> 10%), left-shifted granulocytic series ▪ ↑ lactate dehydrogenase (LDH), serum lactate ▪ ↑ liver enzymes ▪ ↑ C-reactive protein ▪ Severe ▫ ↑ hemoglobin, hematocrit; ↓ albumin; altered coagulation tests ▪ Renal syndrome ▫ ↑ serum creatinine, ↓ glomerular filtration rate (GFR) Serologic tests ▪ IgM/IgG detection through ELISA, strip immunoblot, Western blot, immunofluorescence



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NOTES



NOTES



CALICVIRUSES MICROBE OVERVIEW Genetic material ▪ Single-stranded RNA viruses



Morphology ▪ Small, icosahedral, non-enveloped



Taxonomy ▪ Genera: Norovirus, Sapovirus, Lagovirus, Nebovirus, Vesivirus



Transmission ▪ Ingestion → small intestine → villi infection → malabsorption → osmotic diarrhea



NOROVIRUS osms.it/norovirus PATHOLOGY & CAUSES ▪ Virus known as viral gastroenteritis agent ▫ AKA Norwalk virus ▪ Classified into seven genogroups ▫ I, II, IV → cause human disease Transmission ▪ Fecal-oral ▫ Infected individual: virus in stool < four weeks ▫ Immunocompetent individual: peak concentration 2–5 days post-infection ▪ Direct person-to-person ▪ Contaminated food, water, fomite ▫ Contaminated water in leafy vegetables, oysters, raspberries ▫ Prepared food → contaminated at point of service (e.g. salads, sandwiches) ▪ Droplet spread from vomitus Pathogenesis ▪ Ingestion → small intestine villi infection → disruption of epithelium, anion transport system → malabsorption of D-xylose, fat → osmotic diarrhea



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Small intestine histopathology ▪ Villous shortening, epithelial vacuolization, crypt hypertrophy, microvilli brush border loss, intercellular space widening, lymphocytic proliferation of lamina propria



RISK FACTORS



▪ Blood group antigens ▫ Viral binding preference for A, B antigens genogroup-determinant ▪ Close-quarter residence (e.g. nursing homes, cruise ships)



COMPLICATIONS



▪ Severe dehydration, malnutrition, persistent disease (immunosuppressed individuals)



SIGNS & SYMPTOMS ▪ 12–48 hour incubation period ▪ Acute onset vomiting ▫ Nonbloody, nonbilious ▪ Watery diarrhea ▫ Nonbloody ▪ Fever, abdominal pain, myalgia, malaise



Chapter 59 Calicviruses



DIAGNOSIS ▪ History ▫ Pathogen contact, contaminated food source



LAB RESULTS



▪ Reverse transcriptase polymerase chain reaction (RT-PCR) ▫ Stool



OTHER INTERVENTIONS



▪ Fluid maintenance, repletion ▫ From oral intake → IV fluids ▪ Electrolyte balance



Prevention ▪ Hand hygiene ▪ Environmental fecal contact decontamination ▪ Limited pathogen contact



TREATMENT ▪ No cure



MEDICATIONS



▪ Antimotility agents ▪ Antiemetics ▫ Reserved for individuals unable to take oral hydration



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NOTES



NOTES



CENTRAL NERVOUS SYSTEM INFECTIONS



MICROBE OVERVIEW PATHOLOGY & CAUSES ▪ Rare infections of central nervous system (CNS) by ameba, parasites



RISK FACTORS



▪ Immunosuppression (Acanthamoeba, Toxoplasmosis gondii), immersion in infested water (Naegleria fowleri)



SIGNS & SYMPTOMS ▪ Fever, headache, seizures, focal neurological signs, mental status change



DIAGNOSIS LAB RESULTS



▪ Presence of infectious agent via microscopy, culture, polymerase chain reaction (PCR), presence of specific antibodies



Granulomatous amebic encephalitis ▫ Brain biopsy: trophozoites in perivascular space and thick walled cysts, PCR/DNA probes may show Acanthamoeba



Primary amoebic meningoencephalitis ▪ Lumbar puncture ▫ CSF microscopy: motile amebae/ fluorescent antibody staining ▫ CSF PCR: Naegleria fowleri DNA ▫ CSF culture: Naegleria fowleri can be grown on nonnutrient agar coated with Escherichia coli Toxoplasmosis ▪ PCR (blood, CSF): Toxoplasma gondii DNA (inactive cysts may evade detection) ▪ Antibody titres ▫ IgG: evidence of current/previous infection ▫ IgM: occur in weeks after initial infection ▫ Antibody avidity testing: affinity for antigen increases with duration of infection ▪ Sabin–Feldman dye test: high titers → acute infection ▪ Tissue biopsy: tachyzoites in tissues/ smears



TREATMENT MEDICATIONS



▪ Antifungal, antiparasitic agents



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ACANTHAMOEBA osmosis.org/learn/acanthamoeba PATHOLOGY & CAUSES Genus of amebae ▪ Single-celled eukaryotes ▪ Environmentally ubiquitous organisms ▫ Acanthamoeba spp. isolated from soil, air, fresh water, sewage, seawater, chlorinated swimming pools, domestic tap water, bottled water, hospitals, airconditioning units, contact lens cases ▪ Life stages ▫ Metabolically active trophozoite ▫ Dormant stress resistant cyst ▪ Generally free living bacterivores, can cause human infection (acanthamebiasis) Granulomatous amoebic encephalitis ▪ Infection associated with immunosuppression (e.g. diabetes, HIV/AIDS, hematological malignancy, malnutrition, hepatic cirrhosis, chronic renal failure, systemic lupus, chemotherapy) ▪ Parasite enters body through cuts in skin/ inhalation → hematogenous spread to CNS → invasion of connective tissue → inflammatory response → neuronal damage Endosymbiosis, secondary infection ▪ Several human pathogens infect, replicate within Acanthamoeba ▫ Legionella pneumophila, Pseudomonas aeruginosa, some strains of E. coli, Staphylococcus aureus ▪ Replication inside Acanthamoeba → enhanced growth in human macrophages, increased antibiotic resistance → more virulent, fulminant infections



SIGNS & SYMPTOMS ▪ Fever, headache, seizures, focal neurological signs (e.g. cranial nerve palsies), mental status change (e.g.



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confusion), sepsis → progressive worsening over weeks/months → death



DIAGNOSIS DIAGNOSTIC IMAGING Brain CT/MRI ▪ Meningeal exudate, pseudotumoral lesions, multiple space-occupying lesions with ring enhancement



LAB RESULTS Lumbar puncture ▪ Often contraindicated due to risk of herniation associated with mass lesions ▪ Analytical findings generally nonspecific ▫ Intermediate elevations in white blood cell count, elevated protein, decreased glucose levels ▪ Giemsa staining, microscopy ▫ Trophozoites Tissue biopsy ▪ Brain biopsy ▫ Trophozoites in perivascular space, thick-walled cysts on light microscopy; PCR/DNA probes may reveal Acanthamoeba ▫ Immunocompetent host: granulomatous lesions ▫ Severely immunosuppressed host: insufficient CD+ve T-cells to mount granulomatous response → perivascular cuffing with amoebae in necrotic tissue ▪ If other organs involved (e.g. skin, conjunctiva, lungs) ▫ Trophozoites



Chapter 64 Central Nervous System Infections



TREATMENT MEDICATIONS



▪ Current treatment regimes uncertain (based on in vitro studies, case reports) ▫ Antifungal, antiparasitic agents in combination



▫ Empiric antifungal regime: miltefosine, fluconazole, pentamidine isethionate +/- trimethoprim-sulfamethoxazole, metronidazole, macrolide antibiotic



SURGERY



▪ Single cerebral lesions ▫ Surgical resection



NAEGLERIA FOWLERI (PRIMARY AMEBIC MENINGOENCEPHALITIS) osmosis.org/learn/naegleria_fowleri PATHOLOGY & CAUSES ▪ Thermophilic, free-living ameba, found in bodies of warm (stagnant), freshwater



TYPES



▪ Life cycle, three forms 1. Cyst ▫ Immotile, dormant, survival phase ▫ Smooth, single-layered cell wall with single nucleus, naturally resistant to environmental factors ▫ Formation of cysts induced by unfavorable conditions such as food shortage, overcrowding, desiccation, accumulation of waste products, cold temperatures (< 10° celsius) 2.Trophozoite (ameboid) ▫ Feeding, reproductive, infective phase ▫ Transformation into trophozoites occurs around 25° celsius ▫ Reproduction occurs via binary fission (single cell divides into two offspring), optimal temperature 42° celsius 3.Biflagellate (two flagella) ▫ Mobile, infective phase ▫ Pear-shaped body with two flagella ▫ Flagellate phase occurs when ameba encounters change in fluid ionic



concentration → allows movement to suitable environment ▪ In human tissues Naegleria fowleri exists as ameboid trophozoite; flagellate form may be found in CSF/during initial nasal insufflation Primary amoebic meningoencephalitis ▪ AKA naegleriasis ▪ Rare infection, fatality rate > 95% ▪ Mechanism of entry ▫ Insufflated into sinuses during waterbased activities → attaches to olfactory epithelium → follows olfactory axon through cribiform plate → migration to olfactory bulbs → spread throughout brain → diffuse meningoencephalitis ▪ In tissues, Naegleria fowleri feeds via two mechanisms; feeding on neurological tissue → necrosis, bleeding ▫ Phagocytosis of red, white blood cells ▫ Piecemeal consumption of astrocytes, neurons via amoebostome (actin-rich sucking apparatus extended from cell surface)



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SIGNS & SYMPTOMS ▪ Symptoms appear 1–9 days after nasal exposure → death likely follows within two weeks ▪ Change in sensation of taste, smell; headache, fever, nausea, stiff neck, seizures, coma



DIAGNOSIS DIAGNOSTIC IMAGING Brain imaging ▪ Initially unchanged ▫ Reveals associated complications Leptomeningeal enhancement, diffuse subarachnoid hemorrhage, oedema, hydrocephalus, multiple cerebral infarcts



LAB RESULTS



▪ Lumbar puncture ▫ CSF microscopy: motile amebae/ fluorescent antibody staining ▫ CSF PCR: Naegleria fowleri DNA ▫ CSF culture: Naegleria fowleri can be grown on nonnutrient agar coated with E. coli → drop of CSF of infected individual added, incubated at 37° celsius; clearing of E. coli in thin tracks indicative of trophozoite feeding → likely infection



TREATMENT MEDICATIONS: ▪ Amphotericin B +/- fluconazole ▪ Miltefosine



TOXOPLASMA GONDII (TOXOPLASMOSIS) osmosis.org/learn/toxoplasma_gondii PATHOLOGY & CAUSES ▪ Obligate intracellular parasite capable of infecting nearly all warm-blooded animals ▫ Only definitive hosts: biological family Felidae (e.g. house cats) ▪ 30–50% of global population exposed, may be chronically infected Life cycle ▪ Sexual reproduction ▫ Consumes infected animal meal (e.g. mouse) → parasite survives transit through stomach → infects small intestinal epithelial cells → parasites undergo sexual development, reproduction → millions of thick-walled, zygote-containing, oocytes produced ▪ Felid shedding ▫ Infected epithelial cells rupture →



356 OSMOSIS.ORG



release oocytes into intestinal lumen → shedding in feces → spread via soil, water, food ▫ Oocysts highly resilient; can survive, remain infective for months in cold, dry climates ▪ Infection of intermediate host ▫ Ingestion of oocysts by warm blooded animals (e.g. humans) → oocyst wall dissolved by proteolytic enzymes in stomach, small intestine → frees sporozoites from within oocyst → parasites invade intestinal epithelium, surrounding cells → differentiation into tachyzoites (motile, quickly-multiplying phase) ▪ Asexual reproduction in intermediate host ▫ Tachyzoites replicated inside specialized vacuoles until host cell dies, ruptures → release, hematogenous spread of tachyzoites to all tissues



Chapter 64 Central Nervous System Infections ▪ Formation of tissue cysts ▫ Host immune response → tachyzoite conversion → bradyzoites (semidormant, slowly dividing stage) → inside host cells known as tissue cysts → can form in any organ; predominantly brain, eyes, striated muscle (including cardiac muscle) ▫ Consumption of tissue cysts in meat from infected animal ▫ Primary means of infection (e.g. pork, lamb) ▫ Tissue cysts maintained in host tissue for remainder of life via periodic cyst rupture, re-encysting



RISK FACTORS



▪ Consumption of raw/undercooked meat; ingestion of contaminated water, soil/ vegetables; previous blood transfusion/ organ transplant; transplacental transmission



COMPLICATIONS



▪ Toxoplasmic chorioretinitis ▫ AKA ocular toxoplasmosis ▫ Common cause of posterior segment infection ▫ Majority of cases acquired; also strongly associated with congenital infection



SIGNS & SYMPTOMS ▪ Initial infection (immunocompetent host) ▫ Mild flu-like symptoms (e.g. swollen lymph nodes, headache, fever, fatigue, muscle aches, pains) ▪ Congenital infection ▫ Chorioretinitis (unilateral decrease in visual acuity), hydrocephalus, seizures, lymphadenopathy, hepatosplenomegaly ▪ Chronic/latent infection ▫ Asymptomatic in healthy hosts ▪ Immunocompromised host ▫ Active infection (toxoplasmosis) ▫ Headache, confusion, poor coordination, seizures, cough, dyspnea ▫ Reactivation of latent infection: worsening of immunosuppression due to progression of underlying disease (e.g. HIV/AIDS, iatrogenic immunosuppression) → loss of immune balance → progression to active infection



DIAGNOSIS DIAGNOSTIC IMAGING CT scan with contrast ▪ Multiple 1–3 cm hypodense regions with nodular/ring enhancement predominantly in basal ganglia, corticomedullary junction T2 weighted MRI ▪ Iso/hyper-intense lesions surrounded by perilesional edema Fundoscopy ▪ Toxoplasmic chorioretinitis ▫ Unifocal area of acute-onset inflammation adjacent to old chorioretinal scar



Figure 8.1 A histological section of the cerebrum demonstrating cerebral toxoplasmosis. There are bradyzoites present and a mixed inflammatory infiltrate which includes eosinophils.



LAB RESULTS PCR (blood, CSF) ▪ Toxoplasma gondii DNA (inactive cysts may evade detection) Antibody titres ▪ IgG (persist for life)



OSMOSIS.ORG 357



▫ Evidence of current/previous infection ▪ IgM (acute infection) ▫ Occur in weeks after initial infection, remain detectable for months ▫ Antibody avidity testing may clarify nature of infection; early toxoplasmaspecific IgG has low affinity for toxoplasma antigen; affinity increases with duration of infection ▪ Sabin–Feldman dye test ▫ Requires specialised laboratories (live Toxoplasma gondii required); high titers → acute infection ▫ Patient serum treated with Toxoplasma trophozoites + complement, incubated → methylene blue added (membrane stain) → if anti-toxoplasma antibodies present, complement facilitates lysis of parasite membrane → no staining of lysed membrane ▫ No antibodies in serum → intact membranes → membrane stained blue under microscopy ▪ Tissue (brain/lymph node/muscle) biopsy ▫ Tachyzoites (acute infection) may be demonstrated in tissues/smears



Figure 8.2 An MRI scan of the head in the axial plane demonstrating cerebral toxoplasmosis. There are numerous peripherally enhancing nodules in the basal ganglia.



358 OSMOSIS.ORG



TREATMENT MEDICATIONS



▪ Prevention ▫ Trimethoprim/sulfamethoxazole ▪ Acute infection ▫ Antimalarials: pyrimethamine ▫ Antibiotics: sulfadiazine with pyrimethamine, clindamycin, spiramycin ▪ Latent infection ▫ Cysts not sufficiently penetrated by traditional therapy ▫ Atovaquone (antimalarial) +/clindamycin (lincomycin antibiotic) ▪ Toxoplasmic chorioretinitis ▫ Sight-threatening lesions ▫ Triple therapy: pyrimethamine, sulfadiazine, folinic acid ▫ Mono-antibiotic therapy: trimethoprimsulfamethoxazole, clindamycin, spiramycin



NOTES



NOTES



CESTODES (TAPEWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Human gastrointestinal tract parasites; AKA tapeworms ▫ Adult tapeworms live in intestines ▫ Larvae live in different tissue (brain, liver, eye, etc.) ▪ Tripartite body ▫ Head/scolex (contain suckers, hooks/ attachment organs) ▫ Thin neck ▫ Trunk (made of numerous proglottids) ▪ Hermaphroditic ▫ Each proglottid has male, female organs ▪ Transmission ▫ Egg/larvae-contaminated water/food ingestion



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Poor hygiene Low socioeconomic status Raw/undercooked fish/meat Livestock exposure Living/travelling in endemic areas



COMPLICATIONS ▪ ▪ ▪ ▪



338 OSMOSIS.ORG



Cysticercosis (Taenia) Cyst rupture Intestinal obstruction Malabsorption → vitamin B12 deficiency → megaloblastic anemia



SIGNS & SYMPTOMS ▪ Tapeworm species-dependent ▪ Can be asymptomatic, abdominal pain. nausea/vomiting, weight loss



DIAGNOSIS DIAGNOSTIC IMAGING MRI, CT scan, ultrasound ▪ Cyst presence



LAB RESULTS



▪ Microscopy ▫ Identify eggs/proglottids in stool ▪ Complete blood count (CBC), serology



TREATMENT ▪ Tapeworm species-dependent



MEDICATIONS ▪ Anthelmintics



Chapter 61 Cestodes (Tapeworms)



DIPHYLLOBOTHRIUM LATUM osms.it/diphyllobothrium-latum PATHOLOGY & CAUSES ▪ AKA fish tapeworm ▪ Longest human-infecting tapeworm (4–15m/13–49ft) ▪ Causes diphyllobothriasis in humans ▪ Proglottids ▫ Width > length ▪ Competes for vitamin B12 → vitamin B12 deficiency



CAUSES



▪ Raw/undercooked fish → larvae ingestion



COMPLICATIONS



▪ Tapeworms → mechanical intestinal obstruction ▪ Malabsorption → weight loss ▪ Vitamin B12 deficiency → megaloblastic anemia



SIGNS & SYMPTOMS ▪ Vitamin B12 deficiency ▫ Impaired oxygen delivery: fatigue, activity intolerance, pallor, compensatory mechanisms (↑ heart rate, bounding pulse) ▫ Neuronal demyelination: numbness, tingling, weakness ▪ Weight loss ▪ Abdominal pain



DIAGNOSIS LAB RESULTS



▪ Megaloblastic anemia; e.g. increased mean corpuscular volume (MCV) ▪ Microscopy ▫ Identify eggs/proglottids in stool ▪ ↓ serum vitamin B12



TREATMENT MEDICATIONS ▪ Anthelmintics



OSMOSIS.ORG 339



ECHINOCOCCUS GRANULOSUS (HYDATID DISEASE) osms.it/echinococcus-granulosus PATHOLOGY & CAUSES ▪ Parasitic infection caused by E. granulosus ▫ AKA echinococcosis ▪ Produce protoscoleces ▫ Juvenile scolex invaginated in cysts ▫ Tapeworm maturation in definitive host’s intestine ▪ Humans (incidental hosts); herbivores (intermediate hosts); canids (definitive hosts)



CAUSES



▪ Viable parasite egg-containing food consumption



RISK FACTORS



▪ Parasite/egg-contaminated food/water ingestion ▪ Close contact with infected animals



Figure 61.2 The gross pathology of hydatid cysts excised from the lung.



340 OSMOSIS.ORG



Figure 61.1 A scolex of the organism Echinococcus granulosus, the causative agent of hydatid disease.



COMPLICATIONS



▪ Arise as cysts migrate, grow in size, rupture ▫ Liver: eosinophilia, pruritus, jaundice, urticaria, liver abscess, anaphylaxis ▫ Peritoneal cavity: peritonitis, pancreatitis ▫ Pleural space: abscess formation → pneumothorax/pleural effusion ▫ Bronchial tree: respiratory distress, hemoptysis ▫ Heart: cardiomegaly/pericardial effusion ▫ Kidney: glomerulonephritis ▪ Large cyst compression effect ▫ Heart: large cyst in liver → compression of right heart ▫ Cerebral/spinal cord (CNS): neurological deficits ▫ Liver/biliary tree cysts: obstructive jaundice/cholangitis; venous drainage obstruction → portal hypertension → Budd–Chiari syndrome (abdominal pain, ascites, hepatomegaly)



Chapter 61 Cestodes (Tapeworms)



SIGNS & SYMPTOMS ▪ Initially asymptomatic ▪ Depend on affected organs ▫ Liver: right upper quadrant pain, hepatomegaly, nausea, vomiting ▫ Lungs: cough, chest pain, dyspnea, hemoptysis ▪ Other organs (rarely affected) ▫ Heart: jugular venous distention, dyspnea ▫ Musculoskeletal: diffuse pain, pathologic fractures ▫ Kidney: hematuria, flank pain ▫ CNS: headache, motor deficit, seizure, coma



▪ Puncture-aspiration-injection-reaspiration (PAIR) ▫ Ultrasound/CT scan-guided cyst puncture ▫ Aspirate cystic fluid ▫ Inject scolicidal solution ▫ Reaspirate cystic solution ▫ Repeat procedure until aspirate clears ▫ Fill cyst with isotonic saline



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/MRI/CT scan ▪ Cyst presence



LAB RESULTS



▪ Enzyme-linked immunosorbent assay (ELISA) ▫ Echinococcal antigen detection in cystic fluid ▪ Indirect hemagglutination ▫ Echinococcal antigen detection ▪ Immunodiffusion/immunoelectrophoresis ▫ Echinococcal-specific antibody detection ▪ Biopsy/cyst aspiration



Figure 61.3 A CT scan of the abdomen in the axial plane demonstrating a large hepatic hydatid cyst. The numerous daughter cysts are faintly visible.



TREATMENT MEDICATIONS



▪ Albendazole/ mebendazole ▫ Uncomplicated cases



Figure 61.4 A histological section through a hydatid cyst wall showing a typical laminated structure.



SURGERY



▪ Complicated cases ▫ Rupture, vital structure compression, cysts with diameter > 10cm/3.94in



OSMOSIS.ORG 341



NOTES



NOTES



CHLAMYDIA MICROBE OVERVIEW ▪ Gram-negative, obligate intracellular bacteria ▪ AKA “energy parasites”; rely on host cell for adenosine triphosphate (ATP) synthesis ▪ Primarily infects epithelium, mucous membranes Morphology ▪ Coccoid; cell walls don’t contain peptidoglycan



Replication ▪ Intracellular life cycle: infectious stage (spore-like elementary body) attaches to host cell via endocytosis → reorganizes within cellular vacuole into reticulate body (vegetative form) → reproduces, forms multiple reticulate bodies → forms elementary bodies → released from host cell → continues infectious process



CHLAMYDIA SPECIES (PNEUMONIA) osms.it/chlamydia-species PATHOLOGY & CAUSES ▪ Species of chlamydia; primarily causes community-acquired pneumonia ▪ Transmitted via respiratory secretions ▪ Can also infect endothelial cells → atherosclerosis



342 OSMOSIS.ORG



RISK FACTORS ▪ ↑ risk with age



COMPLICATIONS



▪ Otitis media, sinusitis, parapneumonic effusions, pericarditis



Chapter 62 Chlamydia



SIGNS & SYMPTOMS ▪ Gradual onset ▪ General malaise, myalgia, fever, chills, pharyngitis, hoarseness, sinusitis, cough ▪ Extra-respiratory manifestations: meningoencephalitis, reactive arthritis, myocarditis



DIAGNOSIS



LAB RESULTS



▪ Microbial identification: serology, polymerase chain reaction (PCR), nasopharyngeal swab culture, direct antigen testing ▪ Complete blood count (CBC): normal white blood cell count



OTHER DIAGNOSTICS



▪ History, physical examination: lung sounds (e.g. crackles, wheezing)



DIAGNOSTIC IMAGING Chest X-ray ▪ Unilateral patchy infiltrates



TREATMENT MEDICATIONS ▪ Antibiotics



CHLAMYDIA TRACHOMATIS osms.it/chlamydia-trachomatis PATHOLOGY & CAUSES ▪ Species of chlamydia; primarily affects eyes, urogenital tract ▪ Different serovars cause diverse disease states ▫ A, B, Ba, C: trachoma ▫ D–K: urogenital infection, conjunctivitis ▫ L1, L2, L2a, L2b, L3: lymphogranuloma venereum



RISK FACTORS



▪ Risky sexual practices (e.g. multiple sex partners, unprotected sex) ▪ Impaired mucous membrane barrier (e.g. cervical friability) ▪ History of sexually transmitted disease ▪ Exposure during birth



COMPLICATIONS



▪ Ocular: ophthalmia neonatorum (conjunctivitis), blindness ▪ Genitourinary: pelvic inflammatory disease (PID), PID-associated ectopic pregnancy, infertility, proctitis, cervicitis, urethritis



▪ Chlamydial pneumonia, bronchitis, perihepatitis (Fitz-Hugh–Curtis syndrome); ↑ risk of acquiring/transmitting HIV due to genital inflammation



SIGNS & SYMPTOMS Trachoma ▪ Chronic, granulomatous inflammation of eye → corneal ulceration, scaring, pannus formation → blindness Adult conjunctivitis ▪ Inclusion (purulent erythematous injection of epithelial surface) conjunctivitis, mucopurulent discharge → keratitis Urogenital infections ▪ Individuals who are biologically female ▫ May be asymptomatic ▫ Bartholinitis, cervicitis (mucopurulent endocervical discharge), endometritis, salpingitis, urethritis (dysuria, pyuria) ▫ PID: uterine/adnexal tenderness ▫ Perihepatitis: right upper quadrant (RUQ) pain



OSMOSIS.ORG 343



▪ Individuals who are biologically male ▫ Urethritis: dysuria, watery/mucoid discharge Neonatal conjunctivitis ▪ Eyelid swelling, watery/purulent discharge, red, thickened conjunctiva (chemosis) ▪ Conjunctival scarring, corneal vascularization ▪ ↑ risk of developing C. trachomatis pneumonia Infant pneumonia ▪ Diffuse, interstitial disease; rhinitis, staccato cough



Figure 62.1 Purulent discharge from the cervix of an individual with chlamydia infection.



Lymphogranuloma venereum (LGV) ▪ Anorectal disease: anorectal pain, tenesmus (feeling of incomplete bowel evacuation), rectal bleeding/discharge, constipation ▪ Painless ulcer → inflammation of lymph nodes (preauricular, submandibular, cervical) → progression to systemic symptoms ▪ Population at highest risk: individuals who are biologically male who have same-sex intercourse (MSM)



DIAGNOSIS LAB RESULTS



▪ Microbial identification: nucleic acid amplification test (NAAT)



OTHER DIAGNOSTICS



▪ Clinical presentation, history



TREATMENT MEDICATIONS



▪ Antibiotics ▪ Sexual partners should also be treated



344 OSMOSIS.ORG



Figure 62.2 A cervical smear from an individual infected with Chlamydia trachomatis. There are numerous organisms contained within intracellular vacuoles.



Chapter 2 Acyanotic Defects



NOTES



COCCOBACILLI: AEROBES MICROBE OVERVIEW ▪ Intermediate shape between cocci (spherical bacteria), bacilli (rod-shaped bacteria)



▪ Gram-negative, obligate aerobe, nonmotile, non-spore forming



BORDETELLA PERTUSSIS (PERTUSSIS/WHOOPING COUGH) osms.it/bordetella-pertussis PATHOLOGY & CAUSES ▪ Infectious agent, causes pertussis ▪ Strict human pathogen ▪ Tropism to respiratory epithelium Pathophysiology ▪ Bacteria enters upper respiratory tract, releases toxins ▪ Filamentous hemagglutinin, pertactin, agglutinogen ▫ Anchors to epithelial cells



▪ Tracheal cytotoxin ▫ Paralysis of respiratory cilia → ↑ accumulation of mucus in airways → violent cough reflex ▪ Pertussis toxin ▫ Stimulates T cells to divide, blocks them from leaving blood, migrating into tissues → lymphocytosis ▫ ↑ sensitivity of respiratory tissues to histamine → ↑ vascular permeability → fluid leaks into airway tissues → airway edema → dyspnea



OSMOSIS.ORG 345



▪ Adenylate cyclase toxin ▫ ↑ conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP) within phagocytes → disbalance in cellular signaling mechanism → phagocytes unable to correctly respond to infection, undergo apoptosis Stages of infection ▪ Catarrhal: follows incubation period (approx. one week); lasts two weeks, very contagious ▪ Paroxysmal: 1–6 weeks ▪ Convalescent: 2–3 weeks



RISK FACTORS



▪ Infants too young to have completed immunization ▪ Unimmunized individuals ▪ Debilitation of immune system



COMPLICATIONS



▪ Apparent life-threatening event (ALTE) ▫ Young infants; gasping, cyanosis, apnea ▪ Hypoxia ▫ Seizures, encephalopathy, death ▪ Pneumonia, pneumothorax



SIGNS & SYMPTOMS ▪ Catarrhal: nasal congestion; mild cough; sneezing; low-grade fever; red, watery eyes (similar to common cold) ▪ Paroxysmal: high-pitched whooping during inhalation; uncontrollable coughing fits → vomiting, fainting, rib fracture, petechiae in face, subconjunctival hemorrhages, hernias ▪ Convalescent stage: coughing improvement; decreased paroxysm, whooping; healing of airways



346 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS



▪ Nasopharyngeal swab culture (Bordet– Gengou agar) ▫ Detects microbe; mercury drop colonies ▪ Polymerase chain reaction (PCR) ▫ Detects microbe ▪ Serology ▫ Detects microbe; antibody levels ▪ Complete blood count (CBC) ▫ Leukocytosis (esp. young infants)



OTHER DIAGNOSTICS



▪ History, physical examination ▫ Sudden, dramatic coughing attacks; lung sounds (e.g. whooping)



TREATMENT MEDICATIONS



▪ Prophylactic ▫ Diphtheria, tetanus, acellular pertussis (DTaP) vaccine ▪ Macrolide antibiotics



OTHER INTERVENTIONS



▪ Compulsory isolation of infected individual



Chapter 63 Coccobacilli: Aerobes



FRANCISELLA TULARENSIS (TULAREMIA) osms.it/francisella-tularensis PATHOLOGY & CAUSES ▪ Infectious agent that causes zoonosis tularemia ▪ Facultative, gram-negative intracellular bacteria ▪ Highly infectious, virulent; potential bioterrorism agent Transmission ▪ Direct contact with infected animals (e.g. inoculation of mucous membranes via contaminated hands/infected material) ▪ Ingestion of contaminated water/meat ▪ Airborne spread via contaminated materials (e.g. dust, hay, grass, lab specimens) ▪ Insect vectors ▫ Ticks, mosquitoes, horse flies, fleas, lice Pathophysiology ▪ Francisella tularensis enters body → phagocytosed by macrophages → impairs phagosome-lysosome fusion, rapidly proliferates within macrophage → infected macrophage undergoes apoptosis → bacteria released, infection spread



COMPLICATIONS



▪ Lymph node suppuration, sepsis, renal failure, rhabdomyolysis, hepatitis, pneumonia



SIGNS & SYMPTOMS ▪ Fever, chills, malaise, lethargy, anorexia, chest/muscle soreness ▪ Ulceroglandular: papulo-ulcerative lesion at point of contact with animal/vector; lymphadenopathy ▪ Glandular: lymphadenopathy (no skin lesions) ▪ Oculoglandular: pain/irritation of eye; periorbital edema/erythema; increased tearing; photophobia; regional adenopathy ▪ Oropharyngeal: sore throat; cervical lymph node enlargement; pharyngitis; tonsillitis ▪ Pneumonic: dry cough; breathing difficulties; substernal chest pain ▪ Typhoidal: very high fever; abdominal pain; diarrhea; vomiting; diffuse abdominal tenderness



TYPES



▪ Forms of tularemia: ulceroglandular (75%), glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal



RISK FACTORS



▪ Work-related ▫ Lab workers, farmers, veterinarians, gardeners, hunters, butchers ▪ Skin exposure to vectors (esp. in summer)



Figure 63.1 An ulcer on the skin of an individual with tularemia.



OSMOSIS.ORG 347



DIAGNOSIS LAB RESULTS



▪ Culture ▫ Buffered charcoal yeast extract (BCYE) agar ▪ PCR, direct fluorescent antibody (DFA) test ▫ Detects microbe ▪ Serology ▫ IgM, IgG antibodies appear after 2 weeks



OTHER DIAGNOSTICS



▪ History, physical examination



348 OSMOSIS.ORG



TREATMENT MEDICATIONS



▪ Antibiotics (e.g. streptomycin, gentamicin, doxycycline)



Chapter 2 Acyanotic Defects



NOTES



COCCOBACILLI: FACULTATIVE ANAEROBES



MICROBE OVERVIEW ▪ Intermediate shape between cocci (spherical bacteria), bacilli (rod-shaped bacteria)



▪ Gram-negative, facultative anaerobes, nonmotile, nonspore-forming



BRUCELLA osms.it/brucella PATHOLOGY & CAUSES ▪ Characteristics ▫ Zoonotic infection ▫ Urease, catalase positive ▫ Facultatively intracellular ▫ Sensitive to heat, ionizing radiation, disinfectants, pasteurization ▪ Virulence factors ▫ Lipopolysaccharide (LPS): promotes cell entry, evasion, intracellular killing ▫ Type IV secretion system (key virulence factor): injection of effector molecules into host cell → modifies endoplasmic reticulum, enables replication ▪ Culture ▫ Isolation specimen: blood, bone marrow, body fluids, tissues ▫ Media: biphasic (solid, liquid) RuizCastaneda blood culture/modern automated blood culture systems (faster, more effective) ▫ Raised, convex colonies with smooth, shiny surface ▪ Causative agent of brucellosis ▪ Most common zoonotic infection to cause disease in humans



Transmission ▪ Contact with infected animals (e.g. sheep, cattle, goats, pigs, etc) ▫ Entry of bacteria through skin lesions, conjunctival inoculation, inhalation of contaminated aerosol ▪ Ingestion of contaminated animal products (e.g. unpasteurized milk, cheese; undercooked meat) ▫ Remains viable up to two days in milk at 8°C/46.4°F, three weeks in frozen meat, three months in goat cheese Pathogenesis ▫ Inoculation of bacteria → ingestion by polymorphonuclears, macrophages → passage to local lymph nodes → bacteria replicates intracellularly → some bacteria avoid intracellular killing by different strategies (e.g. inducing phagocyte apoptosis, inhibiting phagocyte-lysosome fusion) → chronic infection



TYPES Acute infection ▪ Localized infection (30% of cases), can affect any organ



OSMOSIS.ORG 349



▫ Skeletal (most common): arthritis, spondylitis, sacroiliitis, osteomyelitis ▫ Pulmonary: bronchitis, interstitial pneumonitis, lobar pneumonia, pulmonary nodules, pleural effusion, empyema, abscesses ▫ Cardiac: endocarditis, myocarditis, pericarditis, endarteritis ▫ Alimentary: cholecystitis, ileitis, colitis, pancreatitis ▫ Reticuloendothelial: reactive hepatitis, granulomas, acute hepatitis with focal necrosis (B. melitensis), formation of noncaseating sarcoidosis-like granulomas (B. abortus), suppurative abscess formation (B. suis) in liver ▫ Genitourinary: orchitis, epididymitis ▫ Hematological: anemia, leukopenia, thrombocytopenia, pancytopenia, disseminated intravascular coagulation ▫ Neurologic: meningitis, encephalitis, myelitis, radiculitis, neuritis, mycotic aneurysms, brain abscess ▫ Ocular: uveitis, keratoconjunctivitis, corneal ulcers, iridocyclitis, nummular keratitis, choroiditis, optic neuritis, papilledema, endophthalmitis ▫ Dermatologic: nonspecific skin eruptions, ulcerations, petechiae, purpura, granumanifestationslomatous vasculitis, abscesses



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Chronic infection ▪ Symptoms persist one year after diagnosis; localized infection, relapse



RISK FACTORS



▪ Occupational exposure ▫ Lab health care workers, farmers, slaughterhouse workers, veterinarians



COMPLICATIONS



▪ Infection during pregnancy → intrauterine infection, premature delivery, spontaneous abortion, miscarriage ▪ Endocarditis damage, destroy heart valves ▪ Leading cause of death by brucellosis ▪ Skeletal ▫ May cause long-term damage, bone/ joint malformations ▪ Neurologic ▫ May lead to permanent brain damage ▪ Ocular ▫ Visual impairment



Chapter 64 Coccobacilli: Facultative Anaerobes



SIGNS & SYMPTOMS ▪ Range from asymptomatic to severe illness ▪ Onset of symptoms can be acute/insidious ▪ Incubation ▫ 1–4 weeks to several months ▪ Acute generalized infection ▫ Acute undulating fever (key sign), arthralgia, myalgia, fatigue, headache, night sweats, malaise, weight loss ▫ Hepatomegaly, splenomegaly, lymphadenopathy ▫ Foul-smelling perspiration (characteristic sign) ▪ Localized infection ▫ Symptoms depend on organ/organ system affected



DIAGNOSIS LAB RESULTS ▪ Rising titers of specific antibodies ▫ Initial rise in IgM class titers, followed in several weeks by predominance of IgG antibodies; both decrease over time with treatment ▪ Anemia, thrombocytopenia Microbe identification ▪ Positive bodily fluids/tissue culture ▪ Serum agglutination, enzyme-linked immunosorbent assay (ELISA) ▪ Polymerase chain reaction (PCR)



▪ Lysis-centrifugation technique



OTHER DIAGNOSTICS



▪ History of travel, food consumption, occupation



TREATMENT MEDICATIONS



▪ Six-week course of doxycycline plus streptomycin/gentamicin/doxycycline plus rifampin ▪ In children < eight years old ▫ Trimethoprim-sulfamethoxazole (TMPSMX) plus rifampin



SURGERY



▪ Surgical interventions sometimes necessary for osteoarticular manifestations (e.g. pyogenic joint effusions), hepatosplenic granulomas/abscesses, cardiac complications (e.g. valve replacement surgery)



OTHER INTERVENTIONS



▪ Prophylaxis ▫ Biosafety level 3 in laboratories recommended while handling Brucella cultures ▫ No vaccines for humans; live attenuated vaccines containing strains of B. abortus, B. melitensis used for animals



OSMOSIS.ORG 351



HAEMOPHILUS DUCREYI osms.it/haemophilus-ducreyi PATHOLOGY & CAUSES ▪ Virulence factors ▫ Lipooligosaccharide ▫ Pili: provides attachment of bacteria ▫ Soluble cytolethal distending toxin, cytotoxic hemolysin, hemoglobinbinding protein, copper-zinc superoxide dismutase, filamentous hemagglutininlike protein, zinc-binding periplasmic protein ▪ Culture ▫ Isolation specimen: genital ulcer swab, lymph node aspirate ▫ Media: enriched growth medium contains factor X (hemin), serum incubated at 33–35ºC/91.4–95°F with CO2; small, heterogenous, gray/ translucent colonies ▪ Causative agent of sexually transmitted genital ulcer called chancroid (AKA ulcus molle), associated inguinal lymphadenopathy ▪ Some strains causes cutaneous ulcers in children in South Pacific, parts of equatorial Africa Transmission ▪ Sexual intercourse (genital ulcers) ▪ Nonsexual transmission (cutaneous ulcers) Pathogenesis ▪ Incubation ▫ 4–10 days ▪ Inoculation through epidermal microabrasions → attachment of bacteria to extracellular matrix in skin via pili,



352 OSMOSIS.ORG



lipooligosaccharide → attachment to cells via specific heat shock protein (GroEL) → cytotoxin release, epithelial injury → formation of erythematous papule → evolves into pustule → pustule ruptures, forms ulcer



RISK FACTORS



▪ Uncircumcised individuals, poverty, multiple sexual partners



COMPLICATIONS



▪ Increases risk for HIV contraction



SIGNS & SYMPTOMS ▪ Single/multiple painful genital ulcers on erythematous base, 1–2cm/0.39–0.79in diameter with sharply demarcated borders; base of ulcer covered with purulent exudate, bleeds easily when scraped ▪ Predilection sites ▫ Prepuce, coronal sulcus, glans penis in individuals who are biologically male ▫ Labia, vaginal introitus, perianal area in individuals who are biologically female ▪ Individuals who are biologically female ▫ Dysuria, dyspareunia, vaginal discharge, rectal bleeding, painful defecation ▪ Inguinal lymphadenopathy in approx. 50% of cases (more common in individuals who are biologically male) ▫ Painful fluctuant buboes (swollen lymph nodes); if untreated, may spontaneously rupture, form draining sinus, releases pus



Chapter 64 Coccobacilli: Facultative Anaerobes



DIAGNOSIS LAB RESULTS Microbe identification ▪ Diagnosis of confirmed chancroid ▫ Culture (not widely available) ▪ Nucleic acid amplification tests ▫ Not available outside of clinical research purposes ▪ Polymerase chain reaction (PCR) multiplex ▫ Detection of bacterial DNA ▪ Histologic characteristics of chancroid



OTHER DIAGNOSTICS



▪ Diagnostic criteria for probable chancroid ▫ ≥ one painful genital ulcers ▫ No evidence of Treponema pallidum infection (by darkfield microscopy/ serologic testing) ▫ No evidence of Herpes simplex virus (HSV) infection ▫ Appearance of genital ulcers, regional lymphadenopathy ▪ Purulent exudate in superficial epidermis with perivascular, interstitial mononuclear infiltrate in dermis



Figure 64.1 An ulcer on the glans penis of a male with chancroid. The ulcer is typically painful, unlike the ulcer of primary syphilis.



TREATMENT MEDICATIONS



▪ Single-dose therapy with azithromycin/ ceftriaxone ▪ Alternative ▫ Multiple-dose therapy with ciprofloxacin/erythromycin



OTHER INTERVENTIONS



▪ Fluctuant lymphadenopathy ▫ Needle aspiration, drainage to prevent spontaneous rupture



OSMOSIS.ORG 353



HAEMOPHILUS INFLUENZAE osms.it/haemophilus-influenzae PATHOLOGY & CAUSES ▪ Haemophilus: blood loving ▪ Characteristics ▫ Catalase, oxidase positive ▪ Virulence factors ▫ Polysaccharide capsule: prevents phagocytosis; causes ciliostasis, evades mucociliary clearance of bacteria; classified into six serotypes based on capsular antigens (A, B, C, D, E, F); some strains unencapsulated (AKA nontypable); most clinical isolates Haemophilus influenzae type B (Hib)/ nontypable ▫ IgA1 protease, adherence factors, antigenic variation, biofilm formation ▪ Gram stain of exudate shows bacteria arranged in chains (“school of fish”) ▪ Culture ▫ Isolation specimen: cerebrospinal fluid (CSF), urine, serum, synovial fluid ▫ Media: chocolate agar/Fildes medium (hemolyzed erythrocytes) with factor X (hemin), V (nicotinamide adenine dinucleotide) supplementation in aerobic, only factor X supplementation in anaerobic environment ▫ Convex, smooth, grey/transparent colonies ▪ Gram-negative coccobacillus → meningitis, respiratory tract infections ▪ Nontypeable strains colonize nasopharynx of 40–80% children, adults ▪ Hib colonizes 3–5% children



TYPES Hib ▪ Epiglottitis in older children, adults ▪ Cellulitis (most common in young children) ▪ Pneumonia ▫ Sometimes with meningitis, epiglottitis ▪ Meningitis, septic arthritis, osteomyelitis



354 OSMOSIS.ORG



Nontypable ▪ Less invasive due to lack of capsule; causes mild localized respiratory tract disease in children, adults ▪ More severe in immunocompromised/ predisposed individuals ▫ Otitis media, sinusitis, purulent conjunctivitis, bacterial pneumonia in children (in low-income countries), neonatal bacteremia ▫ Community-acquired pneumonia in adults with underlying lung disease ▫ Exacerbation of chronic obstructive pulmonary disease (COPD) ▫ Meningitis in individuals with predisposition/conditions causing leakage of CSF fluid (e.g. sinusitis, otitis media, head trauma) Transmission ▪ Direct contact with respiratory tract secretions/airborne respiratory droplets Pathogenesis ▪ Inoculation → passage through upper respiratory tract → adherence to respiratory epithelium, LPS inhibits mucociliary clearance → colonization spreads throughout respiratory tract → sinuses, otitis, pneumonia ▪ IgA1 protease, antigenic variation, paracytosis, biofilm formation → perseverance of bacteria



RISK FACTORS



▪ Viral infection, sickle-cell disease, asplenia, HIV infection, malignancies, congenital deficiencies of complement components



COMPLICATIONS



▪ Nontypable in neonates, immunocompromised individuals → septicemia, meningitis, septic arthritis ▪ Hib meningitis → subdural effusion/ empyema; ischemic/hemorrhagic cortical



Chapter 64 Coccobacilli: Facultative Anaerobes infarction; cerebritis (nonviral parenchymal infection of brain); ventriculitis; intracerebral abscess; hydrocephalus; neurologic sequelae (e.g. permanent sensorineural hearing loss, seizures, intellectual disability) ▪ Hib pneumonia can spread to pericardium → purulent pericarditis



SIGNS & SYMPTOMS Hib ▪ Meningitis ▫ Fever, lethargy, irritability, vomiting, altered mental status ▫ Fulminant course → rapid neurologic deterioration, respiratory arrest ▫ Positive Kernig’s sign: inability to straighten leg when hip flexed to 90º ▫ Positive Brudzinski’s sign: flexing of neck by examiner → flexing of hips, knees ▪ Epiglottitis ▫ Fever, sore throat, difficulty speaking, dyspnea → severe stridor, dysphagia, pooling of secretions, drooling ▫ “Tripod” posture: individual takes sitting position with trunk leaning forward, neck hyperextended, chin thrust forward to get more air through obstructed airway ▪ Cellulitis ▫ Fever; warm, tender area of erythema/ violaceous discoloration on cheek/ periorbital area ▪ Septic arthritis ▫ Fever, pain, swelling, tenderness, decreased mobility of affected joint Nontypeable ▪ Otitis media ▫ Fever, ear pain, irritability, sleep disturbance, otorrhea ▫ Red bulging tympanic membrane with decreased mobility upon pneumatic otoscopy examination ▫ Often conjoined with conjunctivitis ▪ Sinusitis ▫ Fever, persistent purulent nasal discharge or cough > 10 days ▫ Tenderness over involved paranasal sinuses



DIAGNOSIS DIAGNOSTIC IMAGING Laryngoscopy ▪ Red, swollen epiglottis; aryepiglottic folds ▪ Examine with caution; possible laryngeal spasm X-ray ▪ Thumb sign on epiglottis (radiographic corollary of omega sign)



LAB RESULTS Microbe identification ▪ Positive Gram stain, bacterial culture of CSF, synovial fluid, epiglottis, pleural, pericardial, other sterile fluids ▪ Latex agglutination, enzyme immunoassay, coagglutination ▫ Type B capsular antigen detection in CSF, serum, urine ▪ Definitive diagnosis ▫ Culture of fluid obtained by sinus aspiration, tympanocentesis, tracheal/ lung aspiration, bronchoscopy, bronchoalveolar lavage



Figure 64.2 An X-ray image of the chest demonstrating diffuse airway shadows in an individual with bronchopneumonia. H. influenzae is a causative organism of bronchopneumonia.



OSMOSIS.ORG 355



TREATMENT MEDICATIONS Prevention ▪ Conjugate Hib vaccines ▫ Routine vaccination of infants of two months ▪ Rifampin chemoprophylaxis ▫ Individuals in close contact with infected; incompletely vaccinated individuals in households with infants/ children < four years old Hib with meningitis ▪ Third generation cephalosporins ▫ Adults: ceftriaxone



▫ Children: ceftriaxone plus dexamethasone (decreases immune response to released LPS upon bacterial death, lowers chance for destruction of neurons, neurologic sequelae) ▪ Epiglottitis (life-threatening condition; prompt treatment paramount) ▫ Ceftriaxone Nontypable ▪ Amoxicillin/clavulanate, broad-spectrum cephalosporins, macrolides (azithromycin/ clarithromycin), fluoroquinolones



SURGERY



▪ Epiglottitis ▫ Placement of artificial airway



PASTEURELLA MULTOCIDA osms.it/pasteurella-multocida PATHOLOGY & CAUSES ▪ Characteristics ▫ Zoonotic infection (e.g. birds, cats, dogs, rabbits, cattle, pigs); oxidase, catalase, nitrate reduction positive ▪ Virulence factors ▫ Polysaccharide capsule: prevents phagocytosis; divided into serogroups based on capsular antigens (A, B, C, D, E) ▫ Lipopolysaccharide: endotoxin ▫ Sialidases, hyaluronidase, surface adhesins, iron acquisition proteins, pasteurella multocida toxin (PMT) ▪ Culture ▫ Isolation specimen: respiratory tract samples, CSF ▫ Media: sheep blood, chocolate, HS, Mueller–Hinton agar at 37ºC/98.6F; opaque/gray colonies 1–2mm in diameter ▪ Medically important subspecies ▫ P. multocida subsp multocida, P.



356 OSMOSIS.ORG



multocida subsp septica, P. multocida subsp gallicida Transmission ▪ Most commonly cat/dog bites, scratches, licks



TYPES



▪ Soft tissue infections ▫ Cellulitis at site of inoculation (most common) → abscess, necrotizing soft tissue infections, septic arthritis, osteomyelitis ▪ Respiratory infections ▫ Due to underlying chronic pulmonary disease; glossitis, pharyngitis, sinusitis, otitis media, epiglottitis, tracheobronchitis, pneumonia, empyema, lung abscess ▪ Invasive infection (immunocompromised, infants) ▫ Bacteremia, meningitis, intra-abdominal infections (peritonitis, appendicitis), endocarditis, septic arthritis, ocular infection



Chapter 64 Coccobacilli: Facultative Anaerobes Pathogenesis ▪ Inoculation → attachment of bacteria to ECM, cells soft tissue → PMT secretion → tissue inflammation within 24 hours



COMPLICATIONS



▪ Sepsis, septic shock



SIGNS & SYMPTOMS ▪ Soft tissue infections ▫ Wound inflammation, cellulitis with purulent drainage; regional lymphadenopathy ▪ Respiratory tract infections ▫ Fever, malaise, dyspnea, pleuritic chest pain ▪ Sepsis ▫ Purpura fulminans (rash rapidly progresses from petechiae, purpura to gangrene/limb amputation) ▪ Respiratory infection ▫ Wheezing, rhonchi, dullness



DIAGNOSIS LAB RESULTS Microbe identification ▪ Culture, PCR, serological testing



OTHER DIAGNOSTICS



▪ History of animal contact ▫ Cat bites pose higher risk for developing osteomyelitis, septic arthritis



TREATMENT MEDICATIONS ▪ ▪ ▪ ▪



Penicillins Tetracyclines Cephalosporins Quinolones



OSMOSIS.ORG 357



NOTES



NOTES



COMMA–SHAPED RODS MICROBE OVERVIEW ▪ Gram-negative, facultative anaerobes, motile, non-spore forming



CAMPYLOBACTER JEJUNI osms.it/campylobacter-jejuni PATHOLOGY & CAUSES Characteristics ▪ Zoonotic disease ▫ Reservoir in wild, domestic mammals, birds (esp. poultry) ▪ Oxidase +; invasive; microaerophilic; sensitive to heat, desiccation, acidity, irradiation, disinfectants Virulence factors ▪ Fimbriae-like filaments ▫ Promote attachment to intestinal



358 OSMOSIS.ORG



epithelial cells ▪ Possesses single, unsheathed flagellum in one end (monotrichous)/two flagella each at both ends (amphitrichous) ▫ Provide motility, chemotaxis (mucin is chemoattractant → tropism for ileum, colon, rectum) ▪ Surface proteins (eg, PEB1, CadF) promote colonization, invasion of intestinal epithelial cells ▪ Lipopolysaccharide (LPS) ▫ Plays role in adherence, evasion of host immune response (undergoes antigenic variation)



Chapter 65 Comma-shaped Rods Culture ▪ Isolation specimen: stool, food ▪ Media: blood/charcoal agar with microaerophilic atmosphere (5–10% O2, 3–5% CO2), thermophilic environment (optimal 42°C/107.6°F) ▪ C. jejuni: one of most common bacterial causes of gastroenteritis with acute diarrhea Transmission ▪ Fecal-oral, contaminated water Pathogenesis ▪ Incubation period 1–7 days; tropism for distal ileum, colon, rectum ▪ Inoculation of bacteria → passage through upper GI tract → colonization, adherence to surface epithelium of distal ileum, colon → non-inflammatory secretory diarrhea (exact mechanism unknown) ▪ Invasion of intestinal epithelium, proliferation → release of cytolethal distending toxin → cell damage, inflammatory response → dysentery with fecal leukocytes ▪ Rare: translocates into lamina propria, spreads to mesenteric lymph nodes (mesenteric adenitis) → extraintestinal infections (e.g. meningitis, cholecystitis, UTI) ▫ Occurs mostly in immunocompromised



RISK FACTORS



▪ Consumption of undercooked meat/ unpasteurized milk ▪ Underlying conditions/medications that reduce/buffer gastric acidity (e.g. proton pump inhibitors) ▪ Individuals with HIV/AIDS



COMPLICATIONS



▪ Toxic megacolon, massive bleeding, colonic perforation ▪ Reactive arthritis ▪ Associated with Guillain–Barré syndrome ▫ Sialic acid contained bacterial core oligosaccharide can resemble gangliosides → cross-activation of autoreactive T/B cells (molecular mimicry)



SIGNS & SYMPTOMS ▪ Vary in severity depending upon inoculum concentrations; range from asymptomatic carriage to systemic illness ▫ Most episodes mild, self-limiting (up to one week); rarely persists up to several weeks ▪ Fever, myalgia, malaise, headache (early symptoms, 1–2 days); severe periumbilical abdominal pain, cramping, secretory, inflammatory diarrhea, vomiting ▫ Abdominal pain may mimic acute appendicitis ▫ Secretory diarrhea: more common in children ▫ Inflammatory diarrhea: tenesmus, bloody stools, fecal leukocytes



DIAGNOSIS LAB RESULTS



▪ Stool culture ▪ Rapid diagnosis with carbolfuchsin stain/ phase-contrast/dark-field microscopic examination of fresh stool specimen in case of acute manifestation ▪ PCR-based methods, enzyme immunoassays (EIAs) directly from stool



OTHER DIAGNOSTICS



▪ Clinical manifestations ▪ Histology ▫ Acute mucosal inflammation with edema, cellular infiltration of lamina propria, crypt abscess formation



TREATMENT MEDICATIONS



▪ Antibiotics for severe cases, immunocompromised individuals ▫ Erythromycin/azithromycin



OTHER INTERVENTIONS ▪ Replacement of fluids, electrolytes



OSMOSIS.ORG 359



HELICOBACTER PYLORI osms.it/helicobacter-pylori PATHOLOGY & CAUSES Characteristics ▪ Urease +, catalase +, oxidase +; noninvasive ▪ Microaerophilic ▫ Requires oxygen, lower concentrations than present in atmosphere Virulence factors ▪ Possesses 2–7 unipolar sheathed flagella (H-antigen) ▫ Provide motility, chemotaxis (sense pH, move bacteria towards beneficial environment) ▪ Lipopolysaccharide (LPS) ▫ Promotes adherence, causes inflammation ▪ Coccoid form ▫ More resistant form; occurs as adaptation to hostile environment outside human body ▪ Urease ▫ Important for survival, colonization ▪ Mucolytic enzymes ▫ Allow passage through mucus layer to gastric epithelium ▪ Adhesive proteins (Hop proteins) ▪ Vacuolating cytotoxin A (VacA) ▫ Damages epithelial cells; disrupts tight junctions, causes apoptosis ▪ Cytotoxin associated gene CagA (CagA) ▫ Triggers inflammation ▪ Type IV secretion system ▫ Pili-like structure for injection of effectors (e.g. CagA) ▪ Proteases, lipases ▪ Biofilm formation Culture ▪ Isolation specimen: vomitus, diarrheal stools ▪ Media: blood agar/selective Skirrow’s media



360 OSMOSIS.ORG



incubated at 37ºC/98.6°F in 5% oxygen; small, uniformly sized, translucent bacterial colonies ▪ H. pylori: causative agent of most common chronic infection in humans; common cause of duodenal, gastric ulcers, chronic gastritis Transmission ▪ Unknown; fecal/oral, oral/oral transmission suggested ▪ Reservoir ▫ Human (majority of cases); found in primates in captivity, domestic cats, sheep ▪ Also found in municipal water in endemic areas of infection with polymerase chain reaction (PCR) techniques Pathogenesis ▪ Bacterial urease hydrolyzes gastric luminal urea to form ammonia → ↑ gastric pH → formation of protective layer around bacteria → survival in hostile gastric environment ▪ ↑ pH → mucin liquefies → H. pylori passes through mucous layer to surface epithelium via bacterial flagella, mucolytic enzymes → attaches to specific gastric epithelial cell receptors via surface adhesins (Hop proteins) → release of proteases (VacA, CagA) + host immune response → inflammation, tissue injury ▪ Disruption of mucous layer → susceptibility to acid peptic damage ▪ Chronic inflammation, tissue injury together with acid peptic damage → chronic gastritis, peptic ulcers (10–20% risk)



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Low socioeconomic status Increased housing density Lack of running water Genetic susceptibility Swimming in pools, rivers, streams



Chapter 65 Comma-shaped Rods



COMPLICATIONS



▪ Gastric carcinoma (1–2% risk): chronic gastritis → atrophic gastritis, intestinal metaplasia, carcinoma ▫ Chronic inflammation, ↑ TNF, ↑ IL-6, ↑ bacterial proteases → excessive tissue damage, cell mutation → intestinal metaplasia → carcinoma ▪ Gastric mucosa-associated lymphomas due to persistent immune stimulation of gastric lymphoid tissue



▫ Omeprazole/pantoprazole + clarithromycin, amoxicillin: in case of penicillin sensitivity, replace amoxicillin with metronidazole



SIGNS & SYMPTOMS ▪ Majority of cases asymptomatic ▪ Acute infection ▫ Upper abdominal pain, nausea, loss of appetite ▪ Chronic infection ▫ Chronic gastritis: upper abdominal pain, nausea, bloating, vomiting/melena (black stool) ▫ Peptic ulcers: stomach pain/ache; occurs with empty stomach, between meals, early morning



Figure 65.1 Helicobacter organisms in a gastric pit.



DIAGNOSIS LAB RESULTS



▪ Blood antibody test ▪ Stool antigen test ▪ Carbon urea breath test ▫ Individual ingests 14C- or 13C-labelled urea, which bacterium metabolizes, yielding labelled carbon dioxide detectable in breath ▪ Urine enzyme-linked immunosorbent assay (ELISA) test



TREATMENT MEDICATIONS



▪ One-week “triple therapy”: antacid/acidreducing drugs (H2-receptor antagonists/ proton pump inhibitors) + two antibiotics ▫ Bismuth salicylate + metronidazole + tetracycline ▫ Ranitidine bismuth citrate + tetracycline + clarithromycin/metronidazole



OSMOSIS.ORG 361



VIBRIO CHOLERAE (CHOLERA) osms.it/vibrio-cholerae PATHOLOGY & CAUSES Characteristics ▪ Oxidase +; non-invasive; halophilic; genome consists of two circular chromosomes; sensitive to acid, drying ▪ Reservoir: aquatic environments (saltwater, brackish) ▪ Fermentation: glucose, sucrose Virulence factors ▪ Cholera toxin ▫ Only toxigenic strains; responsible for pathogenesis of massive, watery diarrhea; coded by filamentous bacteriophage (CTXΦ) ▪ Other toxins that increase mucosal permeability ▫ Zona occludens toxin (ZOT), accessory cholera enterotoxin (ACE), WO7 toxin 17 ▪ Lipopolysaccharide (LPS) ▫ > 200 serogroups; O1, O139 associated with cholera epidemics ▪ Motility ▫ Single polar flagellum (H-antigen) ▪ Toxin-coregulated pilus (TCP) ▫ Present only in toxigenic strains; promotes adherence, aggregation of bacteria; coded by genes in Vibrio pathogenicity island (VPI) ▪ Mucinase ▫ Digests mucous layer of gastrointestinal (GI) tract Culture ▪ Isolation specimen: stool, rectal swab ▪ Media: thiosulfate citrate bile salts sucrose (TCBS) agar/taurocholate tellurite gelatin agar (TTGA); large, yellow colonies (2–4mm diameter) with opaque centers, translucent edges



362 OSMOSIS.ORG



▪ V. cholerae: diverse species; pathogenic, toxin-producing (toxigenic) variants cause cholera ▪ Cholera characterized by profound secretory diarrhea → rapid, life-threatening dehydration ▪ Transmitted by fecal-oral route/ contaminated food or water Pathogenesis ▪ Inoculation → passage through upper GI tract → rapid movement of bacteria through mucous via flagellum → colonization of small intestine via TCP → releases cholera toxin ▪ Cholera toxin (AB protein toxin) → B subunit binds to GM1 ganglioside on intestinal epithelial cell, allows entry of A subunit → activates G-protein regulated adenylyl cyclase → ↑ intracellular cyclic adenosine monophosphate (AMP) → secretion of chloride, sodium; inhibition of sodium chloride absorption → massive fluid secretion; loss of sodium, chloride, bicarbonate, potassium



TYPES Pathogenic (toxin-producing), nonpathogenic Serological classification: O antigen differences ▪ Serogroup O1 is subdivided into two serotypes (Inaba, Ogawa), two biotypes ▫ El Tor: cause of current global pandemic of cholera ▫ Classical: cause of previous V. cholerae pandemics; now thought extinct ▪ Serogroup O139 ▪ Non-O1/O139



RISK FACTORS



▪ Travel to endemic/epidemic areas ▪ Inadequate access to clean water



Chapter 65 Comma-shaped Rods ▪ Shellfish consumption in areas with sporadic cholera ▪ People with blood group O at higher risk for severe cholera (mechanism unknown)



COMPLICATIONS



▪ If untreated ▫ Dehydration, hypovolemic shock in 4–12 hours, death in 18 hours to several days ▪ Renal failure secondary to hypovolemia ▪ Electrolyte imbalances ▫ Hypokalemia, metabolic acidosis ▪ Pneumonia (esp. in children) due to aspiration of vomit



SIGNS & SYMPTOMS ▪ Incubation period is 28–48 hours ▪ Asymptomatic to severe depending upon strain, inoculum concentration (≥ 108 → severe form) ▪ Abrupt onset of profound watery diarrhea (grey, cloudy, flecked with mucus; “ricewater stool”); painless, without tenesmus; loss of 1 liter of fluid per hour in severe cases ▪ Moderate to severe vomiting, borborygmus, abdominal discomfort ▪ Dehydration ▫ Thirst, dry mucous membranes, decreased skin turgor, sunken eyes, hypotension, weak/absent radial pulse, tachycardia, tachypnea, hoarse voice, oliguria ▪ Altered mental status ▫ Somnolence, restlessness, lethargy



▫ Culture on TCBS agar ▫ Dark field microscopy/dipstick test of stool specimen for rapid confirmation in non-endemic areas (detectable in stool for 1–2 weeks without antimicrobial therapy)



TREATMENT MEDICATIONS



▪ Oral antibiotic treatment reduces duration, severity of disease ▫ Doxycycline for adults ▫ Azithromycin for children, pregnant individuals



OTHER INTERVENTIONS



▪ Prophylaxis ▫ WC-rBS (Dukoral) vaccine: monovalent inactivated oral cholera vaccine containing killed whole cells of V. cholerae O1, additional recombinant cholera toxin B subunit ▫ BivWC (Shanchol) vaccine: bivalent inactivated oral vaccine containing killed whole cells of V. cholerae O1, O139 ▫ CVD 103-HgR/Vaxchora vaccine: attenuated oral vaccine derived from serogroup O1 classical Inaba strain ▪ Rapid, aggressive volume replacement (oral/intravenous fluids) ▪ Adequate nutrition to prevent malnutrition ▪ Correction of electrolyte imbalances ▪ Zinc supplementation reduces duration, severity of disease



DIAGNOSIS LAB RESULTS



▪ Hypoglycemia/hyperglycemia ▪ Hypercalcemia, hypermagnesemia, hyperphosphatemia ▪ ↑ hematocrit due to volume depletion



OTHER DIAGNOSTICS ▪ Clinical presentation ▪ Microbiologic diagnosis



OSMOSIS.ORG 363



NOTES



NOTES



CORONAVIRUSES MICROBE OVERVIEW ▪ Causes respiratory infections ▪ OC43, NL63: most common strains of human coronaviruses (HCoV) ▪ Associated clinical syndromes: common cold, pneumonia, bronchitis, Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV) Genetic material ▪ Positive-stranded RNA viruses Taxonomy ▪ Corona: crown; named after spiked appearance in electron microscopy ▪ Genera: alpha, beta (human pathogens), gamma, delta



364 OSMOSIS.ORG



Morphology ▪ Helical capsid; enveloped (outer lipid membrane) ▪ Structural proteins ▫ Small envelope protein (E) → viral assembly ▫ Hemagglutinin esterase protein (HE) → binds to cell membrane (beta coronaviruses only) ▫ Membrane protein (M) → viral assembly ▫ Nucleocapsid protein (N) → forms nucleocapsid ▫ Spike protein (S) → binds, fuses with host cell membrane



Chapter 66 Coronaviruses



CORONAVIRUS (SARS) osms.it/coronavirus-SARS PATHOLOGY & CAUSES ▪ Causes severe respiratory syndrome (SARS) ▪ B-beta coronavirus: viral pulmonary disease ▪ Viral inoculation of respiratory tract mucosa → cell damage → release of cytokines (interferon-gamma, IL-1, IL-6, IL-12) → inflammation, ↑ secretions ▪ Incubation period: 2–7 days



CAUSES



▪ Direct contact, airborne droplets, fomites



RISK FACTORS



▪ Immunosuppression, healthcare-related occupation, comorbid conditions



COMPLICATIONS



▪ Acute respiratory distress syndrome, multiorgan failure



SIGNS & SYMPTOMS ▪ Prodrome: fever, malaise, headaches, myalgia, chills ▪ Non-productive cough, dyspnea, chest pain ▪ Diarrhea, rhinorrhea, sore throat



▪ Interstitial pulmonary infiltrates



LAB RESULTS Histologic pulmonary tissue observation ▪ Hyaline membranes, edema, fibroblast proliferation Reverse-transcriptase polymerase chain reaction (RT-PCR) ▪ Nasopharyngeal, oropharyngeal, stool, serum samples Serologic tests ▪ Enzyme-linked immunosorbent assays (ELISA) ▪ Fluorescence antigen detection assays Lab tests ▪ Lymphopenia, thrombocytopenia, ↑ lactate dehydrogenase (LDH), ↑ alanine aminotransferase (ALT)



TREATMENT OTHER INTERVENTIONS



▪ Mechanical ventilation in respiratory failure



Prevention ▪ Hand washing ▪ Proper disposal of infected materials (e.g. used tissues) ▪ Mask use within healthcare environment



DIAGNOSIS ▪ Center for Disease Control and Prevention (CDC) ▫ No alternative diagnosis after 72 hours of clinical evaluation ▫ Individual at risk



DIAGNOSTIC IMAGING Chest X-ray



OSMOSIS.ORG 365



NOTES



NOTES



CUTANEOUS FUNGAL INFECTIONS



GENERALLY, WHAT ARE THEY? DIAGNOSIS



PATHOLOGY & CAUSES ▪ Noninvasive fungal infections of skin and its annexes ▫ Limited to stratum corneum ▫ Caused by human skin’s commensal flora



LAB RESULTS ▪ Microscopic observation



OTHER DIAGNOSTICS ▪ Clinical findings upon examination



SIGNS & SYMPTOMS ▪ Skin pigmentation changes ▪ Characteristic lesions: macule, patch, scale, plaque ▪ Occasional pruritus



TREATMENT MEDICATIONS ▪ Antifungal



MALASSEZIA (TINEA VERSICOLOR & SEBORRHOEIC DERMATITIS) osms.it/malassezia PATHOLOGY & CAUSES ▪ Genus of yeast-like fungi ▪ Cause cutaneous infections ▪ Cutaneous commensal flora, mostly lipiddependent (thrive on human sebum), saprophytic (nutrients obtained from dead, organic matter), dimorphic (yeast, hyphal/ mycelial forms)



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TYPES Tinea versicolor ▪ Superficial cutaneous mycosis ▪ AKA pityriasis versicolor ▪ Most common causes: M. globosa, M. furfur, M. sympodialis ▪ Fungus produces azelaic acid → tyrosinase activity (activated by sunlight) → skin pigmentation changes → hypopigmented/ hyperpigmented macules, patches, plaques



Chapter 67 Cutaneous Fungal Infections Seborrheic dermatitis ▪ Chronic, inflammatory dermatitis ▫ Tends to flare, relapse ▫ Likely caused by Malassezia spp. ▪ Fungus produces acids, enzymes, oxygen radicals → cell damage → inflammatory response → erythema, greasy, yellowish scaling (range from mild, flaky to coarse, thick lesions)



RISK FACTORS Tinea versicolor ▪ Most common ▫ Adolescents/young adults ▪ Excessive heat, humidity, perspiration, sunlight ▪ Immunosuppression



Figure 67.1 Tinea versicolor on the abdomen.



Seborrheic dermatitis ▪ Biphasic occurrence ▫ Infants (cradle cap), adolescents/adults ▪ Biologically-male > biologically-female individuals ▪ Comorbidities ▫ HIV/AIDS, Parkinson’s disease



SIGNS & SYMPTOMS Tinea versicolor ▪ Characteristic skin changes ▫ Usually located on abundant sebaceous gland areas (torso, proximal extremities, face, neck) ▪ Light brown in light-skinned individuals; dark brown to gray-black in dark-skinned individuals ▪ Mild erythema, pruritus, scaling ▪ Lesions fail to tan with sun exposure Seborrheic dermatitis ▪ Characteristic skin changes ▫ Usually located on trunk (“petaloid pattern”), scalp (dandruff), eyebrows, eyelids, nasolabial folds, external auditory meatus, anogenital area ▪ Pruritus, erythema, blepharitis ▪ Tends to flare during stress, cold weather ▪ Infants: adherent yellowish scales primarily on vertex of scalp



Figure 67.2 Seborrhoeic dermatitis affecting the nasolabial folds.



DIAGNOSIS LAB RESULTS Tinea versicolor ▪ KOH preparation: microscopic observation → “spaghetti and meatballs” ▫ Spaghetti: hyphae ▫ Meatballs: yeast



OSMOSIS.ORG 367



OTHER DIAGNOSTICS Tinea versicolor ▪ Wood’s lamp examination: yellow to yellow-green fluorescence Seborrheic dermatitis ▪ Clinical findings upon examination



TREATMENT MEDICATIONS Tinea versicolor ▪ Topical agents: antifungal medications, selenium sulfide, zinc pyrithione ▪ Oral antifungal medications if nonresponsive



368 OSMOSIS.ORG



Seborrheic dermatitis ▪ No known cure ▪ Chronic topical agent treatment: antifungal medications, corticosteroids, calcineurin inhibitors ▫ Other topical agents: selenium sulfide, zinc pyrithione, salicylic acid or coal tar (keratolytics) ▪ Oral antifungal agents if non-responsive



Chapter 2 Acyanotic Defects



NOTES



DIPLOCOCCI: AEROBIC MICROBE OVERVIEW ▪ Spherical-shaped bacteria (cocci), appear in pairs as joined cells (diplo) ▪ Gram-negative, aerobes/facultative anaerobes, non-motile, non-spore forming



TYPES Moraxella catarrhalis ▪ Oxidase +, nitrate reduction + (characteristic) ▪ Part of normal respiratory flora, causes opportunistic infections ▪ Virulence factors ▫ Beta-lactamase production → penicillin resistant ▫ DNase production ▪ Culture ▫ Isolation specimen: respiratory secretions, sputum ▫ Media: blood, chocolate agar (round, opaque colonies that turn pink after 48 hours; positive “hockey puck sign”: able to slide colonies across agar with wooden stick without disruption) Neisseria gonorrhoeae ▪ Facultatively intracellular ▪ Oxidase +, catalase + ▪ Fermentation ▫ Glucose; differentiation from N. meningitidis ▪ Virulence factors ▫ LOS/endotoxin: triggers inflammation; undergoes antigenic variation ▫ IgA1 protease: cleaves IgA antibodies; aids in evasion of humoral immune response ▫ Type IV pili: promote adhesion of bacteria to epithelium; undergo phase, antigenic variation



▫ Porins (PorA, PorB): allow movement of ions, nutrients into bacteria, promote invasion into cells ▫ Opa, Opc: promote adhesion, invasion; undergo phase, antigenic variation ▪ Culture ▫ Isolation specimen: urine, vaginal/ endocervical swab, urethral swab; pharyngeal, rectal swab ▫ Media: Thayer–Martin VCN, chocolate agar Neisseria meningitidis ▪ Facultatively intracellular ▪ Oxidase +, catalase + ▪ Fermentation ▫ Maltose, glucose ▪ Present as normal non-pathogenic flora of nasopharynx in 10% of adults ▪ Virulence factors ▫ Capsule: prevents phagocytosis; N. meningitidis subdivided into 13 serogroups based on capsular polysaccharides; A, B, C, W135, Y account for most disease cases ▫ Lipooligosaccharide (LOS)/endotoxin: released in blebs/vesicle-like structures → sepsis, vascular necrosis, hemorrhage into surrounding tissue; levels of LOS closely correlate with prognosis ▫ IgA1 protease: cleaves IgA antibodies; aids in evasion of humoral immune response ▫ Pili: promote adherence of bacteria to nasopharyngeal epithelium; undergo phase, antigenic variation → protect against host immune response, vaccines ▫ Opacity proteins (Opa, Opc): promote adhesion, invasion



OSMOSIS.ORG 369



▫ Factor H binding protein: downregulates alternative complement pathway ▪ Culture ▫ Isolation specimen: blood, cerebrospinal fluid (CSF), petechial scrapings ▫ Media: Thayer–Martin vancomycin, colistin, nystatin (VCN), chocolate agar



MORAXELLA CATARRHALIS osms.it/moraxella-catarrhalis PATHOLOGY & CAUSES ▪ Gram-negative diplococcus → respiratory tract infections, otitis media ▪ Infections caused by M. catarrhalis ▫ Respiratory tract infections (bronchitis, rhinosinusitis, laryngitis, bronchopneumonia, communityacquired bacterial pneumonia) ▫ Otitis media in children < three years of age ▫ Exacerbations of chronic obstructive pulmonary disease (COPD)



RISK FACTORS



▪ Immunocompromised individuals ▪ Individuals with chronic respiratory disease



370 OSMOSIS.ORG



(e.g. COPD, emphysema) ▪ Children < two years of age, elderly



COMPLICATIONS



▪ Rare: bacteremia, septicemia, urethritis, septic arthritis



SIGNS & SYMPTOMS ▪ Acute bacterial rhinosinusitis: fever, nasal obstruction, purulent nasal discharge, facial pain, headache ▪ Otitis media: fever, ear pain, bulging tympanic membrane ▪ Exacerbations of COPD: increased cough, sputum production/change in color, dyspnea



Chapter 68 Diplococci: Aerobic



DIAGNOSIS OTHER DIAGNOSTICS



▪ Clinical presentation ▫ Sufficient for diagnosis ▪ Microbiologic diagnosis



TREATMENT MEDICATIONS ▪ ▪ ▪ ▪



Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole Third-/second-generation cephalosporins Macrolides (e.g. azithromycin, clarithromycin)



NEISSERIA GONORRHOEAE osms.it/neisseria-gonorrhoeae PATHOLOGY & CAUSES ▪ Gram-negative diplococcus → gonococcal disease (gonorrhea, disseminated gonococcemia, gonococcal ophthalmia neonatorum) ▪ Portal of entry ▫ Unprotected sex (vaginal, oral, anal): bacteria attaches, invades genitourinary, rectal, oral epithelium via Opa, Opc, pili → gonorrhea ▫ Rare: invades bloodstream → disseminated gonococcemia, septic arthritis ▫ Perinatal transmission: birth canal of infected mother → gonococcal ophthalmia neonatorum



TYPES



▪ Gonorrhea ▫ Urethritis, cervicitis, proctitis, pharyngitis ▪ Disseminated gonococcemia ▫ Result of spread, intravascular multiplication of N. gonorrhoeae; joints, skin (dermatitis-arthritis syndrome) ▪ Gonococcal ophthalmia neonatorum ▫ Causes gonococcal conjunctivitis



RISK FACTORS



▪ Unprotected sex ▫ Individuals with multiple sexual



partners, sex between individuals who are biologically male (MSM), recent new sexual partner ▪ Low educational, socioeconomic levels ▪ Substance abuse ▪ History of gonorrhea



COMPLICATIONS Gonorrhea ▪ Epididymitis, prostatitis, penile lymphangitis, urethral strictures in individuals who are biologically male; cervical gonorrhea → pelvic inflammatory disease → infertility in individuals who are biologically female Gonococcal ophthalmia neonatorum ▪ Corneal scarring/perforation, blindness



SIGNS & SYMPTOMS Gonorrhea ▪ Some individuals who are biologically male, most individuals who are biologically female (50–80%) asymptomatic ▪ Urethritis: dysuria, urinary urgency, purulent foul-smelling urethral discharge ▪ Cervicitis: lower abdominal discomfort, dyspareunia (pain during sexual intercourse), vaginal pruritus, purulent foulsmelling vaginal discharge



OSMOSIS.ORG 371



▪ Proctitis: anal pruritus, tenesmus, rectal fullness, constipation, purulent anorectal discharge, bleeding ▪ Pharyngitis: sore throat, swollen lymph nodes Disseminated gonococcemia ▪ Fever, chills, generalized malaise ▪ Polyarthralgia (multiple joint pain) ▪ Tenosynovitis (tendon inflammation) ▪ Pustular/vesiculopustular lesions on skin Gonococcal ophthalmia neonatorum ▪ Purulent conjunctival discharge ▪ Swollen eyelids ▪ Conjunctival hyperemia, chemosis



DIAGNOSIS LAB RESULTS Blood tests ▪ ≥ two white blood cells in urethral secretions ▪ ≥ 10 white blood cells on microscopic examination of first void urine ▪ Disseminated gonococcemia ▫ Positive blood culture ▫ Synovial fluid leukocyte count: increased values (50,000 cells/microL) Gram stain ▪ Polymorphonuclear leukocytes with intracellular gram-negative diplococci Nucleic acid amplification testing (NAAT) ▪ For initial diagnosis



TREATMENT MEDICATIONS



Figure 68.1 A neonate with gonococcal ophthalmia neonatorum.



▪ Uncomplicated gonorrhea ▫ Intramuscular injections of ceftriaxone + azithromycin/doxycycline (in case of gonococcal resistance to cephalosporins, potential chlamydia regardless of chlamydial coinfection status)



OTHER INTERVENTIONS



▪ Prophylaxis ▫ No vaccines ▫ Extensive antigenic variations of bacterial components (pili, LOS, opa proteins) prevents development of immunological memory



Figure 68.2 Creamy discharge emanating from the external urethral meatus is typical of genital gonorrhea infection.



372 OSMOSIS.ORG



Chapter 68 Diplococci: Aerobic



NEISSERIA MENINGITIDIS osms.it/neisseria-meningitidis PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Gram-negative diplococcus → meningococcal disease (meningitis, meningococcemia) ▪ Portal of entry ▫ Inhalation of respiratory droplets → bacteria attaches to respiratory epithelium via Opa, Opc, pili → nasopharynx colonization → usually resolves asymptomatically (carriers) ▫ Invades bloodstream → meningococcal disease (rare)



Meningococcemia ▪ Petechial rash caused by destruction of blood vessels, hemorrhage due to endotoxin release; fever, chills; joint, muscle pain



RISK FACTORS



Meningitis ▪ Infants ▫ Early nonspecific: irritability, vomiting, inactivity, poor feeding, temperature instability ▫ Late specific: bulging anterior fontanelle, seizures ▪ Children, adolescents, adults ▫ Early nonspecific: sudden onset of fever, headache, nausea, vomiting, myalgia ▫ Late specific: altered mental status, lethargy, neck stiffness (nuchal rigidity), photophobia ▫ First specific symptoms of sepsis: abnormal skin color (pallor/mottling) which can evolve from nonspecific rash to petechial to hemorrhagic over several hours; cold hands, feet; leg pain ▪ Signs upon physical examination ▫ Positive Kernig’s sign: inability to straighten leg when hip flexed to 90º ▫ Positive Brudzinski’s sign: flexing of neck by examiner → flexing of hips, knees



COMPLICATIONS



Fulminant meningococcemia ▪ Abrupt onset ▪ Rapid enlargement of petechiae/ ecchymoses ▪ Hypotension, tachycardia due to vascular collapse, shock



TYPES



▪ Meningococcemia ▫ Result of intravascular multiplication of N.meningitidis; can occur alone/in conjunction with meningitis ▪ Meningitis ▫ Most common; occurs upon spreading of bacteria to meninges during meningococcemia; usually affects children, adolescents ▪ Fulminant meningococcemia ▫ AKA Waterhouse–Friderichsen syndrome; most severe form of meningococcal sepsis; massive bilateral hemorrhage into adrenal glands



▪ Infants 6–24 months (due to immature immune system, inability to vaccinate) ▪ Living in close quarters (military barracks, dormitories)



▪ Adrenal insufficiency; disseminated intravascular coagulation (DIC); purpura fulminans (cutaneous hemorrhage, necrosis due to vascular thrombosis, DIC); acute respiratory distress syndrome (ARDS); coma, death



OSMOSIS.ORG 373



DIAGNOSIS LAB RESULTS



▪ Fulminant meningococcemia ▫ Adrenal insufficiency signs: ↓ blood glucose, ↑ K+, ↓ Na+, adrenocorticotropic hormone (ACTH) stimulation test (low response) ▫ Thrombocytopenia due to DIC ▫ Metabolic acidosis ▪ Meningococcemia and meningitis ▫ Blood culture and CSF analysis



OTHER DIAGNOSTICS



▪ Physical examination ▫ Characteristic findings of meningitis



TREATMENT MEDICATIONS Prophylaxis ▪ Quadrivalent immunization with purified capsular polysaccharides from serogroups A, C, Y, W135 (group B not available)



Figure 68.3 A petechial rash can be seen in the late stages of meningococcal septicemia.



Meningococcal disease ▪ Antibiotics ▫ Third-generation cephalosporins (e.g. cefotaxime, ceftriaxone)/penicillin G ▪ Chloramphenicol ▫ In case of beta-lactam antibiotics hypersensitivity ▪ Chemoprophylaxis of individuals in close contact with the infected ▫ Rifampin of ciprofloxacin ▪ Hydrocortisone ▫ For adrenal insufficiency



SURGERY



▪ Plastic surgery, skin grafting, amputation to treat tissue necrosis



374 OSMOSIS.ORG



Figure 68.4 The brain of an individual at post mortem following death from bacterial meningitis. Nesseiria meningitidis is the most common causative organism amongst adolescents and young adults.



NOTES



NOTES



ECTOPARASITES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Ectoparasites: arthropods that live on outside of host, extract nutrients at host’s expense ▫ Uncommon: viable parasites transferred without direct host contact



RISK FACTORS



DIAGNOSIS OTHER DIAGNOSTICS History ▪ Including close contacts/living quarters Physical examination ▪ Dermatologic examination



▪ Commonly poor hygiene, close living quarters



TREATMENT MEDICATIONS



COMPLICATIONS



▪ Predicated on individual’s immune status, housing situation



▪ Topical neurotoxins, topical/oral parasidal drugs



OTHER INTERVENTIONS



SIGNS & SYMPTOMS ▪ Pruritus, bite marks, visible body parasites



▪ Proper hygiene, household measures, isolation (if necessary)



PEDICULOSIS CORPORIS, CAPITIS, AND PUBIS (LICE) osms.it/lice PATHOLOGY & CAUSES ▪ Infestation of easily transmissible sucking lice species ▫ Commonly in hairy bodily areas, characterized by local pruritus ▪ Sucking lice infection ▫ (Phylum) arthropoda → (class) insecta → (order) phthiraptera → (suborder)



anoplura → (family) pediculidae/ pthiridae



PATHOLOGY



▪ Lice live human hair → suck blood for nutrients ▫ Bite → saliva injection → anticoagulation effect, ↑ histamine release → maculae cerulea (blue/copperhued bite marks); pruritus



OSMOSIS.ORG 375



▪ Lice require humans for nutritional source (parasites) ▫ Most climates allow mature louse 24 hours of viable life away from human source Transmission ▪ Physical contact ▫ Ideal location: slow-moving, parallel hair fibers ▫ Louse on one hair fiber → transfer to another individual’s hair → lay nits (eggs) on hair 1–2mm off of scalp → nymphs hatch within one week → mature over one week → female lice lay eggs for one month ▪ Fomites



TYPES



▪ Pediculus humanus capitis → head louse ▫ Can survive 24–48 hours without blood meal/separated from host ▪ Pediculus humanus humanus → body louse ▫ Larger than head louse; can survive < 72 hours without blood meal ▪ Phthirus pubis → pubic louse ▫ AKA crab louse; can spread to body



RISK FACTORS



▪ School-aged children ▪ Homeless population ▪ Refugee population (if living in close quarters)



COMPLICATIONS



▪ Co-infections (also carried by louse) ▫ Bartonella quintana → endocarditis ▫ Epidemic typhus ▫ Louse-borne relapsing fever ▫ Trench fever ▪ Adolescents with pubic lice → ↑ gonorrhea/ chlamydial infection risk ▪ Pruritus → skin excoriation → secondary infection ▫ Commonly staphylococcal infection



SIGNS & SYMPTOMS ▪ Site pruritis (head, body, pubis)



376 OSMOSIS.ORG



DIAGNOSIS OTHER DIAGNOSTICS Dermatologic examination ▪ Examination of hair follicles, clothing seams ▪ Nits: more visible than nymphs/lice; most visible (white) after louse released from egg; does not dislodge easily from hair follicle ▪ Body louse → widespread dermatitis ▪ Often linear excoriations ▪ Maculae ceruleae → may have punctal hemorrhages → recent bites ▪ Hyperpigmentation/lichenification → older bites Lymph node examination ▪ Capitis infection → posterior lymphadenopathy



TREATMENT MEDICATIONS Topical benzyl alcohol ▪ Mechanism of action → louse asphyxiation ▫ Difficult for resistance to develop Neurotoxic agents ▪ Resistance develops with ▫ Pyrethrin: botanically-derived neurotoxin ▫ Permethrin: Na+ channel blocker → paralysis → death ▫ Malathion: organophosphate cholinesterase inhibitor



OTHER INTERVENTIONS Hair shaving ▪ Eradicate current infection Mechanical removal ▪ Wet combing → tedious, poor compliance ▫ Pre-treatment: vinegar/formic acid → flattened hair cuticle → better combing efficiency (does not dissolve/loosen nits) Prevention ▪ Proper hygiene



Chapter 69 Ectoparasites ▪ Household ▫ Housemates: examination ▫ Bedmates: prophylactic treatment ▫ Household cleaning: washing > 54°C/130°F; unwashable material → place in sealed plastic bag for two weeks



▪ School ▫ No nit policy (infected children stay home), education, screening during outbreaks



SARCOPTES SCABIEI (SCABIES) osms.it/sarcoptes-scabiei PATHOLOGY & CAUSES ▪ Sarcoptes scabiei mite infection ▫ Elicits strong immune response ▫ Nocturnal pruritus Mite infection ▪ (Phylum) mite → (class) arachnida → (subclass) acari → (order) astigmata → (family) sarcoptidae ▫ Usually obligate human parasite → vars hominis ▫ Sometimes animal mange mites can infest



PATHOLOGY Mite transfer ▪ Direct skin-to-skin contact for 15–20 minutes ▪ Average infested individual carries 5–12 mites ▫ Crusted scabies individuals: > 1000 mites can be shed (transmission through objects more likely) Type IV hypersensitivity reaction ▪ House dust mite cross reactivity ▪ Infestation → ↑ IL-6, vascular epithelial growth factor (VEGF) →TH1-cell activation → IL-2 release → lymphocyte proliferation, differentiation



RISK FACTORS



▪ Overcrowding (including long-term care facilities, prisons), poor hygiene/nutrition, homelessness, dementia, sexual contact



COMPLICATIONS



▪ Infestation → secondary staphylococcal infection ▫ Low-income countries (mostly) ▫ Impetigo → chronic kidney disease ▫ Ecthyma, paronychia, furunculosis



Crusted scabies ▪ AKA Norwegian scabies ▪ Infection commonly scalp, hands, feet → diffuse spread over entire body ▪ Occurs in compromised cellular immunity setting ▫ Acquired immunodeficiency syndrome (AIDS) ▫ Human lymphocytic virus type 1 (HTLV1) ▫ Leprosy ▫ Lymphoma ▫ Long-term topical corticosteroid use ▪ Risk factors: age, Down syndrome ▪ Complications: fissional lesions develop → bacterial entryway → infection ▫ Sepsis, poststreptococcal glomerulonephritis



OSMOSIS.ORG 377



SIGNS & SYMPTOMS Classic scabies ▪ Intense, intractable, generalized pruritus ▪ Nodules, pustules at most intense pruritus sites ▪ Common areas → intertriginous spaces ▫ Anterior axillary folds, webs of fingers, volar aspect of hand/wrist, beltline, penis, areolar region (biologically-female individuals)



Dermatologic examination ▪ Serpiginous keratotic lines (1–4mm) → burrow marks ▫ Often with vesicle on end (housing mite)



Nodular scabies ▪ Hypersensitivity reactions → large, persistent, intensely pruritic 5–6mm nodules ▫ Commonly groin, buttock, axillary folds Crusted scabies ▪ Poorly defined, erythematous patches → scale ▫ Untreated → entire integumental spread → warty appearance (especially over bony prominences); lesions crust, fissure develop → malodorous; nail involvement → thickened, dystrophic, discolored



DIAGNOSIS LAB RESULTS Microscopy ▪ Confirmatory scraping: fluorescein stain → highlights fecal material, ova fragments ▫ Epithelial milieu (eosinophils, lymphocytes, histiocytes) ▫ Crusted scabies: mate capture more likely due to disease burden Polymerase chain reaction assays ▪ S. scabiei DNA polymerase



OTHER DIAGNOSTICS History ▪ Close contact commonly present with concurrent symptoms ▪ Infected individual contact history (may be many weeks prior)



378 OSMOSIS.ORG



Figure 69.1 A high-magnification photograph of a single mite burrow in the skin of an individual with scabies. The mite is at the end of the burrow at the top right of the image.



TREATMENT MEDICATIONS Classic scabies ▪ Permethrin (5%) → synthetic neurotoxin → Na+ channel blocker → paralysis → death ▪ Precipitated sulfur (6%, 10%) in petroleum ▪ Benzyl benzoate (10%, 25%) ▫ Adverse reactions: allergic dermatitis ▫ Contraindications: pregnancy/lactation (neurotoxicity); children < two years old ▪ Oral ivermectin ▫ One dose (200mcg/kg) repeated in 7–10 days Nodular scabies ▪ Topical steroids ▪ Intralesional steroid injection Crusted scabies ▪ Topical, systemic treatment required ▪ Oral ivermectin, topical permethrin (5%)/ benzyl benzoate (5%) ▫ Two week oral regimen, topical therapy



Chapter 69 Ectoparasites persisting after that twice weekly until cure ▫ Treatment cure → active lesion resolution, nocturnal pruritus absence for one week



OTHER INTERVENTIONS



▪ Isolation for infected ▪ Nail clipping ▫ +/- brushing with scabicidal agent ▪ Thorough personal, household material laundering



Prevention ▪ Monosulfiram soap in communities with ↑ ↑ incidence



OSMOSIS.ORG 379



NOTES



NOTES



ENTEROCOCCUS



ENTEROCOCCUS osms.it/enterococcus PATHOLOGY & CAUSES ▪ Gram-positive spherical-shaped bacteria (cocci) ▪ Grow in pairs (diplococci)/short chains ▪ Non-spore forming ▪ Optimal growing conditions: 45ºC/113°F, can withstand up to 60ºC/140°F ▫ Facultatively anaerobic bacteria ▫ 6.5% NaCl, bile-containing media ▪ Characteristics ▫ Catalase negative, pyrrolidonyl arylamidase (PYR) positive ▫ Variable hemolytic activity on blood agar plates; most commonly gamma hemolytic ▪ Common human pathogens: E. faecalis, E. faecium ▪ Important cause of hospital-acquired infections, esp. infective endocarditis, urinary tract infections (UTIs), infections of prosthetic devices (e.g. venus/urinary catheters) ▫ Surface carbohydrates → adherence to cardiac valves → fibrinogen synthesis → valve vegetations → infective endocarditis ▫ Adherence to renal epithelial cells → UTI ▪ Less common associations ▫ Wound, bloodstream, biliary tract, pelvic infections; intraabdominal abscesses



RISK FACTORS



▪ Indwelling medical devices (e.g. central venous, urinary catheterization) ▪ Cardiovascular abnormalities



380 OSMOSIS.ORG



▪ Prolonged hospitalization, mechanical ventilation ▪ Prior antibiotic use, immunodeficiency



COMPLICATIONS



▪ Bacteremia ▫ Immunocompromised individuals



SIGNS & SYMPTOMS ▪ UTIs ▫ Cystitis, pyelonephritis; dysuria, frequency, urgency, suprapubic/flank tenderness ▪ Infective endocarditis ▫ Subacute onset of fever, malaise, peripheral signs (e.g. Janeway lesions, Osler’s nodes), cardiac murmurs (usually left-sided), splenomegaly ▪ Infection of prosthetic devices, wounds ▫ Erythema, swelling, tenderness, warmth



DIAGNOSIS DIAGNOSTIC IMAGING Transthoracic echocardiography; abdominal CT scan; ultrasound ▪ Identify organ involvement



LAB RESULTS



▪ Cultures from infected sites (e.g. blood, urine) ▪ Susceptibility testing ▫ Detect antibiotic resistance



Chapter 70 Enterococcus ▪ Complete blood count (CBC) ▫ ↑ polymorphonuclear cells ▪ Urinalysis ▫ UTI → pyuria, proteinuria, hematuria



TREATMENT MEDICATIONS Antimicrobial therapy ▪ Localized infections ▫ Ampicillin/beta lactamase inhibitors (clavulanate/sulbactam) ▫ Alternative: nitrofurantoin ▪ Serious infections with bacteremia, meningitis, endocarditis ▫ Penicillin/ampicillin + aminoglycoside ▫ Alternative: vancomycin, aminoglycoside ▪ Vancomycin-resistant enterococcal (VRE) infection ▫ Linezolid/daptomycin



SURGERY



▪ Drain abscess ▪ Valve replacement



OTHER INTERVENTIONS



▪ Remove venous/urinary catheters



OSMOSIS.ORG 381



NOTES



NOTES



FILAMENTS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



▪ Gram ⊕ slender bacteria with ⊕ branches (atypical lung disease organisms, capable of affecting any body organ ▪ Atypical organisms → indolent disease → insidious growth → severe disease



RISK FACTORS ▪ Immunodeficiency ▪ Corticosteroid use → iatrogenic immunosuppression



SIGNS & SYMPTOMS ▪ Cough, dyspnea ▫ Indolent course ▫ Common in fever’s absence ▪ Other symptoms ▫ Dependent on organ systems affected by organism



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Localized alveolar infiltrate ▫ Homogeneous, non-segmental, cavitary appearance



382 OSMOSIS.ORG



LAB RESULTS



▪ Tissue biopsy → histological



OTHER DIAGNOSTICS Physical examination ▪ Pulmonary examination ▫ Auscultation: rhonchi (crackles), ↓ breath sounds ▫ Palpation: ↓ tactile fremitus ▫ Percussive dullness



TREATMENT MEDICATIONS ▪ Antibiotics



SURGERY



▪ Resection ▫ Medication non-responsive ▫ Large infections → significant dysfunction



Chapter 71 Filaments



ACTINOMYCES ISRAELII osms.it/actinomyces-israelii PATHOLOGY & CAUSES Microbe characteristics ▪ ⊕ Gram stain ▪ Shape ▫ Filamentous, non-spore-forming, pleomorphic bacilli ▪ Metabolism ▫ Catalase negative, anaerobic/ microanaerobic bacilli ▪ Types ▫ 21 species found in humans ▫ Actinomyces israelii most common ▪ Locations ▫ Normal mouth (by two years old), gastrointestinal (GI) tract, female genitourinary tract flora



PATHOLOGY



Thoracic ▪ Pulmonary → pneumonia ▫ Oropharyngeal content aspiration → bacterial alveoli seeding → immune response, bacterial growth → pneumonia Abdominal & pelvic ▪ Gastrointestinal → appendicitis ▫ Preceding colonic mucosa perforation → unrecognized → months–year course → symptomatic infection ▪ Pelvic → female genitourinary infections ▫ Complicated abortions, infected intrauterine devices (IUDs), endometritis, tubo-ovarian abscess (TOA)



RISK FACTORS



▪ Chronic granulomatous disease



Cervicofacial ▪ Chronic tonsillitis, dental decay, periodontal disease, mastoiditis, otitis media



▪ Uncommon infection source ▪ Mucosal membrane violated → indolent, invasive disease ▫ Commonly co-occurs with another pathogen → micro-O2 Actinomyces environment ▫ Can burrow through soft tissue, bone → small abscesses, drainage tracts ▫ Abscesses: yellow sulfur-containing granules in granulomatous reactive material setting (bacteria found in microfilament tangles, surrounded by neutrophils)



COMPLICATIONS



TYPES



Thoracic ▪ Pneumonitis



Cervicofacial ▪ Osteomyelitis of mandible/maxilla ▫ Resident flora in periodontal pockets, carious teeth, dental plaque, tonsillar crypts



Abdominal & pelvic ▪ Gastrointestinal ▫ Peritoneal, hepatic, pelvic infectious spread



Thoracic ▪ Aspiration history



Cervicofacial ▪ Deep neck tissue infection → retropharyngeal space → mediastinitis ▪ Meningitis → if sinus tracts to posterior neck, spinal cord



OSMOSIS.ORG 383



SIGNS & SYMPTOMS Cervicofacial ▪ Lumpy jaw ▫ Usually in fever’s/other infectious signs’ absence ▪ Progression → oral mucosa, trismus sinus tract draining Thoracic ▪ Fever, cough > three day duration ▪ Auscultation ▫ Rhonchi ▫ ↓ breath sounds ▪ Palpation ▫ ↓ tactile fremitus ▪ Percussive dullness Abdominal & pelvic ▪ Gastrointestinal → appendicitis ▫ Asymptomatic colonic mucosa (micro) perforation → months–years prodrome → symptomatic appendicitis ▫ Nonspecific prodrome: chronic fever, weight loss, diarrhea, constipation, night sweats ▫ Appendicitis: nausea, vomiting, anorexia ▪ Pelvic → female genitourinary infections ▫ Painful abdominal, cervical examination ▫ Purulent vaginal discharge



CT scan ▪ Abdominal, pelvic ▫ Disrupted tissue planes Colonoscopy ▪ Abdominal, pelvic ▫ Normal/thickened mucosal appearance, colitis, ulceration, nodular lesion, buttonlike appendiceal orifice elevation Bedside ultrasound ▪ Abdominal, pelvic ▫ TOA evaluation



LAB RESULTS



▪ Cervicofacial ▫ Monoclonal antibody staining ▫ Polymerase chain reaction (PCR) of 16S rRNA



Cultures (needle aspiration) ▪ Cervicofacial ▫ Histology: granulation tissues with neutrophils, foamy macrophages, lymphocytes, plasma cells (with surrounding fibrosis) ▪ Abdominal, pelvic ▫ Histology: granulation tissue surrounding oval, eosinophilic zones



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Thoracic ▫ Localized alveolar infiltrate: homogeneous; non-segmental, cavitary appearance; can extend past fissure lines → into chest wall Barium enema ▪ Abdominal, pelvic ▫ Luminal narrowing, fistualization, extrinsic compression



384 OSMOSIS.ORG



Figure 71.1 Sulphur granules formed by Actinomyces organisms.



Chapter 71 Filaments



OTHER DIAGNOSTICS History ▪ Thoracic ▫ May have community-acquired pneumonia diagnosis, treatment (without relief within 3–5 days) Physical examination ▪ Cervicofacial ▫ Lymphatic examination ▪ Thoracic ▫ Pulmonary examination



TREATMENT MEDICATIONS



▪ Antibiotics ▫ Prolonged (weeks–months) penicillin V (oral)/penicillin G (intravenous) ▫ Amoxicillin (alternative)



SURGERY



▪ Necrotic disease/especially large abscess formation cases



NOCARDIA osms.it/nocardia PATHOLOGY & CAUSES ▪ Microbe characteristics ▪ ⊕ Gram stain ▪ Shape ▫ Filamentous, branch-forming, bacillus ▫ Branches → beaded appearance (delicate nature of stain → cocci/bacilli fragmentation) ▪ Metabolism ▫ Aerobic, catalase ⊕, urease ⊕ ▪ Types ▫ > 80 species ▫ Around 30 disease-causing in humans ▪ Locations ▫ Saprophyte (organic pathogen) → found in soil, house dust, water (fresh/salt), bathing pools



PATHOLOGY



▪ Direct tissue inoculation ▫ Saprophyte → aerosolization common (↑ ↑ pulmonary infections) ▫ Soil/water contamination (contaminated food → GI disease, skin trauma → cutaneous disease, eye trauma → ocular disease)



▪ Facultative intracellular organism → requires innate host defense mechanisms ▫ Inhalation entry: deficient/ineffective mucociliary clearance, host response → bronchopulmonary disease ▫ Skin trauma entry: deficient keratinized skin barrier → local subcutaneous infection; deficient keratinized cornea → ocular infection ▪ Rapid filamentous growth → ↓ phagocytic clearing ▫ Phagocytosed → ↓ lysosomal destruction (phagocyte-lysosome fusion inhibition; catalase, dismutase production → ↓ reactive oxygen species → pathogen survival)



TYPES Pneumonia ▪ Nocardia asteroides (common pathogen) ▪ > 2⁄3 of total disease ▪ Progression ▫ Empyema, pericardial effusion Primary cutaneous infections ▪ Nocardia brasiliensis (common pathogen) ▪ Cellulitis, ulcers, pyoderma, myocetma



OSMOSIS.ORG 385



▪ Progression ▫ Abscess/nodular development, lymphangitis



RISK FACTORS



▪ ↓ mucociliary clearance ▫ Cystic fibrosis, asthma, bronchiectasis ▪ Immunosuppression ▫ Iatrogenic (most commonly corticosteroid use); lymphoreticular malignancy; chronic obstructive pulmonary disease; chronic granulomatous disease; dysgammaglobulinemia; HIV infection; bone marrow, organ transplant



COMPLICATIONS



▪ Organ dissemination ▫ Pulmonary infection → hematogenous spread (commonly) ▫ Most common: central nervous system (meningitis, cerebral abscess) ▪ Pulmonary ▫ Empyema, pericardial effusion ▪ Cutaneous ▫ Lymphangitis ▪ Ocular ▫ Endophthalmitis (ocular infection)



SIGNS & SYMPTOMS Pneumonia ▪ Acute, subacute, chronic suppurative course ▫ Symptoms may also relapse/remit ▪ Cough, dyspnea common ▫ Anorexia, weight-loss (uncommon) ▫ Hemoptysis (cavitary disease) ▪ Rhonchi (crackles) ▪ ↓ breath sounds, tactile fremitus, +/egophony Local cutaneous infection ▪ Local erythema, warmth, +/- ulceration, nodular growth Neurologic infection ▪ Meningismus, fever, rigors, seizure



386 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary ▫ Homogeneous, non-segmental, cavitary alveolar infiltrate Brain MRI ▪ Neurologic ▫ ↑ T1 imaging intensity → ↑ enhancement (gadolinium)



LAB RESULTS



▪ Tissue biopsy: histology (acid fast stain) ▫ Gram ⊕, branching, beaded filamentous growth



TREATMENT MEDICATIONS Antibiotic monotherapy ▪ Mild/moderate disease ▪ 3–6 months treatment duration ▪ Sulfonamides → trimethoprimsulfamethoxazole (TMP-SMX) ▪ Linezolid ▫ Nocardia 100% sensitive ▫ Limited treatment duration (2–3 weeks) → ineffective monotherapy for complete therapy duration Antibiotic multi-agent therapy ▪ Severe disease ▪ Up to 6–12 months treatment duration ▪ Agents ▫ TMP-SMX + amikacin/carbapenem/ linezolid ▪ Commonly for progressive disease in immunosuppressed individuals/pulmonary, disseminated disease Prevention & vaccine ▪ Daily, full-strength TMP-SMX → secondary prophylaxis ▪ P. jirovecii TMP-SMX prophylaxis (3x/week) → ineffective



Chapter 71 Filaments



SURGERY



▪ Indicated for ▫ Antibiotic-resistant, large cutaneous/ cerebral abscess (craniotomy/aspiration effective) ▫ Empyemas, large fluid collections ▫ Pulmonary nocardiosis → pericarditis (fatal if not performed)



OSMOSIS.ORG 387



NOTES



NOTES



FILOVIRUSES MICROBE OVERVIEW Genetic material ▪ Single-stranded negative-sense RNA virus family; causes viral hemorrhagic fever Taxonomy ▪ Genera: Ebolavirus, Marburgvirus, Cuevavirus Morphology ▪ Enveloped virions; filamentous, nonsegmented morphology Replication ▪ Transcription, replication mediated by virus-encoded polymerase in infected cell cytoplasm ▫ Transcription: negative-sense RNA genome transcribed into monocistronic, polyadenylated RNA species using host cell ribosomes, tRNA etc. → translated into seven proteins ▫ Replication: positive-sense antigenome serves as template for negative-sense genomes



Transmission ▪ Zoonotic infection ▫ Natural host: unknown (bats, especially fruit bats considered infection source) ▫ Intermediate host: Often nonhuman primates (gorillas, chimpanzees) Structural proteins ▪ Viral RNA encodes seven structural proteins ▫ Nucleoprotein ▫ Polymerase cofactor (VP35) ▫ Viral proteins VP40, VP24 ▫ Glycoprotein: projecting spikes from lipid bilayer (attachment to host cell receptors) ▫ Transcription activator ▫ RNA-dependent RNA polymerase



EBOLA VIRUS osms.it/ebola-virus PATHOLOGY & CAUSES ▪ Ebola virus: causative agent of severe, often fatal hemorrhagic fever ▪ Species: Zaire, Sudan, Tai Forest, Bundibugyo, Reston ▪ Transmission ▫ Animal-human: direct infected-animal tissue, body-fluid contact; butchering, consuming undercooked meat



388 OSMOSIS.ORG



▫ Human-human: direct tissue, body fluid contact with ill/deceased ▫ Potential transmission: contaminated surface/object contact



PATHOLOGY



▪ Inoculation → incubation: 6–12 days average (ranges 2–21 days) ▫ Host cell attachment, virus endocytosis → nucleocapsid release in cytoplasm →



Chapter 72 Filoviruses



▪



▪ ▪



▪



replication → nucleocapsid formation → viral shedding, cell necrosis Initially macrophages, dendritic cells infected → sentinel lymph node spread → bloodstream → many cell types infected (endothelial cells, fibroblasts, hepatocytes, epithelial cells, adrenal-gland cells) with lymphocyte/neuron exception ▫ Although uninfected, inflammatory mediators; support signal loss from dendritic cells → “bystander” apoptosis of lymphocytes Multifocal necrosis in various tissues (e.g. liver, spleen) Systemic inflammatory syndrome: proinflammatory mediator, cytokine release from infected macrophages, dendritic cells, necrotic cell breakdown products, etc. → vasodilation, ↑ vascular permeability → vascular leakage, shock, multiorgan failure Dendritic cell dysfunction, “bystander” lymphocyte apoptosis → impaired adaptive immunity



▪ Spontaneous abortion, vaginal bleeding in infected pregnant individuals (100% third trimester maternal, fetal mortality) ▪ Fatality ranges ▫ 40% to 80–90% (depending upon species)



RISK FACTORS



▪ Healthcare workers without appropriate protective equipment, adequate training ▪ Inadequate infected waste product, corpse handling ▪ Sexual intercourse with person recovering from Ebola in previous three months ▪ Travel to endemic/Ebola epidemic areas ▪ Wild animal contact (mostly nonhuman primates)



COMPLICATIONS



▪ Gastrointestinal dysfunction ▫ Fluid loss, hypotension, acute kidney injury, shock ▪ Neurologic ▫ Meningoencephalitis, meningitis ▪ Coagulopathy ▫ Infected macrophages produce tissue factor (TF), stimulate extrinsic coagulation pathway → disseminated intravascular coagulation (DIC) ▪ Respiratory failure ▪ Coinfection/superinfection ▪ Impaired adaptive immunity → bacterial sepsis



Figure 72.1 A scanning electron micrograph of an ebola virus demonstrating the typical filamentous structure seen in its class, Filoviridae.



SIGNS & SYMPTOMS Initial nonspecific symptoms ▪ Fever, chills, fatigue, headache, appetite loss, malaise, sore throat, myalgias, lumbosacral pain Dermatological ▪ Diffuse erythematous; nonpruritic maculopapular/morbilliform rash, especially on torso/face Gastrointestinal ▪ Watery diarrhea (up to 10L/2.2gal); nausea; vomiting; epigastric, abdominal pain; abdominal tenderness



OSMOSIS.ORG 389



Hemorrhage ▪ Commonly hematochezia, followed by hematemesis, melena, metrorrhagia, purpura, petechiae, ecchymoses, mucosal bleeding, venipuncture site bleeding ▫ Often occur later in disease course; not all infected individuals develop significant bleeding; host susceptibilitydependent (genetically determined viral immune response difference), different species’ pathogenicity Neurologic ▪ Meningoencephalitis symptoms (altered level of consciousness, hyperreflexia, myopathy, stiff neck, gait instability, seizure) Ocular ▪ Conjunctival injection, uveitis symptoms (blurred vision, photophobia, blindness) Respiratory ▪ Tachypnea, dyspnea Convalescent period ▪ Can persist > two years often followed by symptoms such as arthralgia, blurred vision, retro-orbital pain, hearing loss, alopecia, difficulty swallowing, insomnia ▪ Infectious virus/viral RNA can persist in body fluid (semen, breast milk, urine, cerebrospinal fluid, aqueous humor) < nine months after not detectable in blood → variable transmission risk



DIAGNOSIS ▪ Diagnostic criteria ▫ Clinical manifestation ▫ Travel to endemic/Ebola epidemic areas (within three weeks prior to disease onset) ▫ Infected individual contact during acute disease



LAB RESULTS



▪ Reverse-transcription polymerase chain reaction (RT-PCR) ▫ Detectable Ebola virus in blood samples within three days after symptom onset ▪ Rapid chromatographic immunoassay (ReEBOV)



390 OSMOSIS.ORG



▪ Laboratory findings ▫ Leukopenia; thrombocytopenia; ↑ ↓ hematocrit; ↑ aspartate aminotransferase (AST), alanine aminotransferase (ALT) ▫ Prolonged prothrombin (PT), partial thromboplastin time (PTT) ▫ Proteinuria, ↑ blood urea nitrogen, ↑ creatinine ▫ Hyponatremia, hypocalcemia, hyperkalemia



TREATMENT ▪ No cure ▪ Infected individual isolation; placement in negative airflow room advised



MEDICATIONS



▪ Complications treatment ▫ Coinfection/superinfection: empiric antimicrobial therapy with broad spectrum antibiotics ▫ Shock: intravenous fluids, vasoconstrictors ▫ Fever reduction: antipyretic agents



OTHER INTERVENTIONS



▪ Complications treatment ▫ Fluid, electrolyte loss correction ▫ Acute kidney injury: renal replacement therapy (dialysis) ▫ Respiratory failure: supplemental oxygen therapy, mechanical ventilation (if necessary, barotrauma risk) ▪ Prevention ▫ Ervebo: FDA-approved vaccine ▫ Proven highly effective, safe during trial conducted in Guinea (2015)



NOTES



NOTES



FLAVIVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



▪ Single-stranded, ⊕-sense, enveloped RNA viruses ▪ AKA arboviruses ▪ > 40 types identified Replication ▪ Cell surface attachment → cytoplasm entry → viral protein translation → viral RNA genome replication → virion formation (encapsidation) → cellular release Transmission ▪ Primarily transmitted via arthropod bites



RISK FACTORS



▪ Recent endemic area travel/residence ▪ Poor insect repellant use ▪ Improper skin coverage (e.g. long sleeve clothing)



SIGNS & SYMPTOMS ▪ Mainly asymptomatic ▪ Others commonly have acute-onset flu-like symptoms ▪ Serious complications/sequelae commonly



characterized by neurologic disease (e.g. seizure, encephalopathy) ▫ Fever, nausea/vomiting



DIAGNOSIS LAB RESULTS



▪ Serology ▪ Time-dependent on infection course, immune response ▪ Reverse transcription polymerase chain reaction (RT-PCR) for viral antigens



OTHER DIAGNOSTICS



▪ Endemic area travel/residence ▪ Presence of mosquito bite(s)



TREATMENT ▪ No cure



MEDICATIONS



▪ Variable vaccine availability ▫ Untenable mainly due to antigenic mutations, multiple genotypes



OTHER INTERVENTIONS ▪ Fluid, electrolyte balance



OSMOSIS.ORG 391



DENGUE VIRUS osms.it/dengue-virus PATHOLOGY & CAUSES ▪ Viral disease, mosquito transmission ▫ Characterized by febrile illness ▫ AKA break-bone fever ▪ Four serotypes ▫ DENV-1 through DENV-4 ▫ IgG response to specific type → lifetime immunity ▫ Limited, transient cross-protectivity across viral types ▪ Vector ▫ Primarily Aedes aegypti and A. albopictus Pathogenesis ▪ Aedes mosquito bite → dengue virus skin introduction → local infection, response → dissemination → viremia (2–6 days later) → circulating leukocyte infection (especially) monocytes → viral replication, release → fever



RISK FACTORS



▪ Endemic area residence ▪ Recent travel



COMPLICATIONS Severe dengue ▪ AKA dengue hemorrhagic fever ▪ Viremia → local hemorrhage → systemic hemorrhage → hemodynamic collapse → shock ▫ Dengue shock syndrome (rare complication—DENV-2 confers highest risk) ▪ Direct bone marrow infection → hematopoietic stem cell infection → ↓ megakaryocyte differentiation (among all other cell lines) → ↓ platelets formed ▫ ↓ Circulating lifetime: virus-antibody complex → circulating platelet adherence → complement destruction



392 OSMOSIS.ORG



▪



▪



▪



▪



of virus-antibody complex → adherent platelet destruction Capillary leak ▫ Direct effect: viral endothelial cell infection → cellular dysfunction → tight junction widening → capillary leak ▫ Indirect: virus-infected monocytes, dendritic cells, mast cells → TNFalpha, IFN-gamma, IL-2, IL-8, vascular endothelial growth factor release, complement activation → ↑ capillary permeability Molecular mimicry ▫ Viral E protein antibody response → plasminogen cross-reaction → inefficient coagulation cascade → hemorrhage Liver failure ▫ Direct viral infection → Kupffer cells, hepatocytes → apoptosis → hepatocellular necrosis, Councilman bodies ▫ Sever disease → shock → liver hypoperfusion → hepatocellular injury, death Central nervous system (CNS) involvement ▫ Rare, direct viral infection of brain parenchyma



SIGNS & SYMPTOMS ▪ High-grade fever (> 38.5°C/101.3°F) ▪ Generalized pain ▫ Abdominal pain/tenderness, headache, joint pain, muscle pain, eye/retro-orbital pain ▪ Nausea/vomiting ▪ Mucosal bleeding ▪ Rash Severe symptoms and signs ▪ Severe bleeding ▪ Fluid accumulation → respiratory distress ▫ Ascites, pleural effusion



Chapter 73 Flaviviruses ▪ Neurologic impairment ▫ Lethargy, seizure, encephalopathy



DIAGNOSIS LAB RESULTS



▪ Leukopenia ▪ Thrombocytopenia ▪ ↑ Hematocrit



TREATMENT MEDICATIONS



▪ No antiviral therapy available ▪ Fever control ▫ Antipyretics



OTHER INTERVENTIONS



Antibody testing ▪ Antigen assay ▫ ⊕ < five days of infection ▪ IgM ▫ ⊕ ≧ three days of infection ▪ IgG ▫ ⊕≧ seven days of infection ▫ May be ⊕ due to prior infection



OTHER DIAGNOSTICS



Positive tourniquet test ▪ Blood pressure cuff insufflation → maintain pressure midway between systolic, diastolic → hold for five minutes → deflate → observe for petechiae ▫ Positive test:10+ petechiae in 2.5cm/1in



▪ Maintain adequate intravascular volume ▪ Shock ▫ Crystalloid fluid resuscitation ▪ Bleeding ▫ Platelet transfusion if severe thrombocytopenia and/or active, uncontrolled bleeding



Prevention ▪ Mosquito control ▫ ↓ Standing water breeding sites ▫ Copepod use (organisms feed on mosquito larvae) ▫ Insecticides ▪ Personal protective measures ▫ Repellant use ▫ Permethrin-treated clothing (Na+ channel blockade → neurotoxicity → paralysis → death; low toxicity in humans)



WEST NILE VIRUS osms.it/west-nile-virus PATHOLOGY & CAUSES ▪ Virus causing mosquito-borne, self-limited disease ▫ Characterized by flu-like symptoms ▫ Potential for severe neurologic sequelae ▪ Vector ▫ Culex mosquito Pathogenesis ▪ Culex mosquito bite → viral replication in skin’s dendritic cells → lymph node migration → further replication →



enters bloodstream → visceral organ dissemination ▫ Complication arise when virus enters bloodstream → crosses blood-brain barrier Transmission ▪ Infected bird (amplifying host) → prolonged viremia → Culex mosquito blood meal → human/other vertebrate bite → blood meal, virus-laden saliva injected→ virus transmission ▪ Viral-load organ/blood donation ▪ Transplacental infection



OSMOSIS.ORG 393



RISK FACTORS



▪ Elderly ▪ Immunosuppressed individuals ▪ Malignancy (especially hematologic malignancies) ▪ Chemokine receptor CCR5 deficiency ▫ Chemokine involved in viral infection immune response (especially brain parenchyma)



COMPLICATIONS



▪ Neurological ▫ Meningitis, encephalitis, tremor, flaccid paralysis, Guillain–Barré syndrome ▪ Ocular ▫ Chorioretinitis, uveitis, optic neuritis ▪ Cardiac ▫ Myocarditis, cardiac arrhythmias ▪ Muscular ▫ Myositis, rhabdomyolysis ▪ Other ▫ Pancreatitis, orchitis, hepatitis, central diabetes insipidus



SIGNS & SYMPTOMS ▪ Abrupt-onset fever, headache, myalgias ▫ Usual presentation is self-limited (AKA West Nile Fever) ▪ Abdominal pain, anorexia, nausea/vomiting, diarrhea, maculopapular rash Neurologic complications ▪ Motor ▫ Tremor, flaccid paralysis (Guillain-Barré complications) ▪ Meningoencephalitis ▫ Meningismus, altered mental status



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Neurologic sequelae → ↑ signal in T2 imaging



394 OSMOSIS.ORG



Nerve action potentials ▪ Normal sensory conduction velocity ▪ Abnormally ↓motor neuron velocity, potentials



LAB RESULTS



▪ Reverse transcription polymerase chain reaction (RT-PCR) ▪ Viral cultures ▪ Cerebrospinal fluid ▫ Severe cases ▫ If present in CSF → neuroinvasive disease likely ▫ Neutrophilic pleocytosis ( 14 days from onset of symptoms



TREATMENT ▪ No cure



MEDICATIONS ▪ Antipyretics



OTHER INTERVENTIONS Mother ▪ Rest ▪ Fluid management, resuscitation Newborn ▪ Nutritional support ▪ Physical therapy ▪ Specialty referral (especially neurology) Prevention ▪ No vaccine available ▪ Personal protective measures in endemic areas ▪ Consultation with physician prior to travel for pregnant individuals ▪ Safe sexual practice ▫ Biologically-male individuals wait at least six months after endemic-area travel for unprotected sex ▫ Biologically-female individuals wait at least eight weeks after endemic-area travel for unprotected sex ▪ Blood donation ▫ Do not donate for at least six months after endemic-area travel



OSMOSIS.ORG 397



398 OSMOSIS.ORG



NOTES



NOTES



GASTROINTESTINAL INFECTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Gastrointestinal tract (GIT) inflammation caused by virus, bacteria, other parasites ▪ GIT mucosa inflammation → ulceration → epithelial disruption → edema, bleeding → fluid, electrolyte loss (diarrhea) → dehydration, electrolyte imbalance, anemia (bloody diarrhea) ▪ Mainly fecal-oral transmission



RISK FACTORS ▪ Living/traveling to endemic areas, youth, immunosuppression (e.g. corticosteroid treatment, HIV co-infection), malnutrition, poor hygiene



DIAGNOSIS ▪ Pathogen-dependent



LAB RESULTS ▪ Stool culture



TREATMENT ▪ Rehydration ▪ Antimicrobial therapy (pathogendependent)



SIGNS & SYMPTOMS ▪ Fever, diarrhea, abdominal pain (cramps) ▪ Dehydration ▫ Sunken eyes, dry mouth, decreased urination, dark yellow urine (deep amber—severe), dry skin, syncope



OSMOSIS.ORG 399



CRYPTOSPORIDIUM osms.it/cryptosporidium PATHOLOGY & CAUSES ▪ Cryptosporidiosis: diarrheal disease caused by Cryptosporidium (intestinal intracellular protozoan parasite) ▪ Life-cycle can be completed in one host ▫ Immunocompetent hosts: self-limited diarrhea ▫ Immunocompromised hosts: lifethreatening complications



CAUSES



▪ Cryptosporidium oocysts (infective form) transmitted via fecal → oral route ▫ Infected individual/animal feces contaminates food; drinking, swimming water → fecally-contaminated food/ water ingestion ▪ Parasites → intestinal epithelial inflammation → villi structure distortion → ↓ absorption, ↑ secretion → watery diarrhea ▫ Sclerosing cholangitis/acalculous cholecystitis, respiratory cryptosporidiosis, pancreatitis



RISK FACTORS ▪ Endemic-area exposure (tropical countries, Kuwait), immune deficiencies, poor hygiene ▪ Interpersonal transmission: sexual partners, daycare centers, household members



COMPLICATIONS ▪ Dehydration, fluid and electrolyte imbalance



SIGNS & SYMPTOMS ▪ Host’s immune status-dependant



400 OSMOSIS.ORG



DIAGNOSIS LAB RESULTS Microscopic oocyte identification ▪ Stool; bile secretion, affected GIT aspirates; affected GIT tissue biopsy; respiratory secretion Polymerase chain reaction (PCR) ▪ More sensitive, specific ▪ Differentiates between Cryptosporidium genotypes Monoclonal antibodies and enzyme immunoassays (EIA) ▪ Monoclonal antibody test against oocyst wall ▪ More sensitive, specific than light microscope



TREATMENT MEDICATIONS



▪ Immunocompetent host: antidiarrheal, antimicrobial agents ▪ Immunocompromised host: antiretroviral therapy (HIV-infected individuals), antimicrobial agents, azithromycin (severe diarrhea)



OTHER INTERVENTIONS



▪ Immunocompetent host: oral/IV fluid/ electrolyte-loss replacement



Chapter 74 Gastrointestinal Infections



Figure 74.1 Cryptosporidium organisms lining the crypt epithelium in an infected individual.



OSMOSIS.ORG 401



ENTAMOEBA HISTOLYTICA (AMOEBIASIS) osms.it/entamoeba-histolytica PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Amebiasis ▫ Caused by Entamoeba histolytica (anaerobic parasitic protozoan) ▪ Trophozoites bind to intestinal epithelial cells in colon, release lytic enzymes (e.g. cysteine proteinases) → epithelial cell lysis → trophozoites lyse inflamed/attracted immune cells → immune cell’s lytic enzymes ↑ release ▫ Intestinal mucosa ulcers → colitis → bowel necrosis → perforation → sepsis ▫ Tissue destruction → mucosa blood vessel injury, malabsorption, ↑ intestinal secretion → bloody diarrhea, amebic dysentery ▫ Blood vessel injury → trophozoites in blood stream → extraintestinal amebiasis (liver, pulmonary, cardiac, brain)



▪ Mostly asymptomatic; bloody diarrhea, mucus in stool (severe dysentery); abdominal pain; fever; weight loss; right upper-quadrant pain, jaundice (liver); cough (pulmonary); dehydration



RISK FACTORS ▪ Endemic-area exposure (Africa, Southern Asia, Central America) ▪ Intimate partner transmission possible ▪ Youth ▪ Malnutrition ▪ Immunodeficiency (e.g. malignancy, corticosteroid treatment, HIV) ▪ Poor hygiene



COMPLICATIONS ▪ Amebic liver abscess rupture ▫ Pericarditis, peritonitis ▪ Toxic megacolon ▪ Cerebral amebiasis → brain abscess → ↑ intracranial pressure ▪ Cutaneous amebiasis ▪ Dehydration



402 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Liver CT scan, MRI, ultrasound ▪ Cystic intrahepatic cavity detection



LAB RESULTS Microscopic identification ▪ Cysts/trophozoites in stool/pus (e.g. liver abscess) Antigen detection ▪ Enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, immunofluorescence PCR ▪ Entamoeba DNA detection Serology ▪ Entamoeba antibodies detection Sigmoidoscopy/colonoscopy ▪ Histological examination biopsies



Chapter 74 Gastrointestinal Infections



TREATMENT MEDICATIONS ▪ Antibacterial agents ▫ Invasive amoebic colitis ▪ Luminal agents ▫ Intraluminal cysts, trophozoites ▪ Metronidazole ▫ Amebic liver abscess ≤ 10cm/3.94in ▪ Broad-spectrum antibiotics ▫ Suspected perforation, bacterial superinfection



SURGERY ▪ ▪ ▪ ▪ ▪



Figure 74.2 Trophozoites of Entamoeba histolytica in a colonic biopsy. The trophozoites have ingested red blood cells.



Massive GIT bleeding Amebic liver abscess > 10 cm/3.94 in Ruptured amebic liver abscess Perforated amebic colitis Toxic megacolon



OTHER INTERVENTIONS ▪ Rehydration



GIARDIA LAMBLIA osms.it/giardia-lamblia PATHOLOGY & CAUSES ▪ Giardiasis ▫ Diarrheal disease caused by Giardia intestinalis/Giardia duodenalis (flagellated protozoan parasite, colonizes small intestine) ▪ Pathogenesis not well understood ▪ Infection causes microvilli shortening → intestinal malabsorption, hypersecretion → diarrhea



CAUSES



▪ Contaminated/untreated water ingestion ▪ Contaminated food (uncommon)



RISK FACTORS ▪ Endemic-area exposure (tropical countries), immunosuppression, comorbidities (e.g. cystic fibrosis), poor sanitation



COMPLICATIONS ▪ Weight loss; dehydration; zinc, disaccharidase deficiency; malabsorption syndrome (adult); growth delay (children)



OSMOSIS.ORG 403



SIGNS & SYMPTOMS ▪ Usually asymptomatic Acute giardiasis ▪ 7–14 days after infection exposure ▪ Diarrhea, malaise, abdominal pain, flatulence, nausea/vomiting, malodorous stool, steatorrhea, fever (uncommon) Chronic giardiasis ▪ > 18 days after infection exposure ▪ Loose stools (not typical diarrhea), profound weight loss (occasionally), abdominal pain, borborygmus (moving gas/fluid → GIT gurgling sound), flatulence, burping, malaise, fatigue, depression



Figure 74.3 Giardia lamblia in a cytology specimen.



DIAGNOSIS LAB RESULTS Antigen detection assays ▪ Trophozoite antigen (stool) detection Nucleic acid amplification assays (NAAT) ▪ Giardia DNA detection Stool microscopy ▪ Giardia cyst detection



TREATMENT MEDICATIONS ▪ Antimicrobial therapy ▫ Paromomycin (pregnant/lactating individuals)



404 OSMOSIS.ORG



Figure 74.4 A duodenal biopsy demonstrating giardia organisms in the duodenal crypt.



NOTES



NOTES



GENERAL INFECTIONS GENERALLY, WHAT ARE THEY? TREATMENT



PATHOLOGY & CAUSES ▪ Localized, systemic disorders caused by microbial infections



SIGNS & SYMPTOMS



MEDICATIONS ▪ Antimicrobials



OTHER INTERVENTIONS ▪ Drainage



▪ See individual conditions



DIAGNOSIS ▪ See individual conditions



ABSCESSES osms.it/abscesses PATHOLOGY & CAUSES ▪ Localized, circumscribed pus collection surrounded by inflamed tissue ▪ May develop in any body region ▫ Superficial (e.g. skin, soft tissue) ▫ Internal (e.g. lung, liver, brain) ▪ Caused by pyogenic bacteria (e.g. S. aureus, S. pyogenes, S. epidermidis, P. aeruginosa) ▪ Bacterial invasion → local inflammatory response ▫ Suppuration (pus production) ▫ Necrosis, liquefaction ▫ Cellular debris accumulation ▪ Loculation, walling off of abscess by adjacent, healthy cells



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Trauma Foreign body presence (e.g. body piercing) Intravenous (IV) drug use Dermatological conditions (e.g. cellulitis) Anatomical involvement-related risks ▫ Examples: ascending infection → pelvic abscess, hematologic spread → central nervous system (CNS) abscess, local spread → liver abscess



COMPLICATIONS



▪ Spread to other tissue ▪ Fistula formation ▪ Sepsis



OSMOSIS.ORG 405



SIGNS & SYMPTOMS ▪ Localized warmth, erythema, swelling, tenderness/pain, induration ▪ Fluctuant mass



DIAGNOSIS ▪ History, physical examination: characteristic findings



DIAGNOSTIC IMAGING CT scan ▪ Central decreased attenuation area with circumferential enhancement ring MRI ▪ T1: central hypointense area ▪ T2: hyperintense ▪ T1, T2: rim is iso- to hypointense Ultrasound ▪ Internal abscess ▫ Homogeneous fluid collection appears as hypoechoic region within tissue ▫ Edema: cobblestone appearance—thin hyperechoic (dark gray) bands, anechoic (black) fluid



Figure 75.1 The clinical appearance of a pilonidal abscess.



LAB RESULTS



▪ Ultrasound-guided needle aspiration ▫ Specimen collection, culture



TREATMENT MEDICATIONS ▪ Antimicrobials



OTHER INTERVENTIONS ▪ Incision, drainage



406 OSMOSIS.ORG



Figure 75.2 A CT scan of the brain in the coronal plane demonstrating a cerebral abscess of the left frontal lobe. The abscess shows typical ring enhancement.



Chapter 75 General Infections



SEPSIS osms.it/sepsis PATHOLOGY & CAUSES ▪ Serious, life-threatening, systemic infection reaction ▫ Microbial host barrier breach (skin, mucous membranes) → provokes host dysregulated immune response → proinflammatory mediator release (e.g. TNF-α, interleukins) → detrimental physiological effects, tissue damage ▫ Endothelial damage, dysfunction; ↑ vascular permeability; microvascular dysfunction; coagulopathies



RISK FACTORS ▪ Bacteremia (most common) Gram-positive organisms ▪ Hospital/intensive care unit (ICU) admission → nosocomial infection ▪ Immune system deficiency ▫ E.g. HIV/AIDS, hematologic malignancy, immunosuppressant medication ▪ Recent surgery/hospitalization → altered microbiome ▪ Indwelling medical device presence ▫ E.g. urinary catheter, venous access device ▪ Bimodal age distribution ▫ Infants, adults ≥ 65 ▪ Community-acquired pneumonia ▪ Chronic disease ▫ E.g. diabetes, heart failure (HF), chronic obstructive pulmonary disease (COPD) ▪ Genetic factors



▪ Respiratory failure ▪ Disseminated intravascular coagulation (DIC) ▪ Metabolic acidosis ▪ Stress ulcer ▪ Treatment complications ▫ E.g. ventilator-associated pneumonia, venous thrombosis ▪ Death



SIGNS & SYMPTOMS General presentation ▪ Fever; tachypnea; tachycardia; hypotension; hypoxemia; ↓ urine output; ↓ PaO2; edema; ileus, ↓ bowel sounds ▪ Altered mental status ▫ Malaise, agitation, lethargy, stupor ▪ Signs of shock ▫ E.g. cool skin, cyanosis, ↑ capillary refill, mottling Quick Sequential Organ Failure Assessment (qSOFA) ▪ Score ≥ 2 → ↑ mortality risk ▪ See table



COMPLICATIONS



▪ Severe sepsis → septic shock ▫ Sepsis-induced vasodilation, hypotension ▫ Unresponsive to fluid resuscitation ▪ Multiple organ dysfunction syndrome (MODS)



OSMOSIS.ORG 407



DIAGNOSIS ▪ History, clinical presentation, physical examination



LAB RESULTS Blood studies ▪ ↑ white blood cell (WBC) count, left shift ▪ ↑ C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) ▪ Indications of organ hypoperfusion, injury, dysfunction ▫ ↑ lactate, ↓ platelets (may precede DIC), ↑ glucose, ↑ creatinine, ↑ bilirubin ▪ Coagulation studies ▫ ↑ international normalized ratio (INR), activated partial thromboplastin time (aPTT) ▪ Blood cultures ▫ Identify pathogen



TREATMENT MEDICATIONS



▪ Antimicrobials ▫ Initial broad-spectrum antibiotics until pathogen identified ▪ Hemodynamic support ▫ Fluid resuscitation ▫ Vasopressors ▪ Infection prevention ▫ Vaccinations for at risk individuals (influenza, pneumonia) ▪ Complication prevention ▫ Proton pump inhibitor



408 OSMOSIS.ORG



SURGERY



▪ Source control ▫ E.g. infected device removal, abscess drainage)



OTHER INTERVENTIONS Hemodynamic support ▪ Invasive monitoring Respiratory support ▪ Supplementary oxygen; mechanical ventilation Infection prevention ▪ Infection control practices ▫ ↓ hospital-acquired infections (ventilator-associated pneumonia, catheter-associated bloodstream infections) Complication prevention ▪ Deep-vein thrombosis prophylaxis ▪ Glycemic control



NOTES



NOTES



GRAM VARIABLE



GARDNERELLA VAGINALIS (BACTERIAL VAGINOSIS) osms.it/gardnerella-vaginalis PATHOLOGY & CAUSES



DIAGNOSIS



▪ Facultative, anaerobic, gram-variable coccobacilli ▪ Microscopically ▫ Very thin gram-positive cell wall appears gram-positive/negative ▪ Non-spore forming, non-motile ▪ Causative agent for bacterial vaginosis (BV) ▫ Disruption of vaginal microbiome ▪ Most common vaginal infection in individuals who are biologically female, age 15–44



LAB RESULTS



RISK FACTORS



OTHER DIAGNOSTICS



▪ Multiple sex partners, douching, smoking



COMPLICATIONS



▪ ↑ risk of contracting HIV, other STDs ▪ Acute cervicitis, endometritis, postabortal infection ▪ During pregnancy ▫ Premature birth, low birthweight



SIGNS & SYMPTOMS ▪ Malodorous (fishy), thin white/gray vaginal discharge ▪ Vaginal pain, itching, burning ▪ Burning with urination



▪ Gram-stain smear of vaginal discharge; using criteria (e.g. Nugent, Hay/Ison) ▪ Affirm VP III ▫ Commercial automated DNA probe assay detects G. vaginalis ▪ OSOM BVBlue test ▫ Chromogenic identifies presence of elevated sialidase enzyme produced by G. vaginalis, other bacteria (e.g. Bacteroides, Prevotella, Mobiluncus)



▪ Requires three of the following Amsel criteria ▫ Characteristic vaginal discharge ▫ pH > 4.5 ▫ Clue cells visible on saline wet mount (vaginal epithelial cells covered with bacteria) ▫ Positive whiff-amine test (combine vaginal discharge sample with 10% KOH → fishy odor)



TREATMENT MEDICATIONS



▪ Antibiotics: metronidazole



OSMOSIS.ORG 409



410 OSMOSIS.ORG



NOTES



NOTES



HEMATOLOGIC INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES Taxonomy ▪ Apicomplexan phylum protozoa → infectious hematological diseases Replication/multiplication ▪ Arthropod transmission Transmission ▪ Multiple life cycle stages (host-, vectordependent)



DIAGNOSIS LAB RESULTS



▪ Blood smear: best intra-erythrocyte location diagnosis



TREATMENT ▪ See individual infections



SIGNS & SYMPTOMS ▪ See individual infections



OSMOSIS.ORG 411



BABESIA osms.it/babesia PATHOLOGY & CAUSES



RISK FACTORS



▪ Malaria-like parasitic infection ▫ Ixodes tick transmission ▪ Phylum Apicomplexa (same as Plasmodium, Toxoplasmosis) ▪ Common species ▫ Babesia microti most predominant (northeast, upper midwest United States) ▫ B. duncani (Western United States) ▫ B. divergens (Europe)



▪ Endemic area resident ▪ Endemic area travel, especially May– September ▪ Blood transfusion (last six months) ▪ Age > 50 ▪ Biologically male ▪ Asplenia ▪ Decreased immunity (malignancy, HIV/ AIDS infection, immunosuppressive drugs) ▪ Coinfection with Borrelia and/or Anaplasma ▪ Premature birth



CAUSES



COMPLICATIONS



▪ Ixodes scapularis tick: only recognized vector ▫ Same tick transmits Borrelia burgdorferi (→ Lyme disease; concurrently infects ⅔ babesiosis-infected individuals) and Anaplasma phagocytophilum (→ human granulocytic anaplasmosis; concurrently infects ⅓ babesiosis-infected individuals) ▫ Contaminated blood transfusion → rare human-to-human transmission ▪ Life cycle ▫ Two hosts: white-footed mouse, Ixodes tick (definitive) ▫ Blood meal → Babesia-infected tick sporozoites into mouse host → sporozoites directly invade mature mouse erythrocytes → sporogony (asexual reproduction; budding) → in blood, some parasites differentiate into male, female gametes → gametes unite → sporogonic cycle → sporozoites → tick bites human → 1–4 week incubation → sporozoites enter erythrocytes → sporogony ▪ Sporogony ▫ Asynchronous with host → no massive hemolysis (versus malaria) ▪ Tick’s nymph stage is most infectious



412 OSMOSIS.ORG



▪ ↑ occurence in anemic/parasitemic individuals ▫ Congestive heart failure ▫ Noncardiac pulmonary edema ▫ Acute respiratory distress syndrome ▫ Splenic infarct ▫ Splenic rupture ▫ Septic shock ▫ Myocardial infarction ▫ Disseminated intravascular coagulation ▫ Death



SIGNS & SYMPTOMS ▪ Mostly asymptomatic, may persist undiagnosed months/years ▪ Blood-stage parasite multiplication → clinical manifestation ▪ Non-specific flu-like symptoms (misdiagnosis common) ▫ Fatigue (gradual onset) ▫ Fever, chills, sweats ▫ Headache, myalgia, arthralgia ▫ Anorexia, nausea ▫ Cough



Chapter 77 Hematologic Infections ▪ Severe manifestations include malaria-like illness (fever, fatigue, malaise) + hemolytic anemia manifestation ▪ B. microti case-fatality rate is 5% ▪ B. divergens infections case-fatality rate is 42% ▫ Disseminated intravascular coagulation, bleeding diathesis ▫ Acute renal failure ▫ Cardiopulmonary complications (e.g. hypotension, poor perfusion, pulmonary edema)



OTHER INTERVENTIONS



▪ Severe disease (parasitemia > 4%) ▫ Antimicrobial + exchange transfusion



Prevention ▪ Personal: avoid endemic areas; long pants, shirts minimize exposed skin ▪ Tick repellant on skin (e.g. DEET) ▪ Post-exposure tick checks ▪ No antibiotic prophylaxis



DIAGNOSIS LAB RESULTS Blood smear ▪ Wright/Giemsa staining ▫ Thin: rapid, ↓ microscopy experience required ▫ Thick: ↑ accurate, ↑ microscopy experience required ▫ Pathognomic tetrad “Maltese cross” visible in erythrocyte Laboratory ▪ Thrombocytopenia ▪ Reticulocytosis ▪ ↓ Hematocrit ▪ ↓ Hemoglobin ▪ ↑ Lactate dehydrogenase ▪ ↓ Haptoglobin ▪ ↑ Liver function tests ▪ ↑ Creatinine Polymerase chain reaction (PCR) ▪ Speciation (useful for low-level parasitemia) Serology ▪ Immunofluorescent antibody testing; species specific



TREATMENT ▪ Asymptomatic: no treatment



MEDICATIONS



▪ Symptomatic disease: azithromycin + atovaquone



OSMOSIS.ORG 413



PLASMODIUM SPECIES (MALARIA) osms.it/malaria PATHOLOGY & CAUSES ▪ Anopheles mosquito vector → parasitic hematologic infection ▪ Four major malarial parasite species ▫ Plasmodium falciparum: most lethal, most drug-resistant (sub-Saharan Africa) ▫ P. vivax: widest geographic distribution, relapsing species ▫ P. ovale: relapsing species (western areas of sub-Saharan Africa) ▫ P. malariae: AKA ‘benign’ malaria (mild course) ▪ P. knowlesi: normally infects macaques, recent cause of human malaria cases



▪ Erythrocytic life cycle stage ▫ In erythrocytes → parasites can undergo asexual schizogony/ sexual differentiation (necessary for transmission) → gametocytes ▪ Asexual schizogony ▫ Trophozoites (parasite name once inside erythrocyte) digest host cell hemoglobin (amino acids, energy source) → schizont → undergoes mitosis → differentiates into merozoites → erythrocyte rupture → merozoite bloodstream release → fever, malarial symptoms



CAUSES



▪ Exoerythrocytic (sporogonic; blood) life cycle stage ▫ Blood-stage gametocytes in other host (e.g. human) → female Anopheles mosquito blood meal → mosquito multiplication, growth cycle → 10–18 day incubation → sporozoites in mosquito salivary gland → human bite → sporozoite inoculation → hematogenous translocation to liver → rapid hepatic parenchymal cell invasion → parasites undergo exoerythrocytic schizogony (asexual multiplication) → development, multiplication → 7–14 day incubation → merozoite development → invade erythrocytes → symptomatic stage develops → P. ovale, P. vivax can differentiate into quiescent stage → hypnozoite → can re-enter into schizogony → reemerge to invade erythrocytes ▫ Blood stage → malaria symptoms ▫ Mosquito vector does not have parasite presence



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Figure 77.1 A peripheral blood film taken from an individual with Plasmodium malariae infection. There is a mature schizont, composed of 6-12 merozoites, contained within a red blood cell. ▪ P. malariae ▫ Low-level persistence possible for decades without diagnosis, treatment ▪ P. vivax ▫ Prefers erythrocytes with Duffy blood group antigen (rare in persons from West and Central Africa); prefers reticulocytes but will also invade mature erythrocytes ▪ Others preferentially invade mature erythrocytes



Chapter 77 Hematologic Infections ▪ P. falciparum ▫ Develop ‘knobs’ on infected erythrocytes in late trophozoite stage → parasitized erythrocytes adhere to capillary endothelium → various organ sequestration (notably brain) → cerebral malaria ▪ Most malaria deaths ▫ Children < five years old in hightransmission areas



COMPLICATIONS



Coma Seizure Severe anemia Acute renal failure ▫ Acute tubular necrosis secondary to hypoperfusion, hypovolemia ▪ Acute respiratory distress syndrome ▪ Shock ▪ Septicemia



▪ ▪ ▪ ▪



SIGNS & SYMPTOMS



RISK FACTORS



▪ Poor rural populations in endemic areas ▪ Proximity to standing water ▫ Larvae breeding site (e.g. agriculture, irrigation ditches) ▪ Travel in endemic areas ▪ Blood transfusion (last six months) ▪ Lack of insect repellant, chemoprophylaxis, personal protective measures (long pants, shirts, mosquito nets) ▪ Duffy blood group antigen-positive individuals



Protective factors ▪ P. falciparum protection: sickle cell trait (heterozygotes) ▪ P. vivax: Duffy blood group antigennegative individuals



▪ Febrile paroxysm (hallmark feature) ▫ 10–12 hours of intense rigors, chills → high fever, profuse diaphoresis ▫ Febrile seizure potential ▪ Non-specific complaints ▫ Headache, malaise, myalgia, arthralgia ▪ Abdominal pain, diarrhea, vomiting ▪ Possibly remarkably asymptomatic between episodes ▪ P. falciparum cerebral effects ▫ Significant morbidity, mortality (delirium, confusion, seizures → declining mental status → coma → death) ▪ Parasitemia, cytokine disturbance → hypotension, metabolic acidosis, hypoglycemia ▪ Anemia (high parasitemia → more pronounced) ▪ Sequestration, red blood cell destruction by spleen → hypersplenism



DIAGNOSIS LAB RESULTS Giemsa stain blood smear ▪ Thin: rapid, ↓ microscopy experience required ▪ Thick: ↑ accurate, ↑ microscopy experience required ▪ P. falciparum: red blood cells contain multiple parasites, ring forms, lack of schizonts ▪ Banana-shaped gametocyte form



OSMOSIS.ORG 415



Rapid diagnostic test ▪ 15–20 minute results ▪ Histidine-rich protein 2: detects P. falciparum PCR ▪ Supportive laboratory results (nondiagnostic) ▫ Normocytic hemolytic anemia ▫ Thrombocytopenia



TREATMENT MEDICATIONS



▪ Severe malaria ▫ Quinidine + doxycycline/tetracycline/ clindamycin/artesunate (test for G6PD deficiency) ▪ Uncomplicated malaria ▫ Chloroquine-sensitive strain: chloroquine phosphate/ hydroxychloroquine (blocks Plasmodium heme polymerase) ▫ Chloroquine-resistant strain: atovaquone-proguanil, mefloquine, artesunate, quinine-based regimens ▪ P. ovale, P. vivax: + primaquine for hypnozoite (test for G6PD deficiency)



OTHER INTERVENTIONS



Figure 77.2 A histological section of the placenta from an individual infected with malaria. The numerous black dots within the red blood cells are malaria organisms.



416 OSMOSIS.ORG



Prevention ▪ Chemoprophylaxis ▪ Avoid outdoors (dusk/dawn) ▪ Reduce exposed skin (long pants, shirts) ▪ Bed netting/mosquito nets ▪ Insect repellent (DEET 30–50%)



NOTES



NOTES



HEPADNAVIRIDAE MICROBE OVERVIEW ▪ Hepadnaviridae: family of DNA viruses, causes liver disease ▪ Produces DNA polymerase with reverse transcriptase, RNAse activity Replication/multiplication ▪ Reverse transcription (RNA intermediate) Structure ▪ Enveloped



▪ Icosahedral capsid ▪ Partially double stranded, partially single stranded circular DNA



COMPLICATIONS



▪ Chronic hepatitis, acute liver failure (fulminant hepatitis), liver cirrhosis, hepatocellular carcinoma (HCC)



HEPATITIS B VIRUS osms.it/hepatitis-b-virus PATHOLOGY & CAUSES ▪ Hepatitis B virus (HBV) ▫ DNA virus: can cause acute/chronic liver disease ▫ Member of Hepadnaviridae family (only human pathogenic species) ▪ Target: hepatocytes, zone I (periportal area) ▪ Incubation period: six weeks to six months Antigens ▪ Hepatitis B surface antigen (HBsAg/ Australia antigen) ▫ Key infection marker ▪ Hepatitis B core antigen (HBcAg) ▫ Not detectable in serum; found in liver with acute/chronic hepatitis B ▪ Hepatitis B e antigen (HBeAg) ▫ Secreted by infected cells; indicates active infection, replication



Transmission ▪ Perinatal (childbirth), parenteral (e.g. IV drug use, blood transfusions), sexual ▪ HBV survives ≥ seven days in environment Highest prevalence ▪ Parts of sub-Saharan Africa, mainly due to perinatal transmission ▪ Lower prevalence areas have greater association with parenteral, sexual transmission



TYPES Acute hepatitis ▪ Liver inflammation for < six months) ▪ HBV penetrates hepatocytes → CD8+ T-lymphocyte activation → cytotoxic killing → hepatocyte apoptosis → liver damage, inflammation ▪ Phases ▫ Early, window (antigens undetectable), recovery



OSMOSIS.ORG 417



▪ Acute liver failure progression: < 1% ▪ Chronic hepatitis progression (in adults): < 5% ▪ Acute liver failure ▫ Acute liver injury (severe hepatocyte necrosis), hepatic encephalopathy, coagulopathy ▫ Excessive immune response → massive hepatocyte lysis ▫ Preexisting liver disease absence ▫ Associated with HBV genotype D Chronic hepatitis ▪ HBsAg persistent for > six months ▪ Pathogenesis ▫ HBV penetrates hepatocytes → insufficient CD8+ T-lymphocyte activation → “immune tolerance” → HBV persistence ▪ Progression to HCC ▫ HBV integrates to host DNA → oncogene activation → oncogenesis ▪ Chronicity depends highly on age at time of infection ▫ Younger age, ↑ chronicity risk ▫ Immunosuppressed, elderly people also more susceptible ▪ Phases ▫ Immune tolerant: no liver inflammation/ fibrosis ▫ Immune active: liver damage, inflammation, possible fibrosis ▫ Immune inactive: ↓ inflammation ▫ Reactivation: liver damage, inflammation, possible fibrosis ▫ “Recovery”: occult HBV, HBsAg negative; still infected, disease inactive (best prognosis)



RISK FACTORS



▪ IV drug use ▪ Healthcare workers ▫ Frequent contact with blades, needles, body fluids ▪ High-risk sexual behavior ▪ Anal intercourse ▪ Previous HIV/hepatitis C infection



418 OSMOSIS.ORG



COMPLICATIONS



▪ HCC, fulminant hepatitis, liver cirrhosis



Hepatic encephalopathy ▪ Excessive nitrogen load, electrolyte disturbances → altered neurologic functions in individuals with severe liver disease Hepatorenal syndrome ▪ Portal hypertension → splanchnic vasodilation → ↓ effective circulatory volume → ↑ renin-angiotensin-aldosterone system → renal vasoconstriction → hepatorenal syndrome (liver dysfunction → kidney failure) Bleeding diathesis ▪ Hypocoagulability → ↑ hemorrhage risk



SIGNS & SYMPTOMS Acute hepatitis ▪ Can be anicteric (not accompanied by jaundice) with non-specific symptoms (e.g. fever, malaise, nausea, vomiting) ▪ Some progress to icteric hepatitis with hepatomegaly, right upper-quadrant pain, jaundice (30%), dark-colored urine (due to conjugated hyperbilirubinemia), pale stool Chronic hepatitis ▪ Mostly asymptomatic/non-specific symptoms until late disease stages ▪ Exacerbations may present as acute hepatitis ▪ Jaundice, ascites, splenomegaly, encephalopathy (e.g. personality changes, ↓ level of consciousness, intellectual impairment, asterixis) may present ▪ Extrahepatic manifestations (occasionally) ▫ Fever, rash, arthralgia, arthritis, glomerulonephritis



DIAGNOSIS LAB RESULTS



▪ HBV DNA detection ▫ Polymerase chain reaction (PCR), in-situ hybridization, Southern hybridization



Chapter 78 Hepadnaviridae Laboratory testing ▪ ↑ alanine aminotransferase (ALT), aspartate aminotransferase (AST) ▫ ALT > AST ▫ Usually ALT in acute hepatitis > 1000 U/L (may be ↓ in chronic hepatitis) ▫ ALT levels take longer than AST to return to normal ▪ ↑ ALT for > six months indicates chronicity ▪ ↑ alpha-fetoprotein (AFP) in HCC ▪ Liver fibrosis ▫ ↓ leukocytes, platelets ▫ AST/ALT > 1 (normal ≈ 0,8) ▫ ↑ total bilirubin ▫ ↓ serum albumin ▫ Delayed prothrombin time, ↑ international normalized ratio (INR) Serologic marker detection through enzyme immunoassay ▪ Hepatitis B surface antigen (HBsAg) ▫ Indicates infection (acute/chronic) ▪ Hepatitis B surface antibodies (Anti-HBs) ▫ Provides HBV infection immunity appears after vaccination/resolved acute hepatitis



▪ IgM antibodies against hepatitis B core antigen (IgM anti-HBc) ▫ Acute infection/chronic hepatitis reactivation phase ▪ IgG antibodies against hepatitis B core antigen (IgG anti-HBc) ▫ Non-specific antibody; may be ↑ during acute, resolved, chronic hepatitis ▪ Hepatitis B e antigen ▫ Active replication, high infectivity ▪ Hepatitis B e antibodies ▫ Low replication, infectivity Liver biopsy ▪ Acute hepatitis ▫ Mononuclear infiltrate ▫ Pericentral inflammation, necrosis ▫ Eosinophilic hepatocytes ▪ Chronic hepatitis ▫ Fibrosis ▫ Nodule formation ▫ Mononuclear portal infiltrate ▫ Some hepatocytes have uniformly dull cytoplasm due to endoplasmic reticulum swelling (“ground glass” hepatocytes)



OSMOSIS.ORG 419



Figure 78.1 Ground glass hepatocytes seen in the liver of an individual with hepatitis B infection.



TREATMENT MEDICATIONS



▪ Antiviral monotherapy ▫ Severe acute hepatitis, pre-existing liver disease, concomitant hepatitis C/D infection, immunocompromised, elderly



Acute hepatitis ▪ Post-exposure prophylaxis ▫ HBV vaccine and immunoglobulin Chronic hepatitis ▪ Combination therapy (e.g. lamivudine, interferon)



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Prevention ▪ HBV vaccine ▪ Recombinant type most commonly used ▫ HBsAg inserted in yeast cells ▪ HBsAg → development of anti-HBsAg → HBV infection immunity ▪ Intramuscular administration ▪ Three doses for coverage (very effective) ▪ Administration regime: 0, 1–2 months, 6–12 months ▫ Infant immunization: first dose at birth ▫ Does not require booster dose (longterm protection)



SURGERY



▪ Acute liver failure ▫ Consider liver transplantation



OTHER INTERVENTIONS



▪ Acute liver failure ▫ Fluid resuscitation, early nutritional support, antiviral therapy (nucleoside/ nucleotide analogues)



Acute hepatitis ▪ Supportive treatment (e.g. fluid therapy, nutrition)



Chapter 78 Hepadnaviridae



HEPATITIS D VIRUS osms.it/hepatitis-d-virus PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Hepatitis D virus (HDV/delta virus): incomplete RNA virus; contributes to acute liver failure development, chronic hepatitis exacerbation in people coinfected/ previously infected with HBV ▪ HDV not member of Hepadnaviridae family ▪ HDV infection inhibits HBV replication due to HBV, HDAg interaction during viral replication ▫ Coinfected individuals: HDV predominant ▫ ↑ inflammatory response (compared to HBV alone) ▫ Poor response to existing HBV treatment ▪ Incubation period ▫ 6–24 weeks



Coinfection ▪ Biphasic course with acute hepatitis symptoms



Structure ▪ Outer envelope made of HBsAg, inner HDV RNA, delta antigen (HDAg)



LAB RESULTS



Transmission ▪ Parenteral, sexual, perinatal (very rare) Satellite virus ▪ Can only infect if host also infected with HBV ▫ Coinfection: simultaneous infection ▫ Superinfection: HDV infection after established HBV infection; more severe



RISK FACTORS



▪ IV drug use, high-risk sexual behavior, HBV presence



Acute liver failure ▪ Systemic symptoms ▫ E.g. fever, malaise, nausea, vomiting) ▫ Hepatomegaly, right upper quadrant pain; sometimes jaundice, dark colored urine, pale stool ▪ Hepatic encephalopathy ▫ Personality changes, ↓ level of consciousness, intellectual impairment, asterixis



DIAGNOSIS ▪ Serologic marker detection ▫ IgM/IgG anti-HDV ▪ PCR assays ▫ HDV RNA detection



TREATMENT MEDICATIONS



▪ Pegylated interferon alpha ▪ Prevention ▫ HBV vaccine



SURGERY



▪ Consider liver transplantation for chronic hepatitis D, acute liver failure



OSMOSIS.ORG 421



NOTES



NOTES



HERPESVIRUSES MICROBE OVERVIEW ▪ Large family of DNA viruses Species known to infect humans ▪ Herpes simplex virus (HSV) ▫ HSV-1, HSV-2 ▪ Varicella-zoster virus (VZV) ▪ Epstein-Barr virus (EBV) ▪ Human cytomegalovirus ▪ Human herpesvirus 6 (roseola) ▪ Human herpesvirus 8 (Kaposi’s sarcoma)



Genetic material ▪ Double-stranded, linear DNA genome encoding 84 proteins Morphology ▪ Icosahedral capsid; enveloped virus Life cycle ▪ Obligate intracellular parasites ▪ Can perpetuate in latent phase ▪ Expression of lytic genes → lytic phase→ host cell death → shedding



CYTOMEGALOVIRUS osms.it/cytomegalovirus PATHOLOGY & CAUSES ▪ Primary infection of immunocompetent individuals usually asymptomatic; lifelong latency ▪ Infects mononuclear leukocytes, endothelial cells



CAUSES



▪ Person-to-person transmission ▫ Kissing; intimate, sexual contact ▪ Vertical transmission ▫ Congenital infection ▪ Blood products/transfusion ▪ Organ/stem cell transplant



RISK FACTORS



▪ Immunocompromised ▫ HIV/AIDS; organ transplant; medications (e.g. steroids, chemotherapy)



422 OSMOSIS.ORG



COMPLICATIONS



▪ Congenital CMV infection ▫ Cognitive, sensorineural deficits



SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Fever, malaise, sore throat, splenomegaly ▪ Individuals with AIDS ▫ Retinitis, colitis, encephalitis, pneumonitis ▪ Individuals with congenital CMV infection ▫ Positive CMV-IgG (if pregnant); intrauterine fetal growth restriction (IUGR), hydrocephalus, microcephaly, intracranial calcification, poly/ oligohydramnios, hepatosplenomegaly



Chapter 79 Herpesviruses



DIAGNOSIS LAB RESULTS



▫ Highly active antiretroviral therapy (HAART) ▫ CMV immunoglobulin G (CMV-IGIV)



▪ Complete blood count ▫ Atypical lymphocytosis, anemia, leukopenia, thrombocytopenia ▪ ↑ serum creatinine, AST, ALT ▪ Serology tests ▫ ↑ CMV-IgM titre; acute infection ▫ ↑ CMV-IgG titre; past infection



TREATMENT ▪ Usually self-limiting



MEDICATIONS



▪ At-risk individuals ▫ Antiviral prophylaxis; IV ganciclovir; oral valganciclovir



Figure 79.1 A colonic biopsy taken from an individual with CMV colitis. The large nuclei that give the virus its name can be clearly seen.



EPSTEIN–BARR VIRUS (INFECTIOUS MONONUCLEOSIS) osms.it/epstein-barr_virus PATHOLOGY & CAUSES ▪ EBV (human herpesvirus 4) ▪ Causes Infectious mononucleosis (glandular fever) ▪ Infection in children ▫ Asymptomatic/mild flu-like symptoms ▪ Infection in adolescents, young adults ▫ Fever, sore throat, enlarged lymph nodes ▪ Lytic, latent life cycle ▫ Lytic in oropharyngeal B cells; latent in lymphocytes



CAUSES



▪ Transmitted through saliva (“kissing” disease), sexual transmission



RISK FACTORS



▪ Multiple sexual partners



COMPLICATIONS



▪ Splenic rupture ▪ EBV infection associated with Hodgkin’s, Burkitt’s lymphoma ▪ Neurologic syndromes (2–4 weeks after initial symptoms) ▫ Guillain-Barré syndrome, cranial nerve palsies (e.g. facial nerve palsy); meningoencephalitis (e.g. aseptic meningitis), transverse myelitis, peripheral neuritis, optic neuritis ▪ EBV can affect, manifest in any organ system ▫ Hepatitis, pneumonia, myocarditis, pancreatitis, acute renal failure, gastric pseudolymphoma



OSMOSIS.ORG 423



▪ Classic triad ▫ Fever; cervical/generalized lymphadenopathy; tonsillar pharyngitis (exudative/non-exudative) ▪ Malaise, hepatosplenomegaly, rash, jaundice, myalgia



morphology (large, irregular nuclei) ▪ ↑ hepatic transaminase (50% of infected individuals) ▪ Monospot test ▫ Positive heterophile antibodies (IgM) ▪ Identification of EBV ▫ EBV-specific antibodies, real-time PCR, EBV DNA detection



DIAGNOSIS



TREATMENT



SIGNS & SYMPTOMS



MEDICATIONS



LAB RESULTS



▪ Complete blood count (CBC) ▫ Lymphocytosis (50%) with atypical



▪ Antipyretics, analgesics ▫ Avoid aspirin; may lead to Reye’s syndrome ▪ Corticosteroid for upper airway obstruction (e.g. prednisolone) ▪ Intravenous immunoglobulin (IVIG) for thrombocytopenia



Figure 79.2 Atypical lymphocytes with bizarre nuclear forms in a peripheral blood film from an individual infected with infectious mononucleosis.



HERPES SIMPLEX VIRUS osms.it/herpes-simplex-virus PATHOLOGY & CAUSES ▪ HSV-1, HSV-2 ▫ Members of herpesviridae family ▪ Causes oral, genital, ocular ulcers ▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth



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▪ Primary infection often symptomatic; replicates in epidermis of skin → travels down nerve endings, axon→ sensory ganglia ▪ Periodic reactivation, subsequent episodes ▫ Virus becomes active in ganglia → transported via axon to skin → replicates in epidermis → sheds → new sores ▫ Often asymptomatic shedding; may feel tingling, burning sensation



Chapter 79 Herpesviruses



TYPES



▪ Infection types ▫ Primary: first infections; seronegative; symptoms more extensive, systemic; greater viral shedding loads ▫ Non-primary: previously infected individuals; serum antibody, humoral immunity (e.g. genital HSV-2 infection in adulthood after oral mucosa HSV-1 infection in childhood) ▫ Recurrent: previously infected individuals; reactivation episodes (e.g. genital HSV-2 infection in adulthood after genital HSV-2 infection in adolescence) ▪ Herpes labialis (AKA oral herpes) ▫ HSV-1 infection of oral mucosa, lips ▪ Genital herpes ▫ HSV-2, HSV-1 infection of genital area ▫ Healing takes 2–4 weeks



SIGNS & SYMPTOMS ▪ Herpes labialis ▫ Painful ulcers around mouth; high fever; sore throat; pharyngeal oedema; myalgia, cervical lymphadenopathy ▫ Recurrent infection: pain, burning, tingling, vesicle formation ▪ Genital herpes ▫ Genital ulceration, vesicles: vulva, cervix, vagina, penis shaft/glans, perineum, buttocks ▫ Genital pain, dysuria, fever, neuralgia ▫ Constipation, rectal pain, tenesmus, proctitis



CAUSES



▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth ▪ Spread person to person; sexual transmission



RISK FACTORS



▪ Genital herpes ▫ Contact with infected individual (producing, shedding virus) ▫ Immunosuppression (e.g. medications, HIV/AIDS) ▫ High-risk sexual behavior (e.g multiple sexual partners, unprotected intercourse, first sexual activity at early age)



COMPLICATIONS



▪ Neonatal HSV infection, meningitis, encephalitis, acute retinal necrosis, uveitis, keratitis, esophagitis



Figure 79.3 Blisters on the lips caused by infection with herpes simplex virus.



DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪



Viral culture HSV polymerase chain reaction (PCR) Direct fluorescent antibody (DFA) test Serological HSV-1/HSV-2 specific IgG assay



OSMOSIS.ORG 425



TREATMENT MEDICATIONS Herpes labialis ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Topical antivirals Genital herpes ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Pregnant: antiviral prophylaxis



OTHER INTERVENTIONS Genital herpes ▪ Pregnant: possible cesarean delivery



Figure 79.4 Blisters on the dorsum of the penis of an individual infected with genital herpes simplex.



HUMAN HERPESVIRUS 6 (ROSEOLA) osms.it/human-herpesvirus-6 PATHOLOGY & CAUSES ▪ Causes roseola (infantum) ▪ Common cause of fever, followed by rash in early childhood, associated with febrile seizures ▪ Incubation period ▫ 1–2 weeks



CAUSES



▪ Asymptomatic contacts ▫ Person-to-person spread by respiratory secretions ▪ Trophic for CD4+ T lymphocytes



426 OSMOSIS.ORG



▪ Following acute infection, remains latent in various tissues



RISK FACTORS



▪ More common in young children (six months–two years) ▪ Immunosuppressed ▫ Bone marrow/organ transplant ▫ Reactivation of latent virus



COMPLICATIONS



▪ Afebrile seizures ▪ Associated with chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus



Chapter 79 Herpesviruses



SIGNS & SYMPTOMS ▪ 3–5 days of high fever; peak in early evening ▪ Exanthem; morbilliform rash appears with defervescence; 3–5mm pink/red macules, papules along trunk, extremities ▪ Diarrhea, tympanic membrane inflammation, upper respiratory symptoms ▪ Nagayama’s spots: enanthem of red papules on soft palate, uvula ▪ Rare ▫ Seizures, periorbital oedema, bulging anterior fontanelle, cervical/occipital/ postauricular lymphadenopathy



TREATMENT ▪ Usually self-limiting



MEDICATIONS



▪ Immunocompromised ▫ Antiviral compounds (e.g. acyclovir, ganciclovir, cidofovir, foscarnet) ▪ Oral hydration, antipyretics (e.g. paracetamol, ibuprofen) ▪ Avoid aspirin; may lead to Reye’s syndrome



DIAGNOSIS LAB RESULTS



▪ Complete blood count ▫ ↓ white blood cells ▪ Detection of HHV-6B/HHV-7 ▫ Viral culture, specific IgG detection



Figure 79.5 A child with roseola infantum, also known as sixth disease. The most common causative agent is human herpes virus six.



HUMAN HERPESVIRUS 8 (KAPOSI'S SARCOMA) osms.it/human-herpesvirus-8 PATHOLOGY & CAUSES ▪ Causes Kaposi’s sarcoma ▫ Low-grade vasoformative neoplasm associated with human herpesvirus-8 (HHV-8) infection/Kaposi’s sarcoma herpesvirus (KSHV) infection



▪ Lesions on mucocutaneous areas; may involve lymph nodes, viscera ▪ Skin lesions ▫ Patch → plaque → ulcerating tumor nodules ▪ Morphology ▫ spindle-shape, vasoformative cells with vascular proliferation, inflammatory cells



OSMOSIS.ORG 427



▪ Spontaneous regression may occur after HAART/immunosuppressive treatment



TYPES



▪ Epidemic AIDS-associated Kaposi’s sarcoma ▫ HIV-positive individuals ▪ Classic sporadic Kaposi’s sarcoma ▫ More common in individuals who are male, older, with Mediterranean/Jewish background ▪ Iatrogenic, transplant-associated Kaposi’s sarcoma ▫ Solid organ transplant individuals ▪ African endemic Kaposi’s sarcoma ▫ More common in central Africa, unrelated to HIV



RISK FACTORS



▪ More common in individuals who are biologically male, > 50 years ▪ Immunosuppression, HIV (co-infection synergistic → aggressive, widespread); drug abuse; immunosuppression therapy



COMPLICATIONS



▪ Secondary skin lesion infection



SIGNS & SYMPTOMS ▪ Skin lesions ▫ Multifocal; asymmetrically distributed; size, colour variation; non-pruritic; papular; nodular; plaque-, bullous-like; indurated; hyperkeratotic ▪ Oral lesions ▫ Hard palate, gingiva, dorsum of tongue ▫ Macules, papules, nodules, exophytic masses ▪ Lymphadenopathy, lymphoedema ▪ Fever, weight loss, night sweats



428 OSMOSIS.ORG



Figure 79.6 The skin of an individual with Kaposi’s sarcoma.



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular/interstitial/alveolar infiltrates; hilar/ mediastinal lymphadenopathy; nodules



LAB RESULTS



▪ HIV test ▪ Positive in AIDS-associated Kaposi’s sarcoma ▪ Fecal occult blood ▫ Positive may indicate intestinal lesions



OTHER DIAGNOSTICS



▪ Lesion, lymph node biopsy of vascular lesion



TREATMENT MEDICATIONS



▪ Delay disease progression ▫ HAART; in HIV infected individuals, HIV suppression may shrink Kaposi’s sarcoma lesions; systemic chemotherapy ▪ Cosmetic ▫ Topical retinoids; intralesional vinblastine



Chapter 79 Herpesviruses



SURGERY



▪ Cosmetic ▫ Surgical excision; cryotherapy; laser therapy (external beam radiation)



Figure 79.7 The histological appearance of a Kaposi sarcoma. The tumor is composed of spindle cells and numerous branching vascular spaces. The occasional spindle cell contains hyaline globules.



VARICELLA ZOSTER VIRUS osms.it/varicella-zoster-virus PATHOLOGY & CAUSES ▪ Double-stranded, linear DNA virus ▫ Causes chickenpox, shingles ▫ Chickenpox: generally benign, selflimited disease in immunocompetent children ▫ Shingles: painful skin rash, can occur in individuals who have recovered from primary VZV infection Primary infection (chickenpox) ▪ Transmission: airborne spread through aerosolized droplets, direct lesion contact ▪ VZV enters respiratory system → lymph node spread → targets skin, mucous membranes → small blood vessel vasculitis → epithelial cell degeneration → fluid-filled vesicles ▫ Incubation period: 14 days ▫ Most infectious: 1–2 days before rash; infectious 3–4 days, until lesions crusted ▫ After symptoms resolve, VZV dormant in nervous system; latent in trigeminal, dorsal root ganglia



Figure 79.8 A child with chickenpox.



OSMOSIS.ORG 429



Secondary infection (shingles) ▪ Occurs when dormant VZV reactivates ▫ Reactivation in dorsal root, cranial nerve ganglia → travels down axons → local skin inflammation innervated by ganglion ▫ Prodromal 2–4 day tingling/localized pain before rash onset



RISK FACTORS Chickenpox ▪ More common in children ▫ 1–9 years old (highest risk) ▪ Non-immunized status ▪ Immunocompromised status Shingles ▪ Primary varicella infection history ▪ More common in adults ▫ > 50 years old (highest risk) ▪ Immunocompromised status ▪ Stress



SIGNS & SYMPTOMS Chickenpox ▪ Fever, headache, malaise, sore throat, tachycardia ▪ Rash characteristics ▫ Generalized pruritic, vesicular rash ▫ “Dew drop on rose petal” appearance ▫ Formation: macules → vesicles → rupture → scab ▫ Vesicles on mucous membranes (e.g. nasopharynx, conjunctiva, mouth, vulva) Shingles ▪ Erythematous, maculopapular lesions evolve into painful vesicular rash ▫ Rash follows dermatomal distribution of cranial nerve/dorsal root ganglion ▫ Thoracic, lumbar dermatomes most commonly affected



COMPLICATIONS Chickenpox ▪ Secondary bacterial infection, cutaneous scarring, encephalopathy, varicella pneumonitis/pneumonia ▪ Central nervous system (CNS) complications ▫ Meningitis, encephalitis, intracranial vasculitis ▪ Congenital varicella syndrome ▫ Limb hypoplasia, paresis, microcephaly, ophthalmic lesions Shingles ▪ Ramsay Hunt syndrome ▫ VZV of geniculate ganglion affects facial nerve; hearing loss, facial weakness ▪ Postherpetic neuralgia, superinfection of skin lesions, encephalitis, Mollaret’s meningitis, zoster multiplex/sine herpete, stroke, myelitis ▪ Herpes zoster ophthalmicus (sightthreatening)



430 OSMOSIS.ORG



Figure 79.9 Herpes zoster, or shingles, affecting the ophthalmic branch of the trigeminal nerve.



Chapter 79 Herpesviruses



TREATMENT MEDICATIONS Chickenpox ▪ Low risk: usually self-limiting ▪ Moderate risk: oral antiviral therapy ▪ High risk: intravenous antiviral therapy; zoster-immune globulin (ZIG) Figure 79.10 Herpes zoster in a dermatomal distribution on the chest.



DIAGNOSIS LAB RESULTS ▪ Microbe identification ▫ PCR: VZV DNA ▫ Viral culture: positive VZV ▫ DFA: VZV antigen



Shingles ▪ Oral/intravenous antiviral therapy ▪ Analgesics ▫ E.g. paracetamol, ibuprofen; topical; opioid ▪ Calamine lotion ▪ Varicella-zoster immune globulin



OTHER INTERVENTIONS



▪ Prevention ▫ Live attenuated VZV vaccine



OSMOSIS.ORG 431



NOTES



NOTES



LEISHMANIA MICROBE OVERVIEW ▪ Flagellated, parasitic protozoan ▪ Contains kinetoplast (form of mitochondrial DNA) ▪ Hosts: humans, canids, rodents, hyraxes Classification ▪ “Old World” ▫ Usually found in Africa, Asia, Middle East, India ▫ Includes Leishmania infantum, L. donovani, L. tropica, L. aethiopica, L. major ▪ “New World” ▫ Usually found in Central, South America; Mexico ▫ Includes L. braziliensis, L. mexicana, L.



infantum (chagasi), L. amazonensis, L. panamensis, L. guyanensis Life stages ▪ Amastigote ▫ Oval; 3–6µm ▫ Intracellular, nonmotile form (no external flagella) ▫ Found in human circulatory system in mononuclear phagocytes ▪ Promastigote ▫ Spindle-shaped; 15–30µm ▫ Extracellular, motile form (long external flagellum) ▫ Found in alimentary tract of sandflies



LEISHMANIA osms.it/leishmania PATHOLOGY & CAUSES ▪ Causes disease leishmaniasis ▪ Spread by female sandflies of genus Lutzomyia/Phlebotomus ▪ Human leishmaniasis characterized by ulcers (e.g. skin, oral, nasal mucosa), systemic illness ▪ Lipophosphoglycan layer helps it survive immune system



TYPES Cutaneous leishmaniasis (CL) ▪ Most common ▪ Usually caused by L. major, L. tropica, L.



432 OSMOSIS.ORG



aethiopica Mucocutaneous leishmaniasis (ML) ▪ Causes mucosal, skin ulcers ▪ Usually caused by L. braziliensis Visceral leishmaniasis (VL) ▪ AKA kala-azar ▪ Most severe, systemic involvement ▪ Usually caused by L. donovani, L. infantum ▪ If recurs post-treatment: post kala-azar leishmaniasis ▪ Resists host’s complement system, prevents natural killer cells ▪ Infected macrophages spread infection ▫ Spleen → splenomegaly ▫ Liver → Kupffer cells with increased size



Chapter 80 Leishmania → liver dysfunction ▫ Bone marrow → hyperplastic → ↓ hematopoiesis → pancytopenia ▫ Lymph nodes → lymphadenopathy



RISK FACTORS



▫ Poverty, malnutrition, poor hygiene; deforestation, urbanization



SIGNS & SYMPTOMS CL ▪ Skin ulcers resembling leprosy lesions ML ▪ Ulcers on oropharyngeal, nose mucosa ▪ Midfacial destruction: nose cartilage/septal granulation, tear; ulcers on palate, uvula, lips ▪ Hoarse voice, gingivitis, periodontitis ▪ Genital mucosal (severe cases) VL ▪ Fever, weight loss, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, abdominal tenderness



TREATMENT MEDICATIONS CL ▪ Topical paromomycin, miltefosine, pentamidine isethionate, fluconazole, ketoconazole ML ▪ Liposomal amphotericin B, miltefosine, pentamidine VL ▪ Liposomal amphotericin B, miltefosine



OTHER INTERVENTIONS Prevention ▪ Nets treated with insecticide while sleeping; over doors, windows ▪ Insect repellents, insecticide-impregnated dog collars ▪ Treat infected dogs



DIAGNOSIS LAB RESULTS



▪ Enzyme-linked immunosorbent assay (ELISA) ▪ Antigen-coated dipsticks ▪ Direct agglutination test



Light microscope ▪ Amastigotes/Leishman-Donovan body visualization: blood, aspirates from marrow, spleen, lymph nodes, skin lesions ▫ Blood, spleen monocytes ▫ Circulating neutrophils, aspirated tissue macrophages



Figure 80.1 A leishmaniasis ulcer on the leg.



Polymerase chain reaction (PCR) ▪ Detects Leishmania kinetoplast DNA (most sensitive, specific)



OSMOSIS.ORG 433



NOTES



NOTES



MYCOPLASMA MICROBE OVERVIEW ▪ Smallest free living organisms ▪ Prokaryotic with absence of cell wall, presence of flexible cell membrane containing cholesterol ▫ Pleomorphic ▫ Not visible on Gram stain ▫ Resistant to beta lactam, glycopeptide antibiotics



▪ Limited metabolic activity → not culturable on standard culture media, require specialized medium (e.g. Eaton’s agar) with sterols, nutrients provided by natural animal protein (e.g. blood serum) ▪ Can grow under aerobic, anaerobic conditions



MYCOPLASMA PNEUMONIAE osms.it/mycoplasma-pneumoniae PATHOLOGY & CAUSES ▪ Species of mycoplasma; primarily affects respiratory tract; usually causes upper respiratory tract infections; can also cause atypical pneumonia ▪ Transmitted through respiratory droplets after close contact with infected individual → attaches to respiratory epithelium with P1 surface protein → hydrogen peroxide, superoxide radicals synthesized by mycoplasma interact with endogenous toxic molecules synthesized by host cells → oxidative stress in respiratory epithelial cells ▪ Macrophages migrate to site of infection → activation and phagocytosis → initiate inflammatory response → T, B lymphocyte proliferation → antibody production, release of inflammatory cytokines → control infection/initiate immune-mediated lung injury ▪ Extrapulmonary disease (rare) ▫ Due to immune mediated injury/cross reactive antibody mechanism/direct invasion



434 OSMOSIS.ORG



▪ Central nervous system (CNS), joints, skin, blood, heart, liver, pancreas affected ▫ CNS is the most common extrapulmonary site; usually encephalitis ▪ Can develop cold agglutinin response (60%) ▫ Autoimmune hemolytic anemia ▫ Coombs positive ▫ Cold (active below 37°C/98.6°F) IgM antibodies against erythrocyte surface antigen due to cross reaction of antigen with mycoplasma antigens → can agglutinate/lyse erythrocytes



RISK FACTORS



▪ Common in children, young adults ▪ Immunocompromised status, smoking, close community living (e.g. nursing homes, dorms)



COMPLICATIONS ▪ Asthma exacerbations ▪ Respiratory failure ▪ CNS involvement



Chapter 81 Mycoplasma ▫ Encephalitis with high mortality rate ▪ Heart involvement ▫ Rhythm disorders, heart failure



SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ Gradual onset ▫ General fatigue, myalgias, headache, low grade fever, sore throat, cough (worsening, frequent, non-productive), chills ▪ Less common ▫ Sinus/ear pain, wheezing ▪ Chest auscultation ▫ Scattered rales, wheezes, rhonchi, crackles ▪ Sinus tenderness ▪ Erythema of tympanic membrane ▪ Pharyngeal erythema ▪ Pulse-temperature dissociation: normal pulse despite fever indicative of atypical pneumonia



DIAGNOSIS LAB RESULTS



▪ Molecular testing with polymerase chain reaction (PCR); most accurate ▪ Serological tests ▫ ≥ four-fold rise in IgM antibodies titers of acute, convalescent sera 2–3 weeks apart using enzyme immunoassay ▫ High titer of IgM antibodies ▫ Cold agglutinins titer ▪ Isolation with culture ▫ Limited use due to slow growth (2–3 weeks), need for specialized media



DIAGNOSTIC IMAGING Chest X-ray/CT scan/high resolution CT scan ▪ Diffuse reticulonodular pattern indicative of interstitial pneumonia ▪ Areas of airspace consolidation (esp. lower lobes) ▪ Thickening of bronchovascular bundle



OTHER DIAGNOSTICS



▪ Histopathology ▫ Inflammation in trachea, bronchioles, peribronchial tissues ▫ Airspaces filled with purulent exudate with polymorphonuclear cells ▪ Physical examination ▫ Vague symptoms (e.g. fatigue) indicative of atypical/“walking” pneumonia



TREATMENT ▪ Most cases mild, self-limited



MEDICATIONS



▪ Atypical pneumonia ▫ Macrolides (e.g, erythromycin, azithromycin); tetracyclines (e.g. doxycycline); fluoroquinolones (e.g., levofloxacin, moxifloxacin)



OSMOSIS.ORG 435



NOTES



NOTES



NEMATODES (ROUNDWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA roundworms ▫ Microfilariae: immature worms ▫ Microfilariae: mature worms ▪ Parasites usually enter body cutaneously ▫ Produce gastrointestinal (GI), occasionally cutaneous symptoms, disease



COMPLICATIONS ▪ Loffler syndrome ▫ Transient pulmonary disease during select nematode development (Necator Americanus, Strongyloides, Ascaris Lumbricoides, Toxocara, Ancylostoma duodenale) ▫ Symptoms: irritating, nonproductive cough, substernal burning discomfort, dyspnea, wheezing, fever, blood-tinged sputum production



SIGNS & SYMPTOMS ▪ GI/localized tissue symptoms, organismdependent



DIAGNOSIS LAB RESULTS



▪ Eosinophilia ▪ Gammaglobulinemia abnormalities (↑/↓ depending on organism)



Serology ▪ IgG levels ▪ Enzyme linked immunosorbent assays (ELISA), western blot



436 OSMOSIS.ORG



TREATMENT MEDICATIONS



▪ Antihelminthic therapy ▫ Nematode location-dependent



Intestinal nematodes ▪ Mebendazole/albendazole ▫ Bind tubulin colchicine-sensitive sites → inhibit microtubule assembly → inhibited glucose uptake (without human effect) → organism death Systemic nematodes ▪ Diethylcarbamazine (DEC) ▫ Piperazine derivative (uncertain mechanism of action) ▪ Ivermectin ▫ Synthetic lactone → negative-charged ion influx via glutamate-sensitive chloride channels → hyperpolarizes cells → helminth cell death ▫ Not macrofilaricidal, pregnancy contraindication



Chapter 82 Nematodes (Roundworms)



ANCYLOSTOMA DUODENALE & NECATOR AMERICANUS osms.it/ancylostoma-duodenale osms.it/necator-americanus PATHOLOGY & CAUSES ▪ Infectious hookworm species Adult morphology ▪ Ancylostoma duodenale ▫ Two ventral plates on buccal capsule’s anterior margin; two large teeth fused at base (male 8–11mm, female 10–13mm long) ▪ Necator americanus ▫ Two dorsal/ventral cutting plates around buccal capsule’s anterior margin, paired subdorsal/subventral teeth (male 7–9mm, female 9–11mm long) ▪ A. duodenale, Necator americanus: most common hookworm species causing helminth gastrointestinal infection ▫ Light infection (< 100 worms) ▫ Moderate infection (100–500 worms) ▫ Heavy infection (500–1000 worms) ▪ Pathophysiology ▫ Hookworm attachment, hyaluronidase release → intestinal wall degradation, capillary laceration → anticoagulant peptides, inhibits platelet function inhibitor production → bleeding facilitation → extravasated blood ingested (approx. 0.5mL daily) ▫ Moderate–heavy infections → chronic iron-deficiency anemia; protein malnutrition Infectious form ▪ Filariform larva Life cycle ▪ Infectious form maturation ▫ Female A. duodenale lays 10,000– 30,000 eggs daily



▫ Female N. americanus lays 5,000– 10,000 eggs daily ▫ Human feces egge release → soil deposition → eggs hatch (24–48 hours—favorable conditions) → rhabditiform larvae (L1) → transformation to infectious filariform larvae (L3) in 5–10 days ▪ Human stages ▫ Filariform larvae skin penetration → passage through veins to heart, lung → pulmonary alveoli penetration, ascend bronchi to pharynx → coughed up/swallowed into small intestine → maturation → intestinal wall attachment via buccal capsule ▪ Some A. duodenale larvae undergo developmental arrest in gut tissues/muscle ▫ Await more favorable environmental conditions (hypobiotic larvae) ▪ Natural life-span ▫ A. duodenale: approx. one year ▫ N. americanus: 3–5 years Transmission ▪ Contaminated soil contact → percutaneous larval penetration ▪ Oral route ▪ Transmammary route



RISK FACTORS



▪ Inadequate clean-water access ▪ Poor sanitary conditions ▪ Walking barefoot (endemic areas)



COMPLICATIONS



▪ Severe iron-deficiency anemia; protein malnutrition → impaired growth, cognitive



OSMOSIS.ORG 437



development (children); heart failure (adults) ▪ Pregnancy ▫ Low birth weight, maternal anemia, ↑ infant mortality



SIGNS & SYMPTOMS ▪ May be asymptomatic Three phases ▪ Cutaneous phase ▫ Local pruritic dermatitis (ground itch) with papular, sometimes vesicular, focal rash at larval penetration site (usually between toes) ▪ Pulmonary phase ▫ Usually asymptomatic, may involve mild cough, pharyngeal irritation, sore throat, fever ▪ Gastrointestinal phase ▫ Midepigastric pain, appetite loss, nausea, diarrhea, vomiting Heavy infection ▪ Hypoproteinemia → weight loss, anasarca, edema ▪ Anemia → fatigue, mental dullness, dyspnea, pallor ▪ Overt gastrointestinal bleeding



DIAGNOSIS DIAGNOSTIC IMAGING Abdominal X-ray ▪ Intestinal worm visualization



LAB RESULTS



▪ Acute infection ▫ Eosinophelia ▪ Chronic infection ▫ Anemia ▪ Kato–Katz method (thick smear) ▪ Polymerase chain reaction (PCR) test



Direct microscopy ▪ Stool specimen egg visualization



438 OSMOSIS.ORG



▫ A. duodenale, N. americanus eggs are morphologically indistinguishable



OTHER DIAGNOSTICS



▪ History ▫ Contaminated-soil skin exposure; endemic-area travel; physical examination



TREATMENT MEDICATIONS



▪ Anthelmintic treatment



Chapter 82 Nematodes (Roundworms)



ANGIOSTRONGYLUS (EOSINOPHILIC MENINGITIS) osms.it/angiostrongylus PATHOLOGY & CAUSES ▪ Parasitic nematode ▫ Causes human GI/CNS disease ▪ Angiostrongylus cantonensis ▫ Medically important species ▫ Causes angiostrongyliasis (most common eosinophilic meningitis cause) Adult morphology ▪ Three outer protective collagen layers; contains fully-developed gastrointestinal tract, simple stomal opening Hosts ▪ Primary intermediate host: snails ▪ Paratenic hosts: fish, frogs, freshwater prawns ▫ Not needed for developmental cycle ▪ Definitive hosts: wild rodents (brown, black rat) ▪ Incidental hosts: humans Life cycle ▪ Infectious form maturation ▫ Worms lay eggs in rat pulmonary artery → spread from lung capillaries to alveoli, larvae hatch → migrate up bronchi, trachea, across epiglottis → swallowed → fecal larvae passage → soil deposition → intermediate-host ingestion ▪ Human stages ▫ Intermediate host larval ingestion (contaminated water/vegetable) → CNS tropism → migration into meningeal capillaries, brain tissue → meningoencephalitis ▪ Larvae usually fail to complete life-cycle, rarely → adult form in human host



Transmission ▪ Intermediate/paratenic host ingestion (raw/undercooked snails, fish, frogs), contaminated vegetables/water Pathophysiology ▪ Post-inoculation, A. cantonensis larvae exhibit neurotropism → meninges, deeper brain tissue invasion → neural-tissue mechanical, toxic byproducts damage; antigen release → meningoencephalitis ▪ Migration to mesenteric arterioles → arteritis, thrombosis, small infarctions ▫ May cause necrotic ulcers → peritonitis, fistula formation



COMPLICATIONS



▪ Long-term encephalitis → permanent nerve damage, intellectual disability, permanent brain damage, death



SIGNS & SYMPTOMS ▪ Incubation period: three weeks–two months ▪ Meninges invasion: meningitis picture ▫ Severe headache, photophobia, stiff neck, fatigue, fever, hyperesthesia, vomiting, paresthesias ▪ Brain parenchyma invasion: encephalitis symptoms (brain location-dependent) ▫ Cognitive impairment, slowed reactions, neuropathic pain, ascending weakness ▫ t quadriparesis, areflexia, respiratory failure, muscle atrophy, death (rare) ▪ Eye invasion: visual impairment, pain, keratitis, retinal edema



OSMOSIS.ORG 439



DIAGNOSIS



TREATMENT



LAB RESULTS



▪ Self-limiting infection (usually)



▪ Cerebrospinal fluid (CSF) ▫ Eosinophilia ▫ ↓ glucose levels (severe meningoencephalitis)



MEDICATIONS



▪ Analgesics, sedatives ▫ Treat headache, hyperesthesia ▪ Corticosteroids ▪ Antihelminthic therapy not advised ▪ Dying parasites, neurologic damage exacerbation → potential inflammatory response



OTHER DIAGNOSTICS



▪ Endemic-area travel history ▪ Physical examination ▪ Clinical presentation



OTHER INTERVENTIONS



▪ CSF drainage ▫ Reduces intracranial pressure, relieve headache



ANISAKIS osms.it/anisakis PATHOLOGY & CAUSES ▪ Zoonotic roundworm ▫ Causes human gastrointestinal, extragastrointestinal disease ▫ Causative anisakiasis agent Adult morphology ▪ Anteriorly-located mouth surrounded by projections; length (2cm/0.8in) Infectious form ▪ L3 larvae Hosts ▪ Natural hosts: marine mammals ▪ Incidental hosts: humans Life cycle ▪ Infectious form maturation ▫ Eggs hatch into larvae (seawater) → larval crustacean ingestion → fish/ squid ingest crustaceans → muscular/ subdermal larval encystation (L3



440 OSMOSIS.ORG



larvae) → marine mammals ingest fish → excystation, maturation, nematode reproduction → fecal egg release ▪ Human stages ▫ Larval ingestion (infected fish) → larvae fail maturation, cannot complete lifecycle Transmission ▪ Raw/undercooked fish ingestion Pathophysiology ▪ Infected fish larvae ingestion → larvae burrow into intestinal wall, die → dead organism → inflammatory response → possible allergic reaction, abscess, mechanical obstruction ▪ If parasites pass into large intestine ▫ Eosinophilic granulomatous response → mimic appendicitis/Crohn’s disease



RISK FACTORS



▪ Raw/undercooked seafood ingestion (common in Japan)



Chapter 82 Nematodes (Roundworms)



COMPLICATIONS



▪ Small bowel obstruction ▪ Intestinal perforation ▪ Peritoneal cavity perforation (extraintestinal anisakiasis) ▪ Eosinophilic gastroenteritis/enterocolitis



SIGNS & SYMPTOMS ▪ Gastric anisakiasis ▫ Acute epigastric pain, nausea, vomiting ▪ Intestinal anisakiasis ▫ Severe abdominal pain, abdominal distension, palpable abdominal mass, intestinal obstruction, bloody diarrhea ▪ Allergic reactions ▫ Urticaria, bronchoconstriction, angioedema, anaphylactic shock



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Parasite visualization ▫ Gastroscopic examination, emesis examination



LAB RESULTS ▪ ↑ serum IgE



TREATMENT SURGERY



▪ Parasite removal (endoscopically, surgically)



ASCARIS LUMBRICOIDES osms.it/ascaris-lumbricoides PATHOLOGY & CAUSES ▪ Intestinal roundworm parasite ▫ Causative ascariasis agent ▪ Adult worm size: 15–30cm/5.9–11.8in ▫ Largest intestinal nematode Life cycle ▪ Female A. lumbricoides lays 200,000 eggs daily; begins egg-laying 9–11 weeks postinfection ▪ Infectious-form maturation ▫ Eggs passed in stool → soil deposition → eggs embryonate; infectious after 2–4 weeks; can survive < ten years (favorable conditions) ▪ Human stages ▫ Egg ingestion → larvae hatch → invade intestinal mucosa → portal circulation → systemic circulation → liver → lungs → larvae mature in alveoli (10–14 days) → ascend bronchial tree, pharynx, swallowed → larvae develop into adult



form in small intestine ▪ Life-span: 10–24 months Pathophysiology ▪ Varies upon life-cycle stage ▫ Pulmonary phase (early): caused by larval migration into lungs → pneumonitis ▫ Intestinal phase: manifestations caused by adult-form presence → mechanical obstruction (degree worm-burdendependent)



RISK FACTORS



▪ Egg-contaminated food/water ingestion (especially pig/chicken liver) ▪ Infected soil (children) ▪ Feco-oral route reinfection



COMPLICATIONS



▪ Intestinal obstruction ▫ May → volvulus, ileocecal



OSMOSIS.ORG 441



▪



▪



▪ ▪



intussusception, gangrene, intestinal perforation Children ▫ Malnutrition/malabsorption, impaired growth, cognitive development Hepatobiliary involvement ▫ Biliary colic, biliary strictures, obstructive jaundice, liver abscesses Pancreatic duct obstruction → pancreatitis Aspiration pneumonia during esophageal migration to trachea



SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ Pulmonary phase (Loffler syndrome): develops 4–16 days post-infection ▫ Dry cough, dyspnea, fever, wheezing, substernal discomfort, blood-tinged sputum; symptoms subside after 5–10 days ▪ Intestinal phase: develops 6–8 weeks postinfection ▫ Abdominal discomfort, anorexia, nausea, vomiting, diarrhea



Barium swallow ▪ Intestinal phase ▫ Defects in filling; if worms ingest contrast, tram-track appearance demonstrated Microscopic examination ▪ Pulmonary phase ▪ Eosinophils, Charcot–Leyden crystals in sputum ▪ Intestinal phase ▪ Eggs/adult form stool visualization (KatoKatz/FLOTAC method)



LAB RESULTS



▪ Pulmonary phase ▫ Peripheral eosinophilia



OTHER DIAGNOSTICS ▪ Exposure/endemic-area travel history



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary phase ▫ May show migratory bilateral oval infiltrates, range from several mm– several cm ▪ Intestinal phase ▫ Adult Ascaris worm visualization, intestinal obstruction CT scan ▪ Pulmonary phase ▫ Multiple nodules, “ground-glass” attenuation ▪ Intestinal phase ▫ “Bull’s eye” appearance (worm crosssection)



442 OSMOSIS.ORG



Figure 82.1 A barium study demonstrating ascariais. There are numerous worms in the distal part of the duodenum and the ileum.



Chapter 82 Nematodes (Roundworms)



TREATMENT MEDICATIONS



▪ Anthelmintic treatment ▫ Only effective in intestinal phase ▫ Pregnancy: pyrantel pamoate



SURGERY



▪ Complete intestinal obstruction, volvulus, intussusception, appendicitis, perforation cases



OTHER INTERVENTIONS



▪ Endoscopic retrograde cholangiopancreatography (ERCP) ▫ Hepatobiliary-involvement cases



Figure 82.2 Ascaris worms emerging from the two free ends of the small intestine during an operation to remove a length of ischemic bowel.



Figure 82.3 Small bowel packed with Ascaris lumbricoides worms. The bowel is distended so greatly that the visceral peritoneum on the antimesenteric border is split.



OSMOSIS.ORG 443



ENTEROBIUS VERMICULARIS (PINWORM) osms.it/enterobius-vermicularis PATHOLOGY & CAUSES ▪ Small roundworm ▫ May infect human colon, rectum ▫ Causative enterobiasis agent Life cycle ▪ Female E. vermicularis lays > 10,000 eggs daily ▪ Perianal fold egg deposition → autoinfection by scratching; contaminated hand, mouth contact → eggs hatch into larvae (small intestine) → adult-form maturation (cecum, appendix) ▪ Life-span: 2–3 months Transmission ▪ Scratching perianal area (autoinfection) → hand–mouth contact ▪ Contaminated hands (person–person) ▪ Contaminated surface contact ▪ Eggs may become airborne, inhaled



▪ High worm burden → abdominal pain, nausea, vomiting



DIAGNOSIS OTHER DIAGNOSTICS



▪ Pinworm paddle/Scotch tape test ▫ Adhesive clear plastic paddle pressed against perianal areas → placed onto glass slide; reveals eggs upon microscopic examination



TREATMENT MEDICATIONS



▪ Anthelmintic treatment



RISK FACTORS



▪ Crowded living conditions ▪ Children 5–10 years old



COMPLICATIONS



▪ Persistent perianal-area scratching, skin tearing → bacterial dermatitis, folliculitis ▪ Adult worms migrate to extraintestinal sites; cause vulvovaginitis, salpingitis, oophoritis, cervical granuloma, peritoneal inflammation



SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Perianal itching (pruritus ani) occurs nocturnally



444 OSMOSIS.ORG



Figure 82.4 Pinworm found incidentally in an appendectomy specimen.



Chapter 82 Nematodes (Roundworms)



GUINEA WORM (DRACUNCULIASIS) osms.it/guinea-worm PATHOLOGY & CAUSES ▪ Water-borne nematode disease ▫ Characterization: rash, GI illness with subcutaneous worm visualization Life cycle/transmission ▪ Infected water → human copepod ingestion → GI, subcutaneous migration, sexual reproduction → pruritus, percutaneous larval eruption upon water-immersion → copepod larval consumption → two molting processes → pathogenic larvae in copepods Pathogenesis ▪ GI symptoms ▫ Ingested copepod death in GI system → larval migration into stomach, intestinal wall → entry into abdominal, retroperitoneal space ▪ Cutaneous symptoms ▫ Larval sexual reproduction → female survival, skin migration → limb waterimmersion → eruption



RISK FACTORS



▪ Rural Eastern-Africa residence/travel



▪ Cutaneous symptoms ▫ Painful papule (2–7cm/0.8–2.8in) → enlarges, ↑ pain → worm emerges through ulceration



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Calcified dead worm in subcutaneous tissue ▫ If worm does not emerge through skin



OTHER DIAGNOSTICS



▪ Endemic-area travel/residence history ▪ Physical examination ▫ Systemic → cutaneous symptom development



TREATMENT OTHER INTERVENTIONS ▪ Worm extraction; careful extraction protocol ▫ Multiple days (centimeters at a time); keeps worm intact, prevents local pruritic, edematous reaction



COMPLICATIONS



▪ Ectopic site migration → abscess development ▫ Lung, eye, pericardium, spinal cord ▪ Broken worm → intensely painful, edematous local, subcutaneous reaction



SIGNS & SYMPTOMS ▪ Systemic symptoms initially ▫ Fever, urticaria, pruritus, dizziness, nausea/vomiting, diarrhea



Figure 82.5 A match stick being used to extract a guinea worm from an ulcer on the leg.



OSMOSIS.ORG 445



Prevention ▪ Community surveillance, transmission methods education ▪ Safe water precautions ▫ Nylon filters for water filtration, insecticides in drinking water courses, water source covering (prevents infected body-part immersion) ▪ Occlusive dressings applied to papules



LOA LOA (EYE WORM) osms.it/loa-loa PATHOLOGY & CAUSES ▪ Vector-borne filarial nematode endemic in Africa ▫ Characterization: transient swelling episodes, subconjunctival adult worm migration ▪ AKA African eye worm ▪ Allergic reaction ▪ Subconjunctival infiltration ▫ Associated with conjunctivitis, eyelid swelling Life cycle/transmission ▪ Vector ▫ Chrysops (biting deer fly; AKA tabanid fly) ▫ Breed in rainforest canopies, lay eggs in muddy swamps; bite humans during daytime ▪ Tabanid fly human bite → filarial larvae transmission → three month maturation process → microfilarial production → bloodstream release ( ↑ release during daytime) → tabanid blood meal (infected individual) → filarial maturation in tabanid fly



RISK FACTORS



▪ Endemic-area residence/travel ▫ Eastern, Central Africa



446 OSMOSIS.ORG



COMPLICATIONS



▪ Onchocerciasis co-infection ▪ Encephalitis (coincident headache, insomnia, coma may result) ▪ Cardiomyopathy (endomyocardial fibrosis) ▪ Nephropathy ▪ Arthritis ▪ Lymphadenitis ▪ Calabar swelling → entrapment neuropathy



SIGNS & SYMPTOMS Allergic reactions ▪ Calabar swellings ▫ 5–20cm/2–7.9in non-erythematous lesions ▫ Transient, local subcutaneous swelling; face, extremities most common; localized pain, itching prior to swelling episodes ▫ Urticaria, pruritus, asthma Subconjunctival eye infection ▪ Commonly non-painful infiltration of eye subconjunctival area; conjunctivitis may occur (with eyelid swelling) ▪ Worm may be visible



Chapter 82 Nematodes (Roundworms)



DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪



Hypergammaglobulinemia ↑ IgE level Worm’s presence (blood smear) Serology ▫ IgG antibodies against L. loa antigens



OTHER DIAGNOSTICS ▪ History, physical examination ▫ Worm detection in subcutaneous tissue, conjunctiva



▫ Onchocerciasis co-infection contraindicated (DEC provokes severe inflammatory skin, eye response; Mazzotti reaction) ▫ Eradication may require multiple treatment rounds ▪ Albendazole ▫ Sterilizes mature worms without microfilarial activity ▪ Antihistamine/corticosteroids ▫ Limits post-treatment immune reactions (e.g. Calabar swelling)



SURGERY



▪ Large worm removal



TREATMENT MEDICATIONS



▪ Diethylcarbamazine (DEC) ▫ Active against L. loa microfilariae, microfilariae (adult worms)



OTHER INTERVENTIONS Prevention ▪ Weekly DEC prophylaxis ▪ Only considered for long-term endemicarea exposure



ONCHOCERCA VOLVULUS (RIVER BLINDNESS) osms.it/onchocerca-volvulus PATHOLOGY & CAUSES ▪ Filarial nematode transmitted by blackflies ▪ Leading preventable blindness cause in sub-Saharan Africa Life cycle/transmission ▪ Simulium blackfly human bite → larvae skin deposited → adult parasite maturation (microfilariae) → subcutaneous/deeper intramuscular tissue migration → fibrous capsule/nodule development → reproduction → microfilarial (immature worm) production, subcutaneous tissue migration → human blackfly bite → microfilarial development into infective larvae (in blackfly)



Ocular onchocerciasis ▪ Common manifestation: West African savanna ▪ Commonly affects anterior eye chamber ▫ Iridocyclitis, glaucoma, uveitis ▪ Posterior chamber may also be affected ▫ Onchochorioretinits, optic atrophy ▪ Ocular involvement degree correlates with symbiotic Wolbachia bacteria quantity Onchocercal skin disease ▪ AKA Leopard/lizard/elephant skin (especially when depigmentation present); common manifestation in African forest areas ▪ Classified by chronicity ▫ Acute/chronic papular onchodermatitis



OSMOSIS.ORG 447



▪ Lichenified onchodermatitis (AKA sowda/ black/dark); epidermal atrophy, elastic fiber breakdown may occur



PATHOLOGY Subcutaneous involvement ▪ Onchocercoma ▪ Dermal O. volvulus → inflammatory response (prostaglandin E2, transforming growth factor-beta-mediated) → nodule formation (onchocercoma); nodules predominate in bony prominence areas, peak inflammatory response occurs upon subcutaneous male O. volvulus death Ocular involvement ▪ Anterior chamber disease ▫ O. volvulus infiltration → immune response, O. volvulus death → Wolbachia release → innate immune response → corneal damage ▪ Posterior chamber disease ▫ O. volvulus infiltration → immune response → cross-reactivity of O. volvulus antigen with retinal pigment epithelial protein → persistent immunologic response → inflammatory limbus, iris, choroid damage



RISK FACTORS



▪ West Africa, Eastern South America travel/ residence ▫ Especially savanna, forest



SIGNS & SYMPTOMS Cutaneous ▪ Pruritus ▪ Nodule development (lymphadenopathy may develop, persist depending on infection duration) ▪ Focal darkening/depigmentation ▪ Epidermal atrophy, hyperpigmentation, hyperkeratosis may be present Ocular ▪ Punctate keratitis → fluffy corneal opacities → eosinophilic infiltrate → sclerosing keratitis → corneal opacification;



448 OSMOSIS.ORG



progressive (eventually irreversible) vision deficit



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Deep ochoceroma detection



LAB RESULTS



▪ Eosinophilia ▪ Hypergammaglobulinemia ▪ PCR assay ▫ O. volvulus



OTHER DIAGNOSTICS



▪ Rheumatologic/dermatologic onchocercoma evaluation



Skin snips ▪ Corneoscleral punch biopsy (ocular involvement)/ disposable razor blade for epidermal sample (cutaneous disease) ▪ 2+ snips taken in areas likely to harbor highest microfilariae concentration ▪ Positive only within 9–15 months postinfection (mature microfilariae produce microfilariae) Patch test ▪ Topical DEC application → local skin reaction assessment ▪ Akin to Mazzotti reaction Fundoscopic and corneal evaluation ▪ Slit-lamp examination reveals wriggling microfilariae ▪ Individuals sit forward for two minutes prior to examination (↑ microfilarial visualization likelihood on chamber examination)



TREATMENT MEDICATIONS



▪ Ivermectin, doxycycline ▫ Ivermectin: kills immature worms only, adult worm repopulate months after treatment



Chapter 82 Nematodes (Roundworms) ▫ Doxycycline: kills Wolbachia (symbiotic bacteria needed for O. volvulus fertility) for 24 months; block reproduction



OTHER INTERVENTIONS Prevention ▪ Protective clothing, insect repellent (especially when blackflies most active— morning/evening)



STRONGYLOIDES STERCORALIS osms.it/strongyloides-stercoralis PATHOLOGY & CAUSES ▪ Filarial disease endemic in tropical areas with characteristic pulmonary infection route, complications include septic shock in immunocompromised individuals ▪ Mild GI, cutaneous, pulmonary inflammation, disease ▫ Dermatitis, urticaria, duodenitis, enterocolitis, pneumonitis ▫ May persist for years Life cycle ▪ Larvae live in fecally-contaminated ground soil → enter human host through broken skin → hematologic spread → pulmonary alveolar sac infiltration, penetration → ascend tracheobronchial tree → swallowed → larval maturation in duodenum, jejunum → larval reproduction, fecal excretion ▪ Autoinfection (single-host life-cycle completion) may occur via larval perianal skin entry



PATHOLOGY



▪ Larvae contaminate skin through breakage → lung migration → inflammation infiltrate → intestinal wall migration → maturation, replication → larval intestinal mucosa penetration → autoinfection



RISK FACTORS



▪ Constipation, diverticula, steroid-use, ↓ bowel motility → ↑ autoinfection likelihood ▪ Hypogammaglobulinemia ▪ Anti-tumor necrosis factor receptor therapy ▪ Organ transplantation, immune suppression



COMPLICATIONS



▪ Hyperinfection (uncontrolled autoinfection → high worm-burden disease) ▫ Immunocompromised individuals ▫ Hematologic parasite spread includes CNS, heart, liver, lungs, endocrine glands ▫ May manifest as septic shock



SIGNS & SYMPTOMS ▪ Immunocompetent individuals ▫ Bloating, diarrhea ▪ Cutaneous ▫ Edema, petechiae, serpiginous/urticarial tracking ▪ Gastrointestinal ▫ Anorexia, nausea, vomiting, epigastric pain (duodenal ulceration cases), malabsorption (chronic enterocolitis) ▪ Pulmonary ▫ Dry cough, throat irritation, dyspnea, wheezing, hemoptysis



OSMOSIS.ORG 449



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary disease ▫ Foci of hemorrhage, pneumonitis, pulmonary edema



LAB RESULTS Organism identification ▪ Stool examination ▫ Low sensitivity due to intermittent larval release ▫ Repeat testing ↑ finding’s reliability ▪ ELISA ▫ Immunocompetent individuals



TREATMENT MEDICATIONS



▪ Ivermectin ▪ Albendazole ▫ May combine with ivermectin in hyperinfection/disseminated disease states



OTHER INTERVENTIONS Prevention ▪ Proper shoe wearing ▫ Prevents broken-skin exposure ▪ Serologic evaluation ▫ Solid organ transplant donors



OTHER DIAGNOSTICS



▪ Endemic-area travel history



Endoscopy ▪ Histopathological (biopsy-driven) diagnosis ▫ Stomach, duodenum, colon evaluation of mucosa appearance



Figure 82.6 A duodenal biopsy containing an entire Strongyloides worm, likely an adult female.



450 OSMOSIS.ORG



Chapter 82 Nematodes (Roundworms)



TOXOCARA CANIS (VISCERAL LARVA MIGRANS) osms.it/toxocara-canis PATHOLOGY & CAUSES ▪ Human roundworm disease: dog, cat, pig vectors characterized by cutaneous/ocular disease ▫ Dogs: toxocara canis ▫ Cats: toxocara cati ▫ Pigs: Ascaris suum Life cycle/transmission ▪ Definitive hosts: cats, dogs, pigs ▪ Accidental hosts: humans ▪ Egg-laden stool → soil contamination → definitive host ingestion → GI tract reproduction → larval gut wall penetration → pulmonary migration, penetration → ascend tracheobronchial tree → swallowed → small intestine worm maturation → reproduction, egg excretion in stool ▪ Paratenic host: non-canine, small mammals; egg ingestion → larval gut wall penetration → tissue migration → cyst formation → human paratenic host ingestion → infection Disease ▪ Ocular involvement: inflammatory granuloma of posterior pole, diffuse endophthalmitis, solitary peripheral retinal granuloma



RISK FACTORS



▪ Raw liver/undercooked meat ingestion (e.g. rabbit, chicken, cattle, pork) ▪ Children ▫ Playground, sandbox use



COMPLICATIONS ▪ Hepatitis ▪ Pneumonitis



▪ Cardiac ▫ Pericarditis, myocarditis ▪ CNS involvement ▫ Myelitis, meningoencephalitis, seizure, cerebral vasculitis ▪ Ocular ▫ Retinal detachment, blindness



SIGNS & SYMPTOMS ▪ Visceral larva migrans ▫ Pruritic urticaria, fever, anorexia, malaise, irritability ▪ Ocular larva migrans ▫ Unilateral vision impairment, uveitis, papillitis, endophthalmitis ▪ Hepatomegaly ▪ Respiratory distress



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Bilateral peribronchial infiltrates CT scan ▪ Chest: multifocal subpleural nodules, “ground-glass” opacities, ill-defined margins ▪ Abdomen: multiple ill-defined lesions in liver parenchyma Ultrasound ▪ Abdomen: may also identify lesions



LAB RESULTS



▪ Leukocytosis ▪ Hypogammaglobulinemia (↑ IgG, IgE) ▪ ELISA



OSMOSIS.ORG 451



▫ IgG antibodies against Toxocara excretory/secretory antigens ▫ Does not differentiate Toxocara canis from cati



OTHER DIAGNOSTICS



▪ Endemic-area travel history ▪ Physical examination



TREATMENT MEDICATIONS



▪ Moderate → severe symptoms ▫ Albendazole



▪ Severe inflammatory disease (myocarditis, pneumonitis, CNS involvement) ▫ Prednisone ▪ Ocular larva migrans ▫ Corticosteroids, albendazole



OTHER INTERVENTIONS Prevention ▪ Hand hygiene practice ▪ Pet feces disposal, deworming ▪ Undercooked meat (especially liver) consumption risk education



TRICHINELLA SPIRALIS osms.it/trichinella-spiralis PATHOLOGY & CAUSES



→ female worm release larvae → striated muscle encystation



▪ Roundworm infection (prevalent worldwide) ▫ Raw/undercooked meat with encysted organism consumption ▪ Trichinella: nine species, twelve genotypes ▫ Animal intermediate host-specific ▫ T. spiralis: most common worldwide; variety of carnivorous, omnivorous animals



Disease ▪ Severity correlates with multiple factors ▫ Number of ingested larvae directly correlates with ingested meat cooking temperature ▫ Trichinella species ▫ Incubation period (shorter correlates with ↑ disease severity) ▪ Gastrointestinal involvement ▫ Maturing larvae burrow in intestinal mucosa ▫ Diarrheal illness, nausea, vomiting ▪ Muscular involvement ▫ Adult worm dissemination into skeletal muscle ▫ Symptom resolution occurs with complete worm encystment ▫ Mild subclinical fatigue, post-exercise weakness persists months–years



Life cycle/transmission ▪ Domestic cycle: involves pigs, rodents ▪ Sylvatic cycle: broad animal range ▫ Bear, moose, wild boar most common human infection sources ▪ Trichinella larvae/mature worm ingestion by intermediate host → GI tract maturation → larvae release, migrate from female worms to striated muscles → encyst → intermediate host consumption (inadequate cooking temperature) → larval ingestion → larvae release in stomach (upon gastric acid, pepsin exposure) → small bowel mucosa invasion → adult worm maturation



452 OSMOSIS.ORG



RISK FACTORS



▪ Undercooked/raw meat consumption



Chapter 82 Nematodes (Roundworms)



COMPLICATIONS



▪ Myositis, myocarditis ▫ Eosinophil-enriched inflammatory response → life-threatening arrhythmia development ▪ Encephalitis, pneumonia ▫ Direct larval parenchyma infiltration, respiratory muscle disease



SIGNS & SYMPTOMS ▪ Gastrointestinal ▫ Nausea/vomiting, abdominal pain, diarrhea ▪ Muscular ▫ Most severe symptoms ▫ Pain (activity-dependent; ↑ muscle use/ strain correlates with ↑ ↑ pain) ▫ Tenderness, swelling, weakness ▪ Other ▫ High fever, periorbital edema, chemosis, visual disturbance ▫ Retinal hemorrhage on fundoscopic examination



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ In severe neurologic-involvement cases ▪ Multifocal cerebral cortex, white matter lesions



LAB RESULTS



▪ Serology ▫ ELISA, western blot, immunofluorescence assays ▫ Antibodies only detectable after 2-3 weeks of disease ▫ Eosinophilia ▫ Leukocytosis ▫ ↑ Muscle enzymes, ↑ creatinine kinase, ↑ lactate dehydrogenase ▪ Muscle biopsy ▫ Near tendinous insertion → highest yield obtained



Figure 82.7 A muscle biopsy containing a Trchinella spp. larva.



TREATMENT MEDICATIONS



▪ Mild disease ▫ Self-resolving ▫ Analgesia, antipyretics ▪ Systemic symptoms ▫ Antiparasitic therapy (assists larval burrowing into intestinal mucosa treatment) ▫ Corticosteroids



OTHER INTERVENTIONS Prevention ▪ Postexposure prophylaxis in suspected cases ▫ Mebendazole within six days of exposure ▪ Undercooked/raw meat consumption risk education, safe cooking practices



OSMOSIS.ORG 453



TRICHURIS TRICHIURA (WHIPWORM) osms.it/trichuris-trichiura PATHOLOGY & CAUSES ▪ Human intestinal parasite (AKA whipworm) ▪ T. Trichiura causative trichuriasis agent Morphology ▪ Adult ▫ 4 cm/1.6 in in length; made of anterior whip-like esophageal portion, posterior intestine/reproductive organ portion ▪ Egg ▫ Prolate spheroids, polar plugs at each end Life cycle ▪ Female T. Trichiura lays 3000–20,000 eggs daily 60–70 days post-infection ▪ Infectious form maturation ▫ Unembryonated egg passage in stool → soil deposition → eggs embryonate, become infectious in 15–30 days ▪ Human stages ▫ Egg ingestion → eggs hatch into larvae in small intestine → larvae mature into adult worms, embed in cecum, ascending colon ▪ Life-span: 1-3 years



RISK FACTORS



▪ Poor hygiene, sanitary conditions; inadequate human fecal disposal; uncooked/contaminated vegetable ingestion



454 OSMOSIS.ORG



COMPLICATIONS



▪ Heavy infection → rectal prolapse ▫ Inflammation, edema caused by high embedded worm quantity in rectum (usually small children) ▪ Persistent blood loss → iron-deficiency anemia ▪ Children ▫ Impaired growth, cognitive development



SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Heavier infection ▫ Abdominal pain, distension, diarrhea, fecal blood/mucus, nocturnal stooling, tenesmus



DIAGNOSIS OTHER DIAGNOSTICS



▪ Kato–Katz thick-smear technique ▫ Eggs in stool visualization



TREATMENT MEDICATIONS



▪ Antihelminthic treatment



Chapter 82 Nematodes (Roundworms)



WUCHERERIA BANCROFTI (LYMPHATIC FILARIASIS) osms.it/wuchereria-bancrofti PATHOLOGY & CAUSES ▪ Mosquito-borne nematode infection ▫ Characterization: lymphatic, subcutaneous involvement → disfigurement, disability ▪ Mosquito species vector geographicspecific (e.g. Culex, Aedes) Life cycle/transmission ▪ Filarial larvae introduction into human skin during mosquito bloodmeal → lymphatic spread → maturation into adult worm → reproduction, microfilarial hematologic release (commonly nocturnal release) → further transmission after infected individual’s mosquito bite Disease ▪ Adenolymphangitis, tropical pulmonary eosinophilia, hydrocele, chronic lymphatic disease



▪ Chyluria ▫ Intestinal lymphatic discharge into pelvis ▫ May → nutritional deficiency (including anemia, hypoproteinemia)



SIGNS & SYMPTOMS ▪ Fever, hydrocele Lymphatic disease ▪ Acute adenolymphangitis ▪ Painful lymphadenopathy, retrograde lymphangitis; self-resolving (4–7 days), may recur multiple times per year ▪ Dilation ▪ Lymphangiectasia ▪ Lymphedema ▫ Pitting edema → non-pitting edema → limb hardening ▫ Hyperpigmentation, hyperkeratosis may occur late in disease



Pathogenesis ▪ Filarial antigens → TH2-type immune response → cytokine production (IL-5, IgE) ▪ Adult worm → mechanical lymphatic disruption → lymphangiectasia, lymphatic dilation ▪ Endosymbiotic bacteria Wolbachia → immune response potentiation



DIAGNOSTIC IMAGING



RISK FACTORS



LAB RESULTS



▪ Sub-Saharan africa, Southeast Africa, India, Pacific island travel/residence



COMPLICATIONS



▪ Lymphedema (AKA elephantiasis) ▫ Chronic lymphatic vessel inflammation → limb swelling



DIAGNOSIS Ultrasound ▪ Lymphatic dilation, lymphangiectasia, adult worms may be visualized



▪ Circulating filarial antigen assays ▫ ELISA: Og4C3 antigen detection ▫ ↑ IgG4 levels indicate active infection ▪ Blood smear ▫ Nocturnal blood draw important to ↑ microfilariae concentration



OSMOSIS.ORG 455



OTHER DIAGNOSTICS ▪ Physical examination ▫ Wriggling adult filariae in lymphatic vessels



TREATMENT MEDICATIONS



▪ DEC ▫ Contraindication: onchocerciasis, severe Loa Loa infection, pregnancy ▫ Doxycycline may be added as combination agent for direct larvicidal activity ▫ ↓ lymphedema effectiveness ▫ Proper skin care, topical antimicrobial administration (antifungal, antibacterial agents), extremity elevation, exercise may ↓ edema over time



SURGERY



▪ Hydrocele complications



456 OSMOSIS.ORG



Figure 82.8 A histological section of a lymph node which contains a filarial worm. The normal lymph node architecture has been replaced with an inflammatory infiltrate composed largely of eosinophils.



OTHER INTERVENTIONS Prevention ▪ Mass drug administration programs ▪ Insecticide-treated bed nets ▪ Repellant, protective clothing in mosquitoendemic regions



Chapter 82 Nematodes (Roundworms)



OSMOSIS.ORG 457



NOTES



NOTES



NON TUBERCULOUS MYCOBACTERIUM



MICROBE OVERVIEW ▪ Pleomorphic acid-fast bacillus; usually rodshaped ▪ Thick waxy coating ▪ Obligate intracellular microorganism ▪ Optimal growing conditions: cool



temperatures (27–33ºC/80.6–91.4°F), aerobic environment ▪ Proliferates slowly; cannot be cultivated in vitro ▪ Appearance: red; Ziehl–Neelsen stain



MYCOBACTERIUM LEPRAE osms.it/mycobacterium-leprae PATHOLOGY & CAUSES ▪ Primarily infects skin, superficial nerves, upper respiratory tract mucosa, eyes ▪ Chronic infection: leprosy; AKA Hansen’s disease ▪ Targets Schwann cells → nerve damage → sensation loss → repeated injuries, infections → gradual destruction of extremities ▪ Infiltration of skin, cutaneous nerves → hypopigmented skin lesions Ridley-Jopling classification ▪ Tuberculoid ▫ ↑ cell-mediated immunity response ▫ AKA paucibacillary (↓ mycobacteria) ▪ Lepromatous ▫ ↓ cell-mediated immunity response ▫ AKA multibacillary (↑ mycobacteria) ▪ Broad disease spectrum ▫ Borderline tuberculoid, mid-borderline, borderline lepromatous, indeterminate



458 OSMOSIS.ORG



RISK FACTORS



▪ Close contact with infected individuals (esp. in areas of poverty), armadillos (enzootic in Dasypus novemcinctus) ▪ Older age, genetic factors, immunosuppression



COMPLICATIONS



▪ Lifelong neuropathy → severe disfigurement, disability ▪ Severe ophthalmic injury → vision loss ▪ Social stigma (falsely believed contagious)



SIGNS & SYMPTOMS ▪ Can be asymptomatic for years ▪ ↓ sensation ▫ Glove, stocking pattern → repeated painless injuries ▪ Hypopigmented/reddish skin lesions, heal spontaneously ▫ Tuberculoid: rare, well-demarcated ▫ Lepromatous: numerous, poorly demarcated



Chapter 83 Non Tuberculous Mycobacterium Nodular swelling (face, earlobes) Body hair loss (esp. eyebrows, eyelashes) Tender, thickened peripheral nerves Ocular involvement ▫ Chronic uveitis (common) ▫ Facial nerve paralysis (lagophthalmos) → corneal exposure, dry eye → corneal ulceration ▪ Late stages ▫ Claw fingers, toes ▫ Foot droop (inability to lift front of foot); peroneal nerve infiltration ▫ Nasal septum destruction → nose collapse (saddle nose)



▪ ▪ ▪ ▪



Figure 83.1 A skin lesion on the scalp of an individual with leprosy.



DIAGNOSIS LAB RESULTS



▪ Skin biopsy of active lesion ▫ Mycobacteria in cutaneous nerve ▪ Polymerase chain reaction (PCR) ▫ M. leprae DNA in tissues



OTHER DIAGNOSTICS ▪ Clinical examination



Figure 83.2 The hands of an individual with leprosy. The distal portions of almost all the digits, aside from one, have been lost.



TREATMENT MEDICATIONS



▪ Multidrug therapy to prevent resistance ▫ Tuberculoid: dapsone, rifampicin; six months ▫ Lepromatous: dapsone, rifampicin, clofazimine; 12 months



OTHER INTERVENTIONS



Figure 83.3 Skin changes on the chest of an individual infected with Mycobacterium leprae.



▪ Bacillus Calmette–Guérin (BCG) vaccination ▫ Administered at birth in regions with increased leprosy rates (e.g. Brazil, India, Indonesia)



OSMOSIS.ORG 459



NOTES



NOTES



OPPORTUNISTIC FUNGAL INFECTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Range of infections caused by fungi; take advantage of weakened immunity (e.g. HIV/ AIDS, malignancy, immunosuppression), altered microbiota, breached integumentary barriers ▪ Present in environment worldwide → immunocompetent, healthy individuals can be exposed without resulting in disease



RISK FACTORS



▪ Immunosuppression (e.g. HIV/AIDS, neutropenia, chemotherapy, hematologic malignancies, transplant recipients)



SIGNS & SYMPTOMS ▪ Primary local cutaneous, pulmonary infection to dissemination to various internal organs



DIAGNOSIS LAB RESULTS



▪ Direct microscopy with staining, culture, tissue biopsy, bronchoalveolar lavage (sputum sample if pulmonary in origin), polymerase chain reaction (PCR)



TREATMENT MEDICATIONS ▪ Antifungals



ASPERGILLUS FUMIGATUS osms.it/aspergillus-fumigatus PATHOLOGY & CAUSES ▪ Saprophytic fungi species responsible for majority of invasive, chronic aspergillosis ▪ Found in soil, compost ▪ Asexual reproduction → production of green pigmented asexual conidia (spores) → aerosolized → individuals inhale everyday → macrophages attempt to clear conidia → secondary inflammation after conidia germinate into hyphal forms → neutrophil recruitment → activation of



460 OSMOSIS.ORG



cellular immunity to kill hyphae ▪ Histopathologically, invasive aspergillosis characterized by progression across tissue planes ▫ Hallmark: vascular invasion → infarction + tissue necrosis ▪ Characteristics of Aspergillus as successful opportunistic pathogen ▫ Ability to grow at 37ºC/98.6°F ▫ Small conidial (2.5–3 micrometers) → buoyant in air for prolonged periods of time → inhaled deeply into lung alveoli



Chapter 84 Opportunistic Fungal Infections ▪ Aspergillus hyphae angioinvasive ▫ Thrombose arteries → hemorrhagic infarcts → abscesses ▪ Suspect in immunocompromised individuals with respiratory distress, fever (despite broad-spectrum antibiotics) ▪ Second most common cause of invasive fungal infections in neutropenic individuals (after Candida species) ▪ Specifically affects pulmonary, sinus, central nervous system (CNS) Diseases ▪ Necrotizing otitis externa ▫ More common in advanced HIV cases ▪ Acute pulmonary aspergillosis ▫ Inhaled conidia ▫ Most common cause of death in persons with chronic granulomatous disease (CGD) ▫ Can spread locally to involve pleura, chest wall, vertebrae → dissemination to other organs



Figure 84.1 Bronchial washing stained with Grocott methenamine silver stain from and individual with pulmonary aspergillosis. The hyphae are uniform, narrow and branch at acute angles. ▪ Cerebral aspergillosis ▫ Occurs in approx. 40% of individuals with invasive aspergillosis ▫ Hematogenous dissemination from extracranial focus (e.g. lung)/direct extension from sinus ▫ Most common brain abscess in stem cell transplant individuals



▪ Pulmonary aspergilloma ▫ Nonsaphrophytic (noninvasive) ▫ Colonization of pre-existing cavities (e.g. tuberculosis, sarcoidosis, bullous emphysema, bronchiectasis) ▫ Occurs in 15–25% of persons with cavitating lung disease from tuberculosis ▫ Lesion impinges on major vessel/airway → massive hemorrhage → hemoptysis ▫ “Fungus ball” ▪ Allergic bronchopulmonary aspergillosis ▫ Exposure to allergens of A. fumigatus → saprophytical growth → colonization of bronchial lumen → persistent bronchial inflammation → IgE-mediated allergic response in airways → hypersensitivity lung disease → bronchial obstruction ▫ Affects those with asthma (1–2%)/cystic fibrosis (1–15%)



RISK FACTORS



▪ Decreased immunity ▫ Malignancy, chemotherapy, transplant (esp. from HLA-mismatched donor), HIV/AIDS, immunosuppressant therapy, neutropenia, prolonged high dose corticosteroid use ▪ Prior pulmonary damage/disease ▪ ↑ age ▪ History of tuberculosis, histoplasmosis, sarcoidosis, bronchiectasis ▪ Cystic fibrosis, asthma (allergic bronchopulmonary aspergillosis)



COMPLICATIONS



▪ Hemorrhage → massive hemoptysis ▪ Widespread bronchiectasis + fibrosis → respiratory failure, death



SIGNS & SYMPTOMS ▪ Acute pulmonary aspergillosis ▫ Unremitting fever in high-risk cases (most common), dry cough, chest pain, dyspnea (more common in persons with diffuse disease), ↑ erythrocyte sedimentation rate (ESR)



OSMOSIS.ORG 461



▪ Invasive sinusitis ▫ Ear/facial pain, discharge, swelling; nasal septum/turbinate pallor; epistaxis; orbital swelling, headache; localized areas of frank crusting, ulceration, blackened necrotic areas ▪ Cerebral infection ▫ Headache, nausea, vomiting; altered mental status, confusion, cranial nerve palsies, hemiparesis ▪ Pulmonary aspergilloma ▫ May be asymptomatic; persistent, productive chronic cough, hemoptysis, weight loss ▪ Allergic bronchopulmonary aspergillosis ▫ Manifestations due to immune system response to A. fumigatus antigens; asthma-like symptoms (e.g. wheezing), eosinophilia ▪ Invasive aspergillosis ▫ Acute onset of fever, cough, respiratory distress, diffuse bilateral pulmonary infiltrates



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Increased sensitivity for radiological diagnosis ▪ Halo sign ▫ Neutropenic individuals (hemorrhagic nodule due to angioinvasion); rim of ground glass opacity surrounding nodule ▪ Air crescent sign ▫ Can develop from halo sign; cavitation → sloughed lung tissue encircled with rim of air MRI ▪ Target sign ▫ Nodule with lower central signal, higher contrast-enhancing signal on periphery; late stage disease ▪ For diagnosis of cerebral aspergillosis; multiple lesions in basal ganglia



462 OSMOSIS.ORG



X-ray ▪ Unilateral infiltrates (interstitial, alveolar, mixed), cavitary lesions, multiple nondefined 1–3cm.0.39–1.18in peripheral nodules coalesce into larger masses



LAB RESULTS Tissue biopsy ▪ Not utilized frequently due to invasive nature; ↑ risk of bleeding or secondary infection in immunosuppressed individuals Cultures ▪ Respiratory tract, sputum cultures commonly negative; rarely diagnosed by blood Bronchoalveolar lavage ▪ Approx. 40% diagnostic yield Serology ▪ Useful for diagnosis of aspergilloma, allergic bronchopulmonary aspergillosis in immunocompetent individual; not useful in immunocompromised Galactomannan antigen testing ▪ Enzyme immunosorbent assay recognizes side chains of galactomannan molecule ▫ Positive: invasive disease ▫ High false-positive rate in neutropenic cases Allergic bronchopulmonary aspergillosis ▪ Eosinophilia, ↑ serum IgE



Figure 84.2 A tissue section containing Aspergillus hyphae and fruiting heads.



Chapter 84 Opportunistic Fungal Infections



TREATMENT MEDICATIONS



▪ Invasive aspergillosis ▫ Voriconazole (preferred over amphotericin B)/caspofungin; azoleresistance developing ▪ Local pulmonary aspergilloma ▫ Percutaneous intracavitary instillation of antifungals



▪ Allergic bronchopulmonary aspergillosis ▫ Corticosteroids (attenuate immune system response) ▫ Antifungal therapy: itraconazole (decrease fungal burden, antigen load) ▫ Preventative long term antifungal therapy in immunocompromised individuals



SURGERY



▪ Local pulmonary aspergilloma ▫ Surgical removal (e.g. lobectomy in massive hemoptysis)



CANDIDA osms.it/candida PATHOLOGY & CAUSES ▪ Oval, budding yeast; forms hyphae, pseudohyphae ▪ Nonpathological colonization of humans → overgrowth leads to pathology ▪ Most common cause of invasive fungal infections in immunocompromised individuals (e.g. neutropenic cases) ▫ C. albicans species most common cause of candidiasis ▫ Increasing proportion of fungal infections caused by nonalbicans Candida species (e.g. C. tropicalis, C. parapsilosis, C. kruseim, C. glabrata) Chronic mucocutaneous candidiasis ▪ Persistent infection of mucous membranes, skin, nails ▪ More commonly affects those with defective T-cell mediated immunity Vulvovaginal candidiasis (VVC) ▪ Originates from spread from GI tract, sexual transmission ▪ Occurs in 75% of healthy individuals who are biologically female ▫ 80–90% caused by C. albicans



▫ 10–20% of those with VVC have severe, recurrent infections; usually from nonalbicans species Candida esophagitis ▪ Most common in severely immunocompromised individuals (e.g. HIV individuals) ▪ May occur in absence of thrush ▪ In individuals with AIDS, can occur simultaneously with cytomegalovirus, herpes simplex infection (HSV) Disseminated/invasive candidiasis ▪ Rare in immunocompetent individuals ▪ Development of invasive disease due to interaction between Candida species virulence factors, colonization burden, host immunological status ▪ Candidemia ▫ Isolation of Candida from blood culture ▪ Candida species exhibit tissue tropism → deep organ involvement (e.g. liver, spleen, brain, bone) in absence of prolonged candidemia



OSMOSIS.ORG 463



RISK FACTORS



▪ Antibiotic therapy, diabetes mellitus (poorly controlled), immunocompromised state (e.g. immunosuppressive therapy, neutropenia, hematologic malignancy, chemotherapy, transplant), chronic granulomatous disease, Job syndrome, impaired cell-mediated immunity, pregnancy, contraceptive use (hormonal/intravaginal, intrauterine devices)



COMPLICATIONS



▪ ▪ ▪ ▪



hypertension, flank mass, pyelonephritis, acute urinary obstruction from fungal mycetoma → hydronephrosis CNS: altered mental status, characteristic symptoms of meningitis Optic: chorioretinal infections, lens abscess Hepatosplenic: right upper quadrant pain; nausea, vomiting; hepatosplenomegaly Other: endocarditis (may be from central vascular catheters), bone/joint infections



▪ Meningoencephalitis ▫ Obstructive hydrocephalus, calcifications, thrombosis ▪ Renal system ▫ Pyelonephritis ▪ Abscesses in multiple organs ▪ Sepsis, septic shock



SIGNS & SYMPTOMS Mucocutaneous growth (most common) ▪ Mouth, oropharynx ▫ AKA thrush ▫ Thick, pearly white, curd-like plaques on oral mucosa ▫ Painful → dysphagia/odynophagia ▫ Otherwise unexplained → suspect HIV infection ▪ Vagina ▫ Thick, cottage-cheese-like, white vaginal discharge ▫ Painless, pruritic ▫ Dysuria possible ▪ Cutaneous candidiasis ▫ Erythematous pruritic patches + satellite lesions ▫ Individuals who are obese, diabetic ▫ Skin folds, underneath breasts ▪ GI tract ▫ May be asymptomatic ▫ Esophagus → odynophagia Disseminated/invasive candidiasis ▪ Candidemia: nonspecific (hard to distinguish from bacteremia); most commonly manifests as persistent fever despite antibiotic therapy ▪ Renal system: candiduria, rising creatinine,



464 OSMOSIS.ORG



Figure 84.3 Oral candidiasis on the tongue of a child who had recently taken oral antibiotics.



DIAGNOSIS LAB RESULTS



▪ Microscopic examination ▫ KOH preparation; visualization of hyphae, pseudohyphae, blastospores ▪ Invasive candidiasis ▫ Blood/tissue culture ▪ PCR ▪ Esophagitis ▫ Tissue biopsy (definitive)



Chapter 84 Opportunistic Fungal Infections



OTHER DIAGNOSTICS



▪ Clinical presentation, history



TREATMENT MEDICATIONS



▪ Oropharyngeal candidiasis ▫ Oral nystatin suspension; clotrimazole troches (dissolves in mouth) ▪ Candida dermatitis ▫ Topical nystatin/miconazole ▪ Vulvovaginal candidiasis ▫ Local miconazole/clotrimazole creams; oral fluconazole



▪ Invasive, systemic candidiasis ▫ Echinocandins; voriconazole, caspofungin (preferred over amphotericin/fluconazole) ▪ Individuals with HIV ▫ Prophylactic antifungals (e.g. oral nystatin, fluconazole)



OTHER INTERVENTIONS



▪ Candida dermatitis ▫ Keep skin dry ▪ Invasive, systemic candidiasis ▫ Immediate removal of all central lines, catheters (Candida can develop rapid biofilms)



CRYPTOCOCCUS NEOFORMANS osms.it/cryptococcus-neoformans PATHOLOGY & CAUSES ▪ Heavily encapsulated, nondimorphic, yeastlike fungus, urease positive ▪ Virulence factors ▫ Grows well in 37ºC/98.6°F environment ▫ Produces polysaccharide capsule, melanin (neurotropism) ▪ Most common cause of fungal meningitis in immunocompromised adults ▪ Found in bird droppings, soil → inhalation of airborne fungi → evident/nonevident pulmonary infection → spreads lymphohematogenously (can affect any organ) → meninges ▪ CNS infection associated with high mortality



COMPLICATIONS



▪ Increased intracranial pressure → herniation → death ▪ May be due to buildup of cryptococcal polysaccharide at arachnoid villi → disruption in cerebrospinal fluid (CSF) reabsorption



RISK FACTORS



▪ Impaired cell-mediated immunity, highdose corticosteroid treatment, hematologic malignancies (e.g. leukemia, lymphoma) ▪ HIV/AIDS (most common immunocompromising state): < 100 cells/ mm3 CD4+ count



Figure 84.4 A histology photomicrograph of the lung.



OSMOSIS.ORG 465



SIGNS & SYMPTOMS ▪ Pulmonary manifestations ▫ Asymptomatic in 1/3 of immunocompetent individuals; fever, cough, pleuritic chest pain, dyspnea, weight loss, hemoptysis ▪ Neurologic manifestations (most common) ▫ Acute/insidious; headache, fever, vomiting, nuchal rigidity, mental status changes/seizures, cryptococcal abscesses (e.g. cryptococcomas, not common) ▪ Skin manifestations (10–15%) ▫ Result of direct hematogenous spread/ extension from bone lesion; single/ multiple pustules/papules → ulcer/ abscess ▪ Bone infection (5–10%) ▫ Pain, swelling; joint involvement; often found incidentally



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Focal/diffuse interstitial infiltrates, hilar lymphadenopathy



LAB RESULTS



▪ CSF ▫ Lymphocytic pleocytosis; ↓ glucose; ↑ protein, opening pressure; results may be unchanged in individuals with AIDS ▪ Direct microscopic analysis of CSF/other body secretions ▫ India ink: capsule visualized with clear halo ▫ Mucicarmine: visualization of red inner capsule ▫ Visualize budding ▪ Culture ▫ Sabouraud glucose agar, incubation up to two weeks ▪ Cryptococcal capsular antigen (serum, CSF, urine, bronchoalveolar lavage) ▫ Most reliable nonculture-based method



466 OSMOSIS.ORG



▪ Latex agglutination test ▫ Detects polysaccharide capsular antigen, ↑ specificity



Figure 84.5 Bronchial washings from an immunocompromised individual with pulmonary cryptococcosis. The cryptococcus spores have a characteristically thick capsule.



TREATMENT MEDICATIONS



▪ Amphotericin B, flucytosine ▪ Prevention in HIV cases with CD4+ cell counts < 100 cells/mm3—fluconazole



OTHER INTERVENTIONS



▪ ↑ intracranial pressure complication treatment ▫ Repeat CSF drainage (most important factor in reducing mortality)



Chapter 84 Opportunistic Fungal Infections



MUCORMYCOSIS osms.it/mucormycosis PATHOLOGY & CAUSES ▪ Several genera of family Mucoraceae causing rapidly progressive, invasive mucormycosis in various body systems ▪ Subphylum Mucoromycotina, order Mucorales ▫ Most human infections from members of family Mucoraceae ▫ Six genera: Rhizopus, Mucor, Actinomucor, Rhizomucor, Apophysomyces ▪ Present in decomposing organic matter (e.g. spoiled food items, soil) ▪ Forms broad, aseptate hyphae branching at right angles by sexual reproduction with formation of zygospores ▪ Inhalation of spores → sinuses, lungs primary location of infection ▪ Immunocompetent host → lung macrophages ingest, kill spores → neutrophils kill hyphae ▪ Immunosuppressed individuals → macrophages fail to stop spore germination ▪ Severe neutropenia/diabetic ketoacidotic individuals → abnormal neutrophil function → increased risk of invasive infection ▪ Angioinvasive mold → results in thrombosis, infarction, necrosis of surrounding tissues Diseases ▪ Rhinocerebral mucormycosis ▫ Necrotic lesion in paranasal sinus → orbit, face, palate, brain ▫ Most common in diabetic ketoacidosis ▫ Progresses rapidly ▪ Pulmonary mucormycosis ▫ Most common in severe neutropenic individuals ▪ Gastrointestinal mucormycosis ▫ Rare, occurs in severely malnourished children



▫ Can affect all segments of GI tract (esp. stomach, small/large intestine, esophagus) ▪ Cutaneous mucormycosis ▫ Due to traumatic implantation of spores from soil (e.g. site of surgical incisions, burn wounds) ▫ Extensive necrotic infection → necrotizing cellulitis ▫ Most common in immunocompetent individuals ▪ Disseminated mucormycosis (involves CNS) ▫ Most common in severe neutropenic individuals following pulmonary infection ▫ Brain (most commonly affected), metastatic necrotic lesions can occur in any organ



RISK FACTORS



▪ DM ▪ Diabetic ketoacidosis state ▫ ↑ risk for rhinocerebral mucormycosis ▪ Leukemia, neutropenia, chemotherapy ▫ ↑ risk of rhinocerebral, pulmonary, disseminated disease ▪ Severe malnutrition ▫ GI mucormycosis ▪ Deferoxamine treatment for iron overload state ▪ Recipient of bone marrow transplant ▪ Prolonged use of corticosteroids/other immunosuppressive therapies ▪ Prolonged use of broad-spectrum antibiotics ▪ IV drug use



COMPLICATIONS



▪ Cavernous sinus thrombosis, cranial nerve palsies (e.g. proptosis, ptosis, dilation, fixation of pupil), vision loss,



OSMOSIS.ORG 467



brain abscess, necrosis of frontal lobes, GI tract perforation, perirenal abscess, renal infarction



SIGNS & SYMPTOMS ▪ Typical course: rapid onset of necrotic lesion → fulminant course requiring aggressive therapy ▪ Rhinocerebral ▫ Black, necrotic lesion on nasal/palatine mucosa; nasal/sinus congestion, pain; epistaxis; fever; edema, induration, necrosis of perinasal, periorbital tissue ▪ Pulmonary ▫ Nonspecific, pneumonia-like; may involve pleuritic chest pain, cough, fever, hemoptysis ▪ GI ▫ Abdominal pain, bleeding (e.g. hematemesis) ▪ Cutaneous ▫ Painful edema, erythema → raised, indurated lesions with black, necrotic center ▪ Disseminated ▫ Altered mental status (e.g. lethargy, obtunded state, confused)



DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Thoracic: nodular lesions, cavitations ▪ Head: extension of infection in sinuses → affecting brain tissue



LAB RESULTS ▪ Histopathological identification ▫ Distinct hyphae; broad irregularly branched with rare septations



468 OSMOSIS.ORG



Figure 84.6 Bronchial washings stained with Papanicolaou stain from an individual with pulmonary mucormycosis. The mucor hyphae contain no septa, are of variable width and branch at a wide angle.



TREATMENT MEDICATIONS



▪ Aggressive antifungal therapy ▫ Amphotericin B



SURGERY



▪ Infected necrotic tissue ▫ Extensive surgical debridement



OTHER INTERVENTIONS



▪ Adjunctive therapy ▫ Hyperbaric oxygen, immune modulation, white blood cell infusion



Chapter 84 Opportunistic Fungal Infections



PNEUMOCYSTIS JIROVECII (PNEUMOCYSTIS PNEUMONIA) osms.it/pneumocystis-jirovecii PATHOLOGY & CAUSES ▪ Opportunistic yeast-like fungi (originally classified as protozoan) responsible for pneumocystis pneumonia ▪ Formerly known as Pneumocystis carinii ▪ Airborne transmission route; human-tohuman route occurs early in life ▪ Immunocompetent individuals may act as asymptomatic reservoirs ▪ 5–7 micrometer cysts contain up to eight pleomorphic intracystic sporozoites → become excysted → form trophozoites ▪ Reside in alveoli ▪ Disease: pneumocystis pneumonia ▫ Occurs exclusively in immunocompromised individuals ▫ Remains localized in lungs ▫ Clinical manifestations due to inflammatory reaction in alveoli lumen/ septum ▫ Fatal if left untreated



RISK FACTORS



▪ Defects in cell-mediated immunity, HIV/ AIDS, severe combined immunodeficiency syndrome, hematological malignancies, transplant recipients, hyper IgM syndrome



SIGNS & SYMPTOMS ▪ Most infections asymptomatic in immunocompetent individuals ▪ Abrupt onset of tachypnea, fever, cough ▪ Respiratory distress



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Diffuse, bilateral ground glass opacities ▪ First appearing in perihilar area → progresses peripherally, apical regions spared



LAB RESULTS



▪ Microscopic examination with silver stain ▫ Disc-shaped yeast ▪ Open lung biopsy ▪ Bronchoalveolar lavage ▪ PCR of sputum/lavage samples ▪ ↓ PaO2 (reflects severity of disease) ▪ Unchanged WBC count



TREATMENT Figure 84.7 A foamy alveolar cast in a bronchial washing taken from an individual with Pneumocystis pneumonia.



MEDICATIONS



▪ Trimethoprim-sulfamethoxazole ▪ Alternatives ▫ Pentamide, dapsone + trimethoprim, atovaquone



OSMOSIS.ORG 469



▪ Prophylactic trimethoprimsulfamethoxazole/pentamide ▫ Individuals with HIV, < 200 CD4+ cells/ mm3



OTHER INTERVENTIONS ▪ Respiratory support



Figure 84.8 A bronchial wash stained with Grocott’s methenamine silver highlighting Pneumocystis spores.



SPOROTHRIX SCHENCKII osms.it/sporothrix-schenckii PATHOLOGY & CAUSES ▪ Chronic subcutaneous thermally dimorphic fungus → sporotrichosis ▪ Found in soil, decomposing vegetation, plant materials (e.g. moss, hay, wood, rose bushes) ▪ Found worldwide, mostly in temperate/ tropical regions (16–22ºC/60.8–71.6°F) ▪ Outside human body grows as filamentous mold; in tissue grows as small budding yeast cells Diseases ▪ Lymphocutaneous sporotrichosis ▫ Follows traumatic inoculation of skin/ subcutaneous tissue (e.g. minor insult from thorns or splinters) → incubation 1–4 weeks → papule develops at site of inoculation → ulceration of primary lesion → nonpurulent, odorless drainage → similar lesions occur along lymphatic channel proximal to primary lesion ▪ Pulmonary sporotrichosis ▫ Following inhalation of Sporothrix conidia ▫ May progress to disseminated disease



470 OSMOSIS.ORG



▪ Osteoarticular sporotrichosis ▫ Most commonly affected joints: knee, elbow, wrist, ankle ▫ Chronic infection with progressive decreased range of motion, pain, swelling ▪ Meningeal sporotrichosis ▫ Rare, mostly in individuals with cellular immune defects (e.g. lymphoma, AIDS) ▫ Chronic course ▪ Disseminated cutaneous sporotrichosis ▫ Rare (< 1%) ▫ Numerous small papules/vesicles → necrotic, ulcerated nodules on trunk, limbs ▫ Follows lymphatic spread



RISK FACTORS



▪ Lymphocutaneous ▫ Exposure due to skin trauma (e.g. living in homes with dirt floors) ▫ Individual with outdoor preoccupation ▫ Contact with cats ▪ Pulmonary ▫ Chronic obstructive pulmonary disease (COPD) ▪ Excessive alcohol use



Chapter 84 Opportunistic Fungal Infections



SIGNS & SYMPTOMS ▪ Lymphocutaneous sporotrichosis ▫ Primary papule → ulcerated lesion; similar lesions visualized along lymphatic channel proximally; chronic, fixed cutaneous lesion ▪ Pulmonary ▫ Fever, night sweats, weight loss, fatigue; dyspnea, cough; purulent sputum; hemoptysis ▪ Osteoarticular sporotrichosis; progressive decreased range of motion, pain, swelling in joints ▪ Meningeal sporotrichosis ▫ Chronic (weeks to months) fever, headache



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Unilateral/bilateral upper lobe cavities ▪ Variable amount of fibrosis ▪ Scattered nodular lesions



LAB RESULTS



▪ Culture (most sensitive) ▫ Tissue biopsy, sputum, body fluid ▫ Sabouraud’s agar at room temperature ▫ Characteristic arrangement of conidia on hyphae ▪ Direct microscopy ▫ Typical oval/cigar-shaped cells ▫ Asteroid bodies of S. Schenckii ▪ CSF analysis ▫ Lymphocytic pleocytosis, ↑ protein, ↓ glucose



OTHER DIAGNOSTICS



▪ Clinical examination, history



Figure 84.10 Sporothrix fungi forming conidia. Figure 84.9 Partially healed skin lesions of sporotrichosis in a typical lymphcutaneous distribution.



TREATMENT MEDICATIONS



▪ Localized: itraconazole ▪ Severe: amphotericin B



OSMOSIS.ORG 471



NOTES



NOTES



ORTHOMYXOVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Associated clinical syndromes: influenza (“the flu”), pneumonia ▪ RNA virus family; causes acute respiratory disease Genetic material ▪ Negative-sense, single-stranded RNA Taxonomy ▪ Genera ▫ Influenza A, Influenza B, Influenza C: infect humans ▫ Influenza D, Isavirus, Thogotovirus, Quaranjavirus ▪ Classified by surface protein ▫ Influenza A, B: hemagglutinin (H) (glycoprotein, allows progeny release); neuraminidase (N) (lectin; binds to host cell through sialic acid residues) ▫ Influenza C: hemagglutinin esterase fusion (F) (binds to host cell) Morphology ▪ Enveloped (outer lipid membrane) ▪ Spherical/filamentous ▪ Size: 50–120nm



472 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ Fever, malaise, myalgia, sore throat, nonproductive cough



DIAGNOSIS ▪ Clinical examination



DIAGNOSTIC IMAGING X-ray ▪ Chest CT scan



LAB RESULTS ▪ Molecular assays ▪ Viral culture



TREATMENT MEDICATIONS ▪ Antiviral therapy



Chapter 85 Orthomyxoviruses



INFLUENZA VIRUS osms.it/influenza PATHOLOGY & CAUSES ▪ Single-stranded RNA virus; causes acute respiratory disease ▪ AKA “the flu” ▪ Incubation: 1–4 days Pathogenesis ▪ Influenza virus penetrates upper respiratory tract → hemagglutinin binds to epithelial cell sialic acid residue → endocytosis → viral replication → neuraminidase releases progeny → viral infection spreads ▪ Viral shedding (progeny release) ▫ Duration: average 4–8 days ▫ Magnitude: ↑ symptoms = ↑ shedding ▪ Influenza A antigen variations → immune evasion, reinfection ▫ Antigenic shift: major changes in H/N proteins (two different influenza virus genome segments reassort) → epidemic/pandemic ▫ Antigenic drift: minor changes in H/N proteins (mutation in H/N gene) → outbreak Taxonomy ▪ Nomenclature: [type] / [original host] / [location of first identification] / [strain number] / [year of origin] ([subtype]) ▫ Host type, subtype included in influenza A viruses only ▫ E.g. H1N1 type A flu virus of duck origin, found in Alberta, Canada, 35th strain, found in 1976 → A/duck/ Alberta/35/76(H1N1)



Pandemics, associated strains ▪ 1918 “Spanish flu” → H1N1 ▪ 1957 “Asian flu” → H2N2 ▪ 1968 “Hong Kong flu” → H3N2 ▪ 2009 (worldwide) → H1N1



RISK FACTORS ▪ Immunosuppression, age ≥ 65 years, age < six months, nursing/chronic care facility resident, pregnancy, chronic disease, morbid obesity



COMPLICATIONS ▪ Secondary bacterial infection (e.g. pneumonia, sinusitis, otitis media, bronchiolitis), acute respiratory distress syndrome, myositis, rhabdomyolysis, myocarditis, pericarditis, encephalitis ▪ Secondary bacterial infections generally due to Streptococcus pneumoniae



SIGNS & SYMPTOMS Uncomplicated influenza ▪ Systemic: fever, malaise, myalgia, headaches, weakness, dizziness ▪ Respiratory: non-productive cough, sore throat, nasal secretion ▪ Mild cervical adenopathy Complicated influenza ▪ Primary influenza pneumonia: fever, dyspnea, cyanosis ▪ Secondary bacterial pneumonia: fever, cough, purulent sputum



Transmission ▪ Direct contact, airborne droplets, fomites Outbreak ▪ Abrupt ▪ Winter; year-round in tropical regions ▪ Duration: 2–3 months



OSMOSIS.ORG 473



DIAGNOSIS ▪ Clinical examination, during outbreak



DIAGNOSTIC IMAGING X-ray ▪ chest CT scan ▪ Primary influenza pneumonia: bilateral reticular/reticulonodular opacities, sometimes consolidation ▪ Secondary bacterial influenza: pulmonary infiltrates



LAB RESULTS



▪ Respiratory tract specimen molecular assay: reverse-transcriptase polymerase chain reaction (RT-PCR) ▪ Rapid antigen test: immunoassay ▪ Respiratory tract specimen viral culture



474 OSMOSIS.ORG



TREATMENT MEDICATION ▪ Severe illness/risk factors → antiviral therapy ▫ Neuraminidase inhibitors; H1N1 commonly resistant ▫ M2 proton channel inhibitors; active against influenza A only ▪ Symptomatic treatment: acetaminophen, non-steroidal anti-inflammatory drugs (NSAID) ▪ Secondary bacterial infection: antibiotics



OTHER INTERVENTIONS ▪ Hydration Prevention ▪ Vaccine ▫ Inactivated (intramuscular/intradermal)/ live attenuated (intranasal); trivalent/ quadrivalent (2 influenza A antigens + 1/2 influenza B antigens); annual, single-dose application (before winter); age ≥ six years ▪ Antiviral prophylaxis (high-risk individual) ▫ Neuraminidase inhibitors ▪ Infection control ▫ E.g. hand hygiene, face mask



NOTES



NOTES



PAPILLOMAVIRUS



HUMAN PAPILLOMAVIRUS osms.it/human-papillomavirus PATHOLOGY & CAUSES ▪ Human papillomavirus (HPV): virus that causes cutaneous and mucosal infections, resulting in warts (verrucae) ▪ > 200 known types; > 40 transmitted through sexual contact ▪ Humans: only host Genetic material ▪ Small, double-stranded, circular DNA virus Taxonomy ▪ Papillomaviridae family Morphology ▪ Non-enveloped, capsid virus



CAUSES



▪ Transmission ▫ Skin-to-skin contact via breaks in epithelium (autoinoculation causes local spread) ▫ Vaginal, anal, oral sexual intercourse ▫ Vertical transmission (congenital infection) ▪ Cutaneous HPV ▫ Infection of the basal stem cells of keratinized skin → viral genome replicates within proliferating cells → infected cell eventually reaches the upper epithelial layers → hyperkeratotic growth ▪ Mucosal HPV ▫ → infection of epithelium → integration into the host genome → flat, papular, or pedunculated growths → high-grade lesions and cancer may develop



RISK FACTORS



▪ Epithelial trauma ▪ Walking barefoot ▪ Occupational ▫ Meat, poultry, and fish handlers ▪ Use of communal showers ▪ Smoking ▪ Early age of first sexual intercourse ▪ Multiple sexual partners ▪ Uncircumcised males ▪ Immunocompromised state; esp. HIV/AIDS



COMPLICATIONS



▪ Some types have oncogenic potential



SIGNS & SYMPTOMS ▪ Common warts: verruca vulgaris (HPV types 2, 4) ▫ Cauliflower-like raised surface located on hands, feet, elbows, knees, subungual/periungual (under, around fingernail/on cuticle; may be painful) ▫ Common in children, adolescents ▪ Plantar: verruca plantaris (HPV type 1) ▫ Located on soles of feet ▫ May induce pain when walking ▪ Flat: verruca plana (HPV types 3, 20, 28) ▫ Flat warts found on arms, face, forehead ▫ Common in children, adolescents ▪ Anogenital: condyloma acuminatum (HPV types 6, 11 low risk; 15 types have oncogenic potential; types 16 and 18 cause 90% of all genital warts)



OSMOSIS.ORG 475



▫ Cervical cancer: types 16 and 18 70% of all cases ▫ Anal cancer: type 16 is the usual cause ▫ Other cancers; e.g. oropharyngeal, vaginal, vulvar, penile cancers usually caused by type 16 ▪ Laryngeal papillomatosis (HPV types 6, 11) ▫ Larynx, respiratory tract



TREATMENT MEDICATIONS



▪ Cutaneous warts ▫ Topical salicylic acid, fluorouracil 5% ▪ Anogenital warts ▫ External warts: podofilox solution or gel, sinecatechins ointment, imiquimod cream



SURGERY



▪ Anogenital warts ▫ Surgical removal



OTHER INTERVENTIONS



▪ Cutaneous warts ▫ May resolve spontaneously ▫ Cryotherapy (liquid nitrogen) ▪ Anogenital warts ▫ External or internal (vaginal, cervical, intra-anal): cryotherapy, trichloroacetic acid, bichloroacetic acid



Figure 86.1 A giant anal condyloma in an immunocompromised male.



DIAGNOSIS LAB RESULTS



▪ Genetic testing: in situ hybridization/ polymerase chain reaction (PCR) ▫ Real-time PCR (detect HPV viral load) ▪ Immunohistochemistry: biomarker detection ▫ E6, E7 mRNA ▫ p16 cell-cycle protein ▪ Cervical lesions: cytology ▫ If positive for abnormal cells: colposcopy and biopsy



476 OSMOSIS.ORG



Prevention ▪ HPV vaccines ▫ Gardasil (quadrivalent), Cervarix (bivalent), 9-valent ▫ Both vaccines protect against HPV 16, 18; Gardasil also protects against HPV 6, 11 ▫ Administered before primary infection occurs (9–13 years old) ▪ Cervical cancer screening ▫ Pap smear ▪ Effective barrier contraception ▫ Condoms (reduces risk; less protection compared to other STIs) ▪ Decrease number of sexual partners



Chapter 86 Papillomavirus



Figure 86.2 The histological appearance of a condyloma. There is hyperkeratosis and parakeratosis. Numerous keratinocytes demonstrate perinuclear clearing known as koilocytosis.



OSMOSIS.ORG 477



NOTES



NOTES



PARAMYXOVIRUSES MICROBE OVERVIEW ▪ Paramyxoviruses: negative-sense singlestranded RNA virus family ▪ Natural hosts: humans, vertebrates, birds ▪ Replication: occurs in cytoplasm; exits by budding ▪ Transmission: air borne particles



▪ Viral structure: enveloped, linear genomes, spherical/pleomorphic ▪ Pathogenic paramyxoviruses: human parainfluenza virus (HPIV), measles, mumps, respiratory syncytial virus (RSV)



HUMAN PARAINFLUENZA VIRUSES (HPIV) osms.it/human-parainfluenza-viruses PATHOLOGY & CAUSES ▪ Croup (laryngotracheobronchitis): infection usually caused by HPIV ▪ Four distinct HPIV serotypes ▫ HPIV-1: croup ▫ HPIV-2: croup; upper, lower respiratory tract illnesses ▫ HPIV-3: bronchiolitis, pneumonia ▫ HPIV-4: infrequently detected ▪ Common respiratory distress cause (children) ▪ Viral infection → infiltration of histiocytes, lymphocytes, other white blood cells → airway inflammation, edema → upperairway obstruction → ↑ breathing work, barky cough, inspiratory stridor (turbulent, noisy airflow), vocal hoarseness



RISK FACTORS



▪ Age ▫ Six months to three years



478 OSMOSIS.ORG



▪ Biologically-male to biologically-female ratio of 1.4:1 ▪ Previous intubation ▪ Hyperactive airways ▪ Congenital airway narrowing ▪ Late autumn (peak case onset)



COMPLICATIONS



▪ Respiratory failure ▪ Bacterial superinfection ▫ Pneumonia, bacterial tracheitis



SIGNS & SYMPTOMS ▪ Prodrome ▫ Upper respiratory tract infection symptoms (coryza, cough, mild fever) ▪ Acute onset: “barking” cough ▪ Inspiratory stridor; biphasic stridor (severe obstruction sign) ▪ Hoarseness



Chapter 87 Paramyxoviruses ▪ Respiratory distress, ↑ breathing work (e.g. suprasternal, intercostal, subcostal retractions) ▪ Agitation ▪ Symptoms worse at night ▪ Asynchronous chest movement ▪ Severe: fatigue, hypoxia, hypercarbia



DIAGNOSIS



TREATMENT MEDICATIONS



▪ Corticosteroids; dexamethasone for antiinflammatory effects ▪ Nebulized epinephrine in moderate, severe croup; temporary airway obstruction relief



OTHER INTERVENTIONS ▪ Provide comfort, avoid child’s further distress



OTHER DIAGNOSTICS Westley score ▪ Severity classification ▪ Calculated on five factors ▫ Level of consciousness, cyanosis, stridor, air entry, retractions ▫ Score between 0–17 classifies case as mild, moderate, severe croup; impending respiratory failure



MEASLES VIRUS osms.it/measles PATHOLOGY & CAUSES ▪ A paramyxovirus that causes measles, a highly infectious illness ▫ Fever, cough, coryza, conjunctivitis, followed by exanthem ▪ Transmitted via person-to person contact, droplets → infects upper respiratory tract epithelial cells Clinical stages (four) ▪ Incubation ▫ 6–21 days ▫ Virus infects respiratory mucosa/ conjunctiva → local replication → lymphatic tissue spread → disseminates via blood circulation → first virema (infection of endothelial, epithelial, monocyte, macrophage cells) ▫ Usually asymptomatic ▪ Prodrome ▫ 2–4 days



▫ Onset of fever, malaise, anorexia, conjunctivitis, coryza, cough ▪ Exanthem ▫ Onset 2–4 days after fever ▫ Erythematous, maculopapular, blanching rash ▫ Begins on face → trunk → extremities ▪ Recovery ▫ Cough persists 1–2 weeks ▫ Immunity thought to be lifelong



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Measles virus exposure Travel to measles-endemic areas No prior measles immunization Failed measles vaccine response Immunocompromised individuals: AIDS, lymphoma/other malignancy, T cellsuppressive medication



OSMOSIS.ORG 479



COMPLICATIONS ▪ Secondary infection ▪ Diarrhea (most common) ▪ Pneumonia (most common children’s death cause) ▪ Otitis media (younger individuals) ▪ Encephalitis, acute disseminated encephalomyelitis, subacute sclerosing panencephalitis ▪ Subacute sclerosing panencephalitis



SIGNS & SYMPTOMS ▪ Prodrome ▫ Fever onset, malaise, anorexia, conjunctivitis, coryza, cough ▪ Koplik’s spots on buccal mucosa (1–2 days before rash onset) ▫ Red spots on erythematous buccal mucosa ▫ Measles pathognomonic ▪ Maculopapular, blanching, erythematous rash (approx. 14 days after initial infection) ▫ Head → trunk → extremities ▪ Persistent cough after resolution ▪ Modified measles ▫ Measles infection in individual with existing measles immunity ▫ Milder symptoms



▪ Atypical measles ▫ Measles virus infection in individuals immunized with killed virus vaccine ▫ Higher, prolonged fever ▫ Dry cough, pleuritic chest pain may present



DIAGNOSIS ▪ Individual presenting with febrile rash, cough, coryza, conjunctivitis



LAB RESULTS ▪ Measles detection; one of following ▫ Enzyme-linked immunosorbent assay (ELISA): positive measles-specific IgM serology (most common) ▫ Measles IgG antibody: ↑ (between acute, convalescent titers) ▫ Reverse transcription polymerase chain reaction (PCR): measles virus RNA detection ▫ In culture: Measles virus isolation



TREATMENT MEDICATIONS



▪ Antipyretics, bacterial superinfection treatment



OTHER INTERVENTIONS



Figure 87.1 Koplik spots on the oral mucosa of an individual infected with the measles virus.



480 OSMOSIS.ORG



▪ Respiratory support, fluids ▪ Vitamin A supplementation ▫ Vitamin A deficiency plays role in delayed recovery, complications ▪ Prevention ▫ No specific antiviral therapy ▫ MMR (measles, mumps, rubella) vaccine ▫ Infection control (airborne transmission precautions for four days after rash onset)



Chapter 87 Paramyxoviruses



Figure 87.2 The histological appearance of the lungs of an individual with measles pneumonia. There are numerous giant cells, the nuclei of which display inclusions.



MUMPS VIRUS osms.it/mumps PATHOLOGY & CAUSES ▪ Causes mumps; largely preventable by vaccination ▫ Fever, headache, malaise, myalgia, anorexia; followed by parotitis ▪ Transmission ▫ Highly contagious ▫ Transmission via respiratory droplets, direct contact, contaminated fomites ▫ Viral shedding begins before symptoms onset ▪ Incubation period: 14–18 days ▪ Outbreaks: schools, military posts, camps, healthcare settings, workplaces ▪ Replication: occurs in upper respiratory tract epithelium → spread via lymphatics → viremia ▪ Lifelong post-infection immunity



RISK FACTORS



COMPLICATIONS



▪ Orchitis/oophoritis, meningitis, encephalitis, pancreatitis, myocardial involvement, arthritis, deafness



SIGNS & SYMPTOMS ▪ Prodrome ▫ Fever, malaise, headache, myalgias, anorexia ▪ Parotitis ▫ Swelling, inflammation, tenderness of parotid gland(s) ▫ May obscure mandible angle ▫ Unilateral/bilateral ▫ Usually 48 hours after prodrome onset ▫ Commonly children 2–9 years old ▫ Stensen duct orifice: may be erythematous, enlarged ▪ Mastitis



▪ Unvaccinated status, international travel, vaccine failure, immunosuppressed individuals, healthcare workers, closecontact



OSMOSIS.ORG 481



DIAGNOSIS ▪ Diagnosis suspected in individuals with parotitis/other salivary gland swelling, orchitis/oophoritis with prodrome, mumps virus exposure



LAB RESULTS ▪ In parotitis setting, diagnosis established by detection of ▫ Mump virus RNA: reverse-transcription PCR (buccal/oral swab) ▫ Serum mumps IgM (may not be detectable until 5 days after symptom onset) ▪ Full blood count ▫ Leukocytosis may be seen ▪ Lumbar puncture indicated in suspected meningitis/encephalitis



TREATMENT ▪ No specific antiviral therapy



MEDICATIONS



▪ Analgesics, antipyretics, non-steroidal inflammatory agents (orchitis/oophoritis)



OTHER INTERVENTIONS ▪ Prevention ▫ Measles, mumps, rubella (MMR) vaccine ▫ Infection control (isolation with droplet precaution until parotid swelling resolved)



482 OSMOSIS.ORG



Figure 87.3 Mumps virus causes parotitis, which presents as swelling at the angle of the jaw, widening the facial outline.



Chapter 87 Paramyxoviruses



RESPIRATORY SYNCYTIAL VIRUS (RSV) osms.it/respiratory-syncytial-virus PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Most common cause of bronchiolitis: viral infection of the lower respiratory tract, blockage of small airways (bronchioles) ▫ May also be caused by rhinovirus, influenza virus ▪ Terminal bronchiolar epithelial cell viral infection → lung epithelial cell damage/ destruction → small bronchi/bronchioles inflammation → edema, mucus production, inflammation → small airways/atelectasis obstruction ▪ Commonly: children < two years old ▪ Often preceded by upper respiratory tract infection symptoms; rhinorrhea, headache, mild fever



▪ Prodrome ▫ Upper respiratory tract infection (rhinitis, fever) ▪ Cough; tachypnea; expiratory wheeze; ↑ breathing work (nasal flaring, grunting, retractions); crackles heard on auscultation; cyanosis



RISK FACTORS ▪ Infants < 12 weeks old, November–May, prematurity, bronchopulmonary dysplasia/ other chronic lung disease history, tobacco smoke exposure, daycare attendance, impaired airway clearance/function (e.g. cystic fibrosis), congenital heart disease, immunodeficiency



COMPLICATIONS



▪ Bacterial pneumonia, apnea, respiratory failure, dehydration, aspiration pneumonia, asthma



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ If differential diagnosis includes pneumonia



OTHER DIAGNOSTICS Pulse oximetry ▪ ↓ oxygen saturation



TREATMENT MEDICATIONS



▪ Oral corticosteroids: prior wheeze history



OTHER INTERVENTIONS ▪ Supplemental oxygen, hydration, mechanical ventilation ▫ Respiratory symptoms peak on days 3–5, begin to resolve



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Chapter 88 Parvoviruses Parvovirus B1 is the smallest known DNA animal virus, coming in at an itty bitty 18 to 28 nanometers in diameter. In comparison, the average size of a single human red blood cell is a whopping 7200 nanometers! While it's mostly known for causing fifth disease, or “slapped cheek syndrome,” in children, parvovirus B19 can also affect adults and it can cause serious illness in individuals with pre-existing conditions like sickle-cell anemia and HIV. Parvovirus B19 is part of the parvoviridae family. It’s a single-stranded DNA virus surrounded by an icosahedral capsid, which is a spherical protein shell made up of 20 equilateral triangular faces. And it’s “naked” because the capsid isn’t covered by a lipid membrane. Parvovirus B19 is primarily transmitted by respiratory droplets when someone coughs or sneezes. You can also catch it via an infected blood transfusion and a pregnant female can also transmit it through the placenta to her unborn child. Now, although the virus first enters cells of the respiratory tract by binding to receptors on host cells, it doesn’t replicate in them. Instead it keeps travelling through cells and into the circulatory system until it reaches bone marrow, where red blood cells are made, a process called erythropoiesis. Once there, parvovirus B19 uses receptor-mediated endocytosis to enter erythroid progenitor cells, also called proerythroblasts, the early cells that eventually become red blood cells. It then uses these cells’ DNA replication machinery in the nucleus to replicate its DNA and assemble new copies of the virus. Why not simply replicate in cells of the respiratory system? Well it turns out that Parvovirus B19 needs two things: it prefers to bind to a specific receptor, the P antigen, which is found in large numbers on proerythroblasts’ cell membrane and it needs cells that pass through the S phase of the cell cycle, which is the phase where cell DNA is replicated. Since the body is constantly producing new red blood cells, there are always proerythroblasts going through the S phase at any given time. As the virus replicates and matures, it produces a protein called non-structural protein 1 or NS1, which is toxic to human cells and causes apoptosis, or cell death. This means that erythropoiesis breaks down, and fewer new red blood cells go into circulation as a result of parvovirus B19 infection. But thankfully this is only temporary. When the cell dies, it bursts open, releasing copies of the virus into the blood, also called viremia. OSMOSIS.ORG 484



Our immune system detects the virus and starts producing specific immunoglobulin M and immunoglobulin G antibodies to fight the infection by forming immune complexes with the parvovirus B19 antigen. For individuals with a functioning immune system, this typically happens between 10 and 14 days after first becoming infected with the virus. Parvovirus B19 is most common in young children and those who live or work with them, like parents, siblings, and daycare workers. Fetuses are at risk of parvovirus B19 if their pregnant mother has never had the virus in the past. Immunocompromised individuals are also particularly at risk of chronic parvovirus B19 infection, since their immune system cannot mount an appropriate response to the virus. The incubation period for parvovirus B19 - basically the period before viremia starts - is between 4 and 14 days, after which symptoms develop. Flu-like symptoms - like a mild fever, headache, and aching muscles - are most common during viremia. Once the immune response begins and the viremia ends, these symptoms go away and some individuals will then develop a rash and/or joint pain. The rash appears as uniform redness of the cheeks, but not the area around the mouth, giving the classic fifth disease “slapped cheek” appearance. A lace-like rash might also appear on the trunk and the limbs. Joint pain and inflammation, or arthralgia and arthritis, linked to parvovirus B19 infection usually affects the small joints of the hands, wrists, feet, and knees, and are often symmetrical, meaning that the same joints on both sides of the body will be affected. Children tend to get the rash whereas adults are more likely to develop joint pain, but it’s not exclusive to either group. There are a few complications caused by parvovirus B19 infection. The decreased red blood cell production can cause transient aplastic crisis in individuals who have underlying conditions like sickle cell anemia, hereditary spherocytosis, and thalassemia. Because they already have fewer red blood cells, the breakdown of erythropoiesis results in severe anemia, with symptoms like pale skin, fatigue, and weakness. Parvovirus B19 in a pregnant female can cause anemia in her fetus. Because there are fewer red blood cells to carry oxygen, the heart will pump a larger volume of blood to give the growing fetus all the oxygen it needs. This raises the pressure inside blood vessels and fluid can start to leak out of capillaries as a result. This can result in hydrops fetalis, or the abnormal accumulation of fluid in soft tissues. OSMOSIS.ORG 485



Chapter 88 Parvoviruses Fetal anemia is also linked to fetal loss, particularly if the parvovirus B19 infection is in the first half of the pregnancy. The good news is that there no fetal defects associated with parvovirus B19 for those fetuses that survive the infection. Lastly, immunocompromised individuals, such as organ transplant recipients and people with HIV, can develop a serious complication from parvovirus B19 called pure red blood cell aplasia. This is a form of chronic, severe anemia where there are very few immature red blood cells in circulation in blood vessels or erythroid progenitor cells in the bone marrow. Symptoms of pure red blood cell aplasia are similar to other forms of anemia, such as lethargy and malaise. Parvovirus B19 infection is usually diagnosed by clinical examination. Blood tests looking for antibodies to the virus - specifically immunoglobulin M and immunoglobulin G - are reserved for atypical presentations of the virus and for pregnant individuals. Another option is polymerase chain reaction, or PCR, which looks for viral DNA. It’s the preferred diagnostic method of parvovirus B19 infection in immunocompromised individuals, who typically do not have high IgM or IgG levels in response to an infection. PCR can also be used on amniotic fluid to diagnose infection in a fetus. When it comes to treatment for parvovirus B19 infection, it varies based on the symptoms. Fifth disease is usually mild and gets better on its own, while a transient aplastic crisis often requires transfusion of blood products. Arthralgia and arthritis are treated with NSAIDs and usually resolve on their own. Chronic infections in immunocompromised individuals are treated with immune globulin intravenous therapy or IVIG, which involves giving antibodies - mostly immunoglobulin G - taken from donor blood plasma. Severe anemia in a fetus between 18 and 35 weeks of gestation can be treated with an intrauterine blood transfusion. Before 18 weeks, the procedure is too difficult technically. After 35 weeks, risks of the transfusion are high compared to simply delivering the baby. Finally, there is no vaccine for parvovirus B19. Preventive measures include proper hand washing with antiseptic soap and water and sanitizing surfaces that would’ve come into contact with respiratory droplets, since the virus can survive on surfaces.



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NOTES



NOTES



PICORNAVIRUSES MICROBE OVERVIEW ▪ Have small, cytoplasmic, single-stranded, linear, positive-polarity RNA Taxonomy ▪ Family Picornaviridae; 35 genera (e.g. Enterovirus, Apthovirus, Cardiovirus, Rhinovirus, Hepatovirus)



Morphology ▪ Non-enveloped ▪ Icosahedral capsid ▪ Diameter ▫ 27–30nm(smallest of RNA viruses) ▪ Genome length ▫ About 2500nm Transmission ▪ Hosts: humans, birds, vertebrates



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COXSACKIEVIRUS osms.it/coxsackievirus PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



HFMD (hand, foot and mouth disease) ▪ Clinical syndrome characterized by oral enanthem; maculopapular/vesicular rash of hands, feet ▫ Common exanthem in children and adults ▫ Most commonly caused by coxsackie A virus



HFMD ▪ Mouth, throat pain ▫ Young children may refuse to eat ▪ Mild fever ▪ Lethargy ▪ Oral enanthem: on tongue, buccal mucosa ▫ Erythematous macules → vesicles with halo of erythema ▪ Exanthem: macular, maculopapular, vesicular; nonpruritic, usually not painful ▫ Involves hands (including palms), feet (including soles), buttocks, legs, arms ▫ Palmer and plantar desquamation 1–3 weeks after presentation



Herpangina ▪ Benign clinical syndrome characterized by fever, papulo-vesiculo-ulcerative oral enanthem ▫ Most commonly caused by coxsackie A virus ▪ Transmission person to person via oralfecal route or respiratory aerosols → incubation for 3–5 days → virus replicates in the submucosal lymphoid tissue of pharynx or lower intestine → spread to regional lymph nodes (minor viremia) → dissemination throughout the body → major viremia



RISK FACTORS



▪ Age ▫ Most common in children 40 years ▫ Individuals with chronic liver disease ▫ Allergy to hepatitis A vaccine



OTHER INTERVENTIONS Prevention ▪ Infection control practices ▫ Handwashing; avoid tap water, raw foods in poorly-sanitized areas



MEDICATIONS



▪ Medications known to cause liver damage should be avoided/used with caution



POLIOMYELITIS (POLIO) osms.it/poliomyelitis PATHOLOGY & CAUSES ▪ Infectious disease caused by poliovirus ▪ Characterized by (rare but devastating) cases of muscle weakness, permanent paralysis ▫ Most infections remain asymptomatic ▫ Some experience minor symptoms (e.g. fever, sore throat, headache) ▫ Some may recover from muscle paralysis ▪ Natural host ▫ Humans ▪ Transmitted by fecal-oral route; less commonly via respiratory droplets ▫ Asymptomatic, infected persons may shed virus ▪ Pathogenesis ▫ Oral entry → poliovirus infects cells



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of mouth, nose, throat → spread to lymphatics → primary replication in tissue of gastrointestinal tract and oropharynx → primary (minor) viremia → invasion of the central nervous system → replication in motor neurons of spinal cord, brain stem, or motor cortex → destruction of motor neurons → secondary (major) viremia and paralysis



RISK FACTORS



▪ Unvaccinated status ▪ Travel to countries endemic for poliovirus



COMPLICATIONS



▪ Post-polio syndrome ▫ Slowly developing muscle weakness similar to initial infection ▪ Bulbar poliomyelitis



Chapter 89 Picornaviruses



▪ ▪ ▪ ▪ ▪ ▪ ▪



▫ Infection of brain stem; may lead to drooling, aspiration pneumonia, respiratory muscle paralysis Skeletal malformations due to muscle paresis, paralysis Equinus foot (club foot) Stunted growth Osteoporosis, bone fractures Urinary tract infections, kidney stones Paralytic ileusv Myocarditis, cor pulmonale



Acute flaccid paralysis ▪ Complete paralysis; spinal, bulbar, bulbospinal ▪ Quadriplegia/respiratory failure ▪ Reflexes absent ▪ Sensation intact



SIGNS & SYMPTOMS Minor illness/minor viremia ▪ Abortive poliomyelitis ▫ Nausea ▫ Vomiting ▫ Abdominal pain ▫ Constipation ▫ Diarrhea ▫ Sore throat ▫ Mild fever ▫ Coryza Major illness/major viremia ▪ Involvement of central nervous system (CNS) ▪ Nonparalytic aseptic meningitis ▪ Headache ▪ Neck, back, abdominal, extremity pain ▪ Fever ▪ Vomiting ▪ Lethargy ▪ Irritability Paralytic disease ▪ Varies from one muscle to muscle group ▪ Reduced tone; often asymmetric ▪ Affects proximal muscles > distal muscles ▪ Affects legs > arms ▪ Worsens over 2–3 days



Figure 89.3 An individual with atrophy of the mucles of the right leg caused by polio.



DIAGNOSIS ▪ Acute-onset flaccid paralysis



LAB RESULTS



▪ PCR detection of poliovirus RNA from cerebrospinal fluid; cerebrospinal fluid (CSF) may also show ↑ leukocytes, ↑ protein ▪ Alternative ▫ Detection by poliovirus isolation, culture (from throat secretions); comparison of viral titers in acute, convalescent sera



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TREATMENT MEDICATIONS Antiviral therapy ▪ Role remains uncertain Prevention ▪ Passive immunization: gamma globulin; reduces infected individuals’ disease severity ▪ Inactivated poliovirus vaccine ▫ Given in high-income countries ▫ Cannot revert to paralytic form ▪ Live attenuated oral poliovirus vaccine ▫ Inexpensive, easy to administer; given in countries where virus endemic ▫ Risk: attenuated virus reverting to paralysis-causing form



OTHER INTERVENTIONS



▪ Physical therapy; respiratory failure → mechanical ventilation ▪ No effective treatment for restoring motor neuron function



Figure 89.4 An individual with polio inside an iron lung, which provided mechanical ventilation by creating negative pressure.



RHINOVIRUS osms.it/rhinovirus → host inflammatory response to virus → elaboration of inflammatory mediators, recruitment of polymorphonuclear leukocytes → symptoms → illness lasts about 1–2 weeks



PATHOLOGY & CAUSES ▪ The causative agent of most common colds ▪ > 100 serotypes ▪ Most frequent human infectious disease, preferentially infecting the upper respiratory tract ▪ Usually causes mild, self-limiting disease, with increased incidence in early autumn (September–November) and in Spring (March–May) ▪ Predisposes to other infections ▫ Otitis media in children, community acquired pneumonia ▪ Potential to infect the lower respiratory tract → exacerbation of asthma, chronic bronchitis ▪ Inoculation of the nose or conjunctiva → intracellular adhesion molecule-1 (ICAM1) attachment → incubation (2–4 days)



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Transmission ▪ Airborne droplet nuclei/aerosols (from sneezing, coughing) ▪ Droplet transmission ▪ Direct contact (e.g. hand contact → rubbing eyes, nasal mucosa) ▪ Fomites



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Fatigue (insufficient sleep) Psychological stress Work in daycare/schools Smoking Underlying chronic disease



Chapter 89 Picornaviruses



COMPLICATIONS ▪ ▪ ▪ ▪



Sinusitis Lower respiratory tract disease Asthma exacerbations Acute otitis media



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪



Cough Coryza Rhinorrhea (clear/purulent) Sore throat Myalgia Fatigue, malaise Headache Anorexia Fever



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Lower respiratory tract infection → chest radiograph



OTHER DIAGNOSTICS



▪ Nasal cavity examination: swollen, erythematous nasal turbinates



TREATMENT MEDICATIONS



▪ Analgesics ▫ Relieve headache, ear pain, myalgia ▫ E.g. acetaminophen, nonsteroidal antiinflammatory drugs ▪ Antihistamine/decongestant combinations ▪ Cough suppressants



OTHER INTERVENTIONS



▪ Zinc supplements at initial infection may reduce duration



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NOTES



NOTES



POLYOMAVIRUS MICROBE OVERVIEW ▪ Small DNA virus → central nervous system, urinary system, skin infection ▪ Poly = multiple, oma = tumor → relationship with multiple tumors ▪ Viral DNA replication, virion assembly occurs inside cell nucleus ▪ Primary infection usually asymptomatic → persistent state Taxonomy ▪ Human polyomavirus species ▫ BK virus ▫ JC polyomavirus ▫ Wu polyomavirus ▫ KI polyomavirus ▫ Merkel cell polyomavirus (MCV) ▫ Trichodysplasia spinulosa virus (TSV)



Morphology ▪ Structure ▫ Double-stranded circular DNA ▫ Icosahedral capsid composed of few proteins: VP1 (cell surface binding), VP2, VP3 ▫ Nonenveloped ▪ Non-structural proteins: large, small T antigens ▫ Initiate viral DNA replication ▫ Oncogenic potential Transmission ▪ Probable transmission routes ▫ Fecal-oral, oral, respiratory



RISK FACTORS ▪ Immunodeficiency



BK VIRUS (HEMORRHAGIC CYSTITIS) osms.it/bk-virus PATHOLOGY & CAUSES ▪ Causes hemorrhagic cystitis ▪ BK virus in hematopoietic stem cell transplant recipients → bladder inflammation → bladder mucosa bleeding ▪ Primary infection usually asymptomatic/ mild respiratory infection → urinary tract infection → virus in bladder mucosal lining, kidneys



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▪ Weak immune system → BK viral replication → cells large, round → separate from basal membrane, cell lysis



CAUSES ▪ ▪ ▪ ▪



Radiation Chemotherapy Immunosuppressive drugs Urinary tract infection (e.g. BK virus, adenovirus)



Chapter 90 Polyomavirus



TREATMENT



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪



MEDICATIONS



Frequent urination Dysuria Hematuria Suprapubic pain



▪ Mesna, chemotherapy co-administered ▫ ↓ hemorrhagic cystitis risk



SURGERY



▪ Cystectomy (severe case)



DIAGNOSIS



OTHER INTERVENTIONS



LAB RESULTS



▪ Polymerase chain reaction (PCR) → infection agent fragments in urine ▪ Urinalysis, cytology ▪ Cystoscopy



▪ Bladder irrigation ▫ Water/sodium chloride solution ▪ Pain management ▪ Hyperhydratation ▪ Hyperbaric oxygen, prostaglandins (↓ efficacy)



JC VIRUS (PROGRESSIVE MULTIFOCAL LEUKENCEPHALOPATHY) osms.it/jc-virus PATHOLOGY & CAUSES ▪ Causes progressive multifocal leukoencephalopathy (PML) ▪ Immunocompromised individuals → JC virus → PML (rare demyelinating disease) ▪ Childhood primary asymptomatic infection → latent JC virus in lymphoid organs, kidneys ▪ Immunodeficiency → virus spreads via blood → infects brain oligodendrocytes, astrocytes → viral replication → cell lysis → myelin sheath loss ▪ Triggers ▫ Immunosuppressive drugs (e.g. Natalizumab) ▫ Immune system disorders (e.g. HIV/ AIDS)



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



Cognitive, mental dysfunction Gait, coordination problem Hemiparesis, monoparesis Double/blurred vision Seizure



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Hypodense lesions affect white matter MRI ▪ T1 image decreased signal ▪ T2 image increased signal



OSMOSIS.ORG 495



▪ Affects subcortical, periventricular white matter (usually) ▪ Absent contrast enhancement



LAB RESULTS Brain biopsy ▪ Large oligodendrocyte nuclei with inclusion bodies ▪ Myelin sheath destruction ▪ Abnormal, enlarged astrocytes ▪ Macrophages engulfing myelin ▪ Immunohistochemistry for JC proteins Cerebrospinal fluid (CSF) analysis ▪ PCR detects viral DNA ▪ ↑ white blood cell count (pleocytosis) ▪ ↑ protein level



Figure 90.1 An MRI scan in the coronal place of the head of an individual with progressive mutlifocal leucoencephalopathy.



TREATMENT ▪ No specific treatment; high mortality



MEDICATIONS



▪ HIV-infected individuals ▫ Start/optimize antiretroviral therapy (ART) ▪ No HIV infection ▫ Stop immunosuppressive therapy ▪ Potentially beneficial drugs ▫ Interleukin-2, cytarabine, chlorpromazine, mefloquine



OTHER INTERVENTIONS ▪ Natalizumab-caused PML ▫ Plasma exchange



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Figure 90.2 Immunohistochemical staining for JC virus protein in the brain of an individual with progressive multifocal leukoencephalopathy. The protein, stained brown, has accumulated in the oligodendrocytes.



Chapter 2 Acyanotic Defects



NOTES



POXVIRIDAE MICROBE OVERVIEW Genetic material ▪ Linear double-stranded DNA



Replication ▪ In host cell cytoplasm



Taxonomy ▪ Poxviridae: family of double-stranded DNA viruses



Associated clinical syndromes ▪ Febrile rash illnesses: smallpox (eradicated), monkeypox ▪ Skin lesions: vesicles, pustules, papules, skin thickening



Morphology ▪ Brick-shaped/ovoid ▪ Enveloped (outer lipid membrane) ▪ Size: 220–450nm



MOLLUSCUM CONTAGIOSUM osms.it/molluscum-contagiosum PATHOLOGY & CAUSES ▪ Molluscum contagiosum virus (MCV): poxvirus; causes papular skin disease ▪ Four subtypes; genotype 1 causes most U.S. cases ▪ Common in children, adolescents ▪ Skin penetration → stratum spinosum replication within keratinocytes → epidermal hypertrophy → papules ▪ Incubation period: 2–6 weeks



COMPLICATIONS



▪ Widespread/refractory lesions in immunosuppressed individuals



CAUSES



▪ Physical contact, autoinoculation, fomites



RISK FACTORS



▪ Contact sports; sexual intercourse with infected individuals; immunosuppression; atopic dermatitis



Figure 91.1 The wart-like lesions caused by molluscum contagiosum infection.



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SIGNS & SYMPTOMS ▪ Dome-shaped, shiny, umbilicated papules (2–5 mm); sometimes polypoid ▪ Lesion distribution: trunk, genitals, intertriginous areas (e.g. axilla, antecubital folds); not on palms, soles ▪ Sometimes pruritus, inflammation, swelling ▪ Molluscum dermatitis: eczematous patches/plaques around papules ▪ Eyelid lesions → keratoconjunctivitis



DIAGNOSIS



Figure 91.2 A histological section through a molluscum wart at low power. There is marked acanthosis and marked hyperplasia causing inversion.



LAB RESULTS



▪ Histologic examination: keratinocyte eosinophilic inclusion bodies (Henderson– Paterson bodies)



OTHER DIAGNOSTICS



▪ Clinical examination: dermoscopy; polylobular, amorphous structures with central umbilication, peripheral blood vessels



TREATMENT ▪ Optional; lesions resolve spontaneously in 6–18 months in immunocompetent individuals



MEDICATIONS Chemical disruption ▪ Topical blistering agent: cantharidin ▪ Antimitotic agent: podophyllotoxin ▪ Topical immunomodulator: imiquimod ▪ Potassium hydroxide (KOH) ▪ Keratinolytic agent: salicylic acid Antiviral treatment ▪ Cidofovir



SURGERY Lesion removal ▪ Cryotherapy, curettage, laser



OTHER INTERVENTIONS Figure 91.3 A histological section through a molluscum wart at high power. The stratum spinosum and granulosum contain eosinophilic inclusions, known as molluscum bodies.



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Prevention ▪ Avoid sharing towels/clothing ▪ Cover lesions with bandage/clothing ▪ Barrier contraception (e.g. condoms)



Chapter 2 Acyanotic Defects



NOTES



REOVIRUSES MICROBE OVERVIEW ▪ Rotavirus: most important Reovirus in clinical practice Genetic Material ▪ RNA viruses with segmented double stranded linear RNA



Morphology ▪ Encapsulated (icosahedral capsid) ▪ Nonenveloped Replication/multiplication ▪ Replicates in cytoplasm



ROTAVIRUS osms.it/rotavirus PATHOLOGY & CAUSES ▪ A major cause of acute diarrhea, especially in children ▫ Most important cause of severe gastroenteritis in infants, young children worldwide ▪ Short incubation period ▫ ↓ activity of brush-border enzymes (such as maltase, lactase) → malabsorption of nutrients → presence of reducing substances in stools → osmotic diarrhea ▫ Direct effects of enterotoxin nonstructural protein 4 (NSP4) on gastrointestinal mucosa (apoptosis of enterocytes) ▫ Activation of enteric nervous system → ↓ absorption of Na+, loss of K+



CAUSES



▪ Transmission by fecal-oral route (ingestion of water/food contaminated by stools) ▫ Spreads easily; minimal infective dose (10 viral particles)



RISK FACTORS



▪ Age ▫ Usually affects children between 6–24 months of age ▪ Cooler months in temperate climates ▪ Hospitalization, long term care facilities, day care centers, kindergartens, college dormitories ▪ Immunodeficiency ▪ Non-immunized status



COMPLICATIONS ▪ Secondary lactase deficiency ▪ Severe dehydration ▫ Shock, multisystem failure ▪ Central nervous system complications ▫ Seizures, encephalopathy ▪ Persistent gastroparesis, diarrhea ▪ Necrotizing enterocolitis ▪ Intussusception ▪ Biliary atresia ▪ Can be fatal



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SIGNS & SYMPTOMS ▪ Average duration: 8 days ▪ Children: watery diarrhea, vomiting, fever ▪ Adults: less severe symptoms



DIAGNOSIS LAB RESULTS Blood tests ▪ ↑ blood urea nitrogen (BUN) ▪ Hyperchloremic acidosis ▪ ↓ serum calcium Stool analysis ▪ Immune based assays ▫ Enzyme linked immunosorbent assay (ELISA), latex agglutination tests (best diagnostic tests); PCR, culture



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TREATMENT OTHER INTERVENTIONS



▪ Most cases are self-limited, do not require pharmacotherapy ▫ Antidiarrheal medications not recommended (they delay elimination of infectious agent from intestines) ▪ ↑ fluid intake; oral rehydration solutions ▪ Good nutrition ▪ If infection is severe ▫ Hospitalization for IV fluids



Prevention ▪ Live attenuated vaccine is indicated routinely for all infants, except for those with history of intussusception/severe combined immunodeficiency (SCID)



Chapter 2 Acyanotic Defects



NOTES



RETROVIRUSES MICROBE OVERVIEW ▪ RNA viruses ▫ Require DNA generation, integration into host DNA → produce viral progeny ▪ Large viral family ▫ Seven genera ▪ Target cells determined by viral glycoprotein spikes on cell membrane → recognized cell surface receptors, coreceptors → viral entry → provirus creation ▫ Viral reverse transcriptase takes singlestranded viral RNA genome → creates linear, double-stranded DNA virus → provirus ▪ Provirus integration (via integrase) into host-cell DNA → viral particle production ▫ Integration stability of provirus, transmission to host-cell progeny determines retroviral infection persistence in host organism Morphology ▪ Lipid-enveloped particles 80–100nm diameter



▪ Protein core ▫ Two linear, ⊕-sense, single-stranded RNA genomes (7–11 kb) ▫ Enzymes (gene locus) needed for viral replication (protease—pol gene, p10 locus; reverse transcriptase—pol gene, p66 locus; integrase—pol gene, p32 locus)



TYPES Human endogenous retroviruses ▪ Proviral DNA/partial genomic sequences integrated into host-genome ▪ Constitutes up to 8% of human DNA ▪ Vertical transmission via germline cells ▪ Translated DNA does not lead to infectious viruses; may → functional proteins Human exogenous retroviruses ▪ Passed horizontally via exposure to blood, sexual secretions, breast milk



HUMAN IMMUNOFEDICIENCY VIRUS osms.it/HIV-(AIDS) PATHOLOGY & CAUSES ▪ HIV: human immunodeficiency virus ▪ Member disease of Lentivirus genus of Retroviridae family ▫ Characterized by immune cell targeting, immunodeficiency



Two pathogenicity targets ▪ Immune system ▫ Mucosal HIV virion infiltration → bloodstream spread → infection of T cells, dendritic cells, macrophages → latency (may be chronic, indolent) → active replication → symptom progression/emergence → further replication→ severe



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immunocompromise, progression to AIDS (acquired immune deficiency syndrome) ▫ HIV infection → targeting, infection of CD4+ cells (e.g. CD4+ T-lymphocytes, monocytes, macrophage) → replication, spread → ↓ CD4+ cells → immunodeficiency ▫ Co-receptor CCR5 important in early infection; persistence ▪ Central nervous system (CNS) ▫ HIV infection → macrophage/microglia infection → abnormal CNS cytokine milieu → neuronal cell death Structure ▪ 110nm diameter spherical virion ▪ Core surrounded by lipid bilayer envelope ▪ Lipid envelope ▫ External glycoprotein gp-120, anchored by gp-41 ▫ Binding sites for host-cell CD4+ receptor (co-receptors—chemokine receptors; especially CCR5, CXCR4) ▪ Core ▫ Two single-stranded RNA copies ▫ Two transfer RNA primers (host-cell origin) ▫ Multiple enzyme copies: reversetranscriptase (RT), integrase, ribonuclease H (RNAse H) ▫ Other proteins: vpr, vif, nef (important in early virion life-cycle) Genome ▪ 9kb ▪ Similar to other retroviruses (six genes—tat, rev, vpr, vpu, vif, nef) ▫ HIV-2 specific: Vpx gene (homologous to gene in simian immunodeficiency virus (SIV); not present in other lentiviruses) Life cycle ▪ Cell contact, fusion: gp-120, CD4+ receptor fusion → gp-120 conformational change → opened gp-120 recognition site → gp-120 binding to host-cell co-receptor (CCR5/CXCR4) → gp-41 conformational change → gp-41 hydrophobic domain exposed → virion lipid bilayer insertion into cell membrane → virus-host-cell membrane



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fusion → viral entry ▪ Viral genome replication: viral RNA transcribed by viral RT in host-cell cytoplasm → HIV provirus production (double-stranded complementary DNA transcript) → transport to nucleus → integrase insertion in cell DNA → viral DNA transcription → viral RNA, protein ▫ Host-cell activation (naive T cells) important factor in determining active vs. latent HIV replication ▫ Antigen/cytokine-mediated T cell activation → NF-KB (nuclear transcription factor) cell stress activation → ↑ NF-KB promoter-associated gene transcription (in HIV proviral DNA) → ↑ viral replication → viral RNA, protein aggregation in cytoplasm → viral protein cleavage (e.g. gag) → viral content assembly → ↑ virion production (↑↑ virion budding → cell death) ▪ Host-cell death: ↑ virion budding → ↑ host-cell plasma membrane permeability; ↑ viral replication → native protein synthesis interference → dysregulated cellular protein concentrations → cell death ▫ Non-cytopathic host-cell HIV infection: HIV infection → inflammasome pathway activation → pyroptosis (inflammatory cytokine, cellular content release) → immune cell recruitment → viral spread (likely plays large role in HIV infection spread) Transmission ▪ HIV-1, HIV-2 ▪ Three transmission modes ▫ Sexual: USA—biologically-male individuals engaging in same-sex sexual contact (MSM) particularly important transmission mode (highest disease incidence → homosexual biologicallymale individuals); global—majority of sexual transmission via heterosexual intercourse; co-existent sexuallytransmitted disease (genital ulceration especially) → ↑ transmission risk during intercourse ▫ Parenteral: non-iatrogenic, intravenous (IV) drug users (shared needles, syringes, other paraphernalia contaminated with HIV ⊕ blood); iatrogenic (hemophiliacs who received



Chapter 93 Retroviruses HIV-contaminated factor VII, IX concentrates; HIV-contaminated blood transfusion recipients; health personnel—e.g. needle-stick injuries) ▫ Vertical, mother-to-infant: in utero, transplacental spread; infected birth canal → delivery → neonatal infection; neonatal HIV ⊕ breast milk ingestion ▪ HIV-2 only ▫ Believed to be zoonosis resulting from SIV cross-speciation infection ▫ Endemic areas correlate with those of sooty mangabey ▫ Less transmissible than HIV-1 Disease ▪ Acute retroviral syndrome ▪ AIDS



AIDS ▪ Persistent fever (> one week); fatigue; weight loss; diarrhea; generalized lymphadenopathy (LAD); serious, opportunistic infection ▪ Secondary neoplasms ▪ Neuropsychiatric disease ▫ Delirium; major depression; mania; schizophrenia; post traumatic stress disorder; substance abuse, addiction (commonly HIV infection risk factor) ▫ Dementia (AKA AIDS dementia complex): cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, cerebral toxoplasmosis, cryptococcal meningitis, CNS lymphoma



TYPES



▪ Likely related to SIV ▪ Two human virus types ▫ HIV-1, HIV-2



RISK FACTORS



▪ West Africa residence (HIV-2), homosexual/ bisexual biologically-male individuals (USA), IV drug users, hemophiliacs, blood (or component) transfusion recipients, maternal HIV infection



COMPLICATIONS



▪ Opportunistic infections, secondary malignancies, AIDS, neuropsychiatric disease



Figure 93.1 An esophaeal biopsy composed of squamous mucosa with candida hyphae. Esophageal candidiasis is a common opportunitic infection in individual with AIDS.



SIGNS & SYMPTOMS Acute retroviral syndrome ▪ Self-resolving, flu-like syndrome; sore throat; myalgias; fever; weight loss; fatigue Chronic infection ▪ Variable ▫ Asymptomatic → minor infection ▫ Oral/vaginal candidiasis, herpes zoster, mycobacterial tuberculosis (especially Sub-Saharan Africa)



Figure 93.2 The histological appearance of mycobacterium avium intracellulare. There are numerous organisms within the cell cytoplasm.



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Chapter 93 Retroviruses



OSMOSIS.ORG 505



DIAGNOSIS



TREATMENT



LAB RESULTS



MEDICATIONS



Serology: enzyme-linked immunoassay (ELISA) ▪ IgG, IgM, p24 antibody testing ▫ Time to positivity: 15–45 days (P24 (viral core protein) earliest positive marker) ▫ May be combined for HIV-1, HIV-2, p24 immunoassay in diagnostic, screening purposes



Highly active antiretroviral therapy (HAART) ▪ Antiretroviral drug combination regimen ▫ Early initiation → ↓ morbidity, ↓ mortality, ↓ transmission risk (regardless of CD4+ count) ▪ Six distinct drug classes ▫ Combination of three drug types used for effective viral load management, combat particular drug class resistance development ▪ Protease inhibitor preferred initial agent ▫ Resistance testing results → narrow therapy ▪ Complications ▫ Immune reconstitution inflammatory syndrome ▫ ↓ in clinical state (symptom return experienced during active viremic phase), despite ↑ CD4+ levels ▫ Believed to be due to reinvigorated host response to high antigenic burden of persistent microbes, remaining viral load



▪ ⊕ Viral RNA level test (> 100,000 copies/ mL) ▫ May be used in indeterminate HIV-1/ HIV-2/ p24 immunoassay ▪ Leukopenia ▫ ↓↓ CD4+ count ▫ CD4+:CD8 ratio < 1



OTHER DIAGNOSTICS ▪ ▪ ▪ ▪



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Flu-like illness Opportunistic infection Needlestick injury with HIV ⊕ individual Unprotected sex with partner of unknown/ HIV ⊕ status



Pre-exposure prophylaxis ▪ Daily tenofovir use can very effectively ↓ transmission



Chapter 93 Retroviruses



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OTHER INTERVENTIONS Monitoring ▪ HIV RNA testing two, four, eight weeks after ART initiation ▫ Continue testing every two weeks until levels below detection limits ▫ Drug resistance testing at 24 weeks if ↑ in RNA viral level/no ↓ in RNA levels ▪ Once viral suppression achieved → repeat testing for RNA levels 3–6 months Screening ▪ One-time for individuals 13–75 years old ▪ Pregnant individuals (even in negative prior pregnancy screening) ▪ Annual/more frequent for high-risk individuals ▫ MSM (USA) ▫ IV drug users ▫ Sex partners of HIV unknown status, HIV ⊕, bisexual, individuals who inject drugs ▪ Blood factor screening ▫ Plasma/recombinant factor hemophiliac recipients



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Opportunistic infection prophylaxis ▪ Determined by CD4+ count ▪ Situational avoidance advised (e.g. cat litter, Toxoplasma exposure) Pre-exposure prophylaxis ▪ Indications ▫ High-risk sexual behavior/drug use ▫ Reliable individual to adhere to daily medication regimen



Chapter 93 Retroviruses



HUMAN T-LYMPHOTROPIC VIRUS osms.it/human_t-lymphotropic_virus PATHOLOGY & CAUSES ▪ Oncogenic retrovirus endemic to certain areas of world → T cell leukemia/lymphoma ▫ AKA HTLV-1 ▫ Genus: Deltaretrovirus ▪ Structure ▫ Enveloped, single-stranded RNA virus ▫ Only human pathogen of oncovirus subfamily ▪ Genome ▫ Contains retrovirus-consistent gag, pol, env, long terminal repeat (LTR) ▫ HTLV-1 specific: tax; encodes protein essential for viral replication; viral RNA transcription stimulation from 5’ LTR ▪ Transmission ▫ Usually via infected T cells (vs. virion particle) ▫ Breastmilk, sexual transmission, blood transfusion, tissue donation, IV drug use, zoonotic transmission (nonhuman primate source) ▪ Disease ▫ Adult T cell leukemia/lymphoma ▫ Myelopathy/tropical spastic paraparesis Targets CD4+ cells ▪ Unlike HIV life cycle, pathogenesis; largely unknown targeting, infection, replication mechanisms ▫ Tumor initiating cell appear to be CD4+ memory T cell with stem-cell-like properties ▪ Distinct from HIV ▫ HTLV-1 → proliferation of T cell population rather than killing of cells



▪ Integrated provirus → mitotic cell division → host cell replication ▫ Low replication rate ▫ Host cell DNA polymerase ensure high transcription fidelity (HTLV-1 genetically stable) Tax-specific oncogenic hallmarks ▪ Inr pro-growth signaling, cell survival ▫ Stimulates AKT (via PI3K), NF-KB, cyclin D2, ↓ CDK inhibitors → ↑ prosurvival, cell growth → polyclonal T cell expansion ▪ Inc genomic instability ▫ Interference with DNA-repair function ▫ Inhibition of cell cycle checkpoints (activated by DNA damage)



RISK FACTORS



▪ Travel/residence in Japan, Caribbean basin, South America, Africa ▫ Sporadic incidence in USA



COMPLICATIONS



▪ Mycosis fungoides ▫ Cutaneous T cell leukemia/lymphoma manifestation ▪ Uveitis ▪ Gastric cancer



Rheumatologic, pulmonary disorders ▪ Chronic inflammatory arthropathy ▫ Shoulder, wrists, knees ▪ Sjögren syndrome ▪ Immune thrombocytopenia



Infectious replication ▪ Integrated provirus re-expression → intracellular virion



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SIGNS & SYMPTOMS Adult T cell lymphotropic leukemia/lymphoma ▪ Skin lesions ▪ Generalized lymphadenopathy ▪ Hepatosplenomegaly Myelopathy/spastic paraparesis ▪ Insidious-onset lower extremity weakness, spasticity ▪ Hyperreflexia, ankle clonus present ▪ ⊕ extensor plantar responses ▪ Lumbar pain ▪ Others ▫ Back pain ▫ Detrusor instability → nocturia, urinary frequency, incontinence ▫ Minor sensory change: paresthesias, ↓ vibrational sense



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Lytic bone lesions



MRI ▪ Tropical spastic paraparesis ▫ Cervical/thoracic cord atrophy ▫ Spinal cord white matter disease



LAB RESULTS



▪ Leukopenia ▪ Hypercalcemia ▪ Histology is variable, with characteristic circulating tumor cells ▫ Medium-sized lymphocytes with condensed chromatin, bizarre hyperlobated nuclei (AKA clover leaf/ flower cells)



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▪ ELISA ▫ Antibody against HTLV-1 virus detection ▪ Western blot ▫ Confirmatory testing for ELISA ▪ Polymerase chain reaction (PCR) ▫ Available for HTLV-1 ▫ Useful with ↑↑ suspicion (ELISA negative) ▪ Flow cytometry ▫ ↑ FoxP3 expression in leukocytes (↑ regulatory T cell-indicative) ▫ Otherwise immunophenotypically mature T lymphocytes



OTHER DIAGNOSTICS



▪ Travel/residence in endemic area



TREATMENT ▪ No therapy proven to benefit affected individuals



MEDICATIONS



▪ Corticosteroid therapy may slow disease course ▪ Antiviral therapy ▫ NRTI zidovudine, IFN-alpha proven beneficial



OTHER INTERVENTIONS Prevention ▪ Endemic area-avoidance when breastfeeding ▪ Blood donor screening ▪ Safe-sex practices ▪ Discourage needle sharing



Chapter 2 Acyanotic Defects



NOTES



RHABDOVIRUSES MICROBE OVERVIEW ▪ Diseases ▫ Rabies encephalitis, vesicular diseases



▪ Genera: Lyssavirus, Vesiculovirus, Sigmavirus, Varicosavirus, Spirivivirus, etc.



Genetic material ▪ Rod-shaped, single-stranded RNA virus



Morphology ▪ Enveloped, bullet-shaped, with helical nucleocapsids, linear genomes



Taxonomy ▪ Order: Mononegavirales ▪ Family: Rhabdoviridae



Transmission ▪ Via bite (infected host’s saliva)



RABIES VIRUS osms.it/rabies-virus PATHOLOGY & CAUSES ▪ Serious central nervous system (CNS) viral zoonotic infection ▪ Virus spreads via nerves (retrograde axoplasmic transport) ▪ Muscle tissue inoculation → incubation (1–3 months), local multiplication → acetylcholine receptor binding → nerve entry → travel via spinal cord axons → brain infection (found in cerebellum Purkinje cells, hippocampal neurons) → encephalitis Advanced-stage ▪ CNS → other organs (salivary glands, cornea, skin, gastrointestinal, etc.) via parasympathetic nervous system



CAUSES



▪ Caused by genus Lyssavirus (multiple species, Rhabdoviridae family)



Transmission ▪ Saliva in virus-infected host bite (dogs, bats, cats, raccoon, foxes, skunks, monkeys, etc.) ▪ Rabies-infected organ/tissue transplantation (rare) ▪ Aerosol transmission (e.g. bat caves) possible



RISK FACTORS



Animal exposure (bite risk) Travel (rabies-endemic Asian/African areas) Age < 15 years Deep bite Head wound (virus → brain transmission risk ↑ ) ▪ No post-exposure prophylaxis ▪ Occupational (laboratory, veterinarian) ▪ Recreational (spelunking → ↑ bat exposure risk) ▪ ▪ ▪ ▪ ▪



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COMPLICATIONS ▪ ▪ ▪ ▪ ▪



Encephalopathy Increased intracranial pressure Coma Permanent neurological deficits Often fatal



SIGNS & SYMPTOMS Prodromal stage ▪ Non-specific symptoms (first week) ▫ Headache; low grade fever, chills; myalgia, weakness, fatigue; malaise, anorexia; nausea/vomiting; sore throat; photophobia (sometimes) ▪ Wound site pain/tenderness/paresthesia/ tingling/itching Encephalitic rabies ▪ AKA furious rabies ▪ Most common form ▪ Involuntary pharyngeal spasms → hydrophobia (fear of water); aerophobia ▪ Fever ▪ Muscle spasms → opisthotonus position ▪ Seizure ▪ ↑ autonomic stimulation ▫ Excess salivation; lacrimation; sweating; mydriasis; impaired temperature homeostasis; tachycardia ▪ Dysphagia ▪ Aggressiveness, agitation, hallucination, confusion ▪ Respiratory distress → coma → respiratory arrest → death Paralytic stage ▪ AKA dumb rabies ▪ Ascending flaccid paralysis ▪ Sphincter atony ▪ Hydrophobia (rare) ▪ Neck stiffness ▪ Cranial nerves palsy ▪ Fasciculations/deep tendon reflex loss ▪ Pharyngeal, diaphragm muscle paralysis → death



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DIAGNOSIS ▪ Clinical Presentation ▫ History of rabid animal bite, rabies infection symptoms/signs



DIAGNOSTIC IMAGING CT scan ▪ Cerebral edema



LAB RESULTS Reverse transcription PCR (RT-PCR) ▪ Saliva ▫ Detects rabies virus RNA Skin punch biopsy ▪ RT-PCR; immunofluorescence staining for viral antigen Cerebrospinal fluid (CSF) ▪ Indirect immunofluorescence, virus neutralization assay ▪ CSF analysis ▫ Pleocytosis, ↑ protein Serum ▪ Anti-rabies virus antibodies in serum appear after first week (if individual not immunized)



OTHER DIAGNOSTICS Post mortem ▪ Brain tissue/other neural tissue examination ▫ Negri bodies, eosinophilic cytoplasmic inclusions in nerve cell cytoplasm (often)



TREATMENT MEDICATIONS



▪ Antivirals ▪ Rabies vaccine ▫ Both post-, pre-exposure prophylaxis ▫ Immunocompetent people: four injections (day 0, 3, 7, 14) ▫ Immunocompromised people: fifth injection (day 28)



Chapter 94 Rhabdoviruses ▫ Previously immunized people: two injections (day 0, 3) ▪ Human rabies immune globulin (HRIG) ▫ Single dose (20 units/kg) injected in, around wound ▫ Remainder administered intramuscular at distant site (e.g. other deltoid)



OTHER INTERVENTIONS Post-exposure prophylaxis (rapid) ▪ Wound cleaning ▫ Water/soap, povidone iodine ▪ Antibiotics/tetanus prophylaxis



Figure 94.1 Multiple Negri bodies in the brain of an individual infected with the rabies virus. The negri bodies form in the Purkinje cells of the cerebellum.



Management ▪ Respiratory (supplemental oxygen, mechanical ventilation), cardiovascular support (fluids) Prevention ▪ Exposed population may receive preexposure prophylaxis ▪ Domestic animal vaccination (especially dogs, cats)



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NOTES



NOTES



RICKETTSIAL DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vector-borne obligate intracellular bacteria; poor Gram staining, rod-shaped structure ▪ Common tropism for endothelial cells → variable amount of hemorrhage, edema, organ dysfunction



SIGNS & SYMPTOMS ▪ Disease-specific; fairly consistent integument manifestations (e.g. rash)



DIAGNOSIS LAB RESULTS



▪ Isolation of Rickettsiae ▫ Inoculation of animal/via cell culture ▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA), western blot, microimmunofluorescent antibody test (detection of bacterial-specific antigens)



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▪ Immunologic detection in tissue ▫ Isolation in epithelial tissue (from integument involvement) ▫ Requires sophisticated laboratory capability (not common in endemic areas of disease) ▪ Polymerase chain reaction (PCR) ▫ Detection of rickettsial DNA



OTHER DIAGNOSTICS ▪ Clinical presentation (disease-specific)



TREATMENT MEDICATIONS



▪ Prompt antimicrobial therapy ▫ Doxycycline (preferred)



Chapter 95 Rickettsial Diseases



ANAPLASMA osms.it/anaplasma PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria, endemic to wooded areas in North America → self-resolving disease, AKA human granulocytic anaplasmosis (HGA) Vector ▪ Anaplasma phagocytophilum: Ixodes tick ▫ Ixodes scapularis: also transmits Borrelia burgdorferi, Babesia spp. in eastern United States (US) ▫ Ixodes pacificus: main vector in western US ▫ Ixodes ricinus: implicated in European disease Life cycle and transmission ▪ Reservoir hosts: deer, white-footed mice (source of disease, not affected by pathogen) ▪ Vector: Ixodes tick (connects organism from reservoir to target) ▪ Human transmission Pathogenesis ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis ▫ P-selectin glycoprotein (identified binding domain for A. phagocytophilum) ▫ Ligand: P-selectin glycoprotein ligand-1 (PSGL-1) required on granulocytes for internalization Disease: HGA ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ systems (without organ failure/endothelial damage)



RISK FACTORS



▪ Residence in/travel to wooded areas in North America ▫ Especially during peak tick activity (e.g. spring, summer) ▪ Direct contact with slaughtered deer ▪ Occupational exposure (e.g. military)



COMPLICATIONS



▪ Co-infection with Borrelia burgdorferi, Babesia spp. ▪ Respiratory insufficiency, renal failure, septic shock ▪ Neurological ▫ Demyelinating polyneuropathy, brachial plexopathy ▪ Serious, fatal opportunistic infections ▫ Herpes simplex esophagitis, invasive aspergillosis,



SIGNS & SYMPTOMS ▪ Onset 1–2 weeks after identified tick bite ▪ Fever, malaise, headache ▪ Rash ▫ Typically trunk (sparing hands, feet), maculopapular (more evident in children) ▪ Gastrointestinal (GI) symptoms infrequent ▪ Neurological (rare) ▫ Mental status change, meningismus, clonus



DIAGNOSIS LAB RESULTS



▪ Leukopenia ▫ Specific to disease (neutropenia) ▪ ↑ hepatic enzymes, lactate dehydrogenase



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▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies of Anaplasma species ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if ↑ fourfold in IgG antibody titer) ▪ Whole blood PCR ▫ Detects epank1 primers on genogroup A. phagocytophilum ▪ Wright stain: morulae of Anaplasma in leukocyte ▫ A. phagocytophila: peripheral blood neutrophils; 25–75% (highest among morulae-producing bacteria)



OTHER DIAGNOSTICS



▪ History ▫ Tick bite in endemic area



TREATMENT MEDICATIONS



▪ Prompt antibacterial management ▫ Doxycycline (if pregnant, rifampin); chloramphenicol



OTHER INTERVENTIONS



▪ Prevention ▫ Avoid tick habitats ▫ Careful inspection after outside activity in wooded areas (esp. in spring, summer); rapid discovery, tick removal < 24–48 hours post bite → effective prophylaxis ▫ Skin application of insect repellants ▫ Proper clothing for outside work/play (light-colored, long pants tucked into socks, long-sleeved shirts)



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Figure 95.1 Mites of the genus Ixodes act as vectors for many rickettsial diseases.



Chapter 95 Rickettsial Diseases



COXIELLA BURNETII (Q FEVER) osms.it/coxiella-burnetii PATHOLOGY & CAUSES ▪ Coxiella burnetii: primarily zoonotic pathogen → febrile illness (after contact with animal amniotic fluid/placental contents) Taxonomy ▪ Order: Legionellales ▪ Family: Coxiellaceae Morphology ▪ Short, pleomorphic rod ▫ Strict intracellular bacterium Life cycle ▪ Source of human infections ▫ Farm animals (e.g. cattle, goats, sheep) ▫ Wild animals (e.g. birds, rabbits, reptiles) ▫ Arthropods (e.g. ticks) ▪ Main reservoir ▫ Ticks Transmission ▪ Inhalation of spores/bacteria ▫ Animal feces, milk, products of conception ▪ Ingestion of contaminated milk ▪ Percutaneous ▫ Crushing of ticks near skin breaks ▪ Vertical spread (transplacental) Pathogenesis ▪ Host cell ▫ Macrophage ▪ Antigenic variation (AKA phase variation) important in virulence ▫ Lipopolysaccharide capsule modifications underly antigenic variation



RISK FACTORS



▪ Occupation involving animal contact (e.g. veterinarian, farmer) ▪ ↑ age ▪ Unpasteurized milk consumption



COMPLICATIONS



▪ Q fever pneumonia, chronic hepatitis, osteomyelitis ▪ Infective endocarditis ▫ Pre-existing heart/valve disease predisposes to endocarditis development ▫ May have secondary, septic embolic manifestation



SIGNS & SYMPTOMS ▪ Q fever (sudden onset) ▫ Fever, headache (often frontal), general malaise, cough, anorexia, myalgia ▪ Pneumonia ▫ Cough, pleural effusion ▪ Hepatitis ▫ Hepatomegaly



DIAGNOSIS LAB RESULTS



▪ ↑ serum hepatic enzymes, leukopenia/ leukocytosis, thrombocytopenia ▪ Immunofluorescent antibody assays: detect IgM/IgG antibodies; differentiate between acute, chronic infection ▫ IgM: detectable 4 days after symptom onset ▫ IgG: detectable 9–14 days after symptom onset ▫ Concentration of serum samples can assist in diagnosis (esp. if vague clinical presentation)



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▪ PCR ▫ Blood/serum detection possible before IgM serology peak ▪ Immunohistochemistry ▪ Culture



OTHER DIAGNOSTICS



▪ History ▫ Animal contact, occupation



▫ Trimethoprim-sulfamethoxazole: pregnant individuals; treat even if asymptomatic ▪ Chronic infection: prolonged therapy ▫ 18 months doxycycline, hydroxychloroquine (monitor serologic response across therapeutic intervention; biannual ophthalmic examinations required)



OTHER INTERVENTIONS



TREATMENT MEDICATIONS



▪ Prompt antimicrobial treatment ▫ Doxycycline: effectiveness of antibacterial agent, severity of complications warrants use despite side effects; shorter therapy for children (14 day course)



▪ Management ▫ Individuals with pre-existing valvulopathy/cardiomyopathy; echocardiogram ▪ Prevention ▫ Whole cell vaccine; recommended for individuals working with farm animals (e.g. farmers, slaughterhouse workers)



EHRLICHIA osms.it/ehrlichia PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria with leukocytic tropism, associated with febrile disease with rare, serious neurologic complication ▫ AKA human monocytic ehrlichiosis (HME) ▪ Characteristics ▫ Small (0.5–1.5 micrometer) gramnegative cocci, (1.8 megabases) genome



TYPES



▪ Ehrlichia ewingii ▫ Southeastern, central United States ▪ Ehrlichia chaffeensis ▫ Northeastern, midwestern United States ▪ Ehrlichia sennetsu ▫ Western Japan



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Vector ▪ Amblyomma americanum (AKA lone star tick) ▫ Ehrlichia ewingii, Ehrlichia chaffeensis Life cycle ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis Pathogenesis ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ system without organ failure/endothelial damage Disease: Sennetsu fever



Chapter 95 Rickettsial Diseases



RISK FACTORS



▪ Residence in/travel to western Japan ▪ Occupational exposure (e.g. military)



COMPLICATIONS



▪ Co-infection with Babesia spp./B. burgdorferi ▪ Encephalitis, seizure ▫ Associated most with E. chaffeensis ▫ May result in persistent neurologic deficit (rare; seen especially in children) ▪ Heart failure, respiratory insufficiency, renal failure, shock



SIGNS & SYMPTOMS ▪ Sennetsu fever ▫ Abrupt-onset fever, chills, headache, malaise, sore throat, myalgias, arthralgias ▪ Atypical rash ▫ Maculopapular with occasional petechiae; located on trunk (sparing hands, feet) ▪ Generalized lymphadenopathy ▫ Most associated with E. sennetsu; includes hepatosplenomegaly ▪ GI ▫ Associated with E. chaffeensis ▫ Anorexia, diarrhea, nausea, vomiting



▪ Leukopenia, thrombocytopenia, anemia, hyponatremia ▪ Hepatic transaminitis: most common in E. chaffeensis infection ▪ Cerebrospinal fluid (CSF) analysis: pleocytosis (mononuclear cells with morulae), ↑ protein



OTHER DIAGNOSTICS



▪ History ▫ Tick bite in endemic area



TREATMENT MEDICATIONS



▪ Prompt antibacterial management: poxycycline, chloramphenicol



OTHER INTERVENTIONS Prevention ▪ Avoidance of tick habitats ▪ Careful inspection after outside activity (esp. in spring, summer) ▫ Rapid discovery, removal < 24–48 hours after bite → effective prophylaxis ▪ Proper skin application of insect repellants



DIAGNOSIS LAB RESULTS



▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies (Ehrlichia species) ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if fourfold increase in IgG antibody titer) ▪ Whole blood PCR: detects 16S rRNA gene ▪ Wright stain: morulae (Ehrlichia) in leukocyte ▫ E. ewingii: in peripheral blood granulocyte ▫ E. chaffeensis: in peripheral blood monocyte



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RICKETTSIA RICKETTSII (ROCKY MOUNTAIN SPOTTED FEVER) osms.it/rickettsia-rickettsii PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular, Gramnegative bacteria endemic to parts of North America → potentially lethal febrile disease ▪ Characteristics ▫ Weakly gram-negative, nonmotile coccobacillus; 0.7–2.0 micrometers: cannot be visualized by traditional staining methods/direct fluorescent antibody techniques ▫ Bacterial contents: ribosome; single, circular chromosome; microcapsule surrounding cell wall (may be important in pathogenicity) Vectors ▪ Dermacentor variabilis (American dog tick) ▫ Eastern, South-central US ▪ Dermacentor andersoni (Rocky Mountain wood tick) ▫ West of Mississippi River ▪ Rhipicephalus sanguineus (common brown dog tick) ▫ Southwestern US ▪ Virulence of strain depends on tick’s feeding status ▫ ↑ feeds → ↑ incubation at high temperatures → ↑ extracellular slime → ↑ virulence (AKA reactivation phenomenon) Life cycle ▪ Tick bite (requires 6–10 hours of feeding) → proliferates by binary fission ▪ Grows in nucleus, cytoplasm of host cells Pathogenesis ▪ Tropism for endothelial cells, downstream systemic effects as sequelae ▪ Endothelial cell entry: rickettsial outer membrane proteins (rOmps) interact with



520 OSMOSIS.ORG



▪



▪



▪



▪



▪



▪



lipopolysaccharides, surface-exposed proteins (SEPs) for entry ▫ rOmps bind Ku70 (membrane protein) → activate Ku70 → recruit ubiquitin ligase → ubiquitination of Ku70 → act upon cAMP receptors protein kinase A, Epac (exchange protein) → rearrangement of host cell actin filaments → rickettsial endocytosis Bacterial spread: R. rickettsii express phospholipase D, tlyC → lyse phagosomal membrane → entry into cytosol → polymerization of host cell monomeric actin filaments → invagination of host cell membranes → passage into neighboring cells Further bacterial spread ▫ Filopodia (from host cell membranes) assist in intercellular movement ▫ Bloodstream, lymphatic spread assist in more distant infection sites Small blood vessel injury (not entirely elucidated) ▫ Associated with phospholipase A activity, protease activity, free radicalinduced lipid peroxidation ▫ Cell necrosis (from other infected cells) → CD8+ T-cell response → endothelial cell injury → immune, phagocytic cellular response → lymphohistiocytic vasculitis Sequelae of small vessel injury: ↑ fluid in interstitial space → exposes brain, lung parenchyma to devastating pathophysiologic consequences Ability to spread cell-to-cell without causing obvious damage ▫ Rarely accumulate in large numbers inside cells Speeds of 4.8m/min ▫ Achieves speed via rapid recruitment, polymerization of host cell actin filaments



Chapter 95 Rickettsial Diseases



RISK FACTORS



▪ Residence in/travel to endemic areas (esp. in spring, summer) ▪ ↑ age (peak: 40–64) ▪ Individuals who are biologically male ▪ Glucose-6-phosphate dehydrogenase (G6PD) deficiency



COMPLICATIONS



▪ Skin necrosis at sites of terminal arterial supply (e.g. fingers, toes, nose, ears, genitals) ▪ Interstitial pneumonitis, myocarditis, encephalitis



SIGNS & SYMPTOMS ▪ Early infection ▫ Fever, headache, malaise, myalgias, arthralgias, nausea (without vomiting), edema (esp. in children) ▪ Rash development (hallmark of infection) ▫ Blanching, erythematous rash ▫ Macules (1–4mm) → petechiae ▫ Ankles, wrist → truncal spread → palms, soles rash (characteristic of late-stage disease) ▪ Confusion, conjunctival erythema, seizures, focal neurologic deficit ▪ Fundoscopic examination ▫ Retinal vein engorgement, arterial occlusion, flame hemorrhage



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Interstitial infiltrates Echocardiogram ▪ Minimal myocardial dysfunction with normal capillary wedge pressure ▪ Consistent with noncardiogenic nature of pulmonary edema (commonly present)



▪ Advanced disease ▫ Hyponatremia (sign of central nervous system involvement); transaminitis; ↑ bilirubin; azotemia (due to hypovolemia); ↑ prothrombin, partial thromboplastin times ▪ CSF ▫ Pleocytosis (monocytic, polymorphonuclear predominance possible), ↑ protein



OTHER DIAGNOSTICS



▪ History ▫ Residence in/travel to endemic area; recollection of tick bite (only 30% of individuals recollect bite)



TREATMENT MEDICATIONS



▪ Early treatment: prompt, empiric antimicrobial therapy with doxycycline (first-line), chloramphenicol (second-line) ▫ Even if mild symptoms (due to potential lethality of bacterial strain); recommended for pregnant individuals, children ▫ Goal: initiate < five days after symptom onset ▫ Duration: until three days after resolution of febrile illness; minimum seven days ▪ Antiemetics, antimotility agents (individuals intolerant of doxycycline)



OTHER INTERVENTIONS



▪ Hemodynamic monitoring in ICU setting; respiratory support; renal replacement therapy, blood transfusions ▪ Prevention ▫ Vigilant detection, early removal of ticks, proper clothing



LAB RESULTS



▪ Thrombocytopenia (worsens with progression of disease)



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RICKETTSIA TYPHI (MURINE TYPHUS) osms.it/rickettsia-typhi PATHOLOGY & CAUSES ▪ Rat-borne zoonotic disease transmitted to humans via flea; flu-like illness; minority of individuals require ICU-level care ▫ AKA murine, endemic, flea-borne typhus Transmission ▪ Zoonotic reservoir: Rattus typhi ▪ Vector: Xenopsylla cheopis (AKA Oriental rat flea) Life cycle ▪ Flea feeds on infected rodent → lifetime infection → fecal bacterial shedding → human contact with flea feces through breaks in skin barrier/inhalation → human disease ▫ Further human infection occurs via body lice passed human-to-human ▪ Replicates in high titers in yolk sacs of embryonated chicken eggs Pathogenesis (not well elucidated) ▪ Perivascular infiltration with lymphocytes, macrophages, plasma, mast cells (on biopsy) ▪ Vasculitis (rare) ▫ Accompanied by mural/intimal thrombi; heart, lungs, kidneys, central nervous system (CNS) ▪ Disease ▫ Mild, flu-like illness



RISK FACTORS



▪ Warmer climates, seaports, major commercial areas



COMPLICATIONS



▪ Shock, sepsis, myocarditis, renal/respiratory failure, severe hemolysis (associated with



522 OSMOSIS.ORG



G6PD deficiency) ▪ Neurological ▫ Meningitis, meningoencephalitis, facial paralysis, hearing loss, ocular abnormalities



SIGNS & SYMPTOMS ▪ Fever (8–16 days after exposure), chills, headache (commonly frontal), myalgia, rash (concurrent with fever; maculopapular, less commonly petechial; spares face, palms, soles), nausea, vomiting



DIAGNOSIS LAB RESULTS



▪ ↑ erythrocyte sedimentation rate (ESR) ▪ Left shifted leukocyte count (absolute neutropenia/lymphopenia possible) ▪ Abnormal hepatic enzymes ▪ Electrolytes ▫ Hyponatremia, hypokalemia, ↑ serum creatinine



TREATMENT MEDICATIONS



▪ Prompt doxycycline antimicrobial therapy ▪ Ciprofloxacin (viable alternative)



OTHER INTERVENTIONS Prevention ▪ Rodent, flea eradication ▪ Rat-proofing homes, food service areas ▪ Protective clothing for occupational exposure to rats



Chapter 2 Acyanotic Defects



NOTES RODS



MICROBE OVERVIEW ▪ Rod shaped bacteria (bacilli), Gramnegative, non-spore forming



BACTEROIDES FRAGILIS osms.it/bacteroides-fragilis PATHOLOGY & CAUSES ▪ Flora of oral cavity, GI tract (primarily large intestine), genitourinary tract of individuals who are biologically female; responsible for variety of infections ▪ Obligately anaerobic, non-motile ▪ Beta lactamase positive → resistance to beta lactam antibiotics ▪ Fastidious → difficult to isolate ▪ Grows in 20% bile ▪ Usually involved in widespread polymicrobial anaerobic Gram-negative bacilli infections (AGNB) ▫ Intra-abdominal, skin/soft tissue, pulmonary



RISK FACTORS



▪ Prior antibiotic use ▪ ↓ blood supply (e.g. trauma, malignancy, surgery, shock, vascular disease) ▪ Tissue necrosis ▪ Disruption of intestinal mucosa ▪ High risk for aspiration pneumonia (e.g. alcoholism, coma, stroke) ▪ Bronchial obstruction → lung abscesses



SIGNS & SYMPTOMS ▪ Foul-smelling discharge, tissue necrosis, formation of abscesses, gas production in tissues/discharges



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Abscesses/presence of gas in infected site ▫ Highly suggestive of anaerobic infection



LAB RESULTS



▪ Rapid enzymatic test ▪ Polymerase chain reaction (PCR) assays ▪ Direct needle aspiration



OSMOSIS.ORG 523



TREATMENT MEDICATIONS



▪ Antimicrobials ▫ Recovered anaerobes mixed with aerobic organisms; clindamycin,



metronidazole, carbapenems, tigecycline, beta-lactam/beta-lactamase inhibitors, cefoxitin



SURGERY



▪ Drain abscesses, relieve obstructions



BARTONELLA HENSELAE osms.it/bartonella-henselae PATHOLOGY & CAUSES ▪ Zoonotic microbe; affects skin (most common), regional lymph nodes, internal organs (e.g. liver, spleen); small, pleomorphic; fastidious, slow growing; requires specific culture conditions; grows in lysis centrifugation tubes; detected with Warthin–Starry (WS)/silver stain ▪ Natural reservoir ▫ Domestic cats, usually young cats ▪ Mode of transmission ▫ Infection follows cat scratch, bite, exposure to cat feces/fleas Commonly associated diseases ▪ Cat-scratch disease (CSD) ▫ Usually affects children ▪ Bacillary angiomatosis (BA) ▫ Rare vasoproliferative disorder; usually occurs in severely immunocompromised individuals (e.g. due to HIV)



COMPLICATIONS CSD ▪ Lymph nodes necrosis; can disseminate, cause life-threatening complications involving visceral organs (e.g. liver, spleen), central nervous system (CNS), eyes BA ▪ Potentially fatal if untreated



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SIGNS & SYMPTOMS ▪ May be asymptomatic CSD ▪ Usually develops 1–3 weeks after inoculation ▪ Regional lymphadenopathy/lymphadenitis (most common) ▫ Usually unilateral; lymph nodes drain site of inoculation; tender, swollen lymph nodes ▪ Rare ▫ Low grade fever, malaise, ↓ appetite, abdominal aches ▪ Cutaneous erythematous lesion at site of inoculation; regresses spontaneously after 1–4 weeks ▪ Visceral organs → hepatomegaly, splenomegaly ▪ Eyes → neuroretinitis, parinaud oculoglandular syndrome ▪ Central nervous system (CNS) → encephalopathy BA ▪ Usually affects skin → red papules, nodules/ subcutaneous masses



DIAGNOSIS LAB RESULTS ▪ Difficult to culture; incubation takes 2–4 weeks ▪ PCR assays



Chapter 96 Rods Biopsy ▪ CSD: granulomatous inflammation of lymph nodes, stellate microabscesses; organisms visualized using WS/silver stain ▪ BA: biopsy of lesions; Bartonella demonstrated with WS stain Serologic test ▪ Indirect immunofluorescence antibody (IFA)/enzyme immunoassay (EIA) Nonspecific findings ▪ ↑ erythrocyte sedimentation rate (ESR), ↑ C-reactive protein (CRP) in CSD



OTHER DIAGNOSTICS



▪ Clinical findings suggestive of Bartonella infection with history of contact with cat



Figure 96.1 The histological appearance of an lymph node excised from an individual with cat-scratch disease. There are numerous neutrophils which form characteristic stellate, or star-shaped, microabscesses.



TREATMENT MEDICATIONS CSD ▪ Usually self-limited within 2–4 months; antimicrobial therapy with azithromycin prevents life-threatening complications; alternative agents include doxycycline, rifampin BA ▪ Erythromycin, doxycycline, tetracycline



Figure 96.2 The histopathological appearance of bacillary angiomatosis. There is a proliferation of small capillaries surrounded by mixed inflammatoru cells, histiocytes and bacterial colonies.



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ENTEROBACTER osms.it/enterobacter PATHOLOGY & CAUSES ▪ Opportunistic microbe; nosocomial, various organ system infections; Enterobacteriaceae family; motile, nonfastidious; fast lactose fermenter, pink colonies on MacConkey agar (lactose containing medium); grows in aerobic, anaerobic conditions, rapidly on selective, nonselective agars; expresses fimbria; hemolysin, urease positive ▪ Commonly isolated species: E. cloacae, E. aerogenes ▪ Natural reservoir ▫ Soil, water, intestinal flora; occasionally respiratory tract ▪ Mode of transmission ▫ Endogenous: transfer from flora to adjacent sterile sites ▫ Exogenous: direct/indirect contact of mucosal surfaces with Enterobacter Commonly associated diseases ▪ Lower respiratory tract infections ▫ Tracheobronchitis, pneumonia, lung abscess, empyema ▪ Urinary tract infections (UTIs) in hospitalized individuals ▫ Cystitis, pyelonephritis, prostatitis ▪ Bloodstream infections (BSI) ▪ Skin, soft tissue infections ▫ Cellulitis, fasciitis, myositis, skin abscesses, wound infections ▪ Intra-abdominal infections ▫ Abscesses, peritonitis following intestinal perforation/surgery ▪ Uncommon ▫ Endocarditis, septic arthritis, osteomyelitis, CNS, ocular infections



RISK FACTORS



▪ More common in neonates, elderly individuals



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▪ Prolonged hospitalization ▪ Invasive procedures (e.g. post-surgery infections) ▪ Prior antibiotic therapy ▪ Invasive devices (e.g. venous catheterization) ▪ Underlying conditions ▫ Malignancy, chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), burns ▪ Mechanical ventilation ▪ Immunosuppression



COMPLICATIONS ▪ Septic shock



SIGNS & SYMPTOMS ▪ Non-specific, depends upon organ system affected ▪ UTIs ▫ Frequency, urgency of urination, dysuria



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Respiratory infections Abdomen CT scan/ultrasound ▪ Abdominal infections



LAB RESULTS



▪ Urinalysis for UTIs



Microbe identification ▪ Gram staining, culture



Chapter 96 Rods



TREATMENT MEDICATIONS



▪ Antimicrobials ▫ Carbapenems, aminoglycosides, fluoroquinolones, trimethoprimsulfamethoxazole, polymyxins



SURGERY



▪ Drain abscesses



OTHER INTERVENTIONS



▪ Remove invasive devices (e.g. central venous catheters)



ESCHERICHIA COLI osms.it/escherichia-coli PATHOLOGY & CAUSES ▪ Frequent cause of variety of infections; Enterobacteriaceae family; encapsulated, motile; certain strains hemolytic (betahemolytic on blood agar); fast lactose fermenter (pink colonies on MacConkey agar); nonfastidious; beta-galactosidase positive (breaks down lactose into glucose, galactose); iron uptake system ▪ AKA E.Coli ▪ Natural reservoir ▫ Intestinal, vaginal flora ▪ Mode of transmission ▫ Person-to-person contact, contaminated food/water, dislocation from intestinal tract ▪ Growing conditions ▫ On selective media; aerobic, anaerobic; eosin-methylene blue (EMB) agar for isolation (colonies with green metallic sheen); 15–45°C/59–113°F (some strains more heat resistant) ▪ Virulence factors ▫ Fimbriae, K-capsule, lipopolysaccharides (LPS) endotoxin ▪ Pathogenic factors ▫ Fimbriae → cystitis, pyelonephritis ▫ K-capsule → pneumonia, neonatal meningitis ▫ LPS endotoxin → septic shock Commonly associated diseases ▪ Genitourinary tract infections



▫ Leading cause of cystitis, pyelonephritis, prostatitis ▪ Intra-abdominal infections ▫ Enteric infections, abscesses, cholecystitis, spontaneous bacterial peritonitis (E. coli most common cause) ▪ Pneumonia ▪ Meningitis (in neonates)



TYPES Enteroinvasive (EIEC) ▪ Invades intestinal mucosa → necrosis, inflammation → dysentery Enterotoxigenic (ETEC) ▪ Heat-labile toxin (LT) → over-activates adenylate cyclase (cAMP) → ↑ Cl- secretion in gut, water efflux ▪ Heat-stable toxin (ST) → overactivates guanylate cyclase (cGMP) → ↓ resorption of NaCl, water in gut ▪ Produces LT, ST → travellers’ diarrhea (watery), mimics Vibrio cholerae illness Enteropathogenic (EPEC) ▪ Adheres to apical surface, flattens villi, prevents absorption → diarrhea Enterohemorrhagic (EHEC) ▪ Most commonly isolated serotype O157:H7 ▪ Produces Shiga-like toxin → enhances cytokine release ▫ Necrosis, inflammation → dysentery ▫ Endothelial damage → formation of microthrombi → hemolysis



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(microangiopathic hemolytic anemia), platelet consumption (thrombocytopenia), ↓ renal blood flow (acute renal failure) → hemolytic uremic syndrome (HUS) ▫ O157:H7 most common serotype



SIGNS & SYMPTOMS ▪ Depends on organ system affected ▪ Clinical manifestations generally nonspecific, except in enteric infections ▫ EHEC: bloody diarrhea, malaise, fever ▫ EIEC: dysentery, mimics shigellosis; bloody diarrhea, abdominal pain, tenesmus ▫ ETEC: watery diarrhea (travellers’ diarrhea), nausea, abdominal pain ▫ EPEC: fever, watery diarrhea; can last > two weeks; typically affects children



DIAGNOSIS LAB RESULTS



▪ Culture to isolate E. coli, gram staining, ↑ fecal leukocytes (except ETEC), PCR assays ▪ Complete blood count ▫ Leukocytosis ▪ Urinalysis in UTIs ▪ Pyuria ▫ Leukocyte esterase + → evidence of white blood cell (WBC) activity ▪ Proteinuria, bacteriuria ▪ Nitrite test + → ↓ urinary nitrates → marker of infection



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TREATMENT MEDICATIONS



▪ Antimicrobial treatment (UTIs, pneumonia, meningitis, intra-abdominal infections, sepsis) ▫ Third-generation cephalosporins, quinolones, doxycycline, trimethoprim/ sulfamethoxazole (TMP/SMZ) ▪ Antidiarrheal medications ▫ Contraindicated in children, EIEC infections ▪ EHEC ▫ Antibiotics contraindicated; can increase risk of HUS, thrombotic thrombocytopenic purpura (TTP) complications ▪ ETEC ▫ Antibiotics useful; reduce diarrhea duration



OTHER INTERVENTIONS



▪ Most enteric infections self-limited, managed conservatively ▫ Fluid, electrolytes correction



Chapter 96 Rods



KLEBSIELLA PNEUMONIAE osms.it/klebsiella-pneumoniae PATHOLOGY & CAUSES ▪ Causative agent of infections, usually occur in immunocompromised individuals; major cause of hospital-acquired infections; Enterobacteriaceae family, facultative anaerobe, nonmotile; possesses prominent polysaccharide capsule; beta-lactamase positive (resistant to ampicillin, amoxicillin; susceptible to cephalosporins); urease positive, lactose fermenter, iron uptake system ▪ Natural reservoir ▫ Flora of human mouth, intestine; soil, water Commonly associated diseases ▪ Pulmonary infections ▫ Pneumonia, empyema, lung abscesses, bacteremia ▪ UTIs ▫ Cystitis, pyelonephritis, prostatitis, abscesses ▪ Pyogenic liver/splenic abscesses ▪ Infective endocarditis ▪ Spontaneous bacterial peritonitis ▪ Endophthalmitis ▪ CNS infections ▪ Meningitis, brain abscesses ▪ Deep neck infections ▪ Skin, soft tissue infections



COMPLICATIONS



▪ Pneumonia can be fatal regardless of treatment



SIGNS & SYMPTOMS ▪ Pneumonia presents as bronchopneumonia/bronchitis (acute onset of symptoms) ▫ Productive cough (e.g. mucoid; bloody sputum, AKA “currant jelly sputum”), high grade fever, chills, chest pain, dyspnea, tachypnea, crackles ▪ UTIS (frequency, urgency, dysuria)



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Findings suggestive of pneumonia



LAB RESULTS



▪ Complete blood count ▫ Leukocytosis ▪ Specimen culture ▫ E.g. blood, sputum, urine ▫ Gram stain: Gram-negative, rod-shaped capsule appears as clear space



TREATMENT



RISK FACTORS



▪ Prolonged hospitalization ▪ Prior use of antibiotics ▪ Prolonged use of invasive devices (e.g. catheters) ▪ Underlying medical conditions ▫ Alcoholism, DM, underlying malignancy, hepatobiliary disease, COPD, renal failure ▪ Use of glucocorticoids



MEDICATIONS



▪ Antimicrobial therapy ▫ Beta-lactams with beta-lactamase inhibitors, cephalosporins, fluoroquinolones, aminoglycosides, carbapenems



SURGERY



▪ Drain abscesses ▪ Debride necrotic issues



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LEGIONELLA PNEUMOPHILA osms.it/legionella-pneumophila PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Gram-negative, facultative intracellular (stain poorly with Gram stain); best visualized by silver stain; appears in specimens as short rod; longer, filamentous in culture; grows best on charcoal yeast extract medium with cysteine, iron; serogroup 1 most commonly associated with human infections ▪ Natural reservoir ▫ Water sources (e.g. air conditioning systems, tubing systems of domestic water supplies, water-cooling towers) ▪ Mode of transmission ▫ Water aerosol inhalation



Legionnaires’ disease ▪ Incubation period ▫ 2–10 days ▪ Atypical pneumonia ▫ Mild cough (may cough bloody mucus), high grade fever, chills, dyspnea, chest pain, rales ▪ GI ▫ Diarrhea, nausea, vomiting, abdominal pain ▪ CNS ▫ Confusion, lethargy, headache, focal neurologic signs, hallucinations



Commonly associated diseases ▪ Legionnaires’ disease ▫ Atypical form of pneumonia ▪ Pontiac fever ▪ Rare self-limited upper respiratory tract infection ▪ Extrapulmonary disease (rare) ▫ Heart most common extrapulmonary site (e.g. myocarditis, endocarditis)



Pontiac fever ▪ Acute onset ▪ Mild, febrile, flu-like syndrome



RISK FACTORS



▪ ↑ age, immunosuppression, smoking, chronic lung disease, organ transplant, renal failure, cardiac disease



COMPLICATIONS



▪ Pneumonia ▫ Progresses rapidly, can be fatal (esp. immunosuppressed individuals) ▪ Renal failure



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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Legionnaires’ disease ▫ Unilateral ▪ Diffuse, patchy inflammation of interstitium → consolidation involving ≥ one lobe



LAB RESULTS ▪ Nonspecific findings ▫ Hyponatremia, thrombocytopenia, leukocytosis, hypophosphatemia ▪ Culture of respiratory specimens ▫ Many neutrophils, few microorganisms ▪ Urinary antigen test using enzyme-linked immunosorbent assay (test of choice along with culture) ▫ Rapid; sensitive, specific; legionella persists in urine for weeks



Chapter 96 Rods ▪ Fluorescent antibody test on sputum specimens ▪ Serological tests ▫ Serum antibodies develop after 8–10 days; fourfold rise in titre/single high titre ▪ PCR using sputum/other specimens (less sensitive than culture)



TREATMENT MEDICATIONS



▪ Atypical pneumonia ▫ Macrolides, tetracyclines. fluoroquinolones, rifampicin



OTHER INTERVENTIONS



▪ Eradication of organism from responsible water source to control disease



NONTYPHOIDAL SALMONELLA osms.it/nontyphoidal-salmonella PATHOLOGY & CAUSES ▪ Causes salmonellosis (foodborne gastroenteritis); Enterobacteriaceae family; motile; encapsulated; facultative intracellular, anaerobes; nonlactose fermenter; oxidase-; possesses type III secretion system, iron uptake system; high infectious dose; H2S production on TSI agar; produces endotoxin ▪ Most common human pathogen ▫ S.enteritidis ▪ Natural reservoir ▫ Humans, animals; poultry, eggs, pets, turtles common sources ▪ Mode of transmission ▫ Food (e.g. undercooked meat, poultry, eggs, milk), fecal-oral route



RISK FACTORS



▪ Age (usually affects young children, older adults); season (peak incidence in summer, fall); low gastric acidity (atrophic gastritis, use of acid-suppressive agents); immunodeficiency; sickle cell disease; hemolytic anemia; alcoholism; cardiovascular dysfunction; malignancies; IV drug use



COMPLICATIONS



▪ Can disseminate via blood → extraintestinal manifestations (e.g. endocarditis, vascular infections, cholecystitis, hepatic/splenic abscesses)



SIGNS & SYMPTOMS ▪ Present 24–48 hours after food ingestion ▪ Loose stools/diarrhea often bloody (can persist for two weeks) ▪ Nausea, vomiting ▪ Fever (resolves within two days) ▪ Abdominal cramps



DIAGNOSIS LAB RESULTS



▪ Stool culture, ↑ fecal leukocytes, blood cultures to detect bacteremia; bone marrow aspiration, culture



TREATMENT MEDICATIONS



▪ Antimicrobial therapy ▫ Generally not required, prolongs duration of fecal shedding of Salmonella, doesn’t shorten duration of symptoms



OSMOSIS.ORG 531



▪ Antibiotics ▫ Only indicated in immunocompromised individuals; antimicrobial agents (e.g. ciprofloxacin)



PROTEUS MIRABILIS osms.it/proteus-mirabilis PATHOLOGY & CAUSES ▪ Common cause of community acquired, nosocomial UTIs (e.g. primarily cystitis, pyelonephritis) ▪ Enterobacteriaceae family; highly motile; nonlactose fermenters; oxidase negative; expresses mannose-resistant hemagglutination, calcium dependent/ independent hemolysins; swarming growth in discontinuous manner on agar media; H2S production on TSI agar; resistance to polymyxins, tetracyclines ▪ Urease positive → converts urea to ammonia, CO2 → ↑ urine pH → ammonia combines with magnesium, phosphate → form magnesium-ammonium-phosphate (struvite) stones ▪ Pr. mirabilis causes 90% of infections ▪ Natural reservoir ▫ Intestinal flora ▪ Virulence factors ▫ Fimbria (important for adherence to tissue) Commonly associated diseases ▪ Urethritis, acute prostatitis, pyogenic liver abscesses



RISK FACTORS



▪ Hospitalization; ↑ age (most common in elderly); multiple prior UTIs; prior use of antibiotics; urinary tract surgery; urinary catheterization; structural abnormalities/ obstructions of urinary tract; underlying medical conditions (e.g. DM, chronic kidney disease); neurogenic bladder; frequent sexual activity



532 OSMOSIS.ORG



COMPLICATIONS



▪ Abscesses, sepsis, meningitis, chronic pyelonephritis, xanthogranulomatous pyelonephritis (chronic destructive granulomatous process of renal parenchyma)



SIGNS & SYMPTOMS ▪ Nonspecific, disease-dependent: symptoms commonly associated with urethritis, acute prostatitis, pyogenic liver abscesses



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan ▪ Kidneys; indicated if therapy fails X-ray ▪ Struvite stones appear radiopaque



LAB RESULTS



▪ Urine culture to isolate Proteus ▪ Complete blood count ▫ Leukocytosis ▪ Urinalysis ▫ Alkaline urine pH (> 7.0), pyuria, bacteriuria



Chapter 96 Rods



TREATMENT MEDICATIONS



▪ Uncomplicated UTIs ▫ Cystitis: TMP/SMX, nitrofurantoin, quinolones, fosfomycin ▫ Pyelonephritis: quinolone/ampicillin, gentamicin/third-generation cephalosporin ▪ Complicated UTIs ▫ E.g. diabetes, nephrolithiasis, pregnancy, anatomic abnormalities of urinary tract ▫ Therapy should be prolonged



SURGERY



▪ Drainage of collections (e.g. perinephric abscesses) ▪ Removal of struvite renal calculus



Figure 96.3 Proteus species spread in a swarming fashion on an agar plate.



PSEUDOMONAS AERUGINOSA osms.it/pseudomonas-aeruginosa PATHOLOGY & CAUSES ▪ One of most common causes of hospitalacquired infections in immunocompromised individuals; motile; aerobic; nonlactose fermenter (derives energy from carbohydrates by oxidation); nonfastidious; oxidase, catalase, elastase, leukocidin, hemolysin positive; resistant to many antibiotics ▪ Grows on variety of culture media ▫ Colonies greenish-blue due to production of procyanin (blue), pyoverdin (yellow-green); fruity, grapelike odor ▪ Natural reservoir ▫ Water, soil sources (e.g. rivers, ponds), animals, plants, hospital equipment; hospitalized individuals asymptomatic carriers ▪ Mode of transmission ▫ Direct contact with contaminated materials/infected individuals



▪ Virulence factors ▫ Exotoxin A → inactivates elongation factor (EF-2) → inhibition of protein synthesis → death of host cells ▫ Phospholipase C → degrades membranes ▫ Endotoxin → fever, shock ▫ Mucoid exopolysaccharide → biofilm formation → protection from immune system Commonly associated diseases ▪ Pneumonia; sepsis; genitourinary tract infections; skin, soft tissue infections; ear infections (e.g. external otitis, chronic otitis media); eye infections (e.g. keratitis); GI infections; bone, joint infections (usually affects vertebral column); infective endocarditis



RISK FACTORS



▪ Prolonged hospitalization, catheterization, IV drug use, severe burns, contact lenses, eye trauma



OSMOSIS.ORG 533



▪ Mechanical ventilation/endotracheal intubation ▫ P. aeruginosa second most common cause of ventilator-associated pneumonia ▪ Cystic fibrosis (CF) → chronic infection with P. aeruginosa ▪ Immune system deficits (e.g. neutropenia, diabetes)



COMPLICATIONS



▪ Sepsis/necrotizing pneumonia can be fatal in immunocompromised individuals ▪ Chronic infections in CF → bronchiectasis, pulmonary fibrosis → pulmonary failure ▪ Disseminated intravascular coagulation due to sepsis ▪ Eye infections → vision loss



SIGNS & SYMPTOMS ▪ Generally nonspecific, depend on organ system ▪ Eye infections (esp. cornea) extremely painful, rapidly destructive ▪ Ecthyma gangrenosum ▫ Due to sepsis, typically appears in immunocompromised individuals ▫ Well-demarcated, black, necrotic cutaneous lesion; rapidly progressive



Figure 96.4 Pseudomonas species will adopt a greenish hue when cultured on cetrimide agar.



534 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pneumonia ▫ Bilateral bronchopneumonia with nodular infiltrates with/without pleural effusion



LAB RESULTS



▪ Culture (blood/other specimens) on selective media ▫ Enhances production of procyanin ▪ Oxidase test ▪ PCR assays ▪ Complete blood count ▫ Leukocytosis ▪ Serological tests ▫ Only individuals with CF/COPD



TREATMENT MEDICATIONS



▪ Antimicrobial therapy ▫ Extended-spectrum penicillins, betalactamase inhibitors, aminoglycosides, carbapenems, monobactams, polymyxins, fluoroquinolones, third/ fourth-generation cephalosporins



Chapter 96 Rods



SERRATIA MARCESCENS osms.it/serratia-marcescens PATHOLOGY & CAUSES ▪ Opportunistic microbe; uncommon cause of variety of hospital-acquired infections; Enterobacteriaceae family; motile; aerobic; slow, weak lactose fermenter; urease positive (struvite stones in individuals with recurrent UTIs); catalase positive; grows on media at 30–37°C/86–99°F, utilize most carbohydrates with production of acid, gas; produces red pigment (prodigiosin) colonies on agar; often resistant to commonly used antibiotics (e.g. ampicillin, macrolides, firstgeneration cephalosporins) ▪ Natural reservoir ▫ Water, soil sources ▪ Virulence factors ▫ Fimbria, cell surface components, longchain LPS, hemolysin Commonly associated diseases ▪ Respiratory infections (e.g. pneumonia), UTIs, wound infections, CNS infections (e.g. meningitis, cerebral abscesses), intra-abdominal infections, septicemia, endocarditis, otitis externa



RISK FACTORS



▪ Neonates, infants ▪ More common in individuals who are biologically male ▪ Prolonged hospitalization; catheterization (e.g. intravenous, urinary catheters); mechanical ventilation; recent surgery/ obstruction of urinary tract; cardiac valve replacement; IV drug use; immune system deficits (e.g. neutropenia, chronic granulomatous disease, DM); head trauma/ brain surgery; contact lenses



COMPLICATIONS



▪ Septic shock, stroke (due to endocarditis)



SIGNS & SYMPTOMS ▪ Nonspecific, depend upon disease ▪ Symptoms associated with respiratory infections, UTIs, wound infections, CNS infections, intra-abdominal infections, septicemia, endocarditis, otitis externa



DIAGNOSIS DIAGNOSTICS IMAGING Chest X-ray ▪ Pneumonia Abdominal ultrasound/CT scan ▪ Abnormalities of urinary tract, intraabdominal infections, abscesses Echocardiography ▪ Valvular vegetations Brain CT scan ▪ Follow with lumbar puncture in individuals with suspected meningitis



Figure 96.5 Serratia marcessens grows red colonies when cultured on agar.



OSMOSIS.ORG 535



LAB RESULTS



▪ Complete blood count ▫ Leukocytosis, ↑ neutrophils with left shift, possible anemia



TREATMENT MEDICATIONS



▪ Antibiotic therapy ▫ Aminoglycosides with antipseudomonal beta-lactam ▫ If infection persists, fluoroquinolones/ carbapenems



SURGERY



▪ Drainage of collections (e.g. abscesses)



SHIGELLA osms.it/shigella PATHOLOGY & CAUSES ▪ Causes acute infectious diarrhea (shigellosis), one of most common causes of bloody diarrhea; Enterobacteriaceae family; facultative anaerobe; nonmotile; nonlactose fermenter; urease, oxidase negative; resistance to low pH of gastric acids; highly virulent; possesses virulence plasmids; invades colonic mucosa via microfold (M) cells of Peyer patches ▪ Natural reservoir ▫ Human only; part of intestinal tract flora ▪ Mode of transmission ▫ Usually fecal-oral route, contaminated water, food; easy person-to-person spread



TYPES



▪ S. dysenteriae: serogroup A ▫ Releases Shiga toxin, causes most severe form of shigellosis ▪ S. flexneri: serogroup B ▪ S. boydii: serogroup C ▪ S. sonnei: serogroup D



COMPLICATIONS ▪ Dehydration (due to fluid loss) ▪ Electrolyte imbalance (e.g. hyponatremia,



536 OSMOSIS.ORG



hypokalemia) ▪ Reiter’s syndrome ▫ Reactive arthritis, urethritis, conjunctivitis ▫ Affects HLA-B27+ individuals ▪ Hemolytic-uremic syndrome ▫ Hemolytic anemia, thrombocytopenia, acute renal failure ▫ Usually in infections due to S. dysenteriae ▪ Toxic megacolon ▪ Intestinal obstruction



SIGNS & SYMPTOMS ▪ Incubation period ▫ 2–3 days/one week ▪ Sudden onset ▫ Abdominal pain ▫ Diarrhea that is initially watery, progresses to bloody (bacillary dysentery) in 50% of cases ▫ Tenesmus ▫ Fever, malaise, headache, anorexia ▪ Less common ▫ Nausea, vomiting



Chapter 96 Rods ▪ Subacute presentation in minority of individuals ▫ Several weeks of waxing/waning diarrhea



DIAGNOSIS DIAGNOSTIC IMAGING Colonoscopy ▪ Hemorrhagic, ulcerated mucosa ▪ Most prominent in left colon, ileum also involved ▪ Pseudomembranes



TREATMENT MEDICATIONS



▪ Antimicrobial therapy ▫ Shorten duration of symptoms, reduce fecal shedding of organisms, risk of complications; azithromycin orally, thirdgeneration cephalosporin parenterally ▪ Antidiarrheal medications contraindicated ▫ Delay fecal shedding of Shigella



OTHER INTERVENTIONS



▪ Most cases self limited (resolve within one week), do not require antibiotics



LAB RESULTS



▪ Stool culture ▪ ↑ leukocytes, blood in feces ▪ PCR testing of stools



YERSINIA MARCESCENS osms.it/yersinia-marcescens PATHOLOGY & CAUSES ▪ Enterobacteriaceae family; facultative anaerobe, intracellular; motility depends on temperature (motile at 25°C/77°F, nonmotile at 37°C/99°F); nonlactose fermenter; oxidase negative ▪ Important human pathogens ▫ Y. pestis, Y.enterocolitica ▪ Natural reservoir ▫ Y. pestis: ground squirrels, gerbils, voles, rats ▫ Y. enterocolitica: cattle, deer, pigs, birds, pigs ▪ Virulence factors ▫ Adhesins to bind to host cell beta 1 integrins, endotoxin, coagulase, fibrinolysin, iron uptake system (mediates iron capture, transport)



TYPES Yersinia enterocolitica ▪ Causes yersiniosis ▫ Gastrointestinal infections (e.g. ileum, appendix, right colon) ▪ Common types ▫ Enterocolitis, terminal ileitis, mesenteric lymphadenitis, pseudoappendicitis ▪ Mode of transmission ▫ Pet feces, inadequately cooked foods, contaminated pork, milk, water Yersinia pestis ▪ Causes human plague ▫ Zoonotic infection, highly fatal if untreated ▪ Subtypes ▫ Wild (sylvatic), urban plague (typically transmitted from rats, more severe)



OSMOSIS.ORG 537



▪ Clinical forms ▫ Bubonic (more common), septicaemic, pneumonic (least common, high mortality rate) ▪ Mode of transmission ▫ Fleas from rats, other rodents



COMPLICATIONS Yersinia enterocolitica ▪ Reiter’s syndrome, myocarditis, erythema nodosum, kidney disease, mucosal ulceration, bowel necrosis (due to mesenteric vessel thrombosis), septicemia (fatal if untreated) Yersinia pestis ▪ Bubonic plague → sepsis → secondary pneumonic plague/meningitis ▪ Systemic plague → hypotension, disseminated intravascular coagulation, multiorgan failure ▪ Pneumonic plague (rapidly fatal if untreated)



SIGNS & SYMPTOMS Yersinia enterocolitica ▪ Enterocolitis (most common) ▫ Abdominal pain, acute diarrhea, low grade fever, nausea, vomiting ▪ Abdominal tenderness ▫ Right lower quadrant, mimics appendicitis (pseudoappendicitis) ▪ Extraintestinal features of pharyngitis, arthralgia, erythema nodosum (painful, red/ purple lesions, resolve spontaneously) Yersinia pestis ▪ Incubation period ▫ 2–8 days ▪ Bubonic plague (sudden onset) ▫ fever; painful lymphadenopathy (bubos), inguinal lymph nodes frequently involved; chills, fatigue ▪ Septicemic plague ▫ Fever; malaise, GI symptoms (nausea, vomiting, diarrhea)



538 OSMOSIS.ORG



▪ Pneumonic plague (sudden onset): ▫ Dyspnea, high grade fever, chest pain, cough with blood-containing sputum



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan ▪ Yersinia enterocolitica: exclude appendicitis Colonoscopy ▪ Yersinia enterocolitica: aphthoid lesions in cecum; elevations, ulcers in terminal ileum Chest X-ray ▪ Yersinia pestis: pneumonic plague



LAB RESULTS Yersinia enterocolitica ▪ Identification of microbe ▪ Stool culture ▫ Cefsulodin-irgasan-novobiocin (CIN) agar ▫ In extraintestinal disease, cultures of lymph nodes/blood may be positive ▪ PCR assays ▪ ↑ leukocytes in stool, blood ▪ Serological tests ▫ Tube agglutination, enzyme-linked immunosorbent assay (ELISA) Yersinia pestis ▪ Nonspecific findings ▫ Leukocytosis, thrombocytopenia ▪ Isolation of organism in blood culture ▫ Positive cultures in individuals with bubonic, septicemic plague ▪ Peripheral blood smear ▫ Wright–Giemsa stain reveals rodshaped bacteria, Wayson stain reveals characteristic “safety pin” appearance ▪ Rapid antigen testing in sputum/serum ▪ Serological tests ▫ Fourfold rise in serum antibody titers between acute, convalescent phase ▪ PCR assays



Chapter 96 Rods



OTHER DIAGNOSTICS Yersinia pestis ▪ Clinical findings suggestive of plague, history of traveling to plague-endemic areas



TREATMENT MEDICATIONS Yersinia enterocolitica ▪ Antimicrobial therapy ▫ TMP/SMX, aminoglycosides ▫ Alternative agents: third-generation cephalosporins, tetracyclines, fluoroquinolones



Figure 96.6 The black, necrotic fingers of a man infected with Yersinia pestis.



Yersinia pestis ▪ Antimicrobial therapy ▫ Aminoglycosides (streptomycin/ gentamicin) ▫ Alternative agents: doxycycline, tetracycline, fluoroquinolones, chloramphenicol



OTHER INTERVENTIONS Yersinia enterocolitica ▪ ↑ fluid intake, good nutrition



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NOTES



NOTES



SPIROCHETES MICROBE OVERVIEW Morphology ▪ Thin-walled, Gram-negative flexible spiral rods ▪ Length: 5–250μm; diameter: 0.1–0.6μm ▪ Unique double membrane separated by periplasmic space



▪ Corkscrew-like motility via axial filament situated lengthwise between inner and outer membranes (endoflagella) Replication ▪ Reproduction: sexual transverse binary fission



BORRELIA BURGDORFERI (LYME DISEASE) osms.it/lyme-disease PATHOLOGY & CAUSES ▪ An obligate parasite that causes Lyme disease, a systemic inflammatory disease ▪ Non-spore forming ▪ Life cycle includes mammals, birds, and ticks (genus Ixodes), principally in North America ▪ Killed when exposed to hypotonic or hypertonic environments, drying, disinfectants (e.g. bleach), or temperatures > 50°C/122°F ▪ Transmission ▫ Via tick bite → enters blood → spreads to tissues and organs; especially joints, heart, nervous system ▪ Infection progresses through three stages 1. Localized disease (occurs 3–30 days after exposure) 2. Disseminated disease (days to months after exposure; multisystem involvement) 3. Late/chronic disease (months to years after exposure)



540 OSMOSIS.ORG



RISK FACTORS ▪ Exposure to ticks in endemic areas ▫ Living in areas bordering forests ▫ Outdoor employment, recreation ▪ Most cases occur in late spring to summer



COMPLICATIONS ▪ Meningitis, cranial neuropathy ▪ Lyme carditis ▫ AV block, myopericarditis ▪ Chronic joint inflammation ▪ Post–Lyme disease syndrome



SIGNS & SYMPTOMS Early signs/symptoms of localized disease ▪ Erythema migrans (EM) rash ▫ Non-painful, gradually expanding “bull’s-eye” rash appearing at the site of tick bite; feels warm to palpation; may itch



Chapter 97 Spirochetes ▪ Constitutional ▫ Low grade fever, chills, headache, fatigue, myalgia, arthralgia, lymphadenopathy Disseminated signs/symptoms ▪ Severe headaches and neck stiffness ▪ Formation of additional EM ▪ Joint pain and swelling; especially knees, other large joints ▪ Facial palsy ▪ Palpitations (Lyme carditis) ▪ Episodic dizziness, dyspnea ▪ Pain ▫ Shooting pains, numbness, or tingling in the hands or feet ▪ Short-term memory loss Late/chronic disease ▪ Presence of nonspecific symptoms (e.g. headache, fatigue, joint pain) that persists after treatment for Lyme disease



DIAGNOSIS LAB RESULTS CDC testing criteria ▪ Two tiered testing for lyme disease ▫ First test: enzyme immunoassay (EIA) or immunofluorescence assay (IFA) ▫ Second test (as needed): IgM and/or IgG western blot Other laboratory findings ▪ Blood chemistry ▫ ↑ ESR, serum creatine phosphokinase, aspartate aminotransferase (AST) and/ or alanine aminotransferase (ALT) ▪ Blood studies ▫ Anemia, leukocytosis, thrombocytopenia



OTHER DIAGNOSTICS ▪ History of exposure to ticks in an endemic area and characteristic clinical presentation



TREATMENT MEDICATIONS ▪ Antibiotics ▫ Doxycycline, amoxicillin, or cefuroxime axetil



Figure 97.1 A bulls-eye-shaped rash, known as erythema migrans, at the site of infection with Borellia burgdorferi, the causative agent of Lyme disease.



OSMOSIS.ORG 541



BORRELIA SPECIES (RELAPSING FEVER) osms.it/borrelia-species PATHOLOGY & CAUSES ▪ Relapsing fever: bacterial infection caused by Borrelia spirochetes Tick-borne relapsing fever (TBRF) ▪ Endemic ▪ Found in endemic areas ▫ Mountainous areas of North America, plateau regions of Mexico, Central and South America, Mediterranean, central Asia, Africa ▪ Caused primarily by Borrelia hermsii, Borrelia turicatae, Borrelia parkeri in North America ▪ Spread by soft tick species Ornithodoros parkeri and Ornithodoros turicata ▪ Risk factors ▫ Occupying rodent-infested cabins, caves, or other dwellings ▫ Camping near rodent nests ▪ Tick attaches to human host (usually at night during sleep) → bites and feeds on blood → saliva and spirochete enter host’s circulation Louse-borne relapsing fever (LBRF) ▪ Epidemic ▪ Caused by Borrelia recurrentis ▪ Spread person-to-person via body louse ▪ Risk factors ▫ Primarily seen in low resource countries ▫ Famines, wars; causes epidemics among refugees, migrant populations ▫ Homelessness (exposure to lice) ▫ Poor hygiene ▪ B. recurrentis grows in the body cavity Pediculus humanus corporis → human host crushes louse/louse feces with fingers → spirochete enters either through bite site, through breaks in the skin caused by scratching, or through conjunctiva when



542 OSMOSIS.ORG



fingers touch eyes After entry into human host ▪ Spirochete divides every 6–12 hours (can number up to 106–108 per mL) → leaves blood and enters tissues: brain, eye, inner ear, liver, heart, testes, and other organs Pattern of intermittent illness ▪ Relapsing fever caused by spirochetemia ▪ Characterized by recurrent episodes of fever and constitutional symptoms with intermittent periods of general well-being ▫ Interval range between fevers is 4–14 days ▫ Pattern of intermittent illness caused by outer membrane lipoproteins called variable major proteins (VMPs) ▫ Employed as multiphasic antigens to evade host adaptive immunity ▫ TBRF: multiple febrile periods last 1–3 days each ▫ LBRF: first episode lasts 3–6 days, followed by a single milder episode Complications ▪ Neurological ▫ Meningitis, subarachnoid hemorrhage, cranial nerve neuritis, Bell’s palsy, hearing loss ▪ Ocular ▫ Iridocyclitis, panophthalmitis, vision loss ▪ Cardiac ▫ Myocarditis, cardiac failure ▪ Respiratory ▫ Bronchopneumonia, acute respiratory distress syndrome ▪ Hematologic ▫ Thrombocytopenia ▪ Other ▫ Hepatitis, splenic rupture ▪ During pregnancy



Chapter 97 Spirochetes ▫ Spontaneous abortion, prematurity, neonatal death ▪ Jarisch–Herxheimer reaction ▫ During treatment with antibiotics → release of proinflammatory cytokines triggered by products released from dead microbes



SIGNS & SYMPTOMS ▪ Characteristics of febrile episodes ▫ Sudden onset of high fever → crisis phase: chills, ↑ ↑ temperature, ↑ HR, ↑ BP → diaphoresis, ↓ fever, ↓ BP ▫ ↑ mortality during crisis and immediate aftermath ▪ Constitutional ▫ Sudden onset of high fever and chills; followed by headache, myalgia, arthralgia, nausea ▪ Neurologic ▫ Dizziness, delirium, stupor, facial palsy ▪ Cardiac ▫ Prolonged QTc interval. ▪ Respiratory ▫ Nonproductive cough, signs of respiratory distress ▪ Hematologic ▫ Epistaxis, petechiae, ecchymoses, blood-tinged sputum ▪ Other ▫ Hepatomegaly, abdominal pain, photophobia, skin rash



DIAGNOSIS LAB RESULTS Visualization of microbe ▪ Blood: thick or thin smears ▫ Giemsa, Wright, or acridine orange stain ▫ Direct or indirect immunofluorescence ▫ Phase contrast or dark field microscopy ▪ PCR, culture, serology ▪ Tissue specimen ▫ Silver stain (e.g. Warthin-Starry, modified Dieterle) ▫ Immunofluorescence



TREATMENT MEDICATIONS ▪ Antibiotics ▫ Penicillin G, ceftriaxone, doxycycline



OTHER INTERVENTIONS Prevention ▪ Avoidance and eradication of vector



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LEPTOSPIRA osms.it/leptospira PATHOLOGY & CAUSES ▪ A spirochete that causes the disease leptospirosis ▫ AKA Weil's disease, Weil–Vasiliev disease, swineherd's disease, rice-field fever, waterborne fever, nanukayami fever, cane-cutter fever, swamp fever, mud fever, Stuttgart disease, canicola fever ▪ Infected mammal excretes microbe in urine which remains viable in stagnant water and wet soil → environmental exposure by humans → microbe usually enters via non-intact skin, mucous membranes, or conjunctivae (rarely via contaminated food, water, or aerosols) ▪ Effects of microbe ▫ Damages blood vessel endothelium → organ damage ▫ Inhibits the Na+-K+-Cl- cotransporter activity in the thick ascending limb of Henle → hypokalemia, hyponatremia



COMPLICATIONS Electrolyte imbalance, kidney failure Hepatitis, hepatic hemorrhage Aseptic meningitis Pulmonary hemorrhage, acute respiratory distress syndrome (ARDS) ▪ Uveitis, optic neuritis ▪ Myocarditis ▪ Rhabdomyolysis ▪ ▪ ▪ ▪



SIGNS & SYMPTOMS ▪ Variable clinical course ▫ Ranges from mild disease that resolves uneventfully to severe and potentially fatal ▪ Common symptoms ▫ Abrupt onset of fever, chills ▫ Headache



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▫ Nonproductive cough ▫ Pharyngitis ▫ Myalgias, arthralgias ▫ Conjunctival suffusion (redness without exudate) ▫ Lymphadenopathy ▫ Jaundice ▫ Uremia, bacteremia, oliguria, hypokalemia



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular densities, consolidation; may have a ground-glass appearance



LAB RESULTS ▪ Identification of microbe ▫ PCR, ELISA, microscopic agglutination ▪ Other laboratory studies ▫ Leukocytosis with left shift ▫ Hypokalemia, hyponatremia ▫ ↑ hepatic transaminases, ↑ direct bilirubin ▫ Urinalysis: proteinuria, pyuria, granular casts, hematuria, ↑ creatine kinase ▫ CSF: neutrophilic pleocytosis, ↑ protein



OTHER DIAGNOSTICS ▪ History and physical examination



Chapter 97 Spirochetes



OTHER INTERVENTIONS



TREATMENT MEDICATIONS ▪ Antibiotics ▫ Doxycycline (mild cases), penicillin (severe cases)



▪ Address complications ▪ Prevention ▫ Avoidance of potential infectious sources of infection, domestic animal vaccination



TREPONEMA PALLIDUM (SYPHILIS) osms.it/syphilis PATHOLOGY & CAUSES ▪ The spirochete bacterium that causes syphilis, a localized and systemic disease ▪ Transmission ▫ Sexually: by direct contact with an infectious lesion (primarily) → enters via microscopic abrasions ▫ Perinatally: crosses placenta easily → congenital syphilis ▪ Progresses through stages ▫ Primary: localized sores (chancre) appear after about three weeks at site of infection ▫ Secondary: 2–8 weeks after chancre resolution, hematogenous bacterial dissemination causes systemic symptoms ▫ Latent: asymptomatic ▫ Tertiary (late): organ damage develops 10–30 years after initial infection ▪ Neurosyphilis and ocular syphilis can occur at any stage ▫ Neurosyphilis begins when the microbe invades the CSF



RISK FACTORS Unprotected sex Multiple sexual partners Biologically male Biologically-male individuals engaging in same-sex sexual contact (MSM) ▪ IV drug use ▪ Existing sexually-transmitted disease, especially HIV ▪ ▪ ▪ ▪



COMPLICATIONS



▪ Cardiovascular: syphilitic aortic aneurysms, dilated aorta, aortic valve regurgitation; coronary artery narrowing ▪ Congenital syphilis: hemolytic anemia, deafness, keratitis, periostitis ▪ Neurosyphilis: dementia, meningitis, brain or spinal cord ischemia/infarction, seizures, ischemic stroke ▪ Ocular syphilis: uveitis, vitritis, retinitis, optic neuropathy, blindness ▪ Otosyphilis: hearing loss, tinnitus



SIGNS & SYMPTOMS Stages ▪ Presentation will vary according to stage of disease ▪ Primary ▫ Chancre: painless ulcers at inoculation site (in contrast to painful lesions seen in genital herpes or chancroid) ▫ Single or multiple; usually firm, round, painless ▫ Heals with or without treatment; treatment prevents progression to secondary stage ▪ Secondary ▫ May be asymptomatic ▫ Rash: diffuse rough, reddish-brown maculopapular on extremities, palms of hands and/or soles of feet, back; raised, gray-whitish lesions on mucous membranes ▫ Condylomata lata



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▫ Myalgia ▫ Fatigue ▫ Lymphadenopathy ▫ Fever ▫ “Moth-eaten” alopecia ▫ Resolves without treatment; treatment prevents progression to latent and tertiary stages ▪ Latent ▫ Positive serology; asymptomatic ▪ Tertiary (late) ▫ Gummas: non-cancerous, granulomatous growths on internal organs, bones, skin; more common in HIV-infected individuals ▫ Evidence of organ involvement; charcot joints, aoritis (due to destruction of vasa vasorum) Complications ▪ Neurosyphilis ▫ Meningitis: headache, nausea and vomiting, stiff neck ▫ Tabes dorsalis: muscle weakness, locomotor ataxia, ↓ proprioception, incoordination ▫ General paresis (paralytic dementia) ▫ Facial and limb hypotonia, intention tremors ▫ Forgetfulness, personality changes ▪ Ocular syphilis ▫ ↓ visual acuity; loss of vision ▫ Argyll Robertson pupil: small pupils that constrict poorly in response to direct light



▪ Serum treponemal tests ▫ Fluorescent treponemal antibody absorption (FTA-ABS) ▫ Treponema pallidum particle agglutination assay (TPPA) ▫ Syphilis enzyme immunoassays (EIAs) ▪ If neurologic symptoms, lumbar puncture and CSF examination ▫ ↑ lymphocytes, ↑ protein ▫ CSF-VDRL reactivity



OTHER DIAGNOSTICS ▪ History and physical examination



Figure 97.2 A painless penile chancre, seen here, is the clinical manifestation of primary syphilis.



Congenital syphilis ▪ Presents with vesicular/bullous rash, rhinitis, hepatosplenomegaly, jaundice, and pseudoparalysis



DIAGNOSIS LAB RESULTS ▪ Identification of microbe ▪ Serum nontreponemal tests (may be nonreactive in late neurosyphilis) ▫ Venereal disease research laboratory (VDRL) ▫ Rapid plasma reagin (RPR)



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Figure 97.3 Condylomata lata, seen here, are the clinical manifestation of secondary syphilis.



Chapter 97 Spirochetes



TREATMENT MEDICATIONS ▪ Parenteral (IM/IV) penicillin G ▫ Doxycycline or tetracycline (PO); ceftriaxone (IM, IV) if penicillin allergy



OTHER INTERVENTIONS ▪ Treat partners ▪ Screening during first prenatal visit (VDRL or RPR)



OSMOSIS.ORG 547



NOTES



NOTES



STAPHYLOCOCCUS MICROBE OVERVIEW ▪ Staphylococcus: genus of Gram-positive bacteria responsible for many diseases ▪ Aerobic, facultative anaerobic ▪ Frequent skin colonization: up to half of population Genetic material ▪ All staphylococci are catalase-positive Taxonomy ▪ Staphylo-: cluster; -coccus: berry Morphology ▪ Organized in grape-like clusters ▪ Gram stain: round, Gram-positive (purple)



bacteria; thick peptidoglycan cell wall Antibiotic resistance mechanisms ▪ β-lactamase: hydrolysis of β-lactam antibiotics; some β-lactam antibiotics are resistant to the enzyme (e.g. oxacillin, nafcillin, flucloxacillin) ▪ mecA gene → penicillin binding protein (PBP2a) → reduced affinity for β-lactam antibiotics; present in methicillin-resistant strains ▪ vanA gene → modifies cell wall peptidoglycans → vancomycin cannot bind to bacteria



STAPHYLOCOCCUS AUREUS osms.it/staphylococcus-aureus PATHOLOGY & CAUSES ▪ Staphylococcus aureus: common bacterium, causes infections in most organ systems ▪ Aureus: golden colonies in mannitol salt agar, due to mannitol fermentation ▪ Skin colonization: approx. 30% of population ▫ Primary colonization site: nostrils ▪ Pathogen transmission: direct contact, fomites Virulence factors ▪ Cytolysins: alpha-toxin, Panton–Valentine leukocidin (PVL); both destroy neutrophils ▫ PVL related to severe skin, lung infections



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▪ Hemolysins: form pores in host cells (e.g. erythrocytes, macrophages, lymphocytes) ▪ Superantigens: enterotoxins, toxic shock syndrome toxin-1 (TSST-1) ▫ Superantigens stimulate activation of excessive amount of T-cells → increased production of cytokines → uncontrolled inflammation ▪ Epidermolytic toxins A and B: skin blistering ▪ Coagulase: activates prothrombin → coagulation ▪ Bacterial spread: protease degrades proteins; lipase degrades lipids ▪ Protein A: inactivates immunoglobulins → phagocytosis evasion ▪ Can form biofilms ▫ Biofilm: adherence of cells to polymer



Chapter 98 Staphylococcus surfaces (e.g. catheters) ▫ Properties allow immune evasion



CAUSES



▪ Common cause of infections and toxinmediated diseases acquired from community/healthcare environment ▫ Endocarditis, ocular infections, pneumonia, meningitis, osteomyelitis, septic arthritis, prosthetic device infections, catheter-associated infections



Skin/soft tissue infections ▪ E.g. surgical site infections, abscesses, impetigo, cellulitis, erysipela, fasciitis, mastitis Toxic shock syndrome (TSS) ▪ Mediated by toxic shock syndrome toxin-1; commonly caused by growth of S. aureus in vagina/surgical sites → multiple organ dysfunction Staphylococcal scalded-skin syndrome (Ritter disease) ▪ Mediated by epidermolytic toxins A and B Foodborne illness ▪ Caused by ingestion of S. aureus endotoxins



SIGNS & SYMPTOMS Skin/soft tissue infections ▪ Erythema, swelling, warmth, localized warmth/fever ▫ Staphylococcal scalded-skin syndrome (Ritter disease): fever, erythema, fluidfilled bullae on the skin → skin loss Systemic infections ▪ Joint pain, abdominal pain, headache, CVA tenderness, new onset heart murmur TSS ▪ Fever, hypotension, rash, coagulopathy, tissue necrosis (site of infection) Foodborne illness ▪ Nausea, vomiting, diarrhea, abdominal pain



DIAGNOSIS LAB RESULTS



▪ Culture-based observation ▫ Clustered golden Gram-positive cocci ▫ Catalase-positive; coagulase-positive ▪ Polymerase chain reaction (PCR) amplification ▪ May be guided by further studies depending on site of infection



RISK FACTORS



▪ Immunosuppression, IV drug use, recent invasive procedure, foreign material in body (e.g. prosthetics, catheters, sutures), dialysis



COMPLICATIONS



▪ Sepsis, bacteremia, invasive infection ▪ Antibiotic resistance: all strains resistant to penicillin G; some strains resistant to methicillin (MRSA) or vancomycin (VRSA); some strains have intermediate resistance to vancomycin (VISA) ▫ Resistant strains are common pathogens in nosocomial infections



Figure 98.1 Staphylococcus takes on a golden colour when cultured with mannitol containing media.



OSMOSIS.ORG 549



TREATMENT MEDICATIONS Topical antibiotics ▪ Superficial skin infections Oral/IV antibiotics ▪ Treatment based on the pathogen’s antibiotic susceptibility



▫ Oxacillin/nafcillin/cefazolin ▫ MRSA: vancomycin/trimethoprimsulfamethoxazole ▫ VRSA: linezolid



SURGERY



▪ Abscess drainage (if applicable) ▪ Foreign material removal in body (if applicable)



STAPHYLOCOCCUS EPIDERMIDIS osms.it/staphylococcus-epidermidis PATHOLOGY & CAUSES ▪ Staphylococcus epidermidis: bacteria commonly associated with infections of surgical sites, indwelling catheters, and prosthetic devices ▪ Part of skin and mucous membrane natural flora ▪ Does not produce exotoxins



CAUSES



▪ Skin/mucous colonization → barrier rupture → infection ▪ Can form biofilms on foreign materials in body; biofilm properties allow immune evasion ▪ Polymer surface adhesion → extracellular matrix production → polysaccharide intercellular adhesin (PIA) secretion → multi-layered bacteria ▪ Common S. epidermidis infections: catheter-associated infection, intravascular catheter infection, prosthetic joint infection, endocarditis (frequently associated with prosthetic valves), surgical site infection



RISK FACTORS



▪ Immunosuppression, neonates, recent invasive procedure, foreign material in the body (e.g. prosthetics, catheters), dialysis



550 OSMOSIS.ORG



COMPLICATIONS



▪ Sepsis, bacteremia ▪ Neonates: pneumonia, urinary tract infections, meningitis, enterocolitis, omphalitis



SIGNS & SYMPTOMS Local ▪ Pain, tenderness, swelling, warmth, erythema, drainage at incisional site Systemic ▪ Fever, hypotension, leukocytosis



DIAGNOSIS LAB RESULTS Culture-based observation ▪ Blood, urine, synovial fluid, surgical site ▫ Clustered Gram-positive cocci ▫ Catalase-positive; coagulase-negative; novobiocin-sensitive PCR amplification



Chapter 98 Staphylococcus



TREATMENT MEDICATIONS



SURGERY



▪ Remove foreign material from body (if applicable)



Oral antibiotics ▪ Empiric treatment: vancomycin ▪ If proven methicillin sensitivity: oxacillin/ nafcillin; may be combined with rifampicin, gentamicin ▪ Fusidic acid for skin infections (if available)



STAPHYLOCOCCUS SAPROPHYTICUS osms.it/staphylococcus-saprophyticus PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Staphylococcus saprophyticus: bacteria that commonly produces urinary tract infections (UTI) in young, biologicallyfemale individuals ▪ Frequently part of vagina’s natural flora ▪ Tropism for urinary tract: surface fibrillar protein (Ssp) and hemagglutinin/adhesin allow pathogen’s adherence to uroepithelial cells ▪ Does not produce exotoxins ▪ Etiologic agent: community-acquired UTIs (occasionally) ▪ Usually presents as symptomatic cystitis (bladder inflammation)



▪ Dysuria (painful urination), urinary urgency, increased urinary frequency, suprapubic pain, occasional hematuria



RISK FACTORS



DIAGNOSIS LAB RESULTS Urinalysis ▪ Presence of leukocytes, erythrocytes, bacteria, negative urine nitrate Culture-based observation ▪ Clustered Gram-positive cocci ▪ Catalase-positive; coagulase-negative; novobiocin-resistant



▪ Biologically-female (shorter urethra), recent sexual activity (“honeymoon cystitis”), diabetes, immunosuppression, indwelling urinary catheter



Quantitative PCR



COMPLICATIONS



MEDICATIONS



▪ Pyelonephritis



TREATMENT ▪ Oral antibiotics ▪ Symptomatic therapy (e.g. phenazopyridine)



OSMOSIS.ORG 551



NOTES



NOTES



STREPTOCOCCUS MICROBE OVERVIEW Morphology ▪ Spherical, Gram-positive bacteria; appear in chains/pairs; catalase, coagulase negative



▪ Produce extracellular substances (e.g. cytolysins, enzymes) → enhance pathogenicity



STREPTOCOCCUS AGALACTIAE (GROUP B STREP) osms.it/streptococcus-agalactiae PATHOLOGY & CAUSES ▪ AKA Group B Streptococcus (GBS) ▪ Encapsulated, facultative anaerobe ▪ Colonizes human genital, gastrointestinal (GI) tracts; upper respiratory tracts of young infants ▪ Beta-hemolytic ▫ Blood agar plates, hemolysins degrade lipid membranes → colonies surrounded by narrow zone of hemolyzed cells → complete (beta-)hemolysis Virulence factors ▪ Complex capsular polysaccharides ▫ Inhibit complement deposition on microbe surface components ▪ Hypervirulent GBS adhesin (HvgA) ▫ ↑ ability to invade blood-brain barrier ▪ Cluster of virulence responder/sensor (CovR/S) mutation ▫ Accelerate failure of amniotic barrier → ↑ ability to penetrate chorioamniotic membranes ▪ Pilins ▫ Act as adhesins → ↑ ability to invade central nervous system, form biofilm



552 OSMOSIS.ORG



▪ Direct cytotoxicity to host phagocytes Common infectious agent ▪ Adults (nonpregnant) ▫ Broad spectrum of infections ▪ Pregnant individuals ▫ Chorioamnionitis ▪ Neonates ▫ GBS infection, sepsis



RISK FACTORS



▪ Adults (nonpregnant) ▫ Chronic disease (e.g. diabetes, liver disease, malignancy; > age 65, esp. residents of nursing homes) ▪ Pregnancy ▪ Neonates ▫ Ascending infection from mother (e.g. rupture of membranes, chorioamnionitis) ▪ Hospitalization ▫ Nosocomial/hospital-acquired infections



Chapter 99 Streptococcus



COMPLICATIONS



▪ Cystitis, pyelonephritis, urethritis, prostatitis; osteomyelitis, septic arthritis; endocarditis; meningitis; pneumonia; sepsis; toxic shock-like syndrome ▪ Neonates ▫ Preterm birth, bacteremia, sepsis, pneumonia, meningitis, neonatal mortality



SIGNS & SYMPTOMS ▪ Fever, chills; malaise; cough ▪ Local tissue infection ▫ Red, warm, swollen, presence of drainage



▪ Hippurate hydrolysis test ▫ Detections hippurate hydrolysis by GBS



OTHER DIAGNOSTICS



▪ Clinical history, physical examination



TREATMENT MEDICATIONS



▪ Antibiotics (e.g. penicillin G, ampicillin)



OTHER INTERVENTIONS ▪ Prenatal screening



DIAGNOSIS LAB RESULTS Identification of microbe ▪ E.g. blood, cerebrospinal fluid ▪ Gram stain, characteristic morphology ▪ Culture ▫ Beta-hemolysis on blood agar ▪ CAMP test ▫ Identifies presence of CAMP factor ▪ Latex agglutination tests ▫ Detects antibodies produced in response to GBS



Figure 99.1 The three classes of streptococcus cultured on a blood agar plate. Alpha (left) shows partial hemolysis, beta (centre) shows complete hemolysis and gamma (right) shows no hemolysis.



STREPTOCOCCUS PNEUMONIAE osms.it/streptococcus-pneumoniae PATHOLOGY & CAUSES ▪ Causative agent for numerous clinical syndromes in children, older adults ▪ Alpha-hemolytic, lancet-shaped diplococci ▪ Lysis by bile (deoxycholate), optochin sensitive ▪ Fastidious; prefers 5% carbon dioxide ▪ Pyogenic



▪ Virulence factors ▫ Resistance to phagocytosis (conferred by 92 polysaccharide serotypes) ▫ Adherence proteins ▫ Biofilm formation ▫ Pneumolysin toxin ▪ Asymptomatic colonization → direct spread from site of colonization,hematogenous spread → clinical syndromes



OSMOSIS.ORG 553



▪ Typical infections caused by S. pneumoniae range from mucosal to invasive diseases ▫ Meningitis ▫ Otitis media ▫ Pneumococcal community-acquired pneumonia ▫ Sinusitis



RISK FACTORS ▪ Age (< 2, ≥ 65 years) ▪ Underlying disease (e.g. liver, kidney, heart, lung, diabetes, malignancies) ▪ Crowded conditions (e.g. daycare centers, military camps, prisons) ▪ Immunodeficiency (e.g. HIV, genetic immune defects, solid organ/bone transplant) ▪ Smoking, alcohol abuse



COMPLICATIONS



▪ Pneumococcal endocarditis, empyema, bacteremia, sepsis



SIGNS & SYMPTOMS ▪ Common clinical presentation ▫ Fever, altered mental status, malaise ▪ Typical findings related to clinical syndrome ▫ Meningitis: headache, neck stiffness ▫ Otitis media: ↓ tympanic membrane mobility/bulging membrane, otorrhea, pain ▫ Pneumonia: cough, bronchial breath sounds, rales ▫ Sinusitis: purulent rhinitis, mucous membrane edema, headache



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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infiltration, consolidation (pneumonia)



LAB RESULTS Identification of organism ▪ Gram-positive diplococci, positive culture, polymerase chain reaction (PCR) ▪ Urine antigen analysis (bacteremia)



OTHER DIAGNOSTICS



▪ Clinical history, physical examination



TREATMENT MEDICATIONS



▪ Antibiotics ▫ Pneumonia: beta-lactam antibiotic ▫ Otitis media: amoxicillin-clavulanate (children) ▫ Sinusitis: amoxicillin (amoxicillin– clavulanic acid may be preferable)



OTHER INTERVENTIONS Prevention ▪ Pneumococcal vaccine



Chapter 99 Streptococcus



STREPTOCOCCUS PYOGENES (GROUP A STREP) osms.it/streptococcus-pyogenes PATHOLOGY & CAUSES ▪ AKA Group A Streptococcus (GAS) ▪ Colonizes human skin, mucous membranes ▪ Cell-wall structure ▫ Peptidoglycan backbone + lipoteichoic acid components → structural stability ▪ Beta-hemolytic ▫ Blood agar plates, hemolysins degrade lipid membranes → colonies surrounded by clear zone of hemolyzed cells → complete (beta-) hemolysis ▪ Primarily infects skin, soft tissue Virulence factors ▪ Vary with specific strain ▪ M proteins ▫ Protect microbe from humoral immune surveillance, phagocytosis by polymorphonuclear leukocytes ▪ Binding proteins ▫ Bind to IgG, IgM, IgA → may interfere with complement activation ▫ Protein F: binds to fibronectin → ↑ adherence to epithelial surfaces ▪ Cytolysins ▫ Streptolysins: bind to cholesterol on eukaryotic cell membranes → cell lysis ▫ Hyaluronidase: hydrolyzes hyaluronic acid → facilitates infection spread ▫ Streptokinase: proteolytically converts bound plasminogen to active plasmin → cleavage of fibrin; medically useful as clot-busting drug ▫ Nicotinamide adenine dinucleotidase (NADase): exact function unclear; likely ↑ invasiveness ▫ Deoxyribonuclease: promotes production of anti-deoxyribonuclease (DNase) antibody following pharyngeal/ skin infections



▪ Pyrogenic exotoxins (type A, B, C) ▫ Induce fever, act as superantigens → T-cell proliferation → ↑ cytokine production → promotes shock ▪ Streptococcal inhibitor of complement (SIC) ▫ Inactivates complement membrane attack complex ▪ Opacity factor (OF) ▫ Lipoprotein lipase Causative agent in several disorders ▪ Pyogenic diseases ▫ Pharyngitis, cellulitis (abscess formation in dermis, subcutaneous fat layers), necrotizing fasciitis (progressive destruction of deep soft tissue), impetigo ▪ Toxigenic disease ▫ Scarlet fever, toxic shock syndrome, GAS endometritis (puerperal sepsis) ▪ Immunologic disease ▫ Rheumatic fever (antibodies against streptococcal cell cross-react with cardiac tissue); poststreptococcal glomerulonephritis (immune complexes deposited in glomeruli)



RISK FACTORS



▪ Susceptible host + encounter with streptococcus expressing specific virulence factors



COMPLICATIONS



▪ Local spread (e.g. otitis media, sinusitis, mastoiditis); tissue destruction; valvular, renal disease; sepsis, shock, multiorgan failure; disseminated intravascular coagulation; pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS)



OSMOSIS.ORG 555



DIAGNOSIS



SIGNS & SYMPTOMS ▪ Pharyngitis ▫ Acute onset of sore throat, fever, pharyngeal edema, patchy tonsillar exudates ▪ Cellulitis ▫ Erythema, edema, abscess formation ▪ Impetigo ▫ Papules, vesicles, pustules surrounded by erythema pustules → breaks down, forms crusts ▪ Scarlet fever ▫ Erythematous rash ▪ Toxic shock syndrome ▫ Shock, multiorgan failure ▪ GAS endometritis ▫ Postpartum fever, uterine tenderness



LAB RESULTS Identification of microbe ▪ Gram positive cocci ▪ Positive culture ▪ Blood studies ▫ Rapid antigen detection test (RADT) for GAS



OTHER DIAGNOSTICS



▪ Clinical history, physical examination



TREATMENT MEDICATIONS



▪ Antibiotics (e.g. penicillin G, clindamycin)



SURGERY



▪ Surgical debridement



STREPTOCOCCUS VIRIDANS osms.it/streptococcus-viridans infections (e.g. abdominal, central nervous system, lung, skin, soft tissue, sepsis) ▫ Abscess formation ▫ Viridans streptococcal shock syndrome



PATHOLOGY & CAUSES ▪ Heterogeneous collection of alpha/ nonhemolytic streptococci, cause variety of diseases ▪ Some species produce greenish color on blood agar plates ▪ Not bile soluble, optochin resistant ▪ Approx. 30 species classified into six groups ▪ Part of microbiome of oropharynx, GI, genitourinary tract ▪ May be invasive, produce variety of diseases ▫ Dental caries, periodontal disease, maxillofacial infections, exudative pharyngitis, infective endocarditis ▫ Invades circulation → systemic



556 OSMOSIS.ORG



RISK FACTORS



Immunocompromised state Periodontal disease More common in children than adults Comorbidities (e.g. mucositis, cystic fibrosis, malignancies) ▪ Altered microbiome ▪ ▪ ▪ ▪



SIGNS & SYMPTOMS ▪ Clinical presentation varies widely depending on infection



Chapter 99 Streptococcus



DIAGNOSIS LAB RESULTS Identification of organism ▪ Gram-positive cocci, positive culture



OTHER DIAGNOSTICS



▪ Clinical history, physical examination



TREATMENT MEDICATIONS



▪ Antibiotics (depending on sensitivity, resistance) ▫ Penicillin + aminoglycoside; broadspectrum cephalosporin, vancomycin



SURGERY



▪ Abscess debridement/drainage



OSMOSIS.ORG 557



NOTES



NOTES



SYSTEMIC MYCOSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES



DIAGNOSIS



▪ Fungal infections in internal organs (esp. lungs)



DIAGNOSTIC IMAGING



CAUSES



LAB RESULTS



▪ Dimorphic species of fungi ▪ Transmitted by spore inhalation; lymphohematogenous dissemination



SIGNS & SYMPTOMS



▪ X-ray, CT scan, MRI



▪ Culture-based observation, direct microscopy, serologic tests, lab tests (e.g. abnormal blood exams)



TREATMENT MEDICATIONS



▪ Cough, chest pain, fever



▪ Antifungal agents



BLASTOMYCES SPP. osms.it/blastomyces PATHOLOGY & CAUSES ▪ Blastomycosis ▫ Systemic fungal infection caused by Blastomyces dermatitidis, B. gilchristii; usually manifests as chronic pneumonia ▪ Incubation period: 3–6 weeks ▪ Spore inhalation → conversion to yeast in lungs → phagocytosis by macrophages → acute suppurative inflammation ▪ Immune response: mainly cellular, mediated by T-lymphocytes, macrophages ▪ Common sites of infection: primarily lungs (90%); skin, bones, genitourinary tract, central nervous system (CNS)



558 OSMOSIS.ORG



Blastomyces spp. ▪ Size: 8–15μm ▪ Broad-based budding (wide connection between two cells before splitting apart during reproduction) ▪ Thermal dimorphism ▫ Mold form (< 37°C/98.6°F): produces spores ▫ Yeast form (37°C/98.6°F): multinucleate; antiphagocytic (e.g. thick cell wall) ▪ Virulence ▫ Thick cell wall: resistance to phagocytosis ▫ BAD-1: cell surface glycoprotein; adhesin ▫ Binds yeast to extracellular matrix, macrophages



Chapter 100 Systemic Mycoses ▫ Blocks production of tumor necrosis factor (TNF) alpha (proinflammatory cytokine) Clinical syndromes ▪ Pulmonary blastomycosis ▫ Pneumonia, mostly chronic ▫ Frequently affects upper lobes ▪ Primary cutaneous blastomycosis ▫ Ulcerative/verrucous skin lesions ▪ Disseminated blastomycosis ▫ Osteomyelitis; prostatitis, epididymoorchitis (inflammation of epididymis/ testicles); meningitis; intracranial abscesses



RISK FACTORS



Outdoor occupations (e.g. farming) Recreational exposure to soil Immunosuppression High prevalence in North America Recent travel to endemic areas (e.g. Ohio, Mississippi river valleys) ▪ Comorbid conditions ▪ ▪ ▪ ▪ ▪



COMPLICATIONS



LAB RESULTS Culture-based observation ▪ tissue, sputum, body fluids ▫ Sabouraud dextrose agar without cycloheximide ▫ Confirmation requires conversion (mold → yeast) at 37°C/98.6°F Direct microscopic examination ▪ Periodic acid–Schiff stain ▪ Differentiation: size, yeast morphology Lab tests ▪ Anemia, leukocytosis, ↑ erythrocyte sedimentation rate Tissue biopsy ▪ Pyogranulomatous response ▪ Skin ▫ Epithelial hyperplasia, intraepidermal abscesses, multinucleated cells ▪ Fungus observation Serologic tests ▪ Polymerase chain reaction (PCR) ▫ Antigen detection assays



▪ Acute respiratory distress, multiorgan disease, chronicity



SIGNS & SYMPTOMS ▪ Cough, fever, weight loss, sputum production, dyspnea, night sweats, chills, hemoptysis, arthralgia, soft tissue swelling ▪ Verrucous skin lesions with irregular borders, ulcerative skin lesions



DIAGNOSIS



TREATMENT MEDICATIONS



▪ Antifungal treatment ▪ Amphotericin B; followed by azole ▫ Liposomal amphotericin B: CNS infections



SURGERY



▪ Resection of abscesses, devitalized bone, empyemas, pericardial effusion



DIAGNOSTIC IMAGING X-ray ▪ Pneumonia ▫ Lobar consolidation, alveolar infiltrates, fibronodular infiltrates, cavitation, nodules, pleural effusion ▪ Osteomyelitis ▫ Well-defined, osteolytic bone lesions



OSMOSIS.ORG 559



COCCIDIOIDES SPP. osms.it/coccidioides ▫ Metalloproteinase: inhibits phagocytosis ▫ Alteration of pulmonary surfactant proteins



PATHOLOGY & CAUSES ▪ Coccidioidomycosis ▫ Systemic fungal infection caused by Coccidioides immitis, C. posadasii; usually manifests as acute pneumonia ▪ AKA San Joaquin Valley Fever/“desert rheumatism” (associated with arthralgia) ▪ Arthroconidium inhalation → conversion to spherules → activation of T-lymphocytes → production of cytokines → inflammation → acute pneumonia ▫ In infected tissue, spherules grow, septate → release endospores → infection spreads ▪ Immune response ▫ Mainly mediated by Th1 cells ▫ Interleukin 17, TNF alpha, interferongamma ▪ Incubation period: 1–4 weeks ▪ Common sites of infection: lungs, skin, bones, CNS ▪ High prevalence areas: arid, dry regions in U.S. (e.g. California, Southwest), Mexico, Central America, South America Coccidioides spp. ▪ Size: 20–70μm ▪ Dimorphism ▫ Mold form: found in soil ▫ Yeast form: parasitic ▪ Produces arthroconidia (barrel-shaped, multinucleated spores) ▫ Production stimulated by human sex hormones ▫ Arthroconidia convert to spherules (2–5μm; in infected tissues) ▪ Infectious particles: arthroconidia ▪ Virulence ▫ Enzyme with elastase activity: ↑ infection, inflammation ▫ Cell surface glycoprotein with adhesin activity



560 OSMOSIS.ORG



Clinical syndromes ▪ Acute pneumonia ▪ Dermatologic lesions ▫ Wart-like lesions on face ▫ Erythema nodosum/multiforme ▪ Osteomyelitis ▪ Meningitis



RISK FACTORS



▪ Outdoor occupations; recreational exposure to soil (e.g. gardening, camping); immunosuppression; recent travel to endemic areas; comorbid conditions



COMPLICATIONS



▪ Adult respiratory distress syndrome; fatal multilobar pneumonia; pyopneumothorax; meningitis; chronicity



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



Mostly mild/asymptomatic Non-specific: fever, malaise Cough, pleuritic pain, hemoptysis, arthralgia Erythema nodosum/multiforme Wart-like lesions on face (e.g. nasolabial folds)



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Pneumonia ▫ Parenchymal infiltrates, thin-walled cavities ▪ Osteomyelitis ▫ Osteolytic bone lesions



Chapter 100 Systemic Mycoses



LAB RESULTS



TREATMENT



▪ Culture-based observation



Serologic tests ▪ IgM, IgG antibody detection (e.g. enzyme immunoassays) ▪ Antigen detection Direct microscopic observation ▪ Spherules in sputum, blood, body fluid samples Lab tests ▪ ↑ erythrocyte sedimentation rate ▪ Eosinophilia (mostly with dissemination)



MEDICATIONS High risk of dissemination ▪ E.g. immunosuppression, pregnancy ▫ azoles Severe ▪ Amphotericin B



SURGERY



▪ Debridement of abscesses, devitalized bone, pyopneumothorax



Extrathoracic tissue biopsy ▪ Essential for diagnosis of Coccidioides dissemination ▪ Pyogranulomatous inflammation ▪ Presence of spherules Spherulin skin test ▪ Positive after resolution; not available in U.S.



Figure 100.1 Numerous spores in the lungs of an individual with coccidioidomycosis.



OSMOSIS.ORG 561



HISTOPLASMA CAPSULATUM osms.it/histoplasma-capsulatum PATHOLOGY & CAUSES ▪ Histoplasmosis ▫ Systemic fungal infection caused by Histoplasma capsulatum; usually manifests as acute pneumonia ▪ Most frequent systemic mycoses in U.S. ▪ Microconidia inhalation → conversion to yeast form → macrophage phagocytosis → inflammation → pneumonia ▪ Immune response: mainly cellular, mediated by T-lymphocytes, macrophages, TNF alpha, interferon-gamma ▪ Infection sites: primarily lungs; may disseminate to other organs Histoplasma capsulatum ▪ Size: 2–3μm x 3–4μm ▪ Thermal dimorphism ▫ Mold form (< 35°C/95°F); produces microconidia (spores, 2–5μm) ▫ Yeast form (37°C/98.6°F) ▪ Infectious particles: microconidia ▪ Bird, bat fecal material promotes growth Pulmonary histoplasmosis clinical syndromes ▪ Pneumonia: acute (diffuse/localized); chronic ▪ Broncholithiasis Disseminated histoplasmosis clinical syndromes ▪ Progressive disseminated histoplasmosis: excessive reticuloendothelial infection ▪ Adrenal perivasculitis (common) ▪ Endocarditis ▪ Mediastinal granuloma ▪ Mediastinitis ▪ Meningitis ▪ Ocular histoplasmosis (e.g. retinal lesions) ▪ Lesions: intestinal (e.g. ulcers, polyps), skin (e.g. dermatitis, papules)



562 OSMOSIS.ORG



RISK FACTORS



▪ Outdoor occupations (e.g. construction, excavation) ▪ Outdoor activities (e.g. camping) ▪ Immunosuppression ▪ High prevalence regions: U.S. (Ohio, Mississippi river valleys), Mexico, Central America, South America ▪ Recent travel to endemic areas ▪ Comorbid conditions ▪ Extremes of age



COMPLICATIONS



▪ Fatal acute diffuse pneumonia, mediastinal granuloma, mediastinitis, chylothorax, pleural effusion



SIGNS & SYMPTOMS ▪ Mostly asymptomatic Acute pulmonary histoplasmosis ▪ Systemic ▫ Fever, headaches, fatigue ▪ Chest pain (pleuritic/substernal), dry cough, myalgia, arthralgia, erythema nodosum/ multiforme Chronic pulmonary histoplasmosis ▪ Systemic ▫ Fever, fatigue, night sweats, weight loss ▪ Productive cough, hemoptysis, dyspnea ▪ Consolidation: dullness to percussion, crackles



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Hilar/mediastinal lymphadenopathy, patchy/ nodular pulmonary infiltrates, occasional cavitation



Chapter 100 Systemic Mycoses



LAB RESULTS



▪ Culture-based observation ▪ Direct microscopic observation



Serologic tests ▪ Antibody detection (e.g. immunodiffusion, complement fixation assays) ▪ Antigen detection in urine, sputum, body fluids (e.g. enzyme immunoassays) Lab tests ▪ Anemia, ↑ erythrocyte sedimentation rate, progressive disseminated histoplasmosis (e.g. pancytopenia) Tissue biopsy ▪ Granulomas, lymphohistiocytic aggregates, mononuclear cell infiltrates, fungi visualization



TREATMENT



Figure 100.2 Grocott methenamine silver stain highlights spores in the lung tissue of an immunocompromised individual with histoplasmosis.



MEDICATIONS



▪ Progressive disseminated/prolonged/severe pulmonary histoplasmosis ▫ Corticosteroids: ↓ inflammation ▫ Antifungal treatment: amphotericin B, azoles



PARACOCCIDIOIDES BRASILIENSIS osms.it/paracoccidioides-brasilienses PATHOLOGY & CAUSES ▪ Paracoccidioidomycosis ▫ Systemic fungal infection caused by Paracoccidioides brasiliensis, P. lutzii; usually manifests as chronic lung disease ▪ AKA South American blastomycosis ▪ Spore inhalation → conversion to yeast form in lungs → phagocytosis by macrophages → inflammation → pneumonia ▪ Immune response: mostly cell-mediated ▪ Common sites of infection: mainly lungs;



oral mucosa, skin, adrenal glands, CNS Paracoccidioides spp. ▪ Size: 4–40μm ▪ Thermal dimorphism ▫ Mold form (22–26°C/71.6–78.8°F): present in soil ▫ Yeast form (37°C/98.6°F): “pilot’s wheel” appearance ▪ Stimulated by sex hormones Clinical syndromes ▪ Acute/subacute paracoccidioidomycosis ( juvenile) ▫ Hepatosplenomegaly,



OSMOSIS.ORG 563



lymphadenopathy, skin lesions, pulmonary manifestations (rare) ▪ Chronic paracoccidioidomycosis (adult) ▫ Progressive pulmonary fibrosis (esp. lower lobes), ulcers (mouth, larynx); adrenal involvement



RISK FACTORS



▪ High prevalence regions: Central, South America (80% in Brazil) ▪ Outdoor occupations ▪ Outdoor activities: contact with soil ▪ More common in individuals who are biologically male ▪ Immunosuppression



COMPLICATIONS



▪ Bone marrow, adrenal dysfunction; chronic respiratory failure



SIGNS & SYMPTOMS ▪ Generally asymptomatic (95%) ▪ Non-specific symptoms: fever, weight loss ▪ Cough, dyspnea, hepatosplenomegaly, lymphadenopathies, odynophagia, sialorrhea, skin lesions (ulcers, nodules) ▪ Compressive manifestations: jaundice (bile duct obstruction)



DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Acute/subacute paracoccidioidomycosis ▫ Lymph node enlargement ▪ Chronic paracoccidioidomycosis ▫ Pulmonary disease: alveolar/interstitial infiltrates, consolidation, masses/ nodules, cavitation ▫ CNS disease: ring enhancing lesions ▫ Articular disease: effusion, erosions, space narrowing



LAB RESULTS



▪ Direct microscopic observation ▪ Culture-based observation



564 OSMOSIS.ORG



Figure 100.3 A child with numerous lesions on the face caused by Coccidioidomycosis brasiliensis. Serologic tests ▪ Detection of antibodies through immunodiffusion



TREATMENT MEDICATIONS



▪ Antifungal treatment: azoles ▪ Trimethoprim-sulfamethoxazole



NOTES



NOTES



TOGAVIRUSES MICROBE OVERVIEW ▪ Pathogenic viruses in Togaviridae family ▪ Capsid symmetry: icosahedral ▪ RNA structure: linear, positive polarity



EASTERN EQUINE ENCEPHALITIS VIRUS (EEEV) osms.it/eastern-equine-encephalitis PATHOLOGY & CAUSES ▪ Highly pathogenic; causes central nervous system illness in humans, horses (equines) ▪ Genus: Alphavirus ▪ Spherical, approx. 69nm diameter (including glycoprotein spikes) ▪ Enveloped, single-stranded, positive-sense RNA genome ▪ Glycoproteins associated with neurovirulence, cellular apoptosis ▪ Potential bioterrorism agent use (aerosol route) ▪ Range ▫ Atlantic, Gulf-coast states in eastern USA ▪ Four lineages ▫ Group I: endemic in North America, Caribbean (causes most human disease) ▫ Groups IIA, IIB, III: primarily cause equine illness in Central, South America ▪ Viral life-cycle: wild birds, Culiseta melanura mosquito (enzootic vector) ▫ C. melanura rarely bites humans ▫ Human transmission requires other mosquito species (e.g. Aedes,



Coquillettidia, Culex) to bridge between infected birds, humans ▫ Infected mosquito bite → 4–10 day incubation period → prodromal period → neurological symptom development occurs rarely



RISK FACTORS



▪ Rural residence; living in/visiting woodland habitats, swampy areas ▪ Outdoor occupation/recreational activity



COMPLICATIONS



▪ Encephalitis; cerebral edema; coma; residual brain damage (mild–severe, esp. young children); death (some)



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Prodromal period: high fever, headache, nausea, vomiting ▪ Neurologic presentation: cranial nerve palsy, seizure, stupor → coma ▪ Infants: fever, bulging fontanel, generalized flaccid/spastic paralysis



OSMOSIS.ORG 565



DIAGNOSIS



TREATMENT



DIAGNOSTIC IMAGING



▪ No specific treatment



MRI ▪ Focal lesions in basal ganglia, thalamus, brainstem



MEDICATIONS



LAB RESULTS



▪ Leukocytosis; left shift ▪ Hyponatremia ▪ Serology ▫ IgM antibody presence ▪ Cerebrospinal fluid (CSF) examination ▪ Lymphocytic pleocytosis, ↑ neutrophils; ↑ protein; IgM antibodies (assay); virus isolation



▪ Supportive: anticonvulsants, corticosteroids (↓ inflammation)



OTHER INTERVENTIONS



▪ Supportive: IV fluid, respiratory support, monitor intracranial pressure ▪ Prevention ▫ Insect repellent (DEET, picaridin, IR3535, oil of lemon eucalyptus) ▫ Protective clothing ▫ Vector control



OTHER DIAGNOSTICS Electroencephalography (EEG) ▪ Generalized slowing; disorganized pattern



RUBELLA VIRUS osms.it/rubella-virus PATHOLOGY & CAUSES ▪ Highly communicable virus → German measles ▪ Enveloped, positive-sense, single-stranded RNA virus ▪ Family: Togaviridae ▪ Genus: Rubivirus ▪ Three structural proteins ▫ C: capsid protein surrounding virion RNA ▫ E1, E2: glycosylated proteins forming transmembrane antigenic sites ▪ Humans are the only natural hosts ▪ Transmission: droplet inhalation/direct contact with infectious nasopharyngeal secretion ▪ Viral contact → 12–23 day incubation → nasopharyngeal cell, regional lymph



566 OSMOSIS.ORG



node viral replication → viremia → maculopapular rash eruption → rash resolution (approx. two days) ▫ Contagious via virus shedding before, after rash appears ▫ ↑ contagiousness during rash eruption ▪ Spreads transplacentally



RISK FACTORS



▪ Unvaccinated ▪ Travel (especially abroad) ▪ Contact with febrile rash individuals



COMPLICATIONS



▪ Thrombocytopenic purpura ▪ Encephalitis (rare) ▪ If infected during pregnancy: congenital rubella syndrome (CRS)



Chapter 101 Togaviruses ▫ ↑ risk of miscarriage, fetal death, stillbirth ▫ CRS: A ToRCHeS (see mnemonic) infection; ↑ first trimester risk; extramedullary hematopoiesis (“blueberry muffin” rash), cataract, heart defect, hearing impairment, intellectual disability



MNEMONIC: ToRCHeS



Perinatal infections passed from mother to child Toxoplasmosis, toxoplasma gondii Other infections Rubella Cytomegalovirus Herpes Simplex virus-2/ neonatal herpes simplex



SIGNS & SYMPTOMS



▫ Reverse transcription-PCR (rubella virus RNA performed on amniotic fluid)



OTHER DIAGNOSTICS



▪ Clinical diagnosis ▪ High suspicion index ▫ Febrile rash, unvaccinated status



TREATMENT ▪ No specific antiviral therapy



OTHER INTERVENTIONS



▪ Infection control measures ▫ Prompt isolation for seven days after rash development ▪ Vaccine: live-attenuated measles-mumpsrubella (MMR)/measles-mumps-rubellavaricella (MMRV) ▫ First dose: 12–15 months old ▫ Second dose: 4–6 years old



▪ Maculopapular rash ▫ Pink/light red macules: coalesce to form evenly-colored desquamating rash ▫ Initially: face → generalized rash within 24 hours ▫ Duration: three days ▪ Lymphadenopathy; primarily posterior auricular/suboccipital lymph ▪ Low-grade fever ▪ Mild nonexudative conjunctivitis ▪ Forchheimer spots on soft palate ▪ Arthralgias ▪ Orchitis ▪ Asymptomatic (half of cases)



DIAGNOSIS LAB RESULTS



▪ Polymerase chain reaction (PCR) testing/ molecular typing ▫ Throat, nasal, urine specimens ▪ Serologic testing ▫ Enzyme immunoassay (EIA) detects rubella-specific IgM antibodies ▪ Pregnancy



Figure 101.1 A child with rubella showing a characteristic maculopapular, erythematous rash.



OSMOSIS.ORG 567



WESTERN EQUINE ENCEPHALITIS VIRUS (WEE) osms.it/western-equine-encephalitis PATHOLOGY & CAUSES ▪ Causes central nervous system illness in humans, horses (equines) ▪ Genus Alphavirus ▪ Spherical, approx. 69nm diameter (including glycoprotein spikes) ▪ Enveloped, single-stranded, positive-sense RNA genome ▪ Contain glycoproteins associated with neurovirulence, cellular apoptosis ▪ Range: most commonly US states, Canadian provinces west of Mississippi River ▪ Virus life-cycle: wild birds, other vertebrates, Culex tarsalis mosquito (enzootic vector) ▫ Culex tarsalis (another human vector) ▪ Potential bioterrorism agent use (aerosol route) ▪ Infected mosquito bite → 2–10 day incubation period → sudden onset of severe headache, fever/chills, dizziness, chills, myalgias, malaise, tremor, irritability, photophobia, neck stiffness → rapid neurological manifestation development → recovery ▫ Most adults: no residual neurological effects ▫ Infants, children: ↑ long-term neurologic sequelae risk



RISK FACTORS



▪ Most cases June–September ▪ Bimodal age pattern: < one year; ↑ risk in elderly ▪ Biologically-female ▪ Rural residence ▪ Outdoor occupation/recreational activity



568 OSMOSIS.ORG



COMPLICATIONS



▪ Encephalitis, coma, respiratory failure, death ▪ Infants: intellectual disability, cerebellar damage, spastic paralysis, developmental delay



SIGNS & SYMPTOMS ▪ Neurological manifestations ▫ Generalized weakness; somnolence; hand, tongue, lip tremor; cranial nerve palsy; motor weakness; ↓ deep tendon reflexes ▪ Infants: poor feeding, fussiness, fever, vomiting, tense/bulging fontanelle



DIAGNOSIS LAB RESULTS



▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA): IgM antibodies ▫ Hemagglutination-inhibition, neutralizing antibody presence ▪ CSF ▫ ELISA: IgM antibodies ▫ Lymphocytic pleocytosis ▫ ↑ protein



TREATMENT ▪ No specific treatment



MEDICATIONS



▪ Supportive: anticonvulsants, corticosteroids



Chapter 101 Togaviruses



OTHER INTERVENTIONS Prevention ▪ Insect repellent (DEET, picaridin, IR3535, oil of lemon eucalyptus) ▪ Protective clothing ▪ Vector control



OSMOSIS.ORG 569



NOTES



NOTES



TREMATODES (FLATWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA flukes; parasitic flatworm; infects internal organs ▪ Phylum: Platyhelminthes Characteristics ▪ Adult morphology: flattened oval/elongated ▪ Structures ▫ Tegmentum (outer body covering) ▫ Ventral, oral suckers ▫ Pharynx → esophagus → caeca ▫ Testes, uterus/ovary (hermaphrodites) ▪ Eggs generally operculated (lidded); except schistosomes ▪ Obligate parasites of mollusks, vertebrates Development 1. Egg 2. Miracidium (ciliated, lacks mouth; infects first intermediate host) 3. Sporocyst (elongated sac, produces rediae) 4. Redia (larval stage with oral sucker) 5. Cercaria (larval stage; may be infectant) 6. Metacercaria (encysted cercaria) 7. Adult



SIGNS & SYMPTOMS ▪ See individual trematodes



570 OSMOSIS.ORG



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Medical imaging (e.g. ultrasound, CT scan, MRI)



LAB RESULTS ▪ E.g. blood tests ▪ Direct microscopy



OTHER DIAGNOSTICS ▪ Serologic tests



TREATMENT MEDICATIONS ▪ Anthelmintic



Chapter 102 Trematodes (Flatworms)



CLONORCHIS SINENSIS osms.it/clonorchis-sinensis PATHOLOGY & CAUSES ▪ Parasitic fluke; invasion of biliary tree → liver infection ▪ AKA Chinese liver fluke ▪ Morphology ▫ Adult: flat, elongated body; 25 x 5mm ▫ Egg: oval-shaped; 30 x 15μm ▪ Intermediate hosts ▫ First: freshwater snail (e.g. Parafossarulus manchouricus) ▫ Second: freshwater fish/shrimp ▪ Reservoirs: cats, dogs ▪ Transmission ▫ Ingestion of raw/undercooked fish/ shrimp ▪ Infectious form: metacercariae ▫ Ingestion of metacercariae → excyst in duodenum → migration to biliary tract → inflammation, epithelial hyperplasia ▪ Endemic to Eastern Asia (e.g. China, Japan, Philippines, Vietnam)



RISK FACTORS ▪ Recent travel to endemic areas ▪ Consumption of raw/undercooked fish/ shrimp



COMPLICATIONS ▪ Pancreatitis, cholangitis, liver abscesses, cholangiocarcinoma



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, CT scan, MRI ▪ Enlarged gallbladder, hepatomegaly, bile duct inflammation, dilated/thickened intrahepatic bile ducts Endoscopy ▪ Visualization of adult organisms



LAB RESULTS ▪ Acute infection ▫ Eosinophilia, ↑ IgE ▪ Chronic infection ▫ ↑ alkaline phosphatase, ↑ bilirubin ▪ Direct microscopy ▫ Detection of Clonorchis eggs in stool samples ▫ Formalin ethyl-acetate concentration technique (FECT) → parasite separation from faeces ▪ Serologic tests ▫ E.g. ELISA ▪ Polymerase chain reaction (PCR)



TREATMENT MEDICATIONS ▪ Anthelmintic (e.g. praziquantel)



SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Acute infection: fatigue, right upper quadrant abdominal pain, indigestion, diarrhea, flatulence ▪ Chronic infection: fatigue, weight loss, abdominal discomfort, diarrhea, dyspepsia, jaundice (severe cases)



Figure 102.1 An adult Clonorchis sinensis worm.



OSMOSIS.ORG 571



PARAGONIMUS WESTERMANI osms.it/paragonimus-westermani PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Parasitic flatworm; causes pulmonary paragonimiasis ▪ AKA Japanese lung fluke ▪ Morphology ▫ Adult: oval-shaped body with spines; 15 x 8mm ▫ Egg: oval-shaped, thick shell; 100 x 55μm ▪ Intermediate hosts ▫ First: freshwater snails (e.g. Semisulcospira spp.) ▫ Second: crustaceans (e.g. crabs, crayfish) ▪ Transmission ▫ Ingestion of raw/undercooked crustaceans (e.g. crab, crayfish) ▪ Infectious form: metacercariae ▫ Ingestion of metacercariae → excyst in duodenum → penetration of peritoneal wall → migration to lungs → encapsulate, mature → inflammation, fibrosis ▪ Endemic to Eastern Asia (e.g. China, Japan, Philippines, Vietnam)



Pulmonary ▪ Early infection ▫ Systemic: fever, malaise ▫ Pulmonary: dyspnea, cough, pleuritic pain ▫ Gastrointestinal: diarrhea, epigastric pain ▪ Late infection ▫ Malaise ▫ Recurrent, chocolate-colored hemoptysis



RISK FACTORS



X-ray, CT scan, MRI ▪ Brain ▫ Skull X-ray: soap-bubble calcifications; calcified cysts ▫ CT/MRI: grape clusters; conglomerated, cystic lesions ▪ Lungs ▫ Pleural effusion, parenchymal cysts/ nodules, cavitary lesions, parasite migration tracts



▪ Poor sanitary conditions ▪ Seafood consumption in endemic areas



COMPLICATIONS ▪ Meningitis, encephalitis, seizures



572 OSMOSIS.ORG



Extrapulmonary ▪ Cerebral: headache, fever, vomiting, seizures, papilledema, paresis/paresthesias, visual disturbances (e.g. diplopia) ▪ Abdominal: nausea/vomiting, hematoquezia (bloody stool), pain, hematuria ▪ Subcutaneous: tender, firm, painless, mobile nodules



DIAGNOSIS DIAGNOSTIC IMAGING



Chapter 102 Trematodes (Flatworms)



LAB RESULTS ▪ Eosinophilia, ↑ IgE ▪ Direct microscopy ▫ Detection of eggs in stool, sputum, bronchoalveolar lavage ▪ Serologic tests ▫ Enzyme-linked immunosorbent assay (ELISA), immunoblot



TREATMENT MEDICATIONS ▪ Anthelmintic (e.g. praziquantel, triclabendazole)



SCHISTOSOMES osms.it/schistosomes PATHOLOGY & CAUSES ▪ Blood flukes; parasitize mesenteric veins/ vesical venous plexus → gastrointestinal/ genitourinary tract infections ▪ AKA bilharziasis/snail fever ▪ Morphology ▫ Adult: elongated body, 1–2cm/0.39– 0.79in ▫ Eggs: not operculated ▪ Intermediate host ▫ Snails ▪ Transmission ▫ Contaminated freshwater contact ▪ Infectious form: cercariae ▫ Contact with cercariae in fresh water → skin penetration → schistosomulae → migration to liver through circulation → adult form → migration to mesenteric venules/vesical venous plexus → egg deposits → inflammation → fibrosis ▪ High-prevalence area is sub-Saharan Africa



RISK FACTORS ▪ More common in individuals who are biologically male, rural areas ▪ Recent contact with fresh water bodies in endemic areas



COMPLICATIONS ▪ Bacteremia, infertility, intestinal obstruction, nephrotic syndrome, renal failure, cardiomegaly, acute myelopathy



Figure 102.2 A scanning electron micrograph of a S. japonicum flatworm.



SIGNS & SYMPTOMS Acute infection ▪ Swimmer’s itch ▫ Pruritic papular/urticarial rash, esp. legs/ feet ▪ Acute schistosomiasis syndrome/Katayama fever ▫ Non-specific symptoms (fever, urticaria, chills, arthralgia, myalgia, headaches) ▫ Angioedema, dry cough, abdominal pain, diarrhea Chronic infection ▪ Intestinal: abdominal pain, poor appetite, diarrhea ▪ Hepatosplenic: hepatosplenomegaly, portal



OSMOSIS.ORG 573



hypertension (e.g. collateral circulation, gastrointestinal bleeding, ascites) ▪ Pulmonary: dyspnea; pulmonary hypertension → cor pulmonale (enlarged right cardiac chambers) ▪ Urogenital: hematuria, pyuria, dysuria, increased urinary frequency ▪ Neuroschistosomiasis (acute myelopathy): seizures, sensory/motor impairment, cerebellar syndrome (incoordination)



prednisone) ▪ Manageme pruritus (e.g. antihistamines)



OTHER INTERVENTIONS ▪ Prevention ▫ Water sanitation programs ▫ Mass therapy ▫ Control of snails (e.g. molluscicides)



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan, MRI, abdominal ultrasound ▪ Brain: contrast-enhancing infiltrates ▪ Bladder: wall irregularities/fibrosis ▪ Liver: widened periportal space, periportal fibrosis, collateral pathways ▪ Lungs: patchy infiltrates, miliary nodules ▪ Spinal cord: radicular thickening, intramyelinic lesions



LAB RESULTS



Figure 102.3 Calcified eggs of the flatworm Schistosoma japonicum in the submucosa of the colon of an individual previously treated for schistosomiasis.



▪ Bladder/rectum biopsy ▫ Egg-filled granulomas in mucosa ▪ Direct microscopy ▫ Detection of eggs in stool/urine samples ▫ Kato–Katz method (thick smear) ▫ FLOTAC stool concentration method ▪ Lab tests ▫ Acute infection: eosinophilia ▫ Chronic infections: anemia ▫ Portal hypertension: thrombocytopenia (splenic sequestration) ▫ Urogenital infection: hematuria/ leukocyturia in urinalysis ▪ Serologic testings ▫ E.g. ELISA, indirect hemagglutination



TREATMENT MEDICATIONS ▪ Anthelmintic (e.g. praziquantel, oxamniquine) ▪ Corticosteroids (e.g. prednisolone,



574 OSMOSIS.ORG



Figure 102.4 A CT scan of the abdomen and pelvis demonstrating calcification of the bladder secondary to schistosomiasis.



Chapter 102 Trematodes (Flatworms)



OSMOSIS.ORG 575



NOTES



NOTES



TRICHOMONA MICROBE OVERVIEW ▪ Trichomonas vaginalis: pear-shaped (pyriform), flagellated protozoa; infects genitourinary tract ▪ Causative agent of trichomoniasis (trich), common sexually transmitted disease (STD) Morphology ▪ Size ▫ 9 x 7 micrometers ▪ Motile via four flagella, undulating membrane



▪ Rigid axostyle runs through cell from anterior to posterior end ▪ Contains hydrogenosomes (unique energyproducing organelles) Replication/Multiplication ▪ Humans only host ▫ Does not survive well in external environments ▫ Multiplies when vaginal pH basic ▫ Incubation period: 5–28 days ▫ No cyst stage



TRICHOMONAS VAGINALIS osms.it/trichomonas-vaginalis PATHOLOGY & CAUSES ▪ Resides in lower genital tract of individuals who are biologically female; urethra, prostate of individuals who are biologically male → trophozoite stage (infective stage) → transmitted sexually → infects squamous epithelium of lower genital tract → replicates by longitudinal binary fission → inflammatory response



RISK FACTORS ▪ Sexual activity with infected partner ▪ Multiple sexual partners ▪ More common in individuals who are biologically female



COMPLICATIONS ▪ ↑ risk of contracting HIV due to genital inflammation



576 OSMOSIS.ORG



▪ Pregnancy ▫ ↑ risk of premature rupture of membranes, preterm delivery, low birth weight ▪ Urethritis, cystitis



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Individuals who are biologically female ▫ Watery, foul-smelling vaginal discharge; burning; pruritus; dysuria, urinary frequency; lower abdominal pain; dyspareunia; vulvar, vaginal erythema ▪ Individuals who are biologically male ▫ Urethral discharge; pruritus; burning after urination/ ejaculation



Chapter 103 Trichomona



DIAGNOSIS LAB RESULTS Microbe identification ▪ Saline microscopy (wet mount of genital secretions) ▫ Characteristic organism ▫ ↑ polymorphonuclear leukocytes ▪ ↑ vaginal pH (> 4.5) ▪ T. vaginalis assay ▫ Detects species-specific ribonucleic acid (RNA); vaginal swab/urine specimen ▪ Nucleic acid amplification testing (NAAT) ▪ Trichomonas rapid test



TREATMENT MEDICATIONS ▪ Systemic 5-nitroimidazole drugs (e.g. metronidazole, tinidazole) ▫ Treat both partners



OTHER INTERVENTIONS ▪ Rate of transmission decreased with consistent use of condoms, spermicidal agents (e.g. nonoxynol-9)



OTHER DIAGNOSTICS ▪ Speculum exam ▫ Punctate hemorrhages cervix (strawberry cervix)



OSMOSIS.ORG 577



NOTES



NOTES



TRYPANOSOMA GENERALLY, WHAT ARE THEY? DIAGNOSIS



PATHOLOGY & CAUSES ▪ Genus of flagellated parasitic protozoa Morphology ▪ Elongated body ▪ Flagellum: forms undulated membrane along body ▪ Kinetoplast: functions as mitochondrion Transmission ▪ Through vectors ▪ Incubation period: 1–2 weeks



▪ ▪ ▪ ▪



Direct microscopy Serologic testings Laboratory findings Additional diagnostic tests may be necessary (severity, infection sitedependent)



TREATMENT ▪ See individual pathogens



SIGNS & SYMPTOMS ▪ See individual pathogens



TRYPANOSOMA BRUCEI osms.it/trypanosoma-brucei PATHOLOGY & CAUSES ▪ Protozoan, extracellular parasite → African trypanosomiasis ▪ AKA “sleeping sickness” ▫ Neurologic alterations during meningoencephalitis stage (e.g. somnolence) Virulence factors ▪ Antigenic variation ▫ Changes variant surface glycoprotein (VSG) → immune response evasion ▪ ↑ interferon gamma → ↑ host T. brucei



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susceptibility (mechanism unknown) Morphologic forms (life-cycle) ▪ Epimastigote → procyclic trypomastigote (in tsetse fly midgut) → metacyclic trypomastigote (infectious form) Subspecies ▪ Trypanosoma brucei rhodesiense (acute, more severe disease course) ▪ Trypanosoma brucei gambiense (progressive, milder disease course) Reservoirs ▪ Domestic animals, lions, hyenas, antelopes



Chapter 104 Trypanosoma brucei Vector ▪ Male/female Glossina flies, AKA tsetse flies ▫ Ideal conditions: warm, humid climate (e.g. near river/lake); altitude < 1800m/5905ft Transmission ▪ Saliva inoculation via fly bite; vertical/ parenteral transmission very rare ▪ Endemic regions: sub-Saharan Africa; Democratic Republic of Congo (most cases) Pathogenesis ▪ Glossina bite → subcutaneous metacyclic trypomastigote inoculation → lymph vessels → bloodstream → ↑ tumor necrosis factor (TNF) alpha, interleukin 6 (IL-6), nitric oxide → ↑ capillary permeability → vasculitis → organ invasion, e.g. central nervous system (CNS) Disease stages ▪ Hemolymphatic (early) stage ▪ Meningoencephalitis (late) stage ▪ Symptom severity related to number of organisms in affected tissue (e.g. blood, CNS)



RISK FACTORS ▪ Recent endemic area travel ▪ Dense vegetation near human settlement



COMPLICATIONS ▪ Meningitis ▪ Myocarditis, heart failure ▪ Aspiration → bacterial pneumonia; associated with altered state of consciousness (meningoencephalitis stage)



SIGNS & SYMPTOMS Hemolymphatic stage ▪ Systemic symptoms ▫ Intermittent fever, headache, malaise, weakness, pruritus, rash ▪ Trypanosomal chancre ▫ Rubbery, painful, erythematous, wellcircumscribed lesion at fly bite site approx. one week post-inoculation



▪ Lymphadenopathy ▫ Winterbottom’s sign: enlarged mobile, soft posterior cervical triangle lymph nodes ▪ Hepatosplenomegaly ▪ Dyspnea ▪ Chest pain ▪ Altered thyroid function ▪ Impotence (biologically-male), amenorrhea (biologically-female) ▪ Pain, Kerandel sign (deep hyperesthesia) Meningoencephalitis stage ▪ AKA “Sleeping sickness” ▪ Cachexia ▪ Sleep disturbances (e.g. diurnal somnolence, nocturnal insomnia) ▪ Headaches ▪ Altered state of consciousness ▪ ↓ cognitive function ▪ Personality, behavioral change ▪ Muscle spasms, ataxia, tremor, flaccid paralysis, choreiform movements ▪ Psychiatric manifestations (e.g. psychosis)



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Cerebral ▫ May show multifocal white matter hyperintensity (indicates late-stage disease)



LAB RESULTS Serologic testings ▪ Card agglutination test for trypanosomiasis (CATT) ▫ Blood + drop of reagent with trypanosomal antigen ▪ Immunofluorescence ▪ Enzyme immunoassays Cerebrospinal fluid (CSF) examination ▪ Disease staging essential ▪ ↑ leukocytes ▪ ↑ proteins ▪ IgM/Trypanosoma presence



OSMOSIS.ORG 579



▪ Morula/Mott cells (pathognomonic) ▫ IgM-filled plasma cells Direct microscopy ▪ Organism observation in lymph node aspiration, bone marrow, CSF, blood (thin/ thick Giemsa-stained smears) Laboratory findings ▪ Hemolytic anemia; leukocytosis; thrombocytopenia; ↑ erythrocyte sedimentation rate; hypergammaglobulinemia; hypoalbuminemia, hypocomplementemia; ↑ C-reactive protein; coagulation abnormalities Histological observation ▪ Meningoencephalitis stage (CSF sample) ▫ Morula/Mott cells in white matter (pathognomonic), edema, microhemorrhages, perivascular proliferation



OTHER DIAGNOSTICS Electroencephalogram (EEG) ▪ Late stage: abnormal, slow delta waves



TREATMENT MEDICATIONS ▪ Antiprotozoal medication ▫ Hemolymphatic stage: pentamidine, suramin ▫ Meningoencephalitis stage: eflornithine, eflornithine + nifurtimox, melarsoprol



OTHER INTERVENTIONS ▪ Prevention ▫ Vector control, surveillance ▫ Protective clothing



TRYPANOSOMA CRUZI osms.it/trypanosoma-cruzi PATHOLOGY & CAUSES ▪ Protozoan, intracellular parasite ▫ Causes American trypanosomiasis, AKA Chagas disease ▪ Morphologic forms (life cycle) ▫ Amastigote (intracellular, no flagellum) → epimastigote (in triatomine midgut) → trypomastigote (infectious form) ▪ Reservoirs ▫ Opossums, armadillos, canines ▪ Vectors ▫ Triatomine bugs (“kissing bugs”) ▫ Common species: Rhodnius prolixus, Triatoma dimidiata, Triatoma infestans ▫ Characteristics: size (2–3cm/0.79– 1.18in); obligated hematogenous; feeds at night; lives in dark, warm sites (e.g. closets, thatched roofs)



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Transmission ▪ Triatomine bite → fecal wound contamination ▪ Contaminated food/water ingestion (infection through mucous membranes) ▪ Parenteral (e.g. blood transfusion, sharing syringes) ▪ Vertical (mother → fetus) Endemic regions ▪ Rural areas of southern U.S., Latin America Pathogenesis ▪ T. cruzi trypomastigote inoculation → bloodstream → organ invasion (heart, enteric nervous system) → interstitial inflammation → tissue destruction → fibrosis Disease stages ▪ Acute phase: 8–12 weeks ▪ Indeterminate phase: decades



Chapter 104 Trypanosoma brucei ▪ Chronic phase: cardiac/gastrointestinal disease



RISK FACTORS ▪ Recent endemic area travel, immunosuppression, blood transfusion, organ transplant, intravenous drug use



COMPLICATIONS ▪ Heart failure, acute myocarditis, meningoencephalitis, systemic/pulmonary embolism, sudden death



SIGNS & SYMPTOMS Acute phase ▪ Mostly asymptomatic ▪ Systemic: malaise, fever, anorexia, headaches ▪ Chagoma: nodular skin lesion at infection site; usually on face/extremities ▪ Romaña’s sign: unilateral eyelid edema, conjunctivitis, preauricular lymphadenitis; follows conjunctival inoculation ▪ Lymphadenopathy ▪ Hepatosplenomegaly Indeterminate phase ▪ Asymptomatic Chronic phase ▪ Cardiac manifestations: dyspnea, fatigue, palpitation, chest pain, edema, mitral/ tricuspid regurgitation murmur, splitting of S2 ▪ Gastrointestinal manifestations: megacolon (constipation, bloating, abdominal pain); megaesophagus (dysphagia, regurgitation) Congenital disease ▪ Systemic: low birthweight, anasarca, fever ▪ Petechiae ▪ Hepatosplenomegaly ▪ Neurologic abnormalities (e.g. hypotonia, tremor)



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Further studies: stage, clinical syndrome dependent



Figure 104.1 The kissing bug, Triatoma infestans, is found in Central and South America and is a vector for Chagas disease.



Chest X-ray, MRI, echocardiogram ▪ Enlarged cardiac silhouette (cardiomegaly) ▪ Pericardial effusion ▪ Valvular regurgitation ▪ Left ventricular aneurysm Barium studies ▪ Megacolon, megaesophagus



LAB RESULTS ▪ Polymerase chain reaction (PCR)



OSMOSIS.ORG 581



▪ Blood culture Direct microscopy ▪ Organism observation in thin/thick blood smears; for acute phase disease (high parasitemia) Serologic testing ▪ E.g. enzyme-linked immunosorbent assay (ELISA), immunofluorescence Xenodiagnosis ▪ Feed laboratory triatomes with person’s blood → examine feces weeks later Cardiac tissue microscopy ▪ Acute disease: intracellular pseudocysts (amastigotes inside myocardiocytes), interstitial inflammation ▪ Chronic disease: mural thrombi, interstitial fibrosis, myocardiocyte necrosis



OTHER DIAGNOSTICS ECG ▪ Arrhythmia evidence: bundle branch/AV block



TREATMENT MEDICATIONS ▪ Antitrypanosomal treatment ▪ Advanced cardiac disease: cardiac arrest prevention, ventricular fibrillation through antiarrhythmic medication



OTHER INTERVENTIONS Prevention ▪ Vector control, treat parasitemia before conception



582 OSMOSIS.ORG



Figure 104.2 Trypanosoma species seen on a peripheral blood smear from an individual with Chagas disease.



NOTES



NOTES



TUBERCULOSIS MICROBE OVERVIEW ▪ Tuberculosis (AKA Mycobacterium tuberculosis) mycobacterium that primarily infects lungs but may infect any bodily organ/tissue ▪ Important properties ▫ Curved rod shaped bacteria often wrapped together in cord-like formations ▫ Obligate aerobe ▫ Impervious to Gram staining due to waxy cell wall composed of fatty acids (e.g., mycolic acid)



▪ ▪ ▪ ▪ ▪



▫ Staining: acid-fast stains like Ziehl– Neelsen, fluorescent stains like auramine/rhodamine Clumped colonies Distinctly slow growing (up to 6 weeks for visible growth) Grown on Lowenstein–Jensen media Resistant to weak disinfectants, can survive on dry surfaces for months Can avoid mucus traps, getting into deep airways (alveoli)



MYCOBACTERIUM TUBERCULOSIS osms.it/mycobacterium-tuberculosis PATHOLOGY & CAUSES TYPES Primary tuberculosis Reactivation tuberculosis ▪ In about 5–10% cases of primary TB Extrapulmonary tuberculosis ▪ May involve any organ (most commonly kidneys, meninges, lymph nodes, etc.) ▪ Systemic miliary tuberculosis



STAGING



▪ Transmitted by inhaling infectious aerosol droplets from individual with active TB (e.g. coughing, sneezing, speaking, etc.) ▪ TB enters lungs, gets phagocytized by macrophages → TB produces enzymes that inhibit lysosome and phagocytic vacuole



fusion → bacteria survives, proliferates, creates localized infection → primary tuberculosis development ▫ TB infiltrated macrophage fusion → Langhans giant cells ▫ Cell-mediated immunity activation → granuloma forms within infected area → caseous necrosis inside granuloma → Ghon focus ▫ Lymphatic dissemination of TB → lymph node caseation ▫ Ghon focus + involved lymph node → Ghon complex ▫ Ghon complex fibrosis, calcification → Ranke complex ▪ Primary infection resolution ▫ Mycobacteria killed by immune system ▫ Bacteria walled off in granuloma remains dormant but viable → latent tuberculosis with no further complications in immunocompetent



OSMOSIS.ORG 583



individuals ▪ Compromised immune system → more caseous necrosis areas → cavity formation → reactivation tuberculosis



RISK FACTORS



▪ Immunocompromised states ▫ HIV ▫ Diabetes mellitus ▫ Hematologic malignancy ▫ Chronic lung disease (especially silicosis) ▫ Malnutrition ▫ Aging ▪ Substance abuse ▫ Alcoholism ▫ Injection drug users ▪ Close contact with individuals with active TB infection ▫ Healthcare providers ▫ Incarceration ▪ Lower-income, medically underprivileged countries ▫ Recent immigrants from highprevalence countries



COMPLICATIONS



▪ Bronchopneumonia ▪ Pneumothorax ▪ Extrapulmonary tuberculosis ▫ Kidney → dysuria, pyelonephritis with sterile pyuria ▫ Meninge → meningitis ▫ Lumbar vertebrae → Pott disease ▫ Liver and gallbladder → hepatitis, obstructive jaundice ▫ Lymph nodes → cervical tuberculous lymphadenitis (scrofula) ▫ Peritonitis ▫ Pericarditis ▪ Systemic infection



584 OSMOSIS.ORG



Figure 105.1 The gross pathological appearance of a Ghon focus.



SIGNS & SYMPTOMS ▪ Primary tuberculosis ▫ Usually asymptomatic (90-95% of cases) ▫ Mild flu-like illness ▫ Rarely pleural effusion ▪ Reactivation tuberculosis ▫ Constitutional symptoms (fever, chills, night sweats, fatigue, appetite loss, weight loss, pleuritic chest pain) ▫ Cough (dry cough, prolonged cough producing purulent sputum, hemoptysis—suggesting advanced TB) ▫ Crepitations during lung auscultation ▪ Extrapulmonary tuberculosis ▫ Depending on affected organ/tissue ▪ Miliary (disseminated) tuberculosis ▫ Can affect any organ (e.g. choroidal tubercles in eye, granulomas within organs) ▫ Weight loss ▫ Fever, chills ▫ Dyspnea



Chapter 105 Tuberculosis



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Used in PPD/IGRAs positive ▪ Ranke complex → sign of healed primary TB ▪ Cavities → active TB sign



Antibiotic resistance ▪ Multiple-drug-resistant TB ▫ Resistant to isoniazid and rifampin ▪ Extensively drug-resistant TB ▫ Resistant to both isoniazid and rifampin, any fluoroquinolone, at least one second-line drug



LAB RESULTS PPD intradermal skin test (tuberculin test) ▪ Screening test for people at high risk for TB ▫ Tuberculin injection between dermal layers, induration area measurement within 48–72 hours ▪ Induration area ≥ 5mm: positive in immunocompromised individuals, persons with primary TB radiographic evidence/ close contact with those with active TB ▪ Induration area ≥ 10mm: positive in residents/immigrants from high-prevalence countries, children > four years of age, high risk populations (e.g., medical employees) ▪ Induration area ≥ 15mm: considered positive in individuals with no known risk factors ▪ Cannot be used for differentiation between active and latent TB ▪ PPD result interpretation ▫ Positive → exposure evidence ▫ False-positive → previously immunized with BCG vaccine ▫ Negative → no exposure evidence ▫ False-negative → sometimes seen in individuals with sarcoidosis, malnutrition, Hodgkin’s lymphoma



Figure 105.2 An X-ray image of the chest demonstrating diffuse interstitial granular densities in an individual with milliary tuberculosis.



Sputum testing ▪ Used for definitive diagnosis ▪ Staining, culture, PCR



OTHER DIAGNOSTICS Interferon gamma release assays (IGRAs) ▪ Alternative for PPD ▪ Unlike PPD, doesn’t show false-positive results in BCG vaccinated



Figure 105.3 Multifocal patchy opacities in the right upper lobe of an individual who presented with night sweats, weight loss and persistent cough. The presenting symptoms and radiological appearance are consistent with pulmonary tuberculosis.



OSMOSIS.ORG 585



TREATMENT MEDICATIONS



▪ Prophylactics ▫ BCG vaccine (some countries) ▪ Latent TB ▫ Isoniazid for 9 months ▪ Active TB ▫ First line anti-TB drugs: isoniazid, rifampin, pyrazinamide, ethambutol/ streptomycin ▪ Antibiotic resistance ▫ For multiple-drug-resistant TB, treatment requires second-line drugs (amikacin, kanamycin, capreomycin)



OTHER INTERVENTIONS



▪ Active TB ▫ Compulsory isolation (until sputum negative for TB)



586 OSMOSIS.ORG



Figure 105.4 The histological appearance of a tuberculosis granuloma. The granuloma is formed of epithelioid macrophages and giant cells with a focus of caseating necrosis at the centre and a rim of lymphocytes at the periphery.



NOTES



NOTES



BONE & JOINT INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Bacterial invasion and destruction of bone and joint cartilage ▪ Caused by bacteria ▫ E.g. Staphylococcus aureus (S. aureus), Mycobacterium tuberculosis (M. tuberculosis), Pseudomonas aeruginosa (P. aeruginosa)



RISK FACTORS



▪ Trauma/open fractures, diabetes/ atherosclerosis, orthopedic implants, existing infection etc.



COMPLICATIONS ▪ ▪ ▪ ▪



Chronic infections Bone fractures Loss of mobility Dissemination of infection



SIGNS & SYMPTOMS



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Detect bone infections CT scan, X-ray ▪ Detect fractures



LAB RESULTS



▪ Blood tests ▪ Needle aspiration: pathogen detection



TREATMENT MEDICATIONS



▪ Before identifying pathogen → general antibiotics ▪ Known pathogen → specific antibiotics



SURGERY



▪ Surgical cleaning



▪ Pain → individual avoids using infected joint Systemic ▪ Fever, chills, weakness, headache Local ▪ Swollen, painful, warm



OSMOSIS.ORG 587



OSTEOMYELITIS osms.it/osteomyelitis PATHOLOGY & CAUSES



▪ Cortical loss ▪ Contrast enhancement of abscess rim



▪ Bacterial infection (S. aureus, M. tuberculosis most common) → bone, bone marrow inflammation ▪ Bacteria → bone via bloodstream, nearby infection, open fractures/orthopedic implants ▪ First week: bacterial reproduction → inflammation → bone necrosis (e.g. sequestrum); if periosteum bursts → abscess ▪ Later: cytokines induce bone resorption → replacement with fibrous tissue → new bone formation around necrotic one (e.g. involucrum)



Nuclear medicine scans ▪ If MRI not attainable: higher radiotracer uptake CT scan, X-ray ▪ not sensitive for 1–2 weeks ▫ Osteopenia (decreased bone density) ▫ Periosteal reaction (thickening of periosteum) ▫ Aggressive infection → Codman’s triangle (lifted periosteum with triangleshaped, ossified edge)



RISK FACTORS



▪ Diabetes, fractures, splenectomy, orthopedic procedures/hardware



COMPLICATIONS



▪ If M. tuberculosis disseminates from joint to vertebra → Pott disease ▪ Inadequate treatment → chronic infection → bone fractures, sepsis



SIGNS & SYMPTOMS Local ▪ Redness, swelling, painful site, sinus connecting to abscess Systemic ▪ Weakness, fever, headache, shivering



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Edema → signal changes



588 OSMOSIS.ORG



Figure 106.1 An X-ray image of the tibia demonstrating a radiolucency with a sclerotic border consistent with a Brodie abscess.



Chapter 106 Bone & Joint Infections ▫ Endosteal scalloping (focal resorption of endosteum) ▫ Advanced osteomyelitis → cortical bone breakage ▫ Peripheral sclerosis (increased density at periphery, lower density centrally)



OTHER DIAGNOSTICS Needle aspiration guided with ultrasound ▪ Specific antibiotic therapy



TREATMENT MEDICATIONS



▪ Long-term intravenous antibiotics



SURGERY Figure 106.2 A plain radiograph of the right lower leg of an individual with postoperative osteomyelitis. The surgical wound started discharging pus two weeks post open reduction. There is medial cortical destruction and loss of trabeculations with lateral cortical thickening.



▪ Surgical removal of dead bone ▪ Severe cases → amputation



SEPTIC ARTHRITIS osms.it/septic-arthritis PATHOLOGY & CAUSES ▪ Joint structures: infected, damaged ▪ Pathogen enters the joint via bloodstream, from nearby infection/directly (e.g. open fracture) ▪ Infection of joint → endotoxin production → cytokine release → neutrophil attraction → inflammation, damage of joint structures



CAUSES



▪ Most commonly S. aureus (any age group), Neisseria gonorrhoeae (N. gonorrhoeae; sexual transmission → adults)



RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪



Diabetes Joint trauma Artificial joint, surgical procedure Osteomyelitis Chronic arthritis (e.g. rheumatoid arthritis) Immunocompromised HIV



SIGNS & SYMPTOMS ▪ Most commonly affects knee; less commonly ankle, hip, shoulder



OSMOSIS.ORG 589



Local ▪ Restricted range of motion; painful, warm, swollen joint Systemic ▪ Fever, weakness



DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan ▪ Normal in early stages ▪ ↑ fluid in synovial part of joint ▪ Narrowing of joint space due to destruction of cartilage ▪ Destruction of bone adjacent to cartilage MRI ▪ Edema around synovium ▪ Assess spread of infection outside the joint Ultrasound ▪ ↑ fluid ▪ Guiding needle for aspiration



Figure 106.3 A red, hot, swollen left knee in an individual with septic arthritis.



TREATMENT MEDICATIONS



Blood test ▪ ↑ white blood cells count (WBC); ↑ sedimentation rate (ESR)



▪ General antibiotics depending on Gram stain of joint fluid ▪ Switch to specific antibiotics once bacteria identified ▪ Pain medications (e.g. NSAIDs, acetaminophen)



Aspiration of joint fluid ▪ → bacterial culture → specific antibiotics



SURGERY



LAB RESULTS



590 OSMOSIS.ORG



▪ Surgically drain, cleanse joint fluid



NOTES



NOTES



BONE & JOINT PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Non-neoplastic disorders affecting bones, joints ▪ Generally result in weakened bones; pathologic fractures, malformations ▪ Include disorders of normal bone structure due to ▫ Impaired bone mineralization (rickets, osteomalacia) ▫ Failure of bone resorption (osteopetrosis, osteosclerosis) ▫ Disorders of bone formation (osteogenesis imperfecta) ▫ Imbalance between bone formation, bone resorption (osteoporosis, Paget’s disease) ▫ Stress injury (Osgood–Schlatter disease) ▫ Impaired vascularization (Legg–Calvé– Perthes disease)



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Most common symptoms include ▫ Bone pain, bone tenderness, pathologic fractures, bone malformations, nerve/ tissue compression



LAB RESULTS



▪ Etiology-dependent ▫ Bone specific alkaline phosphatase, creatinine kinase, Ca2+, serum 25(OH)D levels, etc. ▫ Biopsy: microscopic changes



OTHER DIAGNOSTICS ▪ Clinical presentation



TREATMENT ▪ Causative treatment, palliative treatment (management of symptoms with no effect on course of the disease)



MEDICATIONS



▪ Supplementation therapy (vitamin D) ▪ Bisphosphonate therapy



SURGERY ▪ Surgery



OTHER INTERVENTIONS



▪ Fracture management (braces, intramedullary rods, etc.)



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Lytic/blastic changes ▪ Bone fractures, malformations Bone scan scintigraphy ▪ Extent, distribution of skeletal involvement



OSMOSIS.ORG 591



FIBROUS DYSPLASIA OF BONE osms.it/fibrous-dysplasia-of-bone PATHOLOGY & CAUSES



RISK FACTORS



▪ Rare disorder → normal bone tissue replaced by fibrous tissue ▪ → brittle, weak, fracture-prone bones



▪ Sex ▫ ↑ individuals who are biologically male ▪ Age ▫ Symptoms usually occur in teen years



TYPES



COMPLICATIONS



▪ Monostotic ▫ AKA (McCune–Albright syndrome) ▫ Most common; involves one bone ▪ Polyostotic ▫ Involves multiple bones



CAUSES



▪ Post-zygotic activating mutations of guanine nucleotide stimulatory protein (GNAS) gene, which encodes ɑ subunit of the Gs coupled protein receptor → constitutive receptor activation → replacement of bone with fibrous tissue



▪ Pathologic fractures ▫ Repeated pathologic fractures can → “shepherd crook malformation” (varus angulation of the proximal femur) ▪ Severe scoliosis if spine affected



SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ During teen years ▫ Pain, swelling, pathologic fractures, malformations ▪ Most commonly affects proximal femur, tibia, ribs, skull ▪ Rare case of optic nerves/auditory canal compression ▫ Vision/hearing loss



DIAGNOSIS DIAGNOSTIC IMAGING



Figure 107.1 The histological appearance of bone in an individual with fibrous dysplasia of bone. Normal bone tissue is on the left. The affected bone is composed of thin disordered trabeculae. The bone marrow spaces are packed with fibrous tissue.



X-ray ▪ Well-circumscribed lytic lesions in metaphysis/diaphysis with “ground glass” appearance ▪ Undulating pattern of cortical bone due to endosteal erosion ▪ “Rind sign”: thick, sclerotic bone layer surrounding lytic lesion ▪ Pathologic fracture → periosteal reaction Total body scintigraphy ▪ Identify extent of bone lesions ▫ Increased Tc99 uptake



592 OSMOSIS.ORG



Chapter 107 Bone & Joint Pathology



LAB RESULTS Biopsy ▪ Thin, irregular bony trabeculae; described as “Chinese figures”



OTHER DIAGNOSTICS Clinical presentation ▪ Albright syndrome may present along with endocrine abnormalities; e.g. “café-au-lait” spots, often on neck



TREATMENT



Figure 107.2 An X-ray image of the femurs demonstrating a shepherd’s crook malformation. Both femurs are involved in this case of polyostotic fibrous dysplasia.



▪ Palliative; disease incurable ▪ Asymptomatic: observation ▪ Symptomatic: medications, surgery



MEDICATIONS



▪ Bisphosphonate therapy ▫ Inhibit osteoclast activity, prevent bone loss, decrease bone pain



SURGERY



▪ Curettage; bone grafting; stabilization with plates, screws ▪ Rarely effective; high rate of recurrence



Figure 107.3 A CT scan of the head in the axial plane demonstrating fibrous dysplasia of the squamous temporal bone in a case of monoostotic fibrous dysplasia.



OSMOSIS.ORG 593



LEGG–CALVE–PERTHES DISEASE osms.it/legg-calve-perthes_disease PATHOLOGY & CAUSES ▪ Hip disorder characterized by osteonecrosis of proximal femur head due to compromised blood supply ▪ ↓ blood supply to proximal femoral head → osteonecrosis → infiltration of new blood vessels and resorption of necrotic bone → bone mass loss, growth cessation,weakening of bone ▪ Cause of blood supply disruption (ligamentum teres femoris or medial circumflex femoral artery) unknown



RISK FACTORS



▪ Age ▫ Usually affects children 3–12 years ▪ Sex ▫ ↑ individuals who are biologically male ▪ Heredity ▪ Endocrinologic abnormalities ▪ Hemodynamic disorders ▪ Trauma ▪ Steroid use



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Initial scans often normal; nonspecific effusion of joint (widening of joint space) may be present ▪ As disease progresses ▫ Flattening (coxa plana), fragmentation, demineralization of femoral head with subchondral lucency; proximal femoral neck malformation (coxa magna) Bone scintigraphy ▪ Confirmation and evaluation ▫ Extent of involvement ▪ Focal area of ↓ uptake in femoral head



COMPLICATIONS



▪ Loss of bone mass can → pathologic fractures, malformations (e.g. coxa magna) ▪ ↑ risk of osteoarthritis in adulthood



SIGNS & SYMPTOMS ▪ Intermittent/chronic throbbing hip pain ▪ Referred knee/groin pain exacerbated by movement, especially internal hip rotation, ▪ Soreness, altered gait ▪ Reduced range of motion



594 OSMOSIS.ORG



Figure 107.4 X-ray images of the right hip in a child with Legg–Calvé–Perthes disease. The diagnosis was made at six years (left) and by 8.5 years (right) the epiphysis has completely collapsed due to osteonecrosis.



Chapter 107 Bone & Joint Pathology MRI ▪ Confirmation and evaluation ▫ Extent of involvement ▪ Hypointense bone marrow changes, subluxation of femoral head



TREATMENT SURGERY



OTHER INTERVENTIONS



▪ Traction to remove mechanical pressure, reduce wear ▪ Braces, physiotherapy to restore range of motion ▪ Avoidance of contact sports/games, running, prolonged weight bearing ▫ Swimming, cycling recommended to exercise hip muscles, restore range of motion



▪ External fixation to stabilize hip bone, relieve it from carrying body’s weight ▪ Hip replacement is usually required > age 50



OSGOOD–SCHLATTER DISEASE osms.it/osgood-schlatter_disease PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Traction phenomenon characterized by stress inflammation, stress injury at point of insertion of patellar tendon (apophysitis) on proximal tibial tubercle ▪ AKA apophysitis of tibial tubercle



▪ Swelling, pain at tibial tubercle ▫ Exacerbated by trauma, activity; relieved by rest ▪ Limping; bony prominence of tibial tubercle ▪ Avulsion fracture → acute onset of pain ▪ Usually asymmetric, but often presents bilaterally



CAUSES



▪ Overuse during physical activity ▫ Repetitive quadriceps contraction → traction on tibial tuberosity → microavulsion fractures of tibial tubercle, tendinous inflammation ▪ Severe cases may → complete tibial tubercle avulsion fracture (detachment of tibial tubercle)



RISK FACTORS



▪ Age ▫ ↑ common in 11–14 year olds ▪ Activity level ▫ ↑ common in physically active individuals



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Used only for atypical presentation (pain not related to activity, fever, rash etc.) to exclude other conditions (e.g. osteomyelitis)



X-ray ▪ Elevation of tibial tubercle ▪ Fragmentation of tibial tubercle ▪ Soft tissue swelling ▪ Calcification/thickening of patellar tendon



OTHER DIAGNOSTICS ▪ Clinical presentation



OSMOSIS.ORG 595



TREATMENT MEDICATIONS



▪ Short term analgesics/NSAIDs use



SURGERY



▪ Ossicle resection, excision of tibial tuberosity ▫ If everything fails, for individuals with closed growth plates



OTHER INTERVENTIONS



▪ Usually no treatment required ▪ Physical therapy



Figure 107.5 A lateral X-ray image of the knee in an individual with Osgood–Schlatter disease. There is fragmentation of the tibial tuberosity and overlying soft tissue swelling.



OSTEOGENESIS IMPERFECTA osms.it/osteogenesis-imperfecta PATHOLOGY & CAUSES ▪ Disease characterized by brittle bones prone to fractures due to impaired type I collagen synthesis ▪ Type I collagen ▫ Formation: two ɑ1 chains combine with one ɑ2 chain → triple stranded type 1 procollagen → post-translational modification (folding, cross linking) → strong fibrils with enormous tensile strength ▫ Important for structural integrity of bones, joints, eyes, ears, teeth and skin ▪ Affects primarily bones, but also other tissues containing type I collagen → structural abnormalities in affected tissues



596 OSMOSIS.ORG



TYPES ▪ Previously classified into nine subtypes based on family history, radiologic, clinical features ▪ Included is modified clinical classification → severity Mild (type I) ▪ Mild bone fragility ▪ Variable fracture rate; minimal bone fractures before learning to walk ▪ Minimal malformation, normal stature ▪ Adults at higher risk for hearing loss, premature osteoporosis following menopause



Chapter 107 Bone & Joint Pathology Moderate to severe (types III–IX) ▪ Type III ▫ Most severe type compatible with survival ▪ Moderate to severe rate of fractures ▪ Moderate malformations, short stature ▪ Children ▫ Higher risk of hearing loss ▪ Adults ▫ Earlier onset of hearing loss and premature osteoporosis than in mild form Lethal form (type II) ▪ Most cases die in utero/within first year of life ▪ Severe fractures in utero ▪ Severe deformities; short stature ▪ Pulmonary hypoplasia → respiratory failure



CAUSES



▪ Autosomal dominant mutation of COL1A1 or COL1A2 (>90%), other genes encoding ɑ1, ɑ2 chains of type I collagen → misfolding of collagen proteins, loss of function → bone loss, fragility



SIGNS & SYMPTOMS ▪ Highly variable presentation ▪ Pathologic fractures with minimal/no trauma, malformations, short stature, scoliosis ▪ Skull malformations may cause compression, neurologic symptoms ▪ Blue discoloration/translucency of sclera due to decreased collagen, exposure of choroidal veins ▪ Hearing loss due to abnormalities in middle, inner ear ossicles ▪ Dentinogenesis imperfecta ▫ Small, blue/translucent, worn down teeth ▪ Decreased structural integrity, hypermobility of ligaments, joints, skin ▪ Easy bruising



Figure 107.6 Blue sclera in an individual with osteogenesis imperfecta.



DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Lethal form ▫ Severe micromelia (small, undeveloped extremities) ▫ Decreased bone mineralization → skull compression with transducer pressure ▫ Multiple bone fractures Postnatal X-ray skeletal survey ▪ Mild form ▫ Thinning of cortical bone ▫ Wormian bones may be present (small, irregular bones between cranial sutures) ▪ Moderate to severe form ▫ Cystic metaphyses ▫ Severe osteoporosis ▫ Popcorn calcification of metaphysis, epiphysis of long bones ▫ Vertebral/rib fractures common ▪ Lethal form ▫ Beaded ribs ▫ Severe osteoporosis ▫ Multiple fractures, malformations of long bones



LAB RESULTS



▪ ↑ serum alkaline phosphatase in blood ▪ ↑ Ca2+ in the urine



Biopsy ▪ Disorganized bone; decrease of cortical, trabecular width; cancellous bone volume ▪ Increased bone remodeling



OSMOSIS.ORG 597



Dermal fibroblast culture ▪ Abnormalities in quality/quantity of collagen synthesis Prenatal DNA mutation analysis ▪ For at-risk pregnancies



OTHER DIAGNOSTICS ▪ Clinical presentation



TREATMENT MEDICATIONS



▪ Bisphosphonate treatment for moderate to severe form (e.g. intravenous pamidronate)



SURGERY



▪ Surgical malformity correction ▪ Fracture management with intramedullary rods placement; telescoping rods for actively-growing individuals



OTHER INTERVENTIONS



Figure 107.7 X-ray images of the arms of an individual with osteogenesis imperfecta. There is generalised osteoporosis as well as multiple fractures and malformations..



▪ Physical therapy → prevent contractures, bone loss due to immobility



OSTEOMALACIA osms.it/osteomalacia PATHOLOGY & CAUSES ▪ Inadequate bone mineralization in adults due to lack of vitamin D, Ca2+/PO3▪ AKA rickets (in children) ▪ ↓ Ca2+ inhibits normal mineralization of newly formed osteoid during bone remodelling → weakening, softening of bones



CAUSES ▪ Vitamin D deficiency → insufficient intestinal absorption of Ca2+ ▫ Most common cause ▫ Insufficient sun exposure → UVB rays



598 OSMOSIS.ORG



initiate vitamin D synthesis in the skin ▫ Chronic kidney disease/ liver disease → lack of vitamin D activation ▫ Insufficient intake ▫ Malabsorption syndrome → insufficient intestinal absorption of Ca2+, other minerals ▫ Can occur as adverse effect of long term anticonvulsant use (e.g. phenytoin) ▪ X-linked hypophosphatemia



RISK FACTORS



▪ Limited sun exposure, use of strong sunscreens



Chapter 107 Bone & Joint Pathology ▪ Dietary ▫ Lactose intolerance, vegetarian diet ▪ Darker skin pigmentation



COMPLICATIONS



▪ May → secondary hyperparathyroidism ▪ Prolonged secondary hyperparathyroidism → Ca2+ resorption from bones → osteoporosis



SIGNS & SYMPTOMS ▪ Diffuse bone and joint pain ▪ Proximal muscle weakness ▪ Muscle spasms of hands, feet, tingling/ numbness ▪ Bone fragility, increased risk of fractures with minimal trauma



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ ↓ bone mineral density, AKA osteopenia ▪ Loss of of trabecular bone, thinning of cortical bone ▪ “Looser lines” ▫ Transverse lucencies resembling fractures, AKA pseudofractures ▪ In case of secondary hyperparathyroidism ▫ Subperiosteal resorption of phalanges, bone cysts



LAB RESULTS ▪ ▪ ▪ ▪



↓ Serum 25(OH)D levels ↓ Ca2+, ↓ PO3↑ Parathyroid hormone levels ↑ Alkaline phosphatase due to increased osteoblast activity



Bone biopsy with tetracycline labeling ▪ Rarely done ▪ ↑ unmineralized osteoid volume ▪ ↑ width of osteoid seams ▪ No sign of new bone mineralization



TREATMENT Figure 107.8 An X-ray image of the pelvis of an individual with osteomalacia. There are numerous pseudofractures, or Looser lines, in both the inferior and superior pubic rami.



MEDICATIONS



▪ Oral vitamin D supplementation ▪ Correction of Ca2+ intake



OTHER INTERVENTIONS ▪ Treat underlying cause



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OSTEOPETROSIS osms.it/osteopetrosis PATHOLOGY & CAUSES ▪ Rare genetic disorder characterized by osteoclast dysfunction → hardening of the bone, AKA osteosclerosis ▪ Osteoclasts’ failure to resorb bone → increased density, overgrowth of bones ▪ Despite increased density, bones have disordered architecture, lack flexibility; thus prone to fractures



TYPES Autosomal recessive osteopetrosis, AKA infantile malignant type ▪ Caused by mutations in CA2 gene encoding carbon anhydrase ▪ Deficiency of carbonic anhydrase → inhibition of proton pumping → ↑ pH → osteoclasts fail to resorb bone because acidic environment required → imbalance between bone formation and bone resorption → excess bone formation Autosomal dominant osteopetrosis, AKA adult benign type ▪ Caused by mutations in chloride channel 7 (CLCN7) gene; less severe type ▪ Associated with renal tubular acidosis → deficiency of carbonic anhydrase in kidney



SIGNS & SYMPTOMS Autosomal recessive osteopetrosis ▪ Impaired growth, failure to thrive ▪ Osteomyelitis of mandible ▪ Dental abnormalities ▪ Visual/hearing impairment → sclerosis of skull bones, cranial nerve compression ▪ Hydrocephalus → obstruction of foramen magnum



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▪ Hepatosplenomegaly and hypersplenism ▫ Due to bone marrow replacement and anemia, resulting in extramedullary hematopoiesis ▪ Symptoms of anemia (e.g. weakness, fatigue, pallor) ▪ Symptoms of thrombocytopenia (e.g. bruising, hemorrhage) ▪ Symptoms of leukopenia (e.g. recurrent infections) Autosomal dominant osteopetrosis ▪ Can be asymptomatic; most commonly affects spine, pelvis, base of skull ▪ Vision loss, hearing loss due to sclerosis of skull bones, cranial nerve compression ▪ Pathologic fractures ▪ Osteoarthritis



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Increased thickness, density of bones ▪ “Bone within bone” appearance ▫ Classical for autosomal dominant osteopetrosis ▪ Sclerotic rings in iliac bones ▪ Widened costochondral junctions ▪ Radiolucent metaphyseal bands ▪ Sandwich vertebrae ▫ Peripheral bony sclerosis with central lucency of vertebral body



LAB RESULTS



▪ Hypocalcemia (due to ↓ reabsorption of Ca2+) ▪ ↑ PTH (secondary hypoparathyroidism) ▪ ↑ acid phosphatase ▫ Released from defective osteoclasts ▪ Creatinine kinase (CK-BB) ▪ Released from defective osteoclasts



Chapter 107 Bone & Joint Pathology



TREATMENT MEDICATIONS ▪ ▪ ▪ ▪



Ca2+, PO3-, vitamin D supplementation Osteomyelitis, other infections → antibiotics Anemia → erythropoietin, corticosteroids Leukopenia → gamma interferon



SURGERY



▪ Mend fractures ▪ Bone marrow transplantation



OTHER THERAPIES



▪ Not curable; treatment is supportive ▪ Fractures → braces ▪ Treat dental abnormalities



Figure 107.9 An X-ray image of a child with osteopetrosis. There is loss of bony corticomedullary differentiation and there are lucent metaphyseal bands. There is an incidental large scrotal hernia.



Figure 107.10 A plain chest radiograph of a child with osteopetrosis. There is characteristic widening of the costochondral junctions.



OSTEOPOROSIS osms.it/osteoporosis PATHOLOGY & CAUSES ▪ Characterized by imbalance between bone formation, bone resorption → decreased bone density, pathologic fractures ▪ Caused by increased bone loss/decreased bone mass



RISK FACTORS



▪ Postmenopause (↓ estrogen) ▪ Alcohol consumption, smoking ▪ Immobility, malnutrition/malabsorption (↓ Ca2+)



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▪ Hypogonadal states ▫ Turner’s syndrome, hyperprolactinemia, Klinefelter syndrome, hypothalamic amenorrhea, primary/secondary hypogonadism ▪ Endocrine disorders ▫ Cushing’s syndrome, hyperthyroidism, hyperparathyroidism, diabetes mellitus, acromegaly ▪ Inherited disorders ▫ Osteogenesis imperfecta, Marfan’s syndrome, hemochromatosis ▪ Rheumatologic disorders ▫ Rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus ▪ Medications ▫ Corticosteroids, antiepileptics, anticoagulants, L-thyroxine



Figure 107.11 An MRI scan of the spine in the sagittal plane demonstrating a compression fracture of T12 secondary to osteoporosis.



SIGNS & SYMPTOMS ▪ Asymptomatic until fracture occurs ▪ Pathologic fractures; most commonly vertebral column, ribs, hips, wrists ▪ Compression fractures of vertebral column ▫ Signs: loss of height, hunched posture, kyphosis ▫ Symptoms: sudden back pain, radicular pain, spinal cord compression, cauda equina syndrome ▪ Chronic pain; unlikely without fracture



DIAGNOSIS DIAGNOSTIC IMAGING Dual-energy X-ray absorptiometry (DEXA scan) ▪ ↓ bone mineral density (BMD) ≥ 2.5 SD below the young-adult mean



LAB RESULTS ▪ Identification of potential secondary causes ▫ Complete blood cell count ▫ Ca2+, PO3-, creatinine, 25-hydroxyvitamin D levels ▫ Thyroid-stimulating hormone (TSH) ▫ 24-hour urine for calcium and creatinine



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TREATMENT MEDICATIONS



▪ Ca2+, vitamin D supplementation ▪ Oral bisphosphonates (alendronate or risedronate) ▪ Selective estrogen receptor modulators (raloxifene) ▪ Parathyroid hormone/parathyroid hormone-related protein analog for severe osteoporosis



SURGERY



▪ Prompt surgery in case of hip fracture



OTHER THERAPIES



▪ Fracture management ▪ Lifestyle changes ▫ Exercise; smoking, alcohol cessation



Chapter 107 Bone & Joint Pathology



OSTEOSCLEROSIS osms.it/osteosclerosis PATHOLOGY & CAUSES ▪ Abnormal diffuse/patchy hardening of bone, increased bone density due to impaired bone resorption



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Generalised bone pain ▪ Pathologic fractures



TYPES Acquired ▪ Paget’s disease ▪ Osteogenic bone metastasis (e.g. prostate, breast cancer) ▪ Myelofibrosis ▪ Chronic osteomyelitis ▪ Hypervitaminosis D ▪ Hypoparathyroidism ▪ Schnitzler syndrome Inherited ▪ Osteopetrosis ▪ Pyknodysostosis ▪ Osteopoikilosis



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ ↑ Bone mineral density ▪ Increased bone thickness, density



TREATMENT MEDICATIONS



▪ Ca2+, PO3-, vitamin D supplementation



OTHER INTERVENTIONS ▪ Fracture management



PAGET'S DISEASE OF BONE osms.it/pagets-disease-of-bone PATHOLOGY & CAUSES ▪ Characterized by localized, disordered bone remodeling ▫ Excessive bone resorption → disorganized compensatory bone formation ▪ Three phases of pathogenesis ▫ Lytic phase: osteoclastic hyperactivity → increased rate of localized bone resorption; bone remodeling increased up to 20x



▫ Mixed lytic-blastic phase: compensatory osteoblastic hyperactivity → accelerated bone formation ▫ Sclerotic phase: results in thick, sclerotic, disorganized bone (“woven bone”) prone to fracture; new bone infiltrated by blood vessels (e.g. hypervascular state)



CAUSES



▪ Unclear; possible causes include ▫ Slow virus infection (e.g.



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paramyxoviridae) of osteoclasts ▫ Mutations of SQSTM1, RANK genes involved in osteoclasts’ function regulation



COMPLICATIONS



▪ Osteoarthritis ▫ May distort alignment of bone, associated joint → higher mechanical force; rapid wear, degeneration ▪ Heart failure ▫ Rarely, advanced Paget’s disease → excessive demand on heart due to increased hypervascularity, arteriovenous (AV) shunts in affected bone ▪ Neurologic impairments ▫ Neural tissue compression ▪ Rarely, malignant transformation (osteosarcoma)



SIGNS & SYMPTOMS ▪ Involves one or more bones; not generalized ▪ Most commonly affects pelvis, femur, lumbar vertebrae, skull ▪ Bone pain → microfractures, periosteal changes ▪ Pathologic fractures ▪ Bony malformations ▫ Enlarged skull, AKA “increasing hat size”; spinal kyphosis; bowing of long bones ▪ Increased localized temperature → hypervascularity ▪ Arthritis of associated joints ▪ Hearing impairment → sclerosis of the skull bones, cranial nerve compression ▪ Decreased range of motion



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Osteoporosis circumscripta ▫ Well-defined osteolytic lesions of skull in early course



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Figure 107.12 A CT scan of the head in the sagittal plane. The skull has the typical cotton wool appearance of Paget’s disease of the bone. ▪ “Cotton wool appearance” ▫ Mixed lytic/sclerotic lesions ▪ Looser lines ▫ Transverse lucencies resembling fractures; AKA pseudofractures ▪ Squaring of vertebrae seen on lateral X-ray ▪ Tam O’Shanter sign ▫ Enlarged overriding frontal bone ▪ “Candle flame sign” ▫ Well V-shaped osteolytic lesion; characteristic of lytic phase Bone scan scintigraphy ▪ Focal increased radionuclide uptake



LABORATORY RESULTS Biopsy ▪ Mosaic pattern of lamellar bone ▪ Large, numerous osteoclasts with up to 100 nuclei (normal is 5–10) ▪ Affected bone marrow filled with highly vascular stroma Blood test ▪ ↑ alkaline phosphatase



Chapter 107 Bone & Joint Pathology



TREATMENT MEDICATIONS



▪ Bisphosphonates (zoledronate, risedronate, pamidronate), calcitonin



SURGERY



▪ Correction of fractures, malformations



OTHER INTERVENTIONS Figure 107.13 The histological appearance of bone in the Paget’s disease. Bone formation is increased and highly disordered.



▪ Physical therapy



RICKETS osms.it/rickets PATHOLOGY & CAUSES ▪ Inadequate mineralization of cartilage in children’s growth plates due to lack of vitamin D, Ca2+, or PO3▪ ↓ Ca2+ inhibits normal mineralization of epiphyseal growth plates → accumulation of unmineralized osteoid → softening of the bones, impaired growth and malformations



CAUSES



▪ Most common: vitamin D deficiency → insufficient intestinal absorption of Ca2+ ▪ Insufficient sun exposure → UVB rays initiate vitamin D synthesis in skin ▪ Chronic kidney disease or liver disease → lack of vitamin D activation ▪ Insufficient intake ▫ Malabsorption syndrome → insufficient intestinal absorption of Ca2+ and other minerals ▫ Maternal deficiencies → congenital rickets ▪ X-linked hypophosphatemia



RISK FACTORS



▪ Little sun exposure ▪ Darker pigmented skin ▪ Breastfeeding without vitamin D supplementation



COMPLICATIONS



▪ Bone fractures ▪ Secondary hyperparathyroidism ▪ Increased infection risk



SIGNS & SYMPTOMS ▪ Bone tenderness, pain ▪ Thinned, soft skull bones, AKA craniotabes; delayed closure of fontanelles ▪ Bowed legs or knock knees (genu varum or valgus) ▪ Frontal bossing (enlarged, prominent frontal bone) ▪ Widening of ankles, wrists; bowing of distal radius, ulna ▪ Pigeon chest malformation → Harrison’s groove along thorax’s lower border ▪ Muscle spasms, numbness ▪ Hypoplasia of dental enamel



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LAB RESULTS Blood tests ▪ ↓ Serum 25(OH)D levels ▪ ↓ Ca2+, ↓ PO3▪ ↑ Alkaline phosphatase, ↑ parathyroid hormone levels



Figure 107.14 An X-ray image of both lower limbs demonstrating bowing in an individual with rickets.



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ ↓ bone mineral density, AKA osteopenia ▪ Bowed legs ▪ Widening of epiphyseal growth plate ▪ Thinning of cortical bone ▪ Metaphyseal cupping ▪ Looser lines ▫ Transverse lucencies resembling fractures, AKA pseudofractures ▪ In secondary hyperparathyroidism ▫ Subperiosteal resorption of phalanges, bone cysts



Figure 107.15 An X-ray image of the wrist demonstrating metaphyseal cupping, also known as metaphyseal flaring, in an individual with rickets.



TREATMENT MEDICATIONS



▪ Oral vitamin D supplementation ▪ Correction of calcium intake



OTHER INTERVENTIONS ▪ Treat underlying causes



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NOTES



NOTES



BONE TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Abnormal neoplastic bone tissue growth ▪ Benign tumors more common than malignant



TYPES



▪ Primary tumors: originate from bone (more common) ▪ Secondary tumors: originate from other organs



CAUSES



▪ Unknown



RISK FACTORS



▪ Retinoblastoma, Li–Fraumeni syndrome, chronic inflammation, chronic osteomyelitis, Paget’s disease, bone infarcts, radiation



SIGNS & SYMPTOMS ▪ Usual appearance: long bones (e.g. femur/ tibia), pelvis, vertebra, etc. ▪ Benign tumors usually asymptomatic, undetected (early stages), discovered by accident ▪ Pain, swelling, erythema ▪ Palpable mass, structural malformation ▪ Pathological fracture, restricted motion range



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Benign tumors tend to have more defined edges (circular/oval) CT scan/MRI ▪ Asses relation with other structures Nuclear medicine ▪ Assess skeletal involvement extent, distribution



OTHER DIAGNOSTICS ▪ Biopsy ▫ Histological features



TREATMENT MEDICATIONS ▪ Chemotherapy



SURGERY ▪ Surgery



OTHER INTERVENTIONS ▪ Radiation therapy



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EWING'S SARCOMA osms.it/ewings-sarcoma PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Rare malignant tumor; bone, soft tissue around bone ▪ Small, round blue-stained cells; believed to have neuroectodermal origin



▪ Pelvis, femur, clavicle, humerus, ribs, spine commonly affected ▪ Intense pain (stronger at night); exacerbated by exercise ▪ Soft palpable mass attached to bone; can compress nerves → function loss (e.g. urinary incontinence if sacrum involved) ▪ Swelling, erythema ▪ Systemic symptoms: fever, weight loss can indicate metastases ▫ Lung metastases: most significant cause of death



CAUSES



▪ Translocation fuses two regions together ▫ Ewing sarcoma gene (EWS): chromosome 22 ▫ Friend leukemia insertion (FLI1): chromosome 11 ▫ Newly-formed EWS-FLI1 protein: abnormal transcription factor → induce cell division, malignant transformation



RISK FACTORS



▪ Usually sporadic; occurs in children, young adults ▪ ↑ risk, Ewing’s sarcoma family history



DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Permeative process ▫ Bone appears “moth-eaten” ▪ Periosteal reaction ▫ Rapid tumor growth raises periosteum → laminated “onion skin”-like appearance ▪ Sclerosis MRI ▪ Precise tumor location, size, adjacentstructure relation Positron emission tomography (PET) scan ▪ Metastases search



Figure 108.1 A histological section of a classic Ewing’s sarcoma. The tumor cells are undifferentiated, closely packed and have vague cytoplasmic borders. There are two distinct populations of light and dark cells.



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OTHER DIAGNOSTICS



▪ Tumor biopsy ▫ Small, round, blue cells



Chapter 108 Bone Tumors



TREATMENT MEDICATIONS ▪ Chemotherapy



SURGERY



▪ Tumor removal/limb amputation



OTHER INTERVENTIONS ▪ Radiation therapy



Figure 108.2 An anterior-posterior X-ray of the left shoulder demonstrating a Ewing’s sarcoma of the humeral head.



Figure 108.3 A PET-CT scan in the coronal plane demonstrating a Ewing’s sarcoma of the left proximal femur. The tumor, visible on CT scan corresponds well with the high levels of tracer uptake on the PET scan.



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GIANT-CELL TUMOR OF BONE osms.it/giant-cell_tumor_of_bone PATHOLOGY & CAUSES ▪ Benign tumor ▫ Destructive growth, metastases potential ▪ Tumor mass comprises ▫ Tumor cells: giant multinucleated cells from osteoblastic origin ▫ Non-tumor cells: osteoclasts, their precursors ▪ Tumor cells express RANKL → binds to RANK on osteoclasts, precursors membrane → induce cell division, malignant transformation ▪ ↑ osteoclast number (tumor sometimes called osteoclastoma) + absence of control → bone destruction



SIGNS & SYMPTOMS ▪ Commonly around knee (distal femur/ proximal tibia) ▪ Pain, swelling ▪ Restricted range of motion ▪ Pathological fractures



Figure 108.4 A anterior-posterior radiograph of the wrist demonstrating a giant cell tumor of bone at the subarticular portion of the radius. It has a characteristic soap bubble appearance.



DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Lucent mass; cortical thinning/destruction; pathological fracture; mineralization, sclerosis absence



Figure 108.5 The histological appearance of a giant cell tumor of bone. There are numerous multinucleated osteoclastic giant cells surrounded by smaller mononuclear cells.



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MRI ▪ Homogeneous intensity, well-defined edges Nuclear medicine ▪ “Doughnut” sign ▫ ↑ periphery uptake, ↓ center uptake



Chapter 108 Bone Tumors



TREATMENT SURGERY ▪ Resection



OTHER INTERVENTIONS ▪ Radiation therapy



Figure 108.6 The gross pathological appearance of a giant cell tumor of bone affecting the distal femur.



OSTEOBLASTOMA osms.it/osteoblastoma PATHOLOGY & CAUSES ▪ Benign bone tissue-forming tumor; similar to osteoid osteoma ▪ Comprises many osteoid (not yet mineralized bone tissue), fibrous (woven) bone-producing osteoblasts ▪ May break bone cortex, grow to adjacent soft tissue Figure 108.7 The histological appearance of an osteoblastoma. There is abundant osteoid and woven bone forming trabeculae which are lined by a single layer of osteoblasts.



OSMOSIS.ORG 611



SIGNS & SYMPTOMS ▪ Commonly affects posterior spine, long bones (e.g. femur, tibia) ▪ Dull pain (exacerbated at night) ▪ Not responsive to salicylates ▪ Structural malformations (e.g. scoliosis) ▪ Spinal cord, nerve compression → pain, function loss ▪ Swelling, tenderness, ↓ range of motion



DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Well defined lucent mass ▪ >2cm/0.79in; no periosteal reaction (differs from osteoid osteoma); if arising from cortical bone → thin new bone layer covering ▪ Adjacent sclerosis ▪ Inner calcification MRI ▪ Assess surrounding structure volume, relationship



Figure 108.8 A CT scan of the lower leg in the axial plane demonstrating an osteoblastoma of the fibula.



OTHER DIAGNOSTICS Biopsy ▪ Immature trabeculae with single osteoblast layer ▪ High dilated blood vessel number ▪ Distinguish from osteosarcoma ▫ ↓ mitotic activity ▫ ↓ cell atypia ▫ No cartilaginous matrix ▫ Does not imbue surrounding bone, soft tissue



TREATMENT SURGERY ▪ Excision



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Chapter 108 Bone Tumors



OSTEOID OSTEOMA osms.it/osteoid-osteoma PATHOLOGY & CAUSES ▪ Bone tissue-forming tumor ▫ Benign, similar to osteoblastoma ▪ Tumor mass (nidus) ▫ Good blood supply, comprised of osteoblasts providing osteoid, fibrous bone ▫ Osteoblasts → ↑ prostaglandin E₂ → pain ▪ Nidus produces/envelopes itself in reactive bone



SIGNS & SYMPTOMS ▪ Commonly affects lower-extremity long bones (e.g. femur, tibia), phalanges, spine ▪ Very intense pain (exacerbated at night) ▪ Responsive to salicylates ▪ Painful scoliosis ▪ Swelling, tenderness



DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Well-defined lucent nidus ▫ Surrounded by reactive bone, 50 ▪ History of Ollier disease, Maffucci syndrome, Wilms’ tumor, radiotherapy (rare)



COMPLICATIONS



▪ Pathological bone fracture ▪ Metastasis ▫ Most commonly lungs, bones ▪ Neurovascular structure impingement ▫ Ischemia, venous thrombosis, pseudoaneurysm



Chapter 109 Cartilage Tumors



SIGNS & SYMPTOMS ▪ Painful, progressively enlarging mass; localized swelling; limited range of motion; fatigue; weight loss ▪ Neurovascular involvement ▫ Numbness, weakness, skin discoloration, loss of pulse, claudication



DIAGNOSIS Staging ▪ Based on grade, spread ▫ Intracompartmental, extracompartmental, systemic/regional metastasis



DIAGNOSTIC IMAGING CT scan ▪ Matrix calcification, endosteal scalloping



OTHER DIAGNOSTICS Fine needle/core biopsy ▪ Determines histologic grading ▫ Grade 1: moderately cellular; small, round chondrocyte nuclei; abundant hyaline cartilage matrix; absent mitosis ▫ Grade 2: ↑ cellularity; ↓ chondroid matrix; enlarged chondrocyte nuclei; scattered mitosis evidence ▫ Grade 3: ↑ ↑ cellularity, sparse/ absent chondroid matrix; nuclear pleomorphism; mitosis clearly present



TREATMENT SURGERY



▪ Intralesional curettage + local phenolization/ cryotherapy → cementation/bone grafting ▪ Complete resection



MRI ▪ T1: low–intermediate intensity mass ▪ T2: high intensity mass X-ray ▪ Lytic pattern: calcifications, endosteal scalloping



Figure 109.1 An X-ray of an intramedullary lesion with features of a low-grade chondroid lesion, likely a chondrosarcoma.



OSMOSIS.ORG 617



OSTEOCHONDROMA osms.it/osteochondroma PATHOLOGY & CAUSES ▪ Benign tumor; outgrowth of tubular bone growth plate ▫ Most common benign bone tumor ▫ Average onset age is 10 years ▫ Capped with hyaline cartilage ▫ Can be pedunculated (with stalk)/sessile (broad base without stalk) ▪ Most common localizations: knee (distal femur/proximal tibia), pelvis, scapula



TYPES



▪ Single sporadic mass ▫ Exostosis ▪ Multiple tumors ▫ Condition known as multiple osteochondromatosis



CAUSES



▪ Mutation of EXT1/EXT2 genes involved in heparan sulfate glycosaminoglycan synthesis → local glycosaminoglycan reduction → disruption of cartilage, normal skeletal growth ▪ Radiation-induced ▪ Idiopathic



COMPLICATIONS



▪ Pathologic fracture, bone malformation, bursitis, malignant transformation (more common in multiple osteochondromatosis) ▪ Neurovascular structure impingement ▫ Ischemia, venous thrombosis, pseudoaneurysm



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Figure 109.2 The gross pathology of an osteochondroma. The surface of the tumor is composed of hyaline cartilage and the centre composed of cancellous bone.



SIGNS & SYMPTOMS ▪ Slow-growing palpable mass, pain, impaired range of motion ▪ Neurovascular involvement ▫ Numbness, weakness, skin discoloration, loss of pulse, claudication



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Often found incidentally (e.g. radiographic exam performed for different reason)



CT scan ▪ Evidence of bony lesion and calcification MRI ▪ Further characterizes tumor morphology, cartilage cap thickness (thick cap → suspect malignancy)



Chapter 109 Cartilage Tumors Ultrasound ▪ Identifies pseudoaneurysms, thrombosis, bursitis X-ray ▪ Dense bony spur



TREATMENT SURGERY



▪ Excision ▫ Symptoms occur/malignant progression signs



OTHER INTERVENTIONS Figure 109.3 An X-ray image of the knee demonstrating a tumor with a cortex continual with normal bone, a characteristic feature of an osteochondroma.



▪ Radiological follow-up ▫ Asymptomatic



Figure 109.4 The histological appearance of an osteochondroma. There is a core of cancellous bone with an overlying cap of hyaline cartilage.



OSMOSIS.ORG 619



NOTES



NOTES



HEAD & NECK MUSCULOSKELETAL DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders of ligaments, muscles, tendons, bones inherent to head, neck



SIGNS & SYMPTOMS ▪ Most commonly pain



TREATMENT MEDICATIONS ▪ Anti-inflammatory/muscle relaxant



SURGERY



▪ In refractory cases



OTHER INTERVENTIONS



DIAGNOSIS



▪ Physical therapy



DIAGNOSTIC IMAGING ▪ For confirmation



OTHER DIAGNOSTICS



▪ History, physical examination



TEMPOROMANDIBULAR JOINT DYSFUNCTION osms.it/TMJ-dysfunction PATHOLOGY & CAUSES ▪ Category of conditions affecting jaw, producing pain and/or dysfunction centred around temporomandibular joint (TMJ)



CAUSES



▪ Jaw clenching ▪ Teeth grinding (bruxism)



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▪



▪ ▪ ▪



▫ Nocturnal/diurnal ▫ Commonly occurs with MDMA use Trauma ▫ Reactive oxygen species produced by inflammation → synovial fluid inflammation → cytokine production → TMJ destruction Arthritis Malocclusion/missing teeth Yawning → joint dislocation



Chapter 110 Head & Neck Disorders ▪ Associated diseases ▫ Rheumatoid arthritis (RA) ▫ Psychiatric disorders → major depressive disorder



SIGNS & SYMPTOMS ▪ Pain: dull, constant ache; waxing, waning intensity (e.g. headaches, toothaches, earaches) ▫ Jaw movement exacerbates (e.g eating, talking) ▫ Manifests anywhere trigeminal nerve (cranial nerve V) innervates ▪ Jaw dysfunction → poor eating/talking ability ▪ Tinnitus ▪ Audible popping/clicking of joint



DIAGNOSIS DIAGNOSTIC IMAGING Panoramic X-ray ▪ May reveal frank dislocation of mandible from TMJ



TREATMENT MEDICATIONS



▪ Short-term NSAIDs ▪ Muscle relaxants second line (e.g. cyclobenzaprine) ▪ Benzodiazepines: nocturnal dosing → ↓ nocturnal bruxism



SURGERY



▪ For refractory disorders ▫ Arthroscopy ▫ Individuals with underlying arthritis → synovial space bone fragment removal



OTHER INTERVENTIONS



▪ Pain control ▫ Moist heat, cold compresses, massage, soft diet, avoid strain ▪ Habit adjustment ▫ ↓ pen chewing, change sleeping position, oral appliance use ▪ Physical therapy ▪ Dislocation → mandible reduction ▪ Bruxism causative → splinting



OTHER DIAGNOSTICS History ▪ Bruxism ▪ Trauma Physical examination ▪ ↓ Range of motion ▪ Palpation ▫ Tenderness to examiner’s finger against TMJ when mouth open ▫ Clicking/popping heard/felt when jaw opened/closed ▪ Abnormal cranial nerve examination ▫ Likely trigeminal (CN V) symptom distribution → muscle weakness and/or sensory disturbance



Figure 110.1 An MRI scan of the head in the parasagittal plane demonstrating an anteriorly dislocated disc in an individual reporting symptoms of temporomandibular joint dysfunction.



OSMOSIS.ORG 621



TORTICOLLIS osms.it/torticollis PATHOLOGY & CAUSES ▪ Abnormal posturing of head, neck; various etiologies ▪ AKA cervical dystonia ▪ Sternocleidomastoid (SCM) muscle connect sternums, clavicle (muscle heads) to mastoid process ▪ One/both SCM head shortened/ hypertrophied → contralateral neck flexion, lateral rotation → torticollis



TYPES Congenital ▪ Birthing difficulty → injury → fibroma/ hematoma formation of SCM muscle → abnormal posturing at/soon after birth ▪ Spinal abnormalities ▪ Klippel–Feil syndrome → cervical vertebrae fusion → torticollis ▪ Atlanto-occipital fusion → abnormal articulation/ankylosis of C1, occipital bone → torticollis Iatrogenic ▪ Side effect of dopamine agonist medication (e.g. first-generation antidepressants) Spasmodic ▪ AKA adult-onset/idiopathic ▪ Characterized by tonic/intermittent spasms of cervical muscles in adults



COMPLICATIONS



▪ Permanent musculoskeletal defects ▪ Neurologic defects → spinal cord impingement



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SIGNS & SYMPTOMS ▪ Abnormal posturing of the head and neck ▫ Lateral rotation (laterocollis) ▫ Forward rotation (anterocollis) ▫ Backward rotation (retrocollis) ▪ SCM muscle ▫ Hypertrophied ▫ Nontender



DIAGNOSIS OTHER DIAGNOSTICS



▪ Congenital ▫ Birth trauma/condition ▪ Iatrogenic ▫ Coincide with medication schedule/ change in dosing ▪ Spasmodic ▫ 5% have ⊕ family history ▫ ⅓ have other dystonias



TREATMENT MEDICATIONS Congenital ▪ Muscular etiology → botulinum toxin injections ▫ Botulinum toxin → inhibits zinc endopeptidase → inhibition of neurotransmitter vesicle release → decreased muscle contraction → decreased muscle tone



Chapter 110 Head & Neck Disorders Iatrogenic ▪ Withdrawal/limitation of offending agent ▪ Prescription of a muscle relaxant/ antihistamine Spasmodic ▪ Muscle relaxant ▪ Benzodiazepines ▪ Anticholinergics ▫ Side effects → limited use (dry mouth, blurry vision, urinary retention, tachycardia, nausea, vomiting, anxiety) ▪ Botulinum toxin injections



OTHER INTERVENTIONS Congenital ▪ Muscular etiology → passive neck stretching Spasmodic ▪ Massage ▪ Physical therapy ▪ Behavioral modification ▪ “Sensory trick” ▫ Sensory stimulus (e.g. lightly laying hand on cheek) may relieve muscle contraction



SURGERY Congenital ▪ Vertebral etiology → surgical intervention if severe Spasmodic ▪ Refractory cases → surgical denervation of affected cervical musculature



OSMOSIS.ORG 623



NOTES



NOTES



INFLAMMATORY ARTHRITIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Musculoskeletal disease subset; known immune component underlying disease ▪ Underlying trigger/cause not always understood



SIGNS & SYMPTOMS ▪ Painful, warm, stiff joints ▪ Variable extra-articular symptoms



DIAGNOSIS LAB RESULTS Synovial fluid analysis ▪ Cloudy yellow appearance ▪ White blood cell count (WBC) > 5,000 ▪ Polymorphonuclear neutrophils (PMNs) < 25%



TREATMENT MEDICATION Anti-inflammatory medication ▪ Common NSAIDs ▪ Immunologically-targeted therapy ▫ Anti-cytokine therapy (e.g. adalimumab)



ANKYLOSING SPONDYLITIS osms.it/ankylosing-spondylitis PATHOLOGY & CAUSES ▪ Group: seronegative spondyloarthritides ▪ Characteristics: articular cartilage destruction, bony joint fusion (ankylosis) → primarily spine, sacroiliac joints ▪ AKA rheumatoid spondylitis, Marie– Strümpell disease ▪ Autoimmune self-reactivity believed to underlie pathophysiology ▫ Strong HLA-B27 association (MHC I serotype; positive in 90% of affected individuals)



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▫ Relative risk for HLA-B27 individuals: 100-200x ▫ IL-23 receptor gene also implicated ▫ Abnormal IL-23 cytokine regulation → naive CD4+ T cell → self-reactive Th17 cells ▪ Associated with Crohn’s disease, ulcerative colitis



RISK FACTORS



▪ Biological sex ▫ 3x ↑ individuals who are biologically male



Chapter 111 Inflammatory Arthritis



COMPLICATIONS



▪ Aortic regurgitation ▫ Aortic aneurysm → aortic valve annulus stretched → regurgitation ▪ Uveitis ▪ Enthesitis (tendinous insertion inflammation) ▪ Dactylitis (“sausage fingers”) ▪ Decreased pulmonary function ▪ Thoracic-rib articulation spondylosis → ↓ chest wall expansion across respiratory cycle ▪ Secondary amyloidosis



SIGNS & SYMPTOMS ▪ Symptoms develop teens-20s ▫ Lower back pain, spinal immobility ▪ Peripheral large joints (hips, knees, shoulders) involved in ⅓ of individuals ▪ Morning stiffness; improves throughout day, with exercise ▪ Untreated disease → extenuated kyphosis of spine



DIAGNOSIS DIAGNOSTIC IMAGING Lumbar spine radiograph ▪ Diagnostic → sacroileitis ▪ Progression of early findings ▫ Subchondral erosions (pseudo-widening effect on X-ray) → sclerosis → sacroiliac joint fusion ▪ Late findings (10+ years of disease) ▫ “Bamboo spine”: prominent syndesmophytes (bony growth inside ligaments), diffuse calcification of paraspinal ligaments, spinal osteoporosis



LAB RESULTS



▪ ↑ erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) suggestive, not diagnostic ▪ ⊝ Rheumatoid factor (RF)



Figure 111.1 An X-ray image of demonstrating bamboo spine and the dagger sign in an individual with ankylosing spondylitis.



OTHER DIAGNOSTICS



▪ Family history ▪ Physical examination ▫ ↓ Spine flexion/extension and ↓ lateral range of motion



TREATMENT MEDICATIONS



▪ NSAIDs (maximum daily dosing recommended) ▫ First line for pain, stiffness ▪ TNF-alpha inhibitors ▫ Etanercept: fusion protein (IgG1 Fc region, TNF alpha receptor); intercepts circulating TNF-alpha, competes with body’s TNF alpha receptors ▫ Infliximab, adalimumab, certolizumab: anti-TNF alpha monoclonal antibodies ▫ Sulfasalazine: if TNF-alpha therapy ineffective; recommended for peripheral joint disease



OSMOSIS.ORG 625



OTHER INTERVENTIONS



▪ Exercise therapy ▫ Home exercise therapy/formal physical therapy regimens ▪ Tobacco use cessation ▪ Heat, ice packs



Figure 111.2 The skeleton of an individual with ankylosing spondylitis. The lumbar and cervical spine have ossified completely and become fused.



GOUT osms.it/gout PATHOLOGY & CAUSES ▪ Episodic, arthritic disorder ▪ Monosodium urate crystallization in, around joint spaces; when left untreated, can manifest as tophi in chronic arthritic disorder ▪ Monosodium urate (MSU): purine and pyrimidine (nitrogen containing heterocycles; DNA components) → primary sources of uric acid; released when cells broken down ▫ Limited solubility in plasma (only 6.8mg/ dL) ▫ Poorer solubility in joint space → lower temperature, synovial fluid composition favor precipitation



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▫ Sources of nidus (precipitates crystals) include collagen fibers, chondroitin sulfate, proteoglycans, cartilage fragments ▫ Physiologic pH of 7.4 → uric acid loses cation, adds Na+ → MSU crystals ▪ Damage pathway: MSU precipitate into joints → complement cascade activated, cytokines produced → leukocyte recruitment → macrophages phagocytose MSU → inflammasome activates caspase-1 → produce IL-1 and other proinflammatory cytokines → ↑ ↑ ↑ leukocyte recruitment, cytokine production ▪ Classification ▫ 90% primary/idiopathic ▫ 10% secondary



Chapter 111 Inflammatory Arthritis



CAUSES



▪ ↑ production of uric acid, purines (most common) ▪ Diet high in red meat, shellfish, anchovies, organ meat ▪ ↑ cell turnover ▪ Cancer treatment → tumor lysis syndrome ▪ Polycythemia vera (5–10% develop gout) ▪ Lesch-Nyhan syndrome ▫ Hypoxanthine guanine phosphoribosyl transferase (HGPRT) deficiency interrupts purine salvage pathway → ↑ degradation of purines → ↑ uric acid production ▪ Dehydration, alcoholic beverage consumption → ↓ clearance of uric acid ▪ Chronic kidney disease



RISK FACTORS



▪ Age ▫ 20–30+ years of hyperuricemia → ↑ risk ▪ Biological sex (↑ individuals who are biologically male) ▪ Genetic ▫ HGPRT (X-linked); URAT1, GLUT9 (both involved in urate transport/homeostasis) ▪ Heavy alcohol consumption ▪ Obesity ▪ Drugs that ↓ urate excretion/↑ production (e.g. thiazides, aspirin) ▪ Glucose metabolization abnormalities (e.g. diabetes mellitus) ▪ Chronic lead toxicity → saturnine gout ▫ Most common risk factor in U.S. is moonshine consumption → lead-lined stills



Figure 111.3 Urate crystals will display negative birefringence on polarised light microscopy.



COMPLICATIONS



▪ Gravel/stone passage → renal colic ▪ Renal failure → death in 20% individuals with chronic gout ▪ ↓ quality of life, generally not lifespan



SIGNS & SYMPTOMS Acute, episodic arthritis ▪ Nocturnal onset ▫ Awakening with complaints, e.g. “feeling like toe on fire” ▪ Most severe pain remits within first hours; pain can last days–weeks ▪ Painful, warm, erythematous, and swollen joint → ↓ range of motion → disability First episode ▪ Commonly monoarticular; 50% of cases include first metatarsal joint (aka podagra) ▪ Asymptomatic period months–years → subsequent episodes (mono- or polyarticular) ▫ 90% of other joints involved, progressively (ankle > heels > knees > wrists > fingers > elbows) ▫ ↑ episodes, polyarticular effects without treatment



Figure 111.4 Gout of the great toe presenting as erythema of the overlying skin.



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Chronic disease (tophaceous gout) ▪ On average, around 12 years after initial attack ▪ MSU deposition ( joint spaces/affected cartilage) ▪ Painless, pedunculated mass; palpitation may discolor overlying skin ▪ Joint’s range of motion sometimes limited ▪ Kidney complications take one of two forms ▫ Symptoms of colicky flank pain, hematuria → uric acid nephrolithiasis ▫ ↓ urine output, difficulty voiding → urate nephropathy



DIAGNOSIS DIAGNOSTIC IMAGING Radiographic/ultrasound/CT scan ▪ Joint destruction, bony erosions (rarely present on the first acute episode) ▪ Imaging findings become more likely with disease duration X-ray ▪ Radiolucent uric acid nephrolithiasis



LAB RESULTS Synovial fluid analysis ▪ MSUs in context of acute, arthritic episodes Polarized light microscope ▪ Long, slender needle-shaped crystals in synovial fluid, neutrophil cytoplasm ▫ Negatively birefringent; yellow under parallel light, blue under perpendicular light



OTHER DIAGNOSTICS



▪ Histological analysis of chronic tophaceous arthritis ▫ Large aggregations of MSU surrounded by inflammatory reaction of foreign body giant cells ▫ Hyperplastic, fibrotic, thickened synovium → pannus formation → destruction of underlying cartilage, juxta-articular bony erosions



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Figure 111.5 An X-ray image of the foot showing destruction of the first metatarsophalangeal joint by arthritis secondary to gout. There is an overlying gouty tophus. ▪ Histological analysis of gouty nephropathy ▫ MSU (with/without tophi) deposits in medullary interstitium/tubules



TREATMENT MEDICATIONS Acute flare therapy ▪ Anti-inflammatory treatment ASAP within acute flare → rapid, complete resolution faster ▪ Glucocorticoids (oral and/or intra-articular injections) ▪ NSAIDs (i.e. naproxen, indomethacin) ▪ Colchicine (inhibits leukocyte migration) ▪ Biologic agents (IL-1 inhibitors)



Chapter 111 Inflammatory Arthritis Management and prevention ▪ Limit medications that alter urate balance (e.g. thiazides, aspirin) ▪ Initiate medications that ↓ uric acid levels ▪ Xanthine oxidase (XO) inhibitors (allopurinol, febuxostat) ▫ Mechanism of action: directly inhibits enzyme → urate production, stimulates purine base reutilization → ↓ ↓ ↓ urate concentration ▪ Uricosuric medications (probenecid) ▫ ↑ urate excretion at kidney ▪ Uricase medications (rasburicase) ▫ Mimic enzyme that catalyzes urate conversion → allantoin (more soluble purine degradation product); enzyme absent in humans



OTHER INTERVENTIONS



▪ Benefit largely due to ↓ development/ worsening of obesity, cardiovascular disease, diabetes mellitus



▪ Diet modification ▫ Limit/avoid soda, red meat, seafood ▪ Alcohol moderation ▪ ↑ physical activity



Figure 111.6 The histological appearance of a gouty tophus. There is a large aggregate of urate crystals which is associated with granulomatous inflammation.



JUVENILE IDIOPATHIC ARTHRITIS osms.it/juvenile-idiopathic-arthritis PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Arthritic symptoms of unknown etiology; present < 16 years old for ≥ six weeks ▪ Unknown pathophysiology; appears related to TH1 and TH17 cells → cell mediators ▫ IL-1, IL-17, TNF-gamma



▪ Arthritis ▫ Oligo- or polyarticular involvement; large joints affected > small ▪ Rheumatoid nodules, factor usually absent



RISK FACTORS



▪ HLA and PTPN22 variants



COMPLICATIONS



▪ 10% develop disability in adulthood



DIAGNOSIS LAB RESULTS



▪ Antinuclear antibodies may be ⊕ or ⊝



TREATMENT ▪ Similar to rheumatoid arthritis ▪ Some success with IL-6 R antibody biologic disease-modifying antirheumatic drug (DMARD)



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PSEUDOGOUT osms.it/pseudogout PATHOLOGY & CAUSES ▪ Calcium pyrophosphate (CPP) crystal depositions in articular cartilage ▪ AKA chondrocalcinosis ▪ Unlike gout, hyperuricemia ▫ No known direct substance concentration → ↑ crystal formation ▪ Pathway of joint inflammation, destruction similar to gout ▫ Articular cartilage proteoglycans degraded, serve as nidus for crystal formation around chondrocytes ▫ CPP crystals precipitate around chondrocytes → complement cascade activated, cytokines produced → leukocyte recruitment → macrophages phagocytose MSU (inflammasome activates caspase-1) → produce IL-1, other proinflammatory cytokines → further leukocyte recruitment, cytokine production



CAUSES



▪ Sporadic (idiopathic) ▪ Hereditary ▫ Autosomal dominant version → early manifestation, more severe symptoms ▫ Also associated with osteoarthritis ▫ Mutations in pyrophosphate transport channel ▪ Secondary to previous joint damage, hyperparathyroidism, hemochromatosis, hypothyroidism, ochronosis, diabetes



RISK FACTORS



▪ Age ▫ Usually affects individuals > 50 years; by > 85 years → 30–60% prevalence ▪ ↓ magnesium levels



COMPLICATIONS ▪ Significant joint damage ▫ ≤ 50% of individuals



SIGNS & SYMPTOMS ▪ Episodic joint pain ▫ Knee most commonly affected; followed by wrists → elbows → shoulders → ankles ▪ Duration of several days–weeks ▪ Oligo- or polyarticular ▪ Frequently asymptomatic



DIAGNOSIS OTHER DIAGNOSTICS Histological analysis ▪ Gross ▫ Chalky, white, friable ▪ Microscopic ▫ Aggregates stain as blue/purple, oval ▪ Crystals ▫ Rhomboid, ⊕ birefringent ▪ Crystallization first develops in articular cartilage, menisci, intervertebral discs Physical examination ▪ Acutely painful, inflamed joint; commonly knee



TREATMENT MEDICATIONS Acute flares ▪ NSAIDs ▪ Colchicine ▪ Glucocorticoids Management and prevention ▪ Colchicine



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Chapter 111 Inflammatory Arthritis



OTHER INTERVENTIONS



▪ Treat underlying disorder (if known) ▪ Symptomatic therapy similar to gout treatment



Figure 111.7 A calcium pyrophospahte crystal in joint fluid aspirated from the knee of an individual with pseudogout.



OSMOSIS.ORG 631



PSORIATIC ARTHRITIS osms.it/psoriatic-arthritis PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Group: seronegative spondyloarthritides ▪ Associated with psoriasis ▪ Affects peripheral, axial joints; ligaments, tendons (entheses) ▪ Abnormal T cell response to unknown culprit antigen ▫ TH1, TH17 cells thought responsible → stimulate activated CD8+ T cells → cytokine, growth factor environment change/destroy local tissue ▫ Implicated synovial cell mediators: IL-1, IL-6, TNF-alpha, IL-8 ▫ Synovial fibroblasts interact with immune response → secreting IL-1beta, IL-6, and platelet-derived growth factors (PDGF) ▫ Affected synovia marked with increased vascularity → ↑ leukocytic entryways



▪ Predominantly peripheral arthritis of hands, feet ▪ Distal interphalangeal (DIP) joint first affected, asymmetrically distributed in > 50% of individuals ▪ Sacroiliac joint affected in 20% of individuals ▪ Degree of joint involvement may be mild/ progress → severe, disfiguring disease as in rheumatoid arthritis (RA)



TYPES



▪ Mild: one joint involved/responds to NSAIDs ▪ Moderate-severe: NSAID-resistant ▪ Severe: polyarticular, erosive; functional limitation



CAUSES



▪ Local trauma induces dysregulated immune response → local tissue destruction ▫ AKA Koebner phenomenon ▪ 10% of psoriatic individuals develop arthritis symptoms



RISK FACTORS



HLA-B27 HLA-Cw6 Obesity Associated diseases ▫ Myopathy, enteropathy, AIDS ▪ Age: 30 50 years old



▪ ▪ ▪ ▪



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Figure 111.8 The feet of an individual with psoriatic arthritis. There is inflammation of the ankle and the interphalangeal joints as well as psoriatic nail changes.



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Characteristic “pencil-in-cup” malformation at DIP joint



Chapter 111 Inflammatory Arthritis



OTHER DIAGNOSTICS Histological analysis ▪ Similar to RA, but symptoms not as severe, remissions more frequent, joint destruction less frequent History ▪ 40% of affected individuals have firstdegree relative with psoriatic arthritis Physical examination ▪ Integument examination consistent with psoriasis ▪ Papules, plaques with silver scales on extensor surfaces (fingers, knees, elbows) ▪ Commonly affects scalp, nails (“nail pitting”) ▪ Musculoskeletal examination consistent with arthritis ▪ Asymmetric involvement of both peripheral, axial joints ▪ Commonly affects DIP joints under skin manifestations



Figure 111.9 An X-ray image of the hands of an individual with long-standing psoriatic arthritis which has progressed to arthritis mutilans. Telescoping of the phalangeal joints is visible.



TREATMENT MEDICATIONS Mild disease ▪ NSAIDs Moderate-severe disease ▪ Conventional (DMARD) therapy ▪ Methotrexate (MTX; co-treat with daily folic acid), leflunomide (does not also target skin disease) ▫ Both require eliminating alcohol intake Severe disease ▪ ‘Biologic’ DMARD (e.g. TNF inhibitor) ▪ Etanercept, adalimumab, infliximab, certolizumab ▫ All require latent TB screening before initiation therapy initiation ▪ Anti-IL-17 ‘biologic’ (e.g. secukinumab, ixekizumab, brodalumab)



OTHER INTERVENTIONS



▪ Exercise, physical therapy, occupational therapy ▪ Weight reduction



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REACTIVE ARTHRITIS osms.it/reactive-arthritis PATHOLOGY & CAUSES ▪ Group: seronegative spondyloarthritides ▪ Characterized by triad ▫ Arthritis, nongonococcal urethritis/ cervicitis, conjunctivitis ▪ AKA Reiter syndrome ▪ Hypothesis: autoimmune reaction to prior infection of GU/GI system ▪ Genitourinary triggers: urethritis/cervicitis ▫ Common pathogen: Chlamydia trachomatis ▪ Gastrointestinal triggers: diarrheal illness ▫ Common pathogens: Shigella, Salmonella paratyphi, Yersinia enterocolitica, Campylobacter jejuni ▪ RF ▪ HIV ⊕ ▪ HLA-B27 ⊕ (80+% of affected individuals)



▪ Most asymmetrically affected joints ▫ Ankles, knees, feet; upper extremity involvement less common Other symptoms ▪ Fever, malaise, weight loss, fatigue ▪ Symptoms’ severity waxes, wanes; usually lasts 1.5–6 months ▪ Recurrent arthritic episodes, tendonitis, lumbosacral pain in 50% of individuals ▪ Keratoderma blennorhagicum ▫ Vesiculopustular, waxy lesions on the soles or palms



COMPLICATIONS



▪ Digital tendon sheath synovitis → dactylitis (“sausage” finger/toe) ▪ Tendoligamentous insertion sites ossification → calcaneal spurs, bony outgrowths ▪ Severe spinal disease; becomes indistinguishable from ankylosing spondylitis ▪ Extra-articular involvement ▫ Inflammatory balanitis, conjunctivitis, cardiac conduction abnormalities, aortic regurgitation



SIGNS & SYMPTOMS Arthritic symptoms ▪ Develop several weeks post-initial infection ▪ Common, early symptoms ▫ Joint stiffness, low back pain ▪ Days later ▫ Painful joints, effusion, lack of mobility



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Figure 111.10 Keratoderma blennorhagicum on the feet of an individual with reactive arthritis.



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Involved joint ▫ No specific diagnostic changes ▪ Negative for stress fractures, other forms of arthritis



Chapter 111 Inflammatory Arthritis



LAB RESULTS Synovial fluid analysis ▪ Absence of joint space infection, crystals Cultures ▪ May be helpful if GI/GU symptoms ongoing → identify well-associated bacteria



OTHER DIAGNOSTICS History ▪ Preceding illness, rapid-onset arthritis/ systemic symptoms ▪ Arthritic presentation often too late for stool/urine culture (for GU/GI trigger) Physical examination ▪ Lower extremity joint involvement as above



TREATMENT MEDICATIONS



▪ NSAIDs ▪ Glucocorticoids; intra-articular, systemic formulation available ▪ Resistant/chronic (> six months) disease ▫ DMARD (e.g. sulfasalazine, MTX, azathioprine) ▪ Antibiotics not recommended ▫ Exception: triggering disease process (GI/GU diarrhea/urethritis/cervicitis) ongoing ▪ Skin involvement (if present) → topical salicylates



OTHER INTERVENTIONS



▪ Conjunctivitis (if present) → ophthalmology referral



RHEUMATOID ARTHRITIS osms.it/rheumatoid-arthritis PATHOLOGY & CAUSES ▪ Systemic, chronic, autoimmune inflammatory disorder involving joint synovium ▪ May progress to disfigurement → cartilaginous, bony damage over time ▪ Dual hit hypothesis (genetics and environment) ▫ Genetics: HLA-DR1 or DR4 genetic predisposition → thought to underlie the immune pathogenesis pathway below ▫ Environment: cigarette smoke, pathogen (i.e. gut bacteria) → may contribute to unknown ‘arthrogenic agent’, trigger immune response



PATHOLOGY



▪ CD4+ T cells: react with arthrogenic agent (unknown; thought to be a microbe/ self-antigen) → cytokine production → IFN-gamma (TH1 product) → activate macrophages and synovial cells → synovial, immune cell proliferation → swollen synovial tissue (also known as pannus formation) → IL-17 (TH17 product) → recruit neutrophils and monocytes → TNF-alpha and IL-1 (macrophage product) → stimulate synovial cells → protease release → hyaline cartilage destruction → ↓ cartilaginous buffer → bone on bone articulation → ↑ bone destruction ▪ RANKL (on T cells): activate osteoclasts’ RANK receptor → bone resorption



OSMOSIS.ORG 635



▪ Synovial cells: directly responsible for protease release, contribution to cytokine milieu ▫ Germinal centers within synovium include plasma cells → antibodies against self-antigens, i.e. autoantibodies → specific for citrullinated peptides (CCPs)/arginine residues converted to citrulline ▫ Antibodies against fibrinogen, type II collagen, alpha-enolase, vimentin → form antibody-antigen complexes → deposit into joints ▫ Antibodies (usually IgM or IgA) against Fc regions of IgG antibodies form RF → deposit into joints ▪ Chronic inflammation → angiogenesis → increase inflammatory cell response → further joint involvement Extra-articular involvement ▪ Pyogens (i.e. IL-1) ▫ → Hypothalamus → fever ▪ Skeletal ▫ Protein breakdown ▪ Skin ▫ Macrophage and lymphocytes recruitment → cycle of activation/ recruitment → cells around a central necrotic mass → rheumatoid nodules ▪ Blood vessels ▫ ↑ cytokines and ↑ circulating immune cells → altered endothelial cells → ↑ atheromatous plaques formation ▪ Liver ▫ Under chronic inflammation → ↑ hepcidin production → ↓ iron absorption → anemia ▪ Lung ▫ ↑ fibroblasts → lung fibrosis (AKA Caplan syndrome) → ↓ gas exchange (+/- pleural effusion)



COMPLICATIONS Autoimmune ▪ AA amyloidosis ▪ Sjögren syndrome ▪ Scleritis



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Cardiovascular ▪ ↑ Atheromatous formation → ↑ MI, CVA risk ▪ Pericarditis → ↑ pericardial effusion risk Hematologic ▪ Anemia ▪ Felty syndrome (RA, splenomegaly, neutropenia) Musculoskeletal ▪ Rheumatoid nodules ▫ Can form in any body tissue ▪ Baker (popliteal) cyst formation Neurological ▪ Carpal tunnel syndrome ▪ Mononeuritis multiplex ▪ C1-C2 instability → ↑ risk of subluxation → spinal cord impingement risk → neurologic involvement ▪ Serious complication if unknown at time of intubation Pulmonary ▪ Pleuritis → ↑ risk of pleural effusion (characteristically ↓ glucose, ↓ complement) ▪ Interstitial lung disease ▪ Caplan syndrome



SIGNS & SYMPTOMS Inflammatory polyarthritis ▪ Commonly symmetrically affects multiple (> five) joints ▪ First smaller joints - MCP, PIP, MTP ▪ Avoids DIP joint ▪ Chronic disease → ↑ larger joint involvement Joint characteristics ▪ Warm, red, and painful joints ▪ Morning stiffness (lasting > one hour) Malformation ▪ Ulnar deviation of MCP joints ▪ Boutonniere (buttonhole) malformation ▪ Swan neck



Chapter 111 Inflammatory Arthritis



OTHER DIAGNOSTICS History ▪ Symptoms for > six weeks Physical examination ▪ Inflammatory (warm, stiff, painful) arthritis of > three joints ▪ Characteristic malformations ▫ Ulnar deviation, boutonniere (“buttonhole”) malformation, swan neck malformation



Figure 111.11 Ulnar deviation of the fingers in an individual with rheumatoid arthritis. Extra-articular manifestations ▪ Common, systemic signs ▫ Fever, fatigue, weight loss ▪ Rheumatoid nodules ▫ Commonly arise on extensor surfaces ▪ More varied sequelae in severe and/or chronic disease



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Soft tissue swelling ▪ Bony erosions ▪ ↓ Bone density ▪ Narrowed joint space (late finding)



LAB RESULTS



▪ RF titers ▫ High titers associated with more severe disease ▫ Eventually present in 80% of affected individuals ▪ Anti-citrullinated peptide/protein antibodies (anti-CCP) ▫ Sensitivity 50–75%; specificity > 90% ▪ ↑ ESR, ↑ CRP ▪ Normocytic anemia (anemia of chronic disease)



Figure 111.12 An X-ray image of the hands of an individual with rheumatoid arthritis. There is destruction of the metacarpophalangeal joints, the carpometacarpal joints and the wrist.



TREATMENT MEDICATIONS



▪ NSAIDs ▪ Short-term, low-dose glucocorticoid ▪ DMARD ▫ Hallmark of RA treatment ▫ Methotrexate (give with folic acid to ↓ side effects) ▫ Others: leflunomide, hydroxychloroquine, sulfasalazine ▪ Biologic DMARDs ▫ Adalimumab, etanercept (intercept), infliximab particularly effective (block TNF-alpha, which is thought to underlie most joint damage)



OSMOSIS.ORG 637



▫ Abatacept (suppresses T cells) ▫ Rituximab (suppresses B cells) ▫ Anakinra (blocks IL-1) ▫ Tocilizumab (blocks IL-6)



SURGERY



▪ Only if medication fails ▪ Severe joint malformation ▫ Synovectomy ▪ Severe malformation, disability ▫ Joint replacement



OTHER INTERVENTIONS



▪ Exercise to maintain range of motion and muscle strength



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Figure 111.13 A histological section of a rheumatoid nodule. There is granaulomatous inflammation composed of central fibrinoid necrosis and palisading histiocytes.



NOTES



NOTES



INFLAMMATORY CONNECTIVE TISSUE DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Chronic autoimmune disorders characterized by inflammation; primarily affect connective tissue ▪ Production of autoantibodies → deposition of immune complexes → complement activation → tissue destruction ▪ Inflammatory cytokines stimulate fibroblasts → increased collagen deposition (fibrosis) ▪ Affects multiple organ systems ▫ Skin, heart, respiratory system, urinary, gastrointestinal (GI) tract



CAUSES ▪ Genetic, environmental factors



COMPLICATIONS ▪ Skin necrosis; renal, cardiac failure; pulmonary insufficiency; GI reflux/bleeding



SIGNS & SYMPTOMS ▪ Constitutional symptoms ▫ Low grade fever, fatigue, weight loss ▪ Specific to disease, organ systems affected ▫ “Butterfly skin rash” specific to systemic lupus erythematosus (SLE)



DIAGNOSIS DIAGNOSTIC IMAGING Barium swallow X-ray ▪ GI involvement



LAB RESULTS ▪ Blood tests ▫ Hematologic abnormalities, increased inflammatory markers, complications (e.g. increased creatinine reflecting renal failure) ▪ Serological tests ▫ Antibodies, confirm diagnosis



OTHER DIAGNOSTICS ▪ Physical examination (e.g. characteristic skin rashes) ▪ Pulmonary function tests ▫ Pulmonary involvement



TREATMENT ▪ Usually symptomatic (e.g. analgesics)



MEDICATIONS ▪ Steroids/other immunosuppressive agents ▫ Reduce inflammation



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CREST SYNDROME osms.it/CREST-syndrome PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Form of limited systemic sclerosis ▪ Composed of five features; see mnemonic ▫ Calcinosis: deposition of calcium under skin ▫ Raynaud’s syndrome: episodic, dramatic constriction of arteries in hands ▫ Esophageal dysmotility: atrophied muscle in esophagus without significant inflammation/fibrosis ▫ Sclerodactyly: fibrosis of skin of digits ▫ Telangiectasia: dilation of small blood vessels ▪ Caused by chronic autoimmune inflammation triggered mainly by anticentromere antibodies (ACAs) ▪ More benign clinical course than other forms of sclerosis



▪ Calcific nodules under the skin ▪ White-blue-red transitions in skin color in response to triggers (e.g. low temperature, stress) ▪ Dysphagia (due to esophageal dysmotility) ▪ Sclerodactyly ▪ Telangiectasias (esp. hands, face)



MNEMONIC: CREST



Features of CREST syndrome Calcinosis Raynaud’s syndrome Esophageal dysmotility Sclerodactyly Telangiectasia



COMPLICATIONS ▪ Ischemic ulcers, gangrene, predisposition to chronic skin infections (due to sclerosis, severe ischemia of skin) ▪ Upper GI bleeding (due to mucosal telangiectasias)



Figure 112.1 Sclerodactyly in an individual with CREST syndrome.



DIAGNOSIS LAB RESULTS ▪ Serum blood tests ▫ ↑ ANAs: sensitive for systemic sclerosis ▫ ↑ ACAs: highly specific (limited systemic sclerosis); confirm diagnosis



OTHER DIAGNOSTICS ▪ Clinical history, physical examination



TREATMENT MEDICATIONS



▪ Steroids ▪ If sclerosis progresses, stronger immunosuppressants (e.g. cyclosporine)



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Chapter 112 Inflammatory Connective Tissue Disorders



FIBROMYALGIA osms.it/fibromyalgia PATHOLOGY & CAUSES ▪ Chronic condition of central sensitization; hypersensitivity to pain, sleep disturbances ▫ ↓ serotonin (inhibits pain signals) ▫ ↑ substance P, ↑ nerve growth factor (involved in propagating pain signals) ▫ Predominance in individuals who are biologically female



CAUSES



▪ Genetic factors ▪ Environmental factors (child abuse) ▪ Negative emotions (depression, anxiety, negative beliefs) can amplify pain



SIGNS & SYMPTOMS ▪ Low threshold to pain ▪ Widespread muscle pain ▪ Extreme tenderness in various parts of body ▪ Sleep disturbances → fatigue, headache ▪ Difficulty concentrating, remembering things; AKA “fibro fog”



DIAGNOSIS OTHER DIAGNOSTICS Diagnostic Criteria ▪ Pain in ≥ seven areas of body with symptom severity (SS) of ≥ 5 (of 12)/pain in ≥ five areas of body with SS of ≥ 9 (of 12) ▪ Final score between 0–12 ▪ Symptoms present ≥ three months ▪ Pain not due to another disorder



Symptom severity (SS) measures ▪ Fatigue; waking unrefreshed; cognitive symptoms; somatic symptoms ▫ 0: no problem ▫ 1: slight/mild/intermittent ▫ 2: moderate/considerable/often present ▫ 3: severe, continuous, life disturbing



TREATMENT MEDICATIONS ▪ If non-pharmacologic measures fail, drug therapy ▪ Antidepressants ▫ Inhibit pain by elevating levels of serotonin, norepinephrine ▫ Tricyclic antidepressants (TCAs): amitriptyline first line treatment ▫ Serotonin-norepinephrine reuptake inhibitors (SNRIs): milnacipran ▪ Anticonvulsants ▫ Slow nerve impulses, relieve sleep disturbances



PSYCHOTHERAPY ▪ Cognitive behavioral therapy (CBT) ▫ Manage pain, change negative feelings



OTHER INTERVENTIONS ▪ Physical therapy, relaxation techniques, sleep hygiene to reduce pain, fatigue



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MIXED CONNECTIVE TISSUE DISEASE (MCTD) osms.it/mixed-connective-tissue-disease PATHOLOGY & CAUSES



DIAGNOSIS



▪ Overlap autoimmune syndrome; constellation of SLE, systemic sclerosis, polymyositis; may not occur simultaneously ▪ Can evolve into classic SLE/systemic sclerosis



▪ Confirmation requires characteristic clinical presentation



COMPLICATIONS ▪ Pulmonary hypertension; interstitial lung disease; renal disease



SIGNS & SYMPTOMS ▪ Arthralgias (due to polyarthritis) ▪ Myalgias (due to mild myositis) ▪ Swollen hands with puffy fingers (due to synovitis) ▪ Sclerodactyly ▪ Early development of Raynaud phenomenon ▪ Fatigue ▪ Low-grade fevers



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LAB RESULTS ▪ High serum levels of anti-U1 ribonucleoprotein (anti-U1-RNP) antibodies ▪ High ANAs, RF, anti dsDNA, anti Sm, anti Ro



TREATMENT ▪ Depends on predominant autoimmune disease



MEDICATIONS



▪ Corticosteroids ▫ Suppress immune system



Chapter 112 Inflammatory Connective Tissue Disorders



POLYMYALGIA RHEUMATICA (PMR) osms.it/polymyalgia-rheumatica PATHOLOGY & CAUSES ▪ Immune-mediated rheumatic condition affecting joints, sparing muscles ▪ Most commonly affects shoulder, hip joints ▪ Usually occurs in individuals who are biologically female > 50; mean age 70 ▪ Strongly associated with giant-cell arteritis, AKA temporal arteritis ▪ Can regress without treatment after 1–2 years/remain chronic



CAUSES



▪ Genetic defects: specific allele of human leukocyte antigen (HLA)-DR4 ▪ Environmental factors: exposure to adenovirus/human parvovirus B19



SIGNS & SYMPTOMS ▪ Joint pain, stiffness (shoulder, hip joints) ▫ Often starts unilaterally, progresses to bilateral within few weeks ▫ More severe after prolonged inactivity (e.g. morning) ▫ Typically lasts > one hour ▫ Affects nearby nerves in muscle → muscle pain (referred pain)



▪ Constitutional symptoms ▫ Low grade fever (interleukins act as pyrogens) ▫ Fatigue ▫ Loss of appetite → weight loss ▪ If severe headache, jaw pain, vision problems ▫ Temporal arteritis



DIAGNOSIS LAB RESULTS



▪ Increased serum inflammatory markers ▫ Erythrocyte sedimentation rate (ESR) ▫ C-reactive protein (CRP) ▪ Biopsy ▫ Inflammation in joints



OTHER DIAGNOSTICS ▪ Physical examination ▫ Decreased passive range of motion of affected joints



TREATMENT MEDICATIONS



▪ Low dose of corticosteroids ▫ Suppress immune response



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RAYNAUD'S DISEASE osms.it/raynauds-disease PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Vasospasm of skin arteries in response to triggers, resulting in skin color transitions ▪ Exposure to trigger → stimulation of sympathetic nerves in arteriole walls → vasospasm of arterioles → decrease in blood flow ▪ Usually affects hands, fingers, toes; can affect nose, ears, lips ▪ Common triggers ▫ Emotional stress; low temperatures; nicotine; caffeine; medications that affect sympathetic nervous system (e.g. pseudoephedrine)



▪ Vasospasm → changes in skin color of hands, fingers, toes ▫ White: ischemia ▫ Blue: hypoxia after prolonged ischemia ▫ Red: reactive hyperemia (vasospasm ends, oxygenated blood rushes into tissue) ▪ Raynaud phenomenon ▫ Affects hand fingers, toes symmetrically; severity remains constant ▪ Raynaud syndrome ▫ Asymmetrical; progressive severity ▪ Swelling, numbness, tingling, pain (due to reactive hyperemia)



TYPES Primary: Raynaud phenomenon/disease ▪ Common in pregnant individuals, people who work in jobs involving vibration (e.g. jackhammer) Secondary: Raynaud syndrome ▪ Connective tissue disorders ▫ Systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease ▪ Disorders affecting blood vessels ▫ Buerger’s disease, Takayasu’s arteritis, thromboangiitis obliterans ▪ Medications ▫ Beta blockers, nicotine



COMPLICATIONS ▪ Ulceration, infarction, tissue necrosis, gangrene (if severe)



DIAGNOSIS ▪ Based upon description of episodes



DIAGNOSTIC IMAGING ▪ Nailfold capillary microscopy to examine finger capillaries ▫ Normal appearance: Raynaud phenomenon ▫ Damaged appearance: Raynaud syndrome



TREATMENT MEDICATIONS ▪ Vasodilators (e.g. calcium channel blockers)



SURGERY ▪ If severe, surgery to cut sympathetic nerve fibers supplying affected areas



OTHER INTERVENTIONS ▪ Avoid triggers



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Chapter 112 Inflammatory Connective Tissue Disorders



Figure 112.2 A hand with pale fingers caused by Raynaud’s disease.



SCLERODERMA osms.it/scleroderma PATHOLOGY & CAUSES ▪ AKA systemic sclerosis ▪ Chronic inflammatory autoimmune disease, can result in widespread damage to small blood vessels, excessive fibrosis ▫ T helper cells activated by unknown antigen → release cytokines → stimulate inflammatory cells, fibroblasts → chronic inflammation, excessive collagen deposition ▫ Mediators released by inflammatory cells → damage microvasculature → ischemic injuries, scarring ▪ Primarily affects skin, can involve visceral organs ▫ GI tract, kidneys, heart, muscles, lungs



TYPES Limited (80%) ▪ Skin involvement limited to fingers, forearms, face ▪ Late visceral involvement



▪ Some individuals develop CREST syndrome ▫ Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia ▪ Associated with anticentromere antibodies ▪ Relatively benign Diffuse (20%) ▪ Widespread skin involvement ▪ Early visceral involvement ▪ Rapid progression ▪ Associated with anti-DNA topoisomerase I antibodies ▪ Poor prognosis



RISK FACTORS ▪ More common in individuals who are biologically female (3:1 ratio) ▪ Average age of onset: 35–50 ▪ Genetic factors ▪ Environmental factors (e.g. viruses, toxins, drugs)



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COMPLICATIONS ▪ Excessive skin fibrosis → painful ulcers, disfigurement, disability ▪ Severe internal organ involvement → renal, cardiac failure; pulmonary insufficiency; intestinal malabsorption



SIGNS & SYMPTOMS ▪ Raynaud phenomenon ▫ Precedes other symptoms, present in almost all individuals ▪ Cutaneous changes of face, extremities ▫ Skin thickening, tightening, sclerosis (most common); edema, erythema (precede sclerosis) ▪ GI involvement ▫ Esophageal fibrosis → dysphagia, GI reflux ▫ Small intestine involvement → abdominal pain, obstructions, constipation, diarrhea, malabsorption syndrome (weight loss, anemia) ▪ Pulmonary involvement with interstitial fibrosis ▫ Right-sided cardiac dysfunction/ pulmonary hypertension ▪ Cardiac involvement ▫ Pericardial effusions, myocardial fibrosis → congestive heart failure, arrhythmias ▪ Renal involvement (diffuse disease) → fatal hypertensive crisis (rare)



Figure 112.3 The finger of an individual with systemic sclerosis showing sclerosis, erythema and ulcer formation.



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Upper endoscopy ▫ Esophageal fibrosis/reflux esophagitis



LAB RESULTS ▪ Serologic tests ▫ ↑ ANAs in almost all individuals with systemic sclerosis; low specificity ▫ ↑ ACAs highly specific (limited) ▫ Anti-topoisomerase I antibodies (antiScl-70) highly specific (diffuse) ▪ Complete blood count (CBC) ▫ Anemia due to malabsorption, increased serum creatinine due to renal dysfunction



OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Skin thickening, swollen fingers, Raynaud’s phenomenon, GI reflux ▪ Pulmonary function tests ▫ Restrictive ventilatory defect due to pulmonary interstitial fibrosis



Figure 112.4 A rash on the back of an individual with a form of localised scleroderma known as morphea.



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Chapter 112 Inflammatory Connective Tissue Disorders



TREATMENT ▪ Depends on disease subset, severity of internal organ involvement



MEDICATIONS ▪ Usually symptomatic ▫ Analgesics for musculoskeletal pain



▫ Proton pump inhibitors for gastroesophageal reflux ▫ Calcium channel blockers for Raynaud’s phenomenon ▫ Angiotensin converting enzyme (ACE) inhibitors for renal hypertensive crisis ▪ Immunosuppressive therapy initiation: diffuse skin/severe internal organ involvement



SJOGREN'S SYNDROME (SS) osms.it/sjogrens-syndrome PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Chronic autoimmune inflammatory disease; lymphocytic infiltration, destruction of exocrine glands of eyes, mouth ▪ Proposed mechanisms ▫ Immune reactions against antigens of viral infection of exocrine glands ▫ Autoimmune T cell reaction against unknown self antigen expressed in salivary, lacrimal glands ▪ Variety of extraglandular manifestations may occur ▪ Usually occurs in individuals who are biologically female, 50–60 years



▪ Dry eyes ▫ Irritation, itching, foreign body sensation, keratoconjunctivitis ▪ Oral dryness reflecting salivary hypofunction ▪ Salivary gland enlargement (parotid, submandibular, etc.) ▪ Extraglandular manifestations ▫ Musculoskeletal symptoms (arthralgias, arthritis); rashes; interstitial nephritis, vasculitis



CAUSES



▪ Primary: sicca syndrome ▪ Secondary (to other autoimmune diseases): rheumatoid arthritis (most common)



COMPLICATIONS ▪ Periodontal complications; oral infections; mucosal associated lymphoid tissue (MALT) lymphoma



DIAGNOSIS ▪ Clinical presentation: persistent dry eyes/ mouth, parotid gland enlargement



DIAGNOSTIC IMAGING Parotid gland MRI ▪ Honeycomb pattern Salivary gland ultrasound ▪ Multiple hypoechoic areas



LAB RESULTS



▪ CBC ▫ Leukopenia, thrombocytopenia, anemia ▪ ↑ ESR ▪ Urinalysis



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▫ Proteinuria/hematuria reflecting glomerulonephritis ▪ Labial salivary gland biopsy (confirm diagnosis) ▫ Focal lymphocyte foci (collections of tightly aggregated lymphocytes) ▪ Serologic tests (support diagnosis) ▫ ↑ antinuclear antibodies (ANAs) in 95% of individuals ▫ ↑ rheumatoid factor (RF) in 50–75% of individuals with/without rheumatoid arthritis ▫ Anti-Sjögren syndrome A (SSA) (Ro), Anti-Sjögren syndrome B (SSB) (La) specific to SS, found elevated only in 55%, 40% of individuals, respectively



OTHER DIAGNOSTICS Tear deficiency tests ▪ Schirmer test ▫ Measures reflex tear production; wetting of test paper < 5mm indicative of tear deficiency ▫ Ocular surface staining with Rose Bengal stain and slit-lamp examination—assess tear break-up time (TBUT); TBUT < 10 seconds indicative of tear deficiency ▪ Salivary gland tests ▫ Salivary gland scintigraphy: low uptake of radionuclide characteristic of SS ▫ Sialometry: low volume of saliva indicative of salivary gland hypofunction



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Figure 112.5 A lymphocytic infiltrate in a minor salivary gland excised from an individual with Sjögren’s syndrome.



TREATMENT MEDICATIONS ▪ Mild SS ▫ Secretagogues ▫ Local treatment for ocular, oral dryness (e.g. artificial tears) ▪ Moderate to severe SS ▫ Immunosuppressive treatment



Chapter 112 Inflammatory Connective Tissue Disorders



SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) osms.it/systemic-lupus-erythematosus PATHOLOGY & CAUSES ▪ Chronic systemic autoimmune disorder; wide range of clinical, serological features ▪ Periods of flare-ups, remittance ▪ Environmental triggers damage DNA → apoptosis → release of nuclear bodies ▪ Clearance of apoptotic bodies ineffective due to genetic defects → increased amount of nuclear antigens in bloodstream → initiates immune response → production of antinuclear antibodies → bind to antigens, form immune complexes ▪ Complexes deposit in tissues (e.g. kidneys, skin, joints, heart) → Type III hypersensitivity reaction ▪ Individuals may develop antibodies targeting molecules (e.g., phospholipids) of red, white blood cells → marking them for phagocytosis → Type II hypersensitivity reaction



▪ Antiphospholipid syndrome ▫ Hypercoagulable state; individuals prone to develop clots (e.g. deep vein thrombosis, hepatic vein thrombosis, stroke)



SIGNS & SYMPTOMS ▪ Fever, joint pain, rash in sun-exposed areas ▪ Typical rashes ▫ Malar rash (butterfly rash): over cheeks ▫ Discoid rash: plaque-like/patchy redness, can scar ▫ General photosensitivity: typically lasts few days



RISK FACTORS Genetic defects associated with SLE UV radiation Smoking Viral, bacterial infections Medications (e.g. procainamide, hydralazine, isoniazid, estrogens) ▪ More common in individuals who are biologically female, of reproductive age ▪ ▪ ▪ ▪ ▪



COMPLICATIONS ▪ Cardiovascular disease ▫ Libman–Sacks endocarditis, myocardial infarction (MI) ▪ Serious infections; renal failure; hypertension



Figure 112.6 A butterfly rash on the face of an individual with systemic lupus erythematosus.



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▪ ▪ ▪ ▪



▪ ▪



▪ ▪



Weight loss Ulcers in oral/nasal mucosa Serositis (e.g. pleuritis/pericarditis) Libman–Sacks endocarditis: formation of nonbacterial vegetations on ventricular, atrial valve surfaces; mitral, aortic valves (most common) Myocarditis Renal disorders ▫ Abnormal levels of urine protein, diffuse proliferative glomerulonephritis Neurologic disorders ▫ Seizures, psychosis Hematologic disorders ▫ Anemia, thrombocytopenia, leukopenia



DIAGNOSIS OTHER DIAGNOSTICS Diagnostic criteria (4 of 11) ▪ Malar rash ▪ Discoid rash ▪ General photosensitivity ▪ Oral/nasal ulcers ▪ Serositis ▪ Arthritis in ≥ two joints ▪ Renal disorders ▪ Neurologic disorders ▪ Hematologic disorders ▪ Antinuclear antibodies ▫ Very sensitive, not specific ▪ Other antibodies ▫ SLE specific: anti-Smith, anti-dsDNA ▫ Anti-phospholipid: anticardiolipin (false-positive test for syphilis); lupus anticoagulant (lupus antibody); anti-beta 2 glycoprotein I



TREATMENT ▪ Goal: prevent relapses, limit severity



MEDICATIONS



Figure 112.7 An MRI scan of the head of an individual with SLE who presented with altered mental status and seizures. There a numerous small infarcts suggestive of cerebral vasculitis. The individual improved after treatment with steroids.



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▪ Long term therapy ▫ Antimalarial agents ▪ Mild to moderate manifestations ▫ Non-steroidal anti-inflammatory drugs (NSAIDs), low doses of corticosteroids ▪ Severe/life-threatening manifestations ▫ High doses of corticosteroids, intensive immunosuppressive drugs



OTHER INTERVENTIONS ▪ ▪ ▪ ▪ ▪



Avoid sun exposure Physical exercise Balanced diet Smoking cessation Immunizations



Chapter 112 Inflammatory Connective Tissue Disorders



Figure 112.8 A histological section of a lymph node from an individual with lupus lymphadenopathy. There is necrosis, with an absence of neutrophils, and large numbers of hematoxylin bodies.



Figure 112.9 Histological appearance of the glomerulus in a case of lupus nephritis. There is global mesangial cell proliferation and abundant mesangial matrix.



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NOTES



NOTES



INFLAMMATORY MYOSITIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Multiple disorders involving autoimmune inflammation, injury of skeletal muscles ▪ Most commonly include polymyositis, dermatomyositis, inclusion body myositis ▫ Dermatomyositis predominantly mediated by humoral immune response; polymyositis, inclusion body myositis by cellular immune response



RISK FACTORS



DIAGNOSIS LAB RESULTS ▪ ↑ muscle enzymes, like creatine kinase (CK) ▪ Muscle biopsy ▫ Dermatomyositis: perivascular, perimysial inflammation ▫ Polymyositis: endomysial inflammation ▫ Inclusion body myositis: endomysial inflammation, intracytoplasmic vacuoles with protein depositions



▪ Age (more common in older population) ▪ Dermatomyositis, polymyositis more common in individuals who are biologically female ▪ Inclusion body myositis more common in individuals who are biologically male ▪ Chronic viral infections: human T cell lymphotropic virus Type I (HTLV-1), HIV ▪ Autoimmune diseases ▪ Malignancies



OTHER DIAGNOSTICS



COMPLICATIONS



▪ Corticosteroids, immunosuppressive agents



▪ Dysphagia, pulmonary involvement ▪ Cardiovascular involvement



OTHER INTERVENTIONS



SIGNS & SYMPTOMS ▪ Proximal muscle weakness ▪ Inclusion body myositis ▫ Distal muscle weakness ▪ Dermatomyositis ▫ Skin rashes



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▪ Physical examination ▫ Muscle weakness Electromyography (EMG) ▪ Pathological signals



TREATMENT MEDICATIONS



▪ Physical rehabilitation



Chapter 113 Inflammatory Myositis



DERMATOMYOSITIS osms.it/dermatomyositis PATHOLOGY & CAUSES ▪ Autoimmune disorder leading to destruction of small blood vessels in muscles, skin ▪ Unknown factor activates C3 protein (complement component 3) → formation of membrane attack complex (MAC), accumulation in capillaries → destruction of capillary wall → microinfarctions ▪ Juvenile: around seven years; associated with calcinosis (deposition of calcium in skin) ▪ Adult: > 40; associated with malignancy, treating malignancy may cure myositis



Figure 113.1 A heliotrope rash affecting the eyes of an individual with dermatomyositis.



RISK FACTORS ▪ > 60 years ▪ Malignancy



COMPLICATIONS ▪ Respiratory muscle weakness; dysphagia (if esophagus, pharyngeal muscles involved); interstitial pulmonary disease; cardiovascular involvement



SIGNS & SYMPTOMS ▪ Weakness starts in proximal muscles, slowly progresses (e.g. difficulty getting up) ▪ Heliotrope rash ▫ Purplish eyelids with posible periorbital edema ▪ Gottron papules ▫ Scaling erythema of knuckles, elbow, knees ▪ V-shaped rash on chest



Figure 113.2 Gottron’s papules on the extensor surfaces of an individual with dermatomyositis.



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Malignancy suspected



LAB RESULTS



▪ Blood tests ▫ ↑ CK (muscle cells death) ▫ ↑ aspartate aminotransferase (AST)



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▫ ↑ lactic dehydrogenase (LDH) ▫ Antinuclear antibodies (ANA) ▫ Anti-Mi-2 antibodies (acute phase, better prognosis) ▪ Biopsy ▫ Perivascular, perimysial inflammation ▫ Perifascicular atrophy ▫ “Ghost fibers” (destroyed fibers, can no longer be stained)



OTHER INTERVENTIONS ▪ Physical therapy (preserve muscle strength) ▪ Sunscreen, avoid sun exposure (in skin disease)



OTHER DIAGNOSTICS EMG ▪ Abnormal signals



TREATMENT MEDICATIONS ▪ Corticosteroids (e.g. glucocorticoid) ▪ Immunosuppressive agents (e.g. methotrexate) ▪ IV immune globulins



Figure 113.3 The histological appearance of the skeletal muscle of an individual with dermatomyositis. The perimysium and endomysium have been infiltrated by chronic inflammatory cells, with predilection for the perimysium.



INCLUSION BODY MYOSITIS osms.it/inclusion-body-myositis PATHOLOGY & CAUSES ▪ Idiopathic inflammation of muscles leading to weakness, muscle atrophy ▪ Inflammation, degenerative processes ▪ Unknown factor causes myofibers to present major histocompatibility complex class I (MHC I) → CD8+ T cells gather, recognize MHC I, bind → express perforin → pores form on myofibers membranes → cell degeneration ▪ Accumulation of abnormal amyloidogenic proteins (e.g. beta-amyloid), cytotoxic effect ▫ Causes: misfolding of proteins; damaged/inhibited proteasomes; endoplasmic reticulum stress



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RISK FACTORS



▪ Age > 50 ▪ Chronic viral infections: HTLV-1 ▪ Autoimmune diseases: Sjögren’s syndrome



COMPLICATIONS ▪ Dysphagia (if esophagus, pharyngeal muscles involved)



SIGNS & SYMPTOMS ▪ Slowly progressive muscle weakness, sometimes asymmetric ▫ Proximal leg muscles (difficulty getting up, frequent falls) ▫ Distal arm muscles (weak grip)



Chapter 113 Inflammatory Myositis ▪ As disease progresses ▫ ↑ muscle atrophy ▫ ↓ deep tendon reflexes



DIAGNOSIS LAB RESULTS



▪ Mild ↑ muscle enzymes (e.g. CK) ▪ Muscle biopsy ▫ CD8+ T lymphocytes, macrophages infiltrating non-necrotic myofibers ▫ Vacuoles with amyloides, other protein accumulations (inclusion bodies) ▫ ↑ MHC I on immunostaining



OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Muscle weakness EMG ▪ Polyphasic motor unit action potentials (MUAPs) with small amplitude, short duration



Figure 113.4 Gomori staining highlights the rimmed vacuoles in inclusion body myositis.



TREATMENT MEDICATIONS ▪ Immunosuppressive therapy ▫ Administered when another systemic autoimmune disease present



OTHER INTERVENTIONS ▪ Physical therapy ▫ Muscle strengthening ▪ Speech therapy ▫ If dysphagia present ▪ Occupational therapy



Figure 113.5 A histological section of muscle showing a myofiber vacuole in an individual with inclusion body myositis.



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POLYMYOSITIS osms.it/polymyositis PATHOLOGY & CAUSES ▪ Inflammatory destruction of muscles leading to muscle weakness ▪ Unknown factor induces CD8+ T cells, macrophages to recognize nuclear, cytoplasmic antigens of muscle cells → immune cells surround nonnecrotic muscle cells → muscle cell destruction



vessels; myofibers surrounded by CD8+ T lymphocytes, macrophages



OTHER DIAGNOSTICS ▪ Physical examination ▫ Muscle weakness, tenderness EMG ▪ Low amplitude, short duration potential; repetitive discharges



RISK FACTORS



▪ Autoimmune disease ▪ Chronic viral infection (HIV, HTLV-1)



COMPLICATIONS



▪ Aspiration pneumonia ▪ Interstitial lung disease ▪ Dysphagia → malnutrition, anorexia



SIGNS & SYMPTOMS ▪ Symmetrical weakness of proximal leg, arm muscles (e.g. difficulty climbing stairs) ▪ Neck flexor weakness ▪ Mild myalgia, tenderness ▪ Dysphagia (if esophagus, pharyngeal muscles involved)



Figure 113.6 A muscle biopsy from an individual with polymyositis. The lymphocytes penetrate individual myofibers. In this example, the inflammation has progressed to phagocytic destruction by macrophages.



DIAGNOSIS



TREATMENT



DIAGNOSTIC IMAGING



MEDICATIONS



Chest X-ray, CT scan ▪ Pulmonary involvement



▪ Corticosteroids ▪ Immunosuppressive agents (if nonresponsive to corticosteroids) ▪ IV immune globulins (if severe, lifethreatening)



LAB RESULTS



▪ Blood tests ▫ ↑ CK, aldolase; ANA; antisynthetase antibodies (anti-Jo-1) ▪ Muscle biopsy ▫ Endomysial inflammation; intact blood



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OTHER INTERVENTIONS ▪ Physical therapy (preserve muscle strength)



Chapter 113 Inflammatory Myositis



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NOTES



NOTES



JOINT PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting joints ▪ Most commonly caused by trauma



SIGNS & SYMPTOMS ▪ Asymptomatic or pain during rest/ movement



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Radiography ▪ MRI



LAB RESULTS ▪ Synovial fluid analysis



TREATMENT ▪ Treat symptoms pharmacologically ▪ Surgical procedures



BAKER'S CYST osms.it/bakers-cyst PATHOLOGY & CAUSES ▪ Synovial fluid accumulates in popliteal bursa (between medial head of gastrocnemius, semimembranosus muscles) → swelling ▪ Adults: popliteal bursa communicates with synovial sac; underlying knee joint disease main cause ▫ Knee joint disease → ↑ synovial fluid production → synovial fluid squeezes through valve-like formation into bursa → fluid unable to flow backward → bursa enlarges → lump-like structure in the popliteal fossa ▪ Children: noncommunicating cyst; usually arises as primary process



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CAUSES ▪ ▪ ▪ ▪



Chronic knee joint trauma Osteoarthritis Rheumatoid arthritis Meniscal tears



COMPLICATIONS



▪ Cyst enlargement ▫ In popliteal space → obstruction of veins → lower leg swelling ▫ Extension to calf → swelling, redness, bruising, positive Homan’s sign (calf pain during dorsiflexion of the foot) → similar to deep-vein blood clot ▪ Rupture



Chapter 114 Joint Pathology



DIAGNOSIS



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Stiffness and pain in the knee → worse with prolonged standing



DIAGNOSTIC IMAGING Ultrasound and MRI ▪ Fluid-filled cyst; differentiation between cyst, blood clot X-ray ▪ Bone, joint pathology associated with cyst



OTHER DIAGNOSTICS



▪ Physical examination ▫ Lump in the back of the knee



TREATMENT SURGERY



▪ Surgical excision



OTHER INTERVENTIONS Figure 114.1 An MRI scan of the knee joint in the sagittal plane demonstrating a Baker’s cyst in the popliteal fossa.



▪ Fluid aspiration, glucocorticoid intraarticular injection → ↓ size and inflammation ▪ Treat complications ▫ Leg elevation, resting, analgesics



BURSITIS osms.it/bursitis PATHOLOGY & CAUSES ▪ Inflammation of bursa (small sac located between muscles, tendons, bone structures) ▪ Inflammation of bursa → ↑ production of synovial fluid → enlargement of bursa → ↑ friction during movement → symptomatology ▪ Most commonly affected bursas ▫ Subacromial, olecranon, trochanteric, prepatellar, infrapatellar



CAUSES



▪ Autoimmune disorders ▫ Rheumatoid arthritis, ankylosing spondylitis, scleroderma, systemic lupus erythematosus → chronic course ▪ Overuse/trauma, gout, bacterial infections (septic bursitis) → acute course



OSMOSIS.ORG 659



SIGNS & SYMPTOMS ▪ Joint pain; stiffness of joints; surrounding skin red ▪ Acute bursitis ▫ Tenderness, pain during activation of muscles adjacent to inflamed bursa ▪ Chronic bursitis ▫ Swelling with minimal pain



Figure 114.3 An MRI scan of the elbow demonstrating a high signal fluid collection in the olecranon bursa in an individual with olecranon bursitis. Figure 114.2 An individual with olecranon bursitis.



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Differentiation from Baker’s cyst



LAB RESULTS ▪ Aspiration and analysis of synovial fluid ▫ Infection: ↑ polymorphonuclear leukocytes, proteins, ↓ glucose ▫ Gout: ↑ monosodium urate crystals



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TREATMENT MEDICATION ▪ Non-steroidal inflammatory drugs (NSAIDs) ▪ Injection of steroids, local anesthetics ▪ Septic bursitis ▫ Antibiotics



SURGERY



▪ Surgical excision ▫ Chronic or recurrent bursitis



OTHER INTERVENTIONS ▪ Resting, elevation



Chapter 114 Joint Pathology



OSTEOARTHRITIS osms.it/osteoarthritis PATHOLOGY & CAUSES ▪ Progressive loss of articular cartilage, underlying bone of synovial joints ▪ Articular cartilage damage → chondrocytes replace type II collagen with type I, ↓ proteoglycans → eventual exhaustion, apoptosis of chondrocytes → ↓ elasticity, ↑ cartilage breakdown → clefts in articular surface (fibrillations), “joint mice” in synovial space with inflammation of synovium → bone exposition → rubbing other bone → eburnation (polished ivory look) ▪ Due to damage/inflammation, new bone formation on edges of bone with outward growth → osteophyte (enlargement of the joint with a knob-like look) ▫ Bouchard nodes: proximal interphalangeal finger joints affected ▫ Heberden nodes: distal interphalangeal finger joints affected ▪ Most commonly affected joints ▫ Lower spine, hip, knee, foot and hand joints



CLASSIFICATION



▪ Primary ▫ Usually idiopathic ▪ Secondary ▫ Caused by some other condition (e.g. diabetes, alkaptonuria, hemochromatosis, chronic joint injury)



anabolism of cartilage ▪ Obesity ▫ Excessive load, metabolic disorders affect joints ▪ Genetic disorders ▫ Mutations in cartilage building collagens (types II, IX and XI) ▪ Biological sex ▫ Biologically female more prone ▪ Previous joint injuries ▪ Infection ▪ Neurologic disorders



COMPLICATIONS



▪ Cystic degeneration of subchondral bone ▪ Surrounding ligaments, neuromuscular abnormalities



SIGNS & SYMPTOMS ▪ Sharp pain/burning sensation worsened by prolonged activity ▪ Limited range of motion ▪ Morning stiffness > one hour ▪ No swelling



RISK FACTORS



▪ Aging ▫ Cartilage thinning with ↓ hydratation → protein accumulation, collagen crosslinking → cartilage is more breakable; ↑ calcification of meniscus, cartilage ▪ Inflammation → ↑ proinflammatory cytokines ▫ IL1, IL6, TNF → ↑catabolism/↓



Figure 114.4 Heberden’s node on the distal interphalangeal joint of the right index finger in an individual with osteoarthritis.



OSMOSIS.ORG 661



DIAGNOSIS DIAGNOSTIC IMAGING Radiography ▪ Loss of joint space ▪ Subchondral bone sclerosis MRI ▪ Loss of joint space ▪ Subchondral bone sclerosis ▪ Osteophytes ▪ Visualisation of articular cartilage, surrounding soft tissues CT scan ▪ Displacement of foot, ankle, patellofemoral joint Bone scan ▪ Detect abnormalities



LAB RESULTS ▪ Arthrocentesis



Figure 114.5 An X-ray image of the pelvis demonstrating osteoarthritis of the right hip joint. The femoral head is malformed, there is marked loss of joint space and there are numerous subchondral bone cysts.



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TREATMENT MEDICATIONS



▪ Pain management ▫ Acetaminophen, tramadol, topical and oral non-steroidal anti-inflammatory drugs (NSAIDs) ▪ Intra-articular injections ▫ Corticosteroids ▫ Sodium hyaluronate



SURGERY



▪ Osteotomy ▫ Individuals < 60 years with malalignment of hip, knee joint ▪ Arthroplasty ▪ Stem-cell therapy



OTHER INTERVENTIONS ▪ ▪ ▪ ▪



Exercise Weight loss Physical therapy Electromagnetic field stimulation for individuals with knee osteoarthritis



Chapter 114 Joint Pathology



SLIPPED CAPITAL FEMORAL EPIPHYSIS osms.it/slipped-capital-femoral-epiphysis PATHOLOGY & CAUSES ▪ Anterior displacement of femoral head metaphysis, with epiphysis remaining in hip acetabulum ▪ Caused by growth plate (physis) fracture ▪ Example of type I Salter–Harris fracture usually affecting one hip ▪ Hypertrophy of growth plate → abnormal endochondral ossification, cartilage maturation → growth plate weakness → if too much force generated across growth plate → slippage



COMPLICATIONS



▪ Osteoarthritis ▪ Metaphysis slippage → ↓ blood flow → avascular necrosis ▪ Secondary SCFP affecting other hip; usually within a year of first SCFP ▪ Unstable displacement: ↑ complication rate



SIGNS & SYMPTOMS ▪ Hip, groin, knee pain ▪ Duck-like gait ▪ Hip in external rotation, flexion



CLASSIFICATION



▪ Based on disease course ▫ Acute: > three weeks ▫ Chronic: < three weeks ▫ Acute on chronic: chronic with acute exacerbations ▪ Based on lesion stability ▫ Stable: walking possible with/without crutches ▫ Unstable: walking impossible, even with crutches ▪ Displacement of the femoral head from neck; seen on radiography ▫ Type I: slippage < 33% ▫ Type II: 33–50% ▫ Type III: > 50%



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Obesity ↓ thyroid, growth hormone Osteodystrophy Down syndrome Demographics ▫ Adolescent black males of African descent most commonly affected



Figure 114.6 An X-ray image of the pelvis demonstrating a slipped capital femoral epiphysis on the left side.



OSMOSIS.ORG 663



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Anteroposterior X-ray ▫ Melting ice cream cone appearance visible through line of Klein (virtual line parallel to femoral neck’s upper edge) ▪ Frog-leg X-ray ▫ Straight line through center of femoral neck anterior to epiphysis (rather than central)



TREATMENT SURGERY



▪ Fixation with a cannulated screw ▪ Preventive fixation of the other hip ▫ Children with SCFP before the age of 10 ▫ Persons with endocrinopathies ▪ Osteotomy



MRI, CT scan ▪ Accurate measurements of displacement degree



TRANSIENT SYNOVITIS osms.it/transient-synovitis PATHOLOGY & CAUSES ▪ Inflammation of hip joint synovial membrane ▪ Cause relatively unknown, but may be preceded by upper respiratory tract infection ▪ Most commonly seen in male children 3–10 years ▪ Most commonly limited to one side



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪



May be asymptomatic Tenderness/pain during passive movement One-sided pain in the hip, groin, thigh, knee Antalgic limping



DIAGNOSIS ▪ Diagnosis of exclusion



DIAGNOSTIC IMAGING Ultrasound ▪ Fluids in joint capsule



LAB RESULTS ▪ ▪ ▪ ▪



Slightly ↑ white blood cell count ↑ Erythrocyte sedimentation rate ↑ C-reactive protein Needle aspiration ▫ Differentiation between transient synovitis and septic arthritis



OTHER DIAGNOSTICS



▪ Limited abduction and internal rotation



TREATMENT MEDICATIONS ▪ NSAIDs



OTHER INTERVENTIONS ▪ Massage ▪ Rest



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NOTES



NOTES



LOWER LIMB INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Injury to ligaments, tendons, bony structures of lower extremities



CAUSES



▪ Trauma, sport



SIGNS & SYMPTOMS ▪ Pain, swelling in affected region/joint



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Imaging to confirm



TREATMENT MEDICATIONS Acute ▪ Analgesics (NSAIDs)



SURGERY Therapeutic ▪ Surgical intervention (depending on disability, desire to return to sport/ demanding activity)



OTHER INTERVENTIONS Acute ▪ Rest, ice



OTHER DIAGNOSTICS



▪ History: traumatic event, risk factors review ▪ Physical examination: especially provocative (eponymous) musculoskeletal joint evaluation



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ACHILLES TENDON RUPTURE osms.it/achilles-tendon-rupture PATHOLOGY & CAUSES ▪ Acute, complete disruption of achilles tendon ▫ Commonly traumatic, but can be iatrogenic



CAUSES



▪ Recreational Sports: > 80% of achilles tendon ruptures ▫ Increased activity, shear stress on achilles, direct trauma to tendon ▫ Sudden, forced dorsiflexion of ankle outside normal range of motion



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Age: 30–40 years old Biologically-male individuals Obesity Fluoroquinolone use: unknown mechanism Systemic corticosteroid use



▪ Proximal achilles ▫ Likewise collected proximally Physical examination maneuvers ▪ Calf squeeze test (Simmonds/Thompson test) ▫ Squeezing calf of affected leg does not elicit plantar flexion (very high sensitivity, specificity) ▪ Palpable gap test ▫ Posterior leg palpation at level of achilles to palpate gap in tendon ▪ Knee flexion test (Matles test) ▫ Individual is prone with knees flexed at 90° → observe angle of ankle ▫ Ruptured achilles → acute angle (unopposed dorsiflexion of foot by grativity)



COMPLICATIONS



▪ Re-injury: 10% of individuals with rupture have history of previous rupture



SIGNS & SYMPTOMS ▪ Ankle pain ▪ Poor ambulation



DIAGNOSIS OTHER DIAGNOSTICS Physical inspection ▪ History: sudden, painful pop in lower leg; inability to walk; pain immediately after injury ▪ Calf muscles ▫ Soft, lumped together toward knee



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Figure 115.1 A positive Simmond’s test (left) in an individual with a ruptured achilles’ tendon



Chapter 115 Lower Limb Injury



TREATMENT MEDICATIONS Acute ▪ Analgesics (NSAIDs/acetaminophen)



SURGERY Curative ▪ Orthopedic tendon repair



OTHER INTERVENTIONS Acute ▪ Rest, ice



Figure 115.2 A ruptured achilles tendon prior to surgical repair.



ANTERIOR CRUCIATE LIGAMENT INJURY osms.it/ACL-injury PATHOLOGY & CAUSES ▪ Damage/complete tear of anterior cruciate ligament (ACL) in knee; common in deceleration injuries



CAUSES



▪ Common mechanism: twisting knee after planting foot ▫ Typically, non-contact injury ▫ Common athletic injury



RISK FACTORS



▪ Biologically-female individuals ▪ Valgus knee angulation ▪ ↑ traction ability of field of play ▫ Wet surfaces: rotation/shift of gravity results in slipping, rather than biomechanical injury to body



COMPLICATIONS



▪ Segond fracture: avulsion fracture of lateral aspect of tibial plateau; occurs in most ACL tears



SIGNS & SYMPTOMS ▪ Immediate pain ▪ May have popping sensation/sound at time of injury ▪ Immediate knee swelling → hemarthrosis ▫ Diagnostic maneuvers should be performed immediately after injury for clearest results ▪ Post-injury ▫ Knee may “give out” when walking/ standing



OSMOSIS.ORG 667



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Rule out fractures (nondiagnostic for ligament tears) MRI ▪ Preferred modality to evaluate ligament integrity ▪ Very high sensitivity, specificity Knee arthroscopy



OTHER DIAGNOSTICS Physical inspection ▪ History: pivot sign (knee buckling phenomenon, especially at heel strike phase of walking cycle) ▫ Tibia’s ability to travel anteriorly (without intact ACL) when knee is flexed at 0–30°→ snaps back around 40°+ of flexion ▫ Underlying this phenomenon: role of iliotibial band in knee extension, flexion at different degrees of knee position Physical examination maneuvers ▪ Anterior drawer test ▫ Supine individual: affected leg flexes 90°, foot rests on end of bed → examiner sits on foot of affected leg (to stabilize) → grasps around proximal tibia with both hands → pulls anteriorly on tibia → observes anterior movement level ▫ Normal laxity: < 1cm/0.4in anterior tibial subluxation; negative test, likely intact ACL ▫ ↑ Laxity: > 1cm/0.4in; positive test, likely torn ACL ▪ Lachman test ▫ Supine individual: knee flexed around 20° → examiner flexes knee → grasps around proximal tibia with one hand while stabilizing ipsilateral thigh with other hand → pulls anteriorly on tibia → observes anterior movement level



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▫ Similar endpoints to anterior drawer test ▫ Best sensitivity (85%), specificity (94%) compared to other diagnostic tests



TREATMENT MEDICATIONS Acute ▪ NSAIDs



SURGERY



▪ Complete ACL tears ▪ Reconstruction with neighboring patellar ligament/semitendinosus tendon ▪ Eligibility: severity of symptoms, individual’s future athletic ambitions ▪ Majority of individuals elect for surgical repair ▪ Increased risk of osteoarthritis



OTHER INTERVENTIONS



▪ Rehabilitation: intensive physical therapy



Acute ▪ Rest, ice, compression of injured knee



Figure 115.3 An MRI scan of the knee demonstrating partial disruption of the anterior cruciate ligament.



Chapter 115 Lower Limb Injury



ILIOTIBIAL BAND SYNDROME osms.it/IT-band-syndrome PATHOLOGY & CAUSES



DIAGNOSIS



▪ Painful overuse injury: fibrous band of tissue connects muscles of proximal lower extremity to lateral tibia ▪ Common injury for runners



OTHER DIAGNOSTICS



CAUSES



Physical examination maneuvers ▪ Noble compression test (examiner attempts to recreate pain experienced during training) ▫ Individual lays in decubitus position with affected leg above unaffected → examiner puts one thumb proximal to LPE with pressure → examiner uses other hand to passively move affected about the knee from 0–60° flexion → pain → positive test ▪ Ober test ▫ Individual lies on uninvolved side → flexes hip, knee 90° → knee placed in 5° flexion angle → examiner fully abducts lower extremity being tested → allows force of gravity to adduct extremity until hip cannot adduct any further ▪ Palpation of knee (check for no effusion) ▫ Rule out meniscal injury (lateral knee pain, ⊕ effusion)



▪ Iliotibial band (ITB): involved in knee flexion (at < 30°), knee extension at terminal extension (near 0° flexion); very active in heavy activity → overuse causes inflammation ▪ Greatest tension across ITB occurs at 30° ▫ Runners: position of 30° at foot strike → repeat → inflammation, injury ▫ Cyclists: position of 30° at down-pedal position → repeat → inflammation, injury



RISK FACTORS Intrinsic ▪ Weak hip abductors/flexors ▪ Gastrocnemius, soleus inflexibilty ▪ Leg length discrepancy Extrinsic ▪ Sudden training distance/intensity increase ▪ Running: overstriding, foot eversion (poorly fitted/raised shoes) ▪ Cold weather exercise



SIGNS & SYMPTOMS Knee pain ▪ Sharp/burning, worse during exercise at knee flexion of 30° ▪ Beyond exercise, pain may ache more/be deeper ▪ Location: lateral femoral epicondyle (LPE)



Physical inspection ▪ History: Running/cycling with indolent course of lateral knee pain with training



TREATMENT MEDICATIONS Acute ▪ Analgesics (NSAIDs/acetaminophen)



SURGERY



▪ ITB release: individuals who have failed long-term physical therapy program



OTHER INTERVENTIONS



▪ Exercise adjustment ▫ Address extrinsic risk factors



OSMOSIS.ORG 669



▫ Correct leg length discrepancy with insole lift ▪ Physical therapy ▫ Address strength of hip abduction/ flexion, calf inflexibility Acute ▪ Rest, ice



Figure 115.4 An MRI scan in the coronal plane of the right knee of individual complaining of iliotibial band syndrome symptoms. The band is inflammed with surrouding edema close to its point of insertion.



MENISCUS TEAR osms.it/meniscus-tear PATHOLOGY & CAUSES ▪ Injury to fibrocartilage (medial/lateral) knee pads (provide cushion, increase stability at tibiofemoral articulation interface)



CAUSES



▪ Pathophysiology: planted foot → twisting force at knee → compressional, rotational, shear stress placed on meniscus → tear ▫ Medial meniscus tears > lateral meniscus tears ▫ Medial meniscus firmly attached to medial collateral ligament (MCL) → ↓ mobility of medial meniscus → ↓ force required to tear fibrocartilage ▫ Poor blood supply to meniscus via geniculate arteries → poor healing/



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regenerative capability post injury Young, healthy athletes ▪ Forceful, sudden, decelerating movement while changing direction Elderly ▪ Chronic injury requires less torsional force at knee



RISK FACTORS



▪ Soccer, basketball, American football



COMPLICATIONS ▪ Osteoarthritis



Chapter 115 Lower Limb Injury



SIGNS & SYMPTOMS ▪ Pain at time of injury ▪ Swelling within 24 hours ▪ Clicking/crepitus with walking/knee extension ▪ Inability to fully extend/lock knee: occurs in anterior meniscus tears > posterior meniscus tears



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Non-diagnostic; commonly performed to rule out knee fracture MRI ▪ Most sensitive imaging modality for detecting tears ▫ Medial meniscus: very high sensitivity, specificity ▫ Lateral meniscus: high sensitivity, very high specificity ▪ Indicated for surgical evaluation ▫ Prevalence of MRI-positive meniscal tears in asymptomatic population increases with age



▫ Internal rotation → lateral meniscus moves under femoral condyle ▫ Sensitivity (wide range), specificity (high–very high), ⊕ likelihood ratio (LR) (4.0), ⊝ LR (0.6) ▪ Apley grinding test: tests medial meniscus ▫ Individual lays in prone position → examiner flexes affected knee to 90° → rotates foot laterally → while stabilizing thigh/femur (with examiner’s knee), exerts downward force on tibia ▫ Pain: likely medial meniscal tear ▪ Thessaly test: tests medial, lateral meniscus ▫ Individual stands only on affected leg while holding onto examiner for stability → flexes knee to 20° → rotates knee, body externally/internally ▫ Pain/locking/clicking: positive test ▪ Childress duck-waddle test: tests posterior horn of medial/lateral meniscus ▫ Reserved for athletes fit to complete maneuver ▫ Individual squats, walks forward in squatting position → knees are flexed fully → waddling steps exert posterior pressure on knee ▫ Pain/clicking: positive test



OTHER DIAGNOSTICS Physical inspection ▪ Joint line tenderness (at tibial-femoral interface) because synovial capsule/ collateral ligament accompanies injury; less sensitive/specific finding ▪ Joint effusion likely present Physical examination maneuvers ▪ McMurray test: tests medial, lateral meniscus ▫ Individual is supine with affected knee fully flexed → examiner grasps heel with one hand, around tibial prominence with other hand → exerts rotational force while extending leg → evaluates pain/click/palpable crepitus ▫ External rotation → medial meniscus moves under femoral condyle



Figure 115.5 An arthroscopic view of a torn medial meniscus.



OSMOSIS.ORG 671



TREATMENT SURGERY



▪ Arthroscopic/open surgery ▪ Meniscectomy/repair determined by amount of viable tissue intraoperatively, individual’s timetable to return to sport/ activity ▫ Meniscectomy: faster timetable to return to baseline activity; long-term ↑ osteoarthritis risk



OTHER INTERVENTIONS



▪ Rest: crutches for severe pain, avoidance of positions/activities that exacerbate pain ▪ If knee commonly gives out: patellar restraining brace; sign of poor quadriceps strength ▪ Physical therapy



Acute ▪ Rest, ice



PATELLAR TENDON RUPTURE osms.it/patellar-tendon-rupture PATHOLOGY & CAUSES ▪ Sudden, forced quadriceps contraction against flexed knee, fixed foot



CAUSES



▪ Most common in individuals < 40 years old involved in heavy training regimens/sport ▫ Landing from high jump, making sudden changes in direction at high speed ▪ Traumatic injury (non-athletic): foot/leg is stuck as individual falls backward ▫ Body weight falls backward → large eccentric force on fixed leg → force transmitted to patellar tendon → rupture ▫ Knee typically fully flexed when injury occurs → exposes tendon to most stress



RISK FACTORS



▪ Recent glucocorticoid injection ▪ Sports with explosive jumping: basketball, weightlifting ▪ Heavy training hours: > 20 per week ▪ Biologically-male individuals



COMPLICATIONS



▪ Tibial tuberosity avulsion fracture ▪ Patellar fracture/avulsion



672 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ Painful, popping sensation ▪ Immediate swelling ▪ Antalgic gait: inability to bear weight on affected leg



DIAGNOSIS DIAGNOSTIC IMAGING Bedside Ultrasound ▪ Assists bedside diagnosis X-ray ▪ Evaluation of patellar positioning, potential fracture/avulsion complication MRI ▪ Reserved for unusual presentations: constitutional signs that raise suspicion of tumor



OTHER DIAGNOSTICS Physical inspection ▪ Observation: upward shift of patella (pathognomonic); swelling distal to patella ▪ Strength: inability to maintain straight leg, raise leg against gravity while supine



Chapter 115 Lower Limb Injury



TREATMENT SURGERY



▪ Recommended within one week of injury for improved outcomes



OTHER INTERVENTIONS



▪ Post-operative physical rehabilitation



Figure 115.6 An MRI scan of the knee in the sagittal plane demonstrating a patellar tendon rupture



PATELLOFEMORAL PAIN SYNDROME osms.it/patellofemoral-pain-syndrome PATHOLOGY & CAUSES ▪ Common overuse disorder ▪ Anterior knee pain that cannot be attributed to intra-articular (meniscus)/peripatellar (patellar tendinopathy) pathology



CAUSES



▪ Multifactorial pathophysiology



Intrinsic, anatomical factors ▪ Leg length discrepancy ▪ Abnormal foot morphology ▪ Hamstring inflexibility ▪ Abnormal patellar mobility ▪ Hallux valgus Extrinsic, athletic factors ▪ Exercise overload



RISK FACTORS



▪ Biologically-female individuals (2:1) ▪ Active individuals; teens–20s ▪ Amount of training (ex. distance run) correlates with incidence of disease



SIGNS & SYMPTOMS ▪ Anterior knee pain ▫ Worsened with training, knee extension, especially with squatting, running exercises ▫ May occur with prolonged sitting ▫ May be present for years ▪ Knee occasionally buckles/gives way ▪ Knee clicks/grinds: most evident when climbing stairs



OSMOSIS.ORG 673



DIAGNOSIS



TREATMENT



OTHER DIAGNOSTICS



MEDICATIONS



Physical inspection ▪ History ▫ Absence of traumatic inciting event ▫ Achy/sharp knee pain: typically below patella ▪ Leg length discrepancy > 1cm/0.4in → poor biomechanics when running → predisposes individual to knee injury ▫ < 0.5cm/0.2in leg length discrepancy is common → no increased risk of injury



Acute ▪ NSAIDs (naproxen): short-term use (2–3 weeks) recommended



Physical examination maneuvers ▪ Palpation ▫ Nontender patella, patellar tendon, quadriceps tendon ▪ Tests ▫ Squatting: most individuals experience pain ▫ Patellar glide with extended knee: examiner moves patella laterally ▫ Lateral movement ↑ ¾ patellar width abnormal



OTHER INTERVENTIONS



▪ Lower extremity muscle strengthening ▪ Stretching: especially hamstrings ▪ Patellar bracing/taping



Acute ▪ Pain control: avoidance of painful exercise (stair/hill running); substitution of less stressful exercise (stationary bike exercises)



SPRAINED ANKLE osms.it/sprained-ankle



TYPES



Medial ankle sprain ▪ Infrequent injury ▪ Eversion of foot to medial deltoid ligament complex ▪ Ligament strong enough that medial malleolus fracture is more common than ligament sprain



Lateral ankle sprain ▪ Most common ▪ Inversion of plantar-flexed foot → stretches ankle’s lateral ligament complex ▪ Lateral ligament: anterior talofibular ligament (ATFL), calcaneofibular ligament, posterior talofibular ligament



Syndesmotic sprain ▪ AKA high ankle sprain ▪ Injury to interosseous membrane between tibia, fibula ▫ Foot is dorsiflexed/ankle eversion ▪ Higher rate of injury in contact sports (American football)



PATHOLOGY & CAUSES ▪ Common ankle injury from foot hypereversion/inversion



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Chapter 115 Lower Limb Injury



▪ Higher rate of chronic ankle sprains → recurrent ankle sprains → ossification of interosseous membrane



SIGNS & SYMPTOMS ▪ Pain over lateral/medial ankle (depending on eversion/inversion mechanism) ▪ Swelling hours after inciting event ▪ Inability to ambulate



DIAGNOSIS



▫ Anterior drawer test (ATFL integrity test): individual places affected foot in neutral position (slightly plantar-flexed, inverted) → examiner stabilizes lower leg with one hand → grasps heel with other while foot rests on examiner’s anterior arm → anterior pull of foot → ↑ laxity of joint (vs. unaffected foot) → likely lateral sprain, ATFL instability ▫ Talar tilt test (calcaneofibular integrity test): individual places affected foot in neutral position → examiner grasps foot → passive inverts at ankle → ↑ inversion of ankle (vs. unaffected side) → likely lateral sprain, calcaneofibular instability



DIAGNOSTIC IMAGING X-ray ▪ Evaluate for malleolar, distal fibular, talar dome fracture, syndesmotic separation complication



OTHER DIAGNOSTICS Physical inspection ▪ History ▫ Mechanism of foot inversion/eversion ▫ Prior ankle injuries ▫ Ability to walk after injury: correlates with fracture complication ▪ Observation: swelling/ecchymosis Physical examination maneuvers ▪ Palpation ▫ Fibula, distal tibia: syndesmotic injury ▫ Foot: lateral, medial surface for evaluation of medial, lateral ligament complex pain ▫ Thompson test: rule out achilles pathology ▪ Maneuvers of passive inversion/eversion (replicate pain) ▫ Squeeze test (syndesmotic evaluation): examiner compresses fibular against tibia at level of mid-calf → pain in region of ATFL → likely syndesmotic sprain ▫ External rotation stress test (syndesmotic evaluation): examiner stabilizes leg proximal to ankle → grasps plantar aspect of foot → externally rotated → pain in region of ATFL → likely syndesmotic sprain



TREATMENT MEDICATIONS Acute ▪ NSAIDs



SURGERY



▪ Reserved for ligament rupture in setting of chronic ankle instability



OTHER INTERVENTIONS



▪ Rehabilitation: physical therapy



Acute ▪ Rest: limit weight bearing, use crutches if individual is unable to bear weight ▪ Ice ▪ Early application of compressive wrapping → ↓ swelling ▪ Elevation of ankle → ↓ swelling



OSMOSIS.ORG 675



UNHAPPY TRIAD osms.it/unhappy-triad PATHOLOGY & CAUSES ▪ Severe knee injury, typically after trauma, that results in trio of ACL, medial collateral ligament (MCL), lateral meniscus tears



CAUSES



▪ During contact sports, forceful blow to posterolateral aspect of knee, with planted foot (lower body tackle from behind in rugby/American football) ▪ Pathophysiology: posterior force tears ACL → abnormal ↑ anterior glide of tibia relative to femur → medial rotation of tibia → tear of MCL with shearing force → further knee instability → increased rotational force → lateral meniscal tear



COMPLICATIONS ▪ Osteoarthritis



Figure 115.7 An MRI scan of the knee in the coronal plane demonstrating a complete tear of the medial collateral ligament. Injury to the medial collateral ligament is one part of the unhappy triad



SIGNS & SYMPTOMS ▪ Pain ▪ Hemarthrosis ▪ Popping/multiple pops



DIAGNOSIS OTHER DIAGNOSTICS Physical examination maneuvers ▪ ACL maneuvers ▫ Anterior drawer test ▫ Lachman test ▪ MCL maneuvers ▫ Examiner stabilizes affected leg with one hand → exerts valgus stress on lateral aspect of knee → pain and ↑ laxity → likely MCL tear ▪ Lateral meniscus maneuvers ▫ McMurray testing



676 OSMOSIS.ORG



TREATMENT MEDICATIONS Acute ▪ NSAIDs



SURGERY



▪ ACL repair: athletes/ individuals who desire return to play/demanding activity ▪ Lateral meniscus repair vs. meniscectomy



OTHER INTERVENTIONS Acute ▪ Rest ▪ Ice ▪ Elevation/compression → ↓ swelling ▪ Knee brace: ACL, MCL recovery; overall knee stability



NOTES



NOTES



MUSCLE TUMORS



RHABDOMYOSARCOMA (RMS) osms.it/rhabdomyosarcoma PATHOLOGY & CAUSES ▪ Highly malignant tumor arising from skeletal muscle cells



TYPES Alveolar Embrional ▪ Most common, frequently children ▫ Botryoid, spindle-cell rhabdomyosarcoma Pleomorphic (anaplastic) ▪ Worst outcome, frequently adults



Figure 116.1 The histological appearance of a rhabdomyosarcoma, alveolar subtype. The cells are small, with little cytoplasm with bland chromatin structures visible.



CAUSES



▪ Genetic translocation determining fusion of two genes which encode two transcription factors ▫ FOXO1, PAX3 ▪ FOXO1-PAX3 fusion protein interferes with differentiation-driven gene expression program → poorer outcome



RISK FACTORS



▪ Syndromes, congenital anomalies (e.g. Li–Fraumeni syndrome, neurofibromatosis type I, Beckwith–Wiedemann syndrome, Costello syndrome)



COMPLICATIONS



Figure 116.2 The histological appearance of a rhabdomyosarcoma, embryonal subtype. The tumor is composed of numerous round or spindled cells, either with minimal or abundant eosinophilic cytoplasm.



▪ Metastasis ▪ Bone marrow involvement: anemia, thrombocytopenia, neutropenia



OSMOSIS.ORG 677



TREATMENT



SIGNS & SYMPTOMS ▪ Palpable mass ▫ Localization: head/neck, genitourinary tract, limbs, abdomen ▪ Depending on tumor size ▫ Hematuria, urinary obstruction (genitourinary tract involvement) ▫ Sinusitis, headache, cranial nerve alterations, ear discharge, orbital swelling (head involvement)



MEDICATIONS



▪ Polychemotherapy ▪ Immunotherapy



SURGERY ▪ Resection



OTHER INTERVENTIONS ▪ Radiation therapy



DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI, ultrasound ▪ Determines local invasion, metastasis



LAB RESULTS



▪ Liver, renal function tests ▪ Complete blood count ▫ Anemia, pancytopenia ▪ Biopsy ▫ Microscopic analysis ▫ Immunohistochemical studies showing muscle tissue-characteristic proteins ▫ Genetic sequencing



678 OSMOSIS.ORG



Figure 116.3 The gross pathological appearance of a rahbdomyosarcoma, embryonal subtype. The tumor is poorly circumscribed with a firm texture and is cream to white in color.



NOTES



NOTES



MUSCULOSKELETAL CONGENITAL MALFORMATIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Soft tissue structure/bone growth/ development errors ▪ Present at birth (often) ▪ Isolated, or + associated anomalies



OTHER DIAGNOSTICS ▪ Clinical evaluation



TREATMENT SURGERY



▪ See individual disorders



SIGNS & SYMPTOMS ▪ Disease-dependent malformations



DIAGNOSIS



OTHER INTERVENTIONS



▪ May resolve with age ▪ Conservative treatment (e.g. occupational therapy, splinting)



DIAGNOSTIC IMAGING E.g. X-ray, CT scan



ARTHROGRYPOSIS osms.it/arthrogryposis PATHOLOGY & CAUSES ▪ Rare, non-progressive congenital disorder ▫ Multiple joint contractures ▫ AKA arthrogryposis multiplex congenita ▪ Decreased fetus movement in utero → fibrous connective, adipose tissue replaces muscle tissue → muscle shortening → joints fixed → affected joints unable to extend, flex ▪ Potential associated syndrome/disease (e.g. pulmonary hypoplasia, cryptorchidism, intestinal atresia, gastroschisis) ▪ Intelligence typically normal



TYPES Amyoplasia ▪ Most common type; sporadic cases ▪ Affects most joints ▪ Four limbs involved symmetrically Distal arthrogryposis ▪ Hands, feet (mainly) ▪ Potential specific gene defect association Syndromic ▪ Primary neurological/muscle disease association



OSMOSIS.ORG 679



CAUSES



▪ Neurologic disorder (e.g. anterior horn disease) ▫ 70–80% of cases ▪ Crowding in utero ▫ Uterine malformation (e.g. intrauterine fibroids) ▫ Multiple gestation pregnancy ▪ Oligohydramnios ▫ Amniotic fluid volume low/abnormally distributed ▪ Maternal disorder (e.g. multiple sclerosis) ▪ Genetic disorder (e.g. spinal muscular atrophy type I) ▪ Muscle/connective tissue disorder (e.g. dystrophy, myopathy)



DIAGNOSIS ▪ Physical examination



DIAGNOSTIC IMAGING Ultrasound ▪ 50% of diagnoses prenatal ▫ Low mobility/abnormal fetus position MRI



LAB RESULTS



▪ Test for cause (e.g. chromosomal microarray analysis for chromosomal abnormalities, muscle biopsy for myopathic disorders)



COMPLICATIONS



▪ Can’t walk/delayed walking ▪ Psychosocial effects (e.g. shame, depression, social anxiety)



SIGNS & SYMPTOMS ▪ Congenital malformations present ▪ Typically affects all joints (potentially leg/ arm joints only) ▪ Affected joints contracted (flexion/ extension) ▪ Internal shoulder rotation ▪ Wrist, digit flexion ▪ Elbow, knee extension ▪ Hip dislocation ▪ Club feet ▪ Muscle weakness (especially amyoplasia)



Figure 117.1 Contractures in the hands of an individual with arthrogryposis.



680 OSMOSIS.ORG



TREATMENT SURGERY



▪ E.g. wrist surgery



OTHER INTERVENTIONS



▪ No curative method ▫ Increase joint mobility, muscle strength, adaptive use pattern development ▪ Occupational therapy ▫ Joint manipulation, casting ▪ Limb movement-enhancing devices ▪ Splinting



Chapter 117 Musculoskeletal Congenital Malformations



CLUBFOOT osms.it/clubfoot PATHOLOGY & CAUSES ▪ Common congenital malformation; one/ both feet rotated ▫ AKA talipes equinovarus ▪ Talus malformation ▫ Feet, calf, peroneal muscles’ medial side developed abnormally ▪ Isolated or can be associated with developmental dysplasia of hip, Larsen syndrome (+ other hip, knee, elbow malformations), spina bifida, arthrogryposis



TYPES



COMPLICATIONS ▪ Walking difficulty/inability ▪ Post-treatment recurrence ▪ Psychosocial effects



SIGNS & SYMPTOMS ▪ Bilateral (50% of cases) ▪ Three components ▫ Hindfoot equinus ▫ Midfoot varus ▫ Forefoot adduction ▪ Individuals walk on feet sides (typically) ▪ Affected foot potentially smaller



Congenital ▪ Affects bones, muscles, tendons, blood vessels Syndromic ▪ Additional anatomic malformations and/or chromosomal/genetic abnormalities Positional ▪ Fetal position (e.g. breech presentation), often restrictive uterine environment (e.g. oligohydramnios)



CAUSES



▪ Idiopathic (most cases) ▪ Structural anomalies ▪ Chromosomal/genetic abnormalities



RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪



Biologically male (2:1 male:female) Early amniocentesis Genetic factors Family history Multiple gestation pregnancy Oligohydramnios Uterine abnormality Fetal neuromuscular disorders



Figure 117.2 A neonate with club feet.



DIAGNOSIS ▪ Clinical diagnosis at birth



DIAGNOSTIC IMAGING Ultrasound ▪ Prenatal ▫ Abnormal foot positioning



OSMOSIS.ORG 681



LAB RESULTS



▪ Amniocentesis ▫ Karyotype detects chromosomal abnormality (e.g. aneuploidy)



OTHER INTERVENTIONS



▪ Conservative therapy ▫ Bracing, proper foot positioning, casting (Ponseti method)



TREATMENT SURGERY



▪ Sometimes required (e.g. Achilles tenotomy → release tightness)



CONGENITAL HIP DYSPLASIA osms.it/congenital-hip-dysplasia PATHOLOGY & CAUSES ▪ Congenital malformation; abnormal acetabulum, proximal femur development → hip joint mechanical instability ▫ AKA developmental hip dysplasia/ congenital hip dislocation ▫ Presents at birth/childhood ▪ Joint ligament laxity/abnormal utero positioning → abnormal development, contact between acetabulum, femoral head ▪ Possible conditions associated (e.g. Ehlers– Danlos, spina bifida)



TYPES Dislocation ▪ Femoral head completely outside acetabulum Subluxation ▪ Femoral head partially outside acetabulum Dislocatable ▪ Femoral head within acetabulum at rest, examination maneuvers dislocate easily (unstable hip joint) Subluxatable ▪ Femoral head loose within acetabulum, examination partially dislocates (mildly unstable hip joint)



682 OSMOSIS.ORG



Reducible ▪ Femoral head outside acetabulum at rest, maneuvers can locate within acetabulum Dysplasia ▪ Abnormally-shaped hip joint (usually shallow acetabulum)



RISK FACTORS



▪ Breech presentation ▪ Other anomalies present (e.g. congenital torticollis, congenital foot malformation) ▪ Family history ▪ Swaddling practices ▪ Biologically female ▪ First-born infant ▪ Oligohydramnios ▪ Limited fetal mobility



COMPLICATIONS



▪ Affected leg shorter, painful hip joint ▪ Osteoarthritis ▪ Decreased motion range → restricted hip joint adduction, flexion ▪ Asymmetric gait ▪ Low back pain ▪ Femoral head necrosis ▪ Psychosocial effects



Chapter 117 Musculoskeletal Congenital Malformations



SIGNS & SYMPTOMS ▪ Severity-, age-dependent ▪ Usually unilateral, left hip ↑ affected (20% of cases bilateral) ▪ Hip instability ▫ Ortolani maneuver: infant supine, hips/ knees flexed 90o; hip abducted, pulled anteriorly → dislocated femoral head slides back into acetabulum → palpable/ audible clunk ▫ Barlow maneuver: infant supine, hips/ knees flexed 90o; hip abducted, pushed anteriorly → femoral head slides out of acetabulum → clunk ▪ Asymmetric thigh, groin skin creases ▪ Galeazzi sign ▫ Knee height difference when infant supine (hips flexed, knees bent, feet on examining table) posterior displacement in dysplastic hip → affected side’s knee lower ▪ Adductor spasm → limited hip abduction ▪ Pain (uncommon)



DIAGNOSIS ▪ Clinical evaluation



DIAGNOSTIC IMAGING Hip ultrasound, X-ray ▪ To detect abnormal acetabulum development, femoral head position



Figure 117.3 A plain radiograph of the pelvis of an infant with severe congenital hip dysplasia. There is complete dysplasia of both acetabula and superior dislocation of the femoral heads.



TREATMENT ▪ Early treatment critical ▫ Obtain, maintain concentric hip reduction



SURGERY



▪ Closed/open hip reduction



OTHER INTERVENTIONS



▪ Abduction splinting ▫ Device holds affected hip abducted, externally rotated (e.g. Pavlik harness)



OSMOSIS.ORG 683



CRANIOSYNOSTOSIS osms.it/craniosynostosis PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Premature calvarial suture closure → craniofacial malformation ▪ Abnormal dural attachments → tensile forces prevent bone growth → early suture fusion ▪ Abnormal skull growth ▫ ↓ in perpendicular direction to fused suture ▫ ↑ in parallel direction to accommodate brain growth ▪ Most cases isolated, sporadic; possibly genetic syndrome (e.g. Apert syndrome, Crouzon syndrome)



▪ Phenotypes: variable head shape, facial features (suture-dependent) ▫ Sagittal suture fused → narrow, long skull (scaphocephaly/dolichocephaly) ▫ Coronal/lambdoid sutures fused → diagonal skull malformation, asymmetric orbits (plagiocephaly) ▫ Metopic suture fused → narrow, triangle-shaped forehead + prominent midline ridge (trigonocephaly) ▫ Multiple sutures fused → Kleeblattschädel anomaly/microcephaly ▫ Coronal sutures fused bilaterally → short, broad skull (brachycephaly) ▫ Coronal suture fuses + any other suture → oxycephaly



TYPES ▪ Classified by affected suture ▫ Sagittal (most common) ▫ Coronal ▫ Metopic ▫ Lambdoid ▫ Multiple sutures



RISK FACTORS



▪ Multiple pregnancies ▪ Uterine abnormalities



COMPLICATIONS



▪ ↑ intracranial pressure ▫ Vomiting, papilledema, headache ▪ ↓ brain growth ▪ Vision, hearing, speech, feeding impairments ▪ Neurodevelopmental delay ▪ Obstructive sleep apnea ▪ Abnormal head shape → psychosocial effects Figure 117.4 Facial features of an child with craniosynostosis in Apert syndrome.



684 OSMOSIS.ORG



Chapter 117 Musculoskeletal Congenital Malformations



DIAGNOSIS ▪ Physical examination



DIAGNOSTIC IMAGING X-ray, CT scan ▪ Identify fusion, malformation extent



LAB RESULTS



▪ Cephalometry → precisely measure head dimensions ▪ Genetic testing → identify mutations ▪ Funduscopy → detect papilledema



Figure 117.5 Syndactyly seen in an individual with Apert syndrome, which also causes craniosynostosis.



TREATMENT SURGERY



▪ Reconstruct craniofacial structure



FLAT FEET osms.it/flat-feet PATHOLOGY & CAUSES ▪ Common malformation; moderate/complete foot arch flattening ▫ AKA pes planus/fallen arches ▫ Congenital/adult-acquired ▪ Children: abnormal foot muscle, tendon, bone development ▪ Adults: ↑ activity of proteolytic enzymes → break down muscle tendons → foot arch falls



TYPES Rigid pes planus ▪ ↓ tarsal and subtalar joint range of motion + arch does not increase with toe raising



Flexible pes planus ▪ Physiologic or pathologic causes related to associated conditions (e.g. ligamentous laxity, foot muscle motor weakness, bony abnormalities, generalized syndromes) ▪ Type I ▫ Most common type ▫ Calcaneovalgus heel (depressed longitudinal arch that is associated with varying amounts of heel eversion) ▫ Functional flat foot ▪ Type II ▫ Hypermobile flat foot ▫ Lax ligamentous and tight heel cords ▪ Type III ▫ Clinical pes planus ▫ Involves tibialis posterior tendon dysfunction ▫ Often seen in dancers, ice skaters, athletes (e.g. basketball, tennis, soccer, ice hockey)



OSMOSIS.ORG 685



RISK FACTORS



▪ Loose connective tissue (e.g. Ehlers–Danlos syndrome) ▪ Neuromuscular conditions (e.g. cerebral palsy) ▪ Tarsal coalition (abnormal tarsal bone connection) ▪ Peroneal spasticity ▪ ↑ physical activity ▪ ↑ stress to foot ▪ Injury ▪ Increasing age (relatively common in biologically-female individuals > 40 years old) ▪ Obesity ▪ Rheumatoid arthritis ▪ Pregnancy (↑ elastin)



COMPLICATIONS ▪ ▪ ▪ ▪



Knee, hip, back pain Progress to high arches (adolescence) Abnormal gait → injuries Tendonitis



SIGNS & SYMPTOMS ▪ Normal foot arch absent (flat) ▪ Foot sole presses ground almost completely ▪ Abnormal gait ▫ ↑ inward foot roll (overpronation) ▪ May involve foot, ankle, knee, hip, back pain



DIAGNOSIS ▪ Clinical evaluation ▪ Wet footprint test ▫ Individual wets feet, stands on paper → footprint with ↑ surface area



DIAGNOSTIC IMAGING Feet X-ray ▪ Talonavicular coverage angle → abnormal lateral rotation ▪ ↓ calcaneus, inferior foot angle (calcaneal pitch) ▪ ↑ long talus axis, first metatarsal bone angle (Meary’s angle) ▪ The anteater nose sign ▫ Anterior tubular elongation of the superior calcaneus; approaches/ overlaps the navicular indicated calcaneonavicular coalition



TREATMENT ▪ Sometimes unnecessary (arch may develop)



SURGERY



▪ Resection of abnormal bridge of bony, cartilaginous, or fibrous tissue (e.g. calcaneonavicular coalition)



OTHER INTERVENTIONS



▪ Conservative treatment ▫ Supportive shoes ▫ Orthotics (insoles stop inward roll) ▫ Casting ▫ Analgesics (e.g. NSAIDs) ▫ Physical therapy



Figure 117.6 Complete collapse of the longitudinal arch has resulted in complete contact of the sole of the foot with the ground.



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Chapter 117 Musculoskeletal Congenital Malformations



GENU VALGUM osms.it/genu-valgum PATHOLOGY & CAUSES ▪ Knee malformation: knees bend towards each other ▫ Typically resolves by age nine ▫ AKA “knock-knees” ▫ Less common than genu varum



CAUSES ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪



Physiologic (age 2–5) Poor nutrition Obesity Lower extremity fracture Calcium deficiency Vitamin D deficiency Skeletal dysplasia Neoplasm Idiopathic



COMPLICATIONS ▪ ▪ ▪ ▪



Knee osteoarthritis Injuries Knee chondromalacia Psychosocial effects



SIGNS & SYMPTOMS ▪ Knee malformation ▫ Knee joint’s proximal portion bends inwards ▫ Knee joint’s distal portion bends outwards ▪ Can’t touch knees, feet together ▪ Gait abnormalities ▪ Pain (uncommon)



Figure 117.7 An individual with genu valgum of the left leg secondary to surgery and radiotherapy to treat a synovial sarcoma of the lateral distal femoral epiphysis as a child. The medial epiphysis continued to grow whilst growth of the lateral epiphysis was stunted.



DIAGNOSIS ▪ Clinical evaluation



DIAGNOSTIC IMAGING X-ray ▪ Both legs (hips to feet) in standing position



OSMOSIS.ORG 687



TREATMENT ▪ Treatment of underlying causes (e.g. vitamin D deficiency)



SURGERY



▪ If malformation persists after age 10 ▫ Medial distal femoral epiphysis stapling ▫ Total knee replacement



OTHER INTERVENTIONS ▪ Orthotic devices ▪ Bracing



Figure 117.8 An X-ray image of the affected knee. The medial head is much larger than the lateral head.



GENU VARUM osms.it/genu-varum PATHOLOGY & CAUSES ▪ Most common knee malformation: knees bow ▫ AKA bow-legs



CAUSES



Physiologic (birth to 18 months) Vitamin D deficiency (e.g. rickets) Poor nutrition Other musculoskeletal conditions (e.g. skeletal dysplasia) ▪ Infection/tumors/lower extremity fracture → abnormal leg growth ▪ Blount disease ▪ ▪ ▪ ▪



COMPLICATIONS



▪ Knee osteoarthritis



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▪ Psychosocial effects



SIGNS & SYMPTOMS ▪ Knee malformation ▫ Knee’s distal portion bends inwards ▫ Proximal portion bends outwards (like archer’s bow) ▪ Usually bilateral



DIAGNOSIS ▪ Clinical evaluation



DIAGNOSTIC IMAGING X-ray ▪ Both legs (hips to feet) in standing position



Chapter 117 Musculoskeletal Congenital Malformations



TREATMENT ▪ Treatment of underlying causes (e.g. vitamin D deficiency)



SURGERY



▪ If malformation persists



OTHER INTERVENTIONS ▪ Splinting ▪ Bracing



Figure 117.9 An X-ray image of a child with rickets displaying genu varum.



PECTUS EXCAVATUM osms.it/pectus-excavatum PATHOLOGY & CAUSES ▪ Congenital thoracic wall malformation: chest appears caved-in ▫ Most common anterior chest wall disorder ▫ AKA funnel chest ▪ Abnormal sternum, rib cage growth ▪ Unknown cause ▫ Possibly: increased intrauterine pressure, increased sternum traction, abnormal cartilage development ▪ Usually sporadic



RISK FACTORS



▪ Biologically male (3–5:1 male:female) ▪ Family history ▪ Connective tissue disorders (e.g. Marfan syndrome, Ehlers–Danlos) ▪ Neuromuscular diseases ▪ Genetic conditions (e.g. Noonan syndrome) ▪ Rickets ▪ Congenital diaphragmatic hernia



COMPLICATIONS



▪ Cardiorespiratory function impairments ▪ Psychosocial effects



OSMOSIS.ORG 689



LAB RESULTS



▪ Pulmonary function tests ▫ Normal forced vital capacity ▫ Total lung capacity, residual volume may be abnormal



OTHER DIAGNOSTICS



▪ Cardiology exams (e.g. electrocardiogram, echocardiography) ▫ Abnormalities if heart compression, rotation ▪ Exercise testing ▫ Impairment severity correlates with defect’s degree



Figure 117.10 An individual with pectus excavatum.



SIGNS & SYMPTOMS ▪ Physical ▫ Chest malformation: sternum’s lower end depressed, lower ribs may protrude, narrowed chest wall diameter ▫ Displaced heartbeat ▫ Heart murmurs ▫ Diminished lung sounds ▫ Exercise intolerance ▪ Potential chest/back pain ▪ Respiratory symptoms ▫ Shortness of breath, tachypnea



DIAGNOSIS ▪ Clinical evaluation



DIAGNOSTIC IMAGING Chest CT scan ▪ Determine severity; assess lung, heart effects



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Figure 117.11 A CT scan of the chest in the axial plane demonstrating pectus excavatum.



TREATMENT ▪ Some cases resolve spontaneously (usually worsens in adolescence)



SURGERY



▪ Moderate/severe pectus excavatum



Chapter 117 Musculoskeletal Congenital Malformations



PIGEON TOE osms.it/pigeon-toe PATHOLOGY & CAUSES ▪ Common developmental variation: toe inward rotation ▫ AKA in-toeing ▪ Typically resolves spontaneously ▪ Results from intrauterine molding



CAUSES



▪ Metatarsus adductus (most common in infants < one year old) ▪ Internal tibial rotation (most common between age 1–4) ▪ Increased femoral anteversion (most common in children > three years old)



DIAGNOSIS ▪ Clinical evaluation



DIAGNOSTIC IMAGING X-ray ▪ Assess severity



TREATMENT TREATMENT



▪ Observation ▪ Surgery rarely recommended



COMPLICATIONS



▪ Long-term functional problems (rare)



SIGNS & SYMPTOMS ▪ Abnormal toe rotation when walking/ standing ▫ Metatarsus adductus: inward forefoot rotation ▫ Tibial torsion: inward shin bone twisting ▫ Femoral anteversion: inward femur twisting ▪ Non-flexible/flexible (if malformation can be hand-straightened)



OSMOSIS.ORG 691



NOTES



NOTES



SKELETAL DYSPLASIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting bone development



CAUSES



▪ Inherited/sporadic (de novo) genetic mutation



COMPLICATIONS



▪ Caused by bone malformations, depend upon affected bones



SIGNS & SYMPTOMS ▪ Commonly involve growth impairment, bone malformation



DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan/MRI ▪ Bone malformation, impaired ossification visualization ▪ Bone-age estimation Ultrasound ▪ Prenatal diagnosis



TREATMENT SURGERY



▪ Bone malformation correction if warranted/ desired



ACHONDROPLASIA osms.it/achondroplasia PATHOLOGY & CAUSES ▪ Genetic disorder, causes dwarfism with disproportionate short stature ▪ Relatively normal-sized torso, short limbs, normal–large head (macrocephaly) with prominent forehead (hence “disproportionate dwarfism”) ▪ Average height ▫ Biologically-male: 131cm/4’4’’ ▫ Biologically-female: 123 cm/4’



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CAUSES ▪ Heterozygous “gain-of-function” mutation in fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4; individuals with homozygous mutation usually do not survive ▫ Mutated receptor displays “constitutive activity” (activated in ligand binding absence) → inhibits chondrocyte proliferation ▫ Endochondral ossification affected → inhibits long bone elongation (e.g. humerus, femur)



Chapter 118 Skeletal Dysplasia ▫ Intramembranous ossification less affected → relatively normal flat bone growth (e.g. skull, ribs) ▪ Autosomal dominant inheritance pattern (20%); sporadic mutation in most cases (80%)



COMPLICATIONS



▪ Eustachian tube narrowing → recurrent middle ear infection ▪ Narrowing of ▫ Lumbar spinal canal → spinal stenosis ▫ Foramen magnum → cervical medullary compression ▪ Venous obstruction at sigmoid sinus → hydrocephalus ▪ Midface retrusion → obstructive sleep apnea ▪ Obesity



▪ Small flat squared iliac wings (“mickey mouse ear”) ▪ Fibular overgrowth ▪ Metaphyseal flaring: diaphysis narrowing, metaphysis widening



LAB RESULTS



▪ DNA test ▫ FGFR3 mutation-positive



TREATMENT SURGERY



▪ Bone malformation correction warranted/ desired



SIGNS & SYMPTOMS ▪ Long bone malformations ▫ Rhizomelic (proximal) limb shortening ▫ Varus/valgus leg malformations ▫ Short metacarpals ▫ Short phalanges (brachydactyly) ▫ Trident hand (fingertips cannot touch) ▪ Flat bone malformations (less common) ▫ Enlarged head ▫ Frontal bossing (prominent forehead) ▫ Flattened nasal bridge (saddle nose malformation) ▫ Narrow foramen magnum ▫ Spinal kyphosis/lordosis



DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Skull width to femur length ratio higher than normal



Figure 118.1 An X-ray image of the knee of an individual with achondroplasia. There is flaring of the distal femoral metaphysis typical of the disease.



X-ray/MRI/CT scan ▪ Large skull with small skull base ▪ Narrow foramen magnum, spinal canal ▪ Short, flattened vertebral bodies



OSMOSIS.ORG 693



CLEIDOCRANIAL DYSPLASIA osms.it/cleidocranial-dysplasia PATHOLOGY & CAUSES ▪ AKA cleidocranial dysostosis ▪ Skeletal dysplasia ▫ Predominantly affects intramembranous ossification-derived bone development ▫ Clavicles (cleido-), skull bones (-cranial) ▪ Abnormal teeth development, delayed cranial fontanelle closure, clavicle underdevelopment/absence, distinctive craniofacial features



CAUSES



▪ Heterozygous runt-related transcription factor 2 (RUNX2) gene mutation (transcription factor involved in osteoblast, chondrocytes differentiation → delayed ossification; 30% of cases are idiopathic) ▪ Autosomal dominant inheritance pattern, can be sporadic



COMPLICATIONS



▪ Osteoporosis (adults)



SIGNS & SYMPTOMS ▪ Dental abnormalities ▫ Supernumerary teeth (up to 13), delayed/failed permanent teeth eruption, abnormal deciduous dentition ▪ Delayed cranial fontanelle closure → soft skull areas ▪ Short stature ▪ Hypoplastic/aplastic clavicles → shoulder hypermobility ▪ Maxilla, mandibular prognathism hypoplasia ▪ Midface hypoplasia, flattened nasal bridge ▪ Frontal/parietal bossing ▪ Abnormal ear ossicles → hearing loss



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Figure 118.2 Retained deciduous teeth in the mouth of an individual with cleidocranial dysplasia.



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Hypoplastic/aplastic clavicles ▪ Widened fontanelles ▪ Wormian bones (multiple small bones between sutures) ▪ Frontal/parietal bossing ▪ Supernumerary teeth ▪ Supernumerary ribs ▪ Iliac bone hypoplasia ▪ Symphysis pubis widening (diastasis) ▪ Small, highly positioned scapulas



LAB RESULTS ▪ Genetic testing (confirmation)



TREATMENT SURGERY



▪ Bone malformation correction if warranted/ desired



Chapter 118 Skeletal Dysplasia



Figure 118.3 A chest radiograph of a neonate with absent clavicles, consistent with a diagnosis of cleidocranial dysplasia. Figure 118.4 An X-ray image of the skull of a child with cleidocranial dysplasia. There is bitemporal bossing and a widened frontal fontanelle. The posterior lambdoid suture (not visible) contains multiple wormian bones.



OSMOSIS.ORG 695



NOTES



NOTES



SPINAL DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders affecting spinal column ▫ Includes vertebrae, intervertebral discs, surrounding structures



RISK FACTORS



▪ Obesity, extreme exercise/any factor that ↑ spinal column pressure



COMPLICATIONS



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Detects soft tissue involvement ▫ Intervertebral discs, ligaments, nerves X-ray ▪ May show osteoarthritis signs ▫ Joint pain narrowing, bony spurs



▪ Nerve compression, arthritis, progressive degenerative disease



SIGNS & SYMPTOMS ▪ Localized pain, stiffness, limited range of motion ▪ Spine shape irregularities ▪ Compression → pulmonary, cardiac, gastrointestinal disorders ▪ Neurologic signs ▫ Numbness, paresthesia, weakness, tingling (if nerves affected)



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TREATMENT SURGERY



▪ If cause irreversible, condition advanced



OTHER INTERVENTIONS



▪ Malformation ▫ Bracing ▪ Physical rehabilitation, analgesia



Chapter 119 Spinal Disorders



DEGENERATIVE DISC DISEASE osms.it/degenerative-disc-disease PATHOLOGY & CAUSES ▪ Progressive intervertebral disc breakdown ▪ Most common back-pain source ▪ Accrual of factors → intervertebral disc’s nucleus pulposus (mostly water) dehydration → ↓ proteoglycan, collagen → ↓ padding between vertebrae → unable to absorb shock → disc collapse → annular tears, herniation of disc contents into spinal canal → nerve root irritation → nerve impingement → pain



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Evaluates spinal canal, visualizes space available for neural structures ▪ ↑ signal on T2-weighted images indicate disc dehydration ▪ Detects annular tears X-ray ▪ Detects fracture



CAUSES



▪ Multifactorial ▫ Accumulation of natural stress, minor injury throughout life ▫ Genetic predisposition



RISK FACTORS



▪ Genetic predisposition, advanced age, menopause, repeated spinal trauma



COMPLICATIONS



▪ Spine collapse, disc herniation, compression fracture, bony spur growth, neurologic deficit, myelopathy, vertebral artery compression



SIGNS & SYMPTOMS ▪ Back pain (not correlating to damage’s extent), ↓ range of motion ▪ Pain may radiate ▪ Tingling, paresthesia, numbness ▪ Muscle weakness/atrophy ▪ ↓ deep tendon reflexes ▪ Headache, dizziness, vertigo



Figure 119.1 An MRI scan of the spine.



TREATMENT MEDICATIONS



▪ Pain management ▫ Non steroidal anti-inflammatory drugs (NSAIDs), local/epidural corticosteroids



OSMOSIS.ORG 697



SURGERY



▪ Corpectomy ▫ Vertebral portion removal → enlarge intervertebral space ▪ Discectomy ▫ Herniated disc portion removed ▪ Nerve root injection



▪ Intervertebral disc arthroplasty ▫ Degenerated discs replaced with artificial discs ▪ Laminotomy ▫ Lamina removal → relieve nerve root pressure



KYPHOSIS osms.it/kyphosis PATHOLOGY & CAUSES ▪ Exaggerated cervical, thoracic, sacral spinal convex curvature ▪ Greek κυφός kyphos, meaning “hump” ▪ Cobb angle: used to measure extent of curvature ▫ Angle > 45° classified as kyphosis ▪ Damage to vertebrae, intervertebral discs/ supporting ligaments/muscles → weightbearing forces asymmetry → further damage to high-pressure area structures → “wedge-shaped” vertebra → spinal curving



TYPES



▪ May also be caused by trauma/iatrogenic causes (surgery)



Postural ▪ Most common, occurs all ages Structural ▪ Osteoporosis, tumors, tuberculosis (Gibbus malformation), ankylosing spondylitis, fractures, arthritis Congenital ▪ Vertebral malformation/in utero fusion Scheuermann’s kyphosis ▪ Adolescent onset, type of osteochondrosis (disordered cartilage ossification) ▪ Vertebral disc intrudes into end plates in anterior ossification areas (Schmorl’s nodes on X-ray)



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RISK FACTORS



▪ Poor posture, weak back muscles, older age, vertebral fracture, osteoporosis, degenerative disc disease, arthritis ▪ Genetic disease affecting bone, ligaments ▫ Osteogenesis imperfecta, Marfan syndrome, Ehler–Danlos syndrome, mucopolysaccharidosis, glycogen storage disease



COMPLICATIONS



Sternal/vertebral fracture Cardiac disease Imbalance → fall, fracture risk Neurologic ▫ Nerve compressions ▪ Respiratory ▫ ↓ pulmonary function ▪ Gastrointestinal dysfunction ▫ Dysphagia, reflux, hernias



▪ ▪ ▪ ▪



SIGNS & SYMPTOMS ▪ Anterior thoracic pain, dyspnea, limited mobility ▪ Convex spinal curvature ▪ Dysphagia, reflux



DIAGNOSIS ▪ Clinical diagnosis ▫ Curvature measurement using flexicurve ruler



Chapter 119 Spinal Disorders



DIAGNOSTIC IMAGING X-ray ▪ Sagittal plane: > 45° Cobb angle ▫ Lines drawn above first, last deviating vertebra → draw perpendicular lines to those → angle where they close is Cobb angle



TREATMENT SURGERY ▪ Reserved for significant pulmonary/ neurologic impairment cases



OTHER INTERVENTIONS



▪ Milwaukee brace ▫ Improves proprioception, helps support back muscles ▪ Physical therapy strengthens back muscles ▪ Pain management Figure 119.2 A lateral X-ray image of the spine demonstrating marked thoracic kyphosis secondary to Scheuermann’s disease.



LORDOSIS osms.it/lordosis PATHOLOGY & CAUSES ▪ Exaggerated inward curvature of lumbar, cervical spine ▪ Greek lordōsis, from lordos, meaning “bent backward” ▪ Bone/neuromuscular imbalance → weightbearing force asymmetry → further damage to high-pressure area structures/ compensatory muscle spasms → spinal curving



CAUSES ▪ High spine flexibility, lower limb imbalance ▪ Hip imbalance; improper lifting, squatting



▪ Muscle strength imbalance (e.g. weak hamstrings; tight hip flexors) ▪ Obesity ▪ Osteoporosis ▪ Spondylolisthesis, discitis ▪ Temporary lordosis during pregnancy



RISK FACTORS



▪ Poor posture, muscle strength imbalance ▪ Musculoskeletal ▫ Osteoporosis, spondylolisthesis ▪ Genetic ▫ Achondroplasia, Ehler–Danlos syndrome



OSMOSIS.ORG 699



COMPLICATIONS



▪ Degenerative disc disease, nerve compression



SIGNS & SYMPTOMS ▪ Lower-back pain ▪ Apparent ↑ lower-back curvature



DIAGNOSIS ▪ Physical examination reveals ↑ degree of lower-back curvature, muscle tightness



DIAGNOSTIC IMAGING MRI ▪ Detects nerve compression X-ray ▪ Confirms curvature degree ▪ Lamina, neural arch of vertebrae may form divert ‘V’ on anteroposterior lumbar spine radiograph



TREATMENT OTHER INTERVENTIONS



▪ Boston brace ▫ ↓ disc stress, muscle strengthening ▪ Physical therapy to strengthen, balance back muscles ▪ Pain management



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Figure 119.3 A lateral X-ray image of the spine in an individual with hyperlordosis of the lumbar spine.



Chapter 119 Spinal Disorders



SCOLIOSIS osms.it/scoliosis PATHOLOGY & CAUSES ▪ Lateral spinal curvature in coronal plane, commonly coexists with rotational curvature ▪ Bone/neuromuscular imbalance in vertebral/ paravertebral area → weight-bearing force asymmetry → further damage to highpressure area structures → spinal curving ▪ Sometimes associated with kyphosis, lordosis Classification according to etiology ▪ Structural (intrinsic) ▪ Postural (compensatory)



▪ Bone tumors, neuromuscular/neural disorders (e.g. Duchenne muscular dystrophy) ▪ Advanced bone maturity at presentation, biologically-female individuals ▫ More severe progression



COMPLICATIONS



▪ Chest wall abnormalities → respiratory compromise, cardiac complications ▪ Low self-esteem, depression ▪ Spinal nerve damage, hemiplegia



Classification according to shape ▪ C/S shaped ▪ Direction ▫ Projection of curvature apex defined with segment involved (most common right-thoracic with left-lumbar presentation)



CAUSES



▪ Congenital ▪ Idiopathic ▫ Most common; infantile, juvenile, adolescent/early–late onset ▫ Multifactorial (environmental, genetic factors) ▪ Secondary ▫ Osteopathic (Marfan syndrome), neuromuscular, neuropathic (neural palsy), myopathic, neurofibromatosis



RISK FACTORS



▪ Family history ▪ Obesity ▪ Lower limb fracture → limb length difference → compensatory scoliosis ▪ Sudden growth



Figure 119.4 An individual with thoracic and lumbar scoliosis. The uneven position of the scapulae is clearly visible.



OSMOSIS.ORG 701



SIGNS & SYMPTOMS ▪ Visible spinal curvature, fanning of ribs on one side, uneven musculature ▪ Back pain ▪ Difficulty breathing ▪ Intestinal compression → gastrointestinal difficulty



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Cobb angle ▫ Lines drawn above first, last deviating vertebra → draw perpendicular lines to those → Cobb angle > 10°



OTHER DIAGNOSTICS Physical examination ▪ Adams Forward Bend Test ▫ Shows torsion, shoulder, pelvis misalignment, unparallel scapulae



TREATMENT SURGERY



▪ Cobb angle > 45° ▫ Vertebral fusion surgery



OTHER INTERVENTIONS



▪ Cobb angle < 30° ▫ Watchful waiting (frequent check ups estimating curve angle, physical therapy) ▪ Cobb angle > 30° ▫ Boston brace



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Figure 119.5 A plain chest radiograph demonstrating spinal scoliosis.



Chapter 119 Spinal Disorders



SPINAL DISC HERNIATION osms.it/spinal-disc-herniation PATHOLOGY & CAUSES ▪ Middle portion of intervertebral disc (anulus pulposus) herniates through tear in outer portion (anulus fibrosus) of disc ▫ AKA slipped disc ▪ Weakening of intervertebral disc’s outer circle → outer ring tear → inner ring bulging out of spinal column → local nerve compression ▪ Disc protrusion ▫ Outer ring intact but middle portion of disc bulges ▫ May → herniation



RISK FACTORS



▪ Obesity, advanced age, heavy lifting, degenerative disc disease, trauma



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Confirm diagnosis



OTHER DIAGNOSTICS History ▪ History of heavy lifting, bone degenerative disease Clinical exam ▪ Straight leg raise test ▫ Individual lies supine, clinician passively raises leg → pain indicates disc herniation



COMPLICATIONS



▪ Nerve impingement ▪ Sciatica ▪ Cauda equina syndrome (compression of nerve roots controlling bowel, bladder, legs)



SIGNS & SYMPTOMS ▪ Continuous pain in certain position, level dependent on injury extent, often unilateral (may present bilaterally) ▪ Sciatica ▫ Lumbar/sacral nerve root compression → pain radiating down legs ▪ Other symptoms ▫ Sensory: numbness, paresthesia ▫ Motor: chronic atrophy, weakness



Figure 119.6 An MRI scan of the spine in the sagittal plane demonstrating protrusion of the L4/L5 and L5/S1 intervetebral discs.



OSMOSIS.ORG 703



TREATMENT MEDICATIONS ▪ Pain, inflammation control ▫ NSAIDs, local corticosteroids



SURGERY



▪ Repair ▫ In neurologic signs, nerve compression cases



OTHER INTERVENTIONS



▪ Physical rehabilitation, weight loss



SPINAL STENOSIS osms.it/spinal-stenosis PATHOLOGY & CAUSES ▪ Common chronic condition characterized by narrowing of spinal canal/intervertebral foramina ▫ More common in cervical, lumbar regions



CAUSES



▪ Aging ▫ Bone spurs grow into canal, ligaments thicken, slipped discs ▪ Skeletal disease (e.g. rheumatoid arthritis, osteoarthritis, Paget disease, ankylosing spondylitis, spondylosis, degenerative disc disease) ▪ Congenital (e.g. achondroplasia, spinal dysraphism) ▪ Other causes ▫ Trauma, fracture, neoplasm, idiopathic



RISK FACTORS



▪ Obesity, advanced age, family history



COMPLICATIONS



▪ Cauda equina syndrome



704 OSMOSIS.ORG



▫ Bilateral leg weakness, urinary incontinence ▫ Spinal cord narrowing → nerve root compression (L3–S4) → bowel incontinence/sexual dysfunction ▫ Neurologic emergency (requires immediate surgical decompression)



SIGNS & SYMPTOMS ▪ Canal diameter < 10mm ▪ Neurogenic claudication ▫ Discomfort, sensory loss/leg weakness (buttocks, calves) ▫ Symptomatic when active (e.g. walking, standing); with lumbar extension ▫ Relieved by rest, lying down, waist flexion (squatting, leaning forward) ▫ Back pain may coexist ▪ Radicular pain ▫ Pain radiates along dermatome ▪ Neurologic symptoms ▫ Typically bilateral if nerve compression is involved ▫ Numbness, weakness, paresthesia, limb pain, urinary/bowel incontinence, sexual dysfunction



Chapter 119 Spinal Disorders



DIAGNOSIS DIAGNOSTIC IMAGING CT myelogram ▪ Shows detailed spinal canal contours (if MRI contraindicated) MRI ▪ Spinal canal narrowing, nerve compression



TREATMENT MEDICATIONS



▪ Pain medications (NSAIDs), epidural steroid injections



SURGERY



▪ Decompression (advanced disease, complications)



Figure 119.7 An MRI scan of the cervical spine demonstrating spinal stenosis from C3 to C6 resulting in cord compression.



OTHER INTERVENTIONS



▪ Physical therapy, weight loss



SPONDYLITIS osms.it/spondylitis PATHOLOGY & CAUSES ▪ Chronic vertebrae, vertebral joint inflammation ▪ AKA spondyloarthritis ▪ Autoimmune/infectious agent attacks vertebra → inflammatory cells invade site → inflammation, damage to bone, cartilage; thick paravertebral ossification formation ▪ Spondylodiscitis ▫ Vertebrae, intervertebral disc inflammation



CAUSES



▪ Infectious ▪ E.g. Pott’s disease (osteoarticular tuberculosis); Staphylococcus aureus



▪ Autoimmune ▪ Ankylosing spondylitis, rheumatoid arthritis



RISK FACTORS



▪ Family history ▪ Immunocompromised state ▪ Spinal surgery/invasive intervention history



COMPLICATIONS ▪ ▪ ▪ ▪



Osteoporosis, osteopenia Fractures Neurologic Spinal cord compression, cauda equina syndrome



OSMOSIS.ORG 705



SIGNS & SYMPTOMS ▪ Localized pain ▫ Segment-dependent ▪ Gradual symptom onset ▫ Autoimmune disease ▪ Limited movement ▪ Spinal stiffness ▪ Symptoms worse in morning, improve with exercise



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Shows calcifications in column; may reveal erosive disease X-ray ▪ Asymmetric parasyndesmophytes visualization (paravertebral soft-tissue calcifications)



OTHER DIAGNOSTICS



▪ History of joint pain ▪ Positive autoimmune disease/exposure history



TREATMENT MEDICATIONS



▪ Infectious cause ▫ Antibiotics ▪ Autoimmune disease ▫ Disease modifying rheumatoid medications (sulfasalazine, local corticosteroids) ▪ Pain management (NSAIDS, opioids); severity-dependent



SURGERY



▪ Severe cases



OTHER INTERVENTIONS



▪ Physical therapy to strengthen back muscles



LAB RESULTS



▪ Blood tests ▫ Infectious cause ▪ Genetic testing ▫ Autoimmune cause



SPONDYLOLISTHESIS osms.it/spondylolisthesis PATHOLOGY & CAUSES ▪ Spontaneous anterior/posterior vertebral body slippage over one below it ▫ Most commonly affects lumbosacral articulation ▪ Vertebral joint dysfunction → joint instability → vertebral body slipping from original position



706 OSMOSIS.ORG



CAUSES



▪ Lytic/isthmic ▫ Most common ▫ Multiple pars interarticularis microfractures; usually affects athletes ▪ Degenerative ▫ Pseudospondylolisthesis, arthritis, osteoporosis ▪ Dysplastic ▫ Congenital posterior spinal dysplasia elements; usually presents with adolescent growth spurt



Chapter 119 Spinal Disorders ▪ Pathologic ▫ Vertebral lesions; neoplastic/infectious infiltration ▪ Traumatic ▫ Facet(s)/pars interarticularis fracture; post-surgical complication



RISK FACTORS



Genetic predisposition Competitive sports (dancing, gymnastics) Extreme growth spurt, muscle weakness Spinal malformation (Scheuermann’s kyphosis) ▪ Biologically-female individuals ▪ ▪ ▪ ▪



COMPLICATIONS



▪ Intervertebral disc degeneration ▪ Spinal stenosis



SIGNS & SYMPTOMS ▪ Chronic back pain/stiffness, posterior leg compartment tightness ▫ Pain ↑ with activity, ↓ with rest ▪ Limited range of motion ▪ Change in gait (often waddling) ▪ Forward flexion with development of transverse abdominal crease ▪ Hip, knee flexion malformations ▪ Sciatic nerve involvement signs (radiating pain down legs)



DIAGNOSIS DIAGNOSTIC IMAGING X-ray or CT scan ▪ Shows altered vertebral body alignment



TREATMENT MEDICATIONS



▪ Pain management (e.g. NSAIDs)



SURGERY



▪ Repair ▫ If persistent pain/neurologic symptoms, vertebral sliding is > 50%



OTHER INTERVENTIONS



▪ Orthoses (lumbar corset) ▫ May help reestablish proprioception, strengthen muscles ▪ Physical therapy to strengthen back muscles



Figure 119.8 A lateral X-ray image of the spine demonstrating spondylolisthesis at L5/ S1.



OSMOSIS.ORG 707



Figure 119.9 A CT scan of the spine in the sagittal plane demonstrating spondylolisthesis of the L5/S1 intervertebral joint.



SPONDYLOLYSIS osms.it/spondylolysis PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Pars interarticularis vertebral defect, mostly lumbar area ▫ May be unilateral/bilateral ▪ Extreme lumbar spine stress → spinal overextension with rotation → vertebral arch fracture/separation



▪ Pain, lumbar spine pressure sensation, focal tenderness ▪ Unilateral pain radiates into corresponding side’s leg ▪ Painful lumbar spine extension ▪ Antalgic gait ▫ Stance phase of gait shorter than swing phase as means of avoiding pain ▪ ↑ lumbar lordosis ▪ Hamstring tightness



CAUSES



▪ Unknown, occasionally appears asymptomatically



RISK FACTORS



▪ Extreme sports during adolescence



COMPLICATIONS



▪ Sciatica, spondylolisthesis, spinal malformations



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Chapter 119 Spinal Disorders



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Used if neurological findings; visualizes soft tissue, neural structures X-ray/CT scan ▪ Lucency in region of pars interarticularis ▪ Description ▫ Collar/“broken neck on the Scotty dog” in lateral oblique view



OTHER DIAGNOSTICS



Figure 119.10 A CT scan of the spine in the sagittal plane demonstrating spondylolisthesis of the L5/S1 intervertebral joint.



▪ Clinical exam ▫ Stork test (ask to stand on one leg, lift the other hip), tenderness on palpation in fracture area



TREATMENT MEDICATIONS



▪ Pain management



OTHER INTERVENTIONS



▪ Boston brace ▪ Physical therapy to strengthen back muscles



Figure 119.11 A plain radiograph of the spine shows the “scotty dog sign” in a case of spondylolysis.



OSMOSIS.ORG 709



SPONDYLOSIS osms.it/spondylosis PATHOLOGY & CAUSES ▪ Spinal column degeneration, compression ▪ Spinal osteoarthritis → degeneration of vertebral bodies, joints, foramina → intervertebral space narrowing → compression, damage to nerve roots



CAUSES



▪ Osteoartritis, trauma, postural



RISK FACTORS



▪ Obesity, older age, hyperkyphosis/ hyperlordosis



COMPLICATIONS



▪ Nerve compression, vertebrobasilar insufficiency, spinal disc protrusion, myelopathy



SIGNS & SYMPTOMS ▪ Progressive pain in affected spinal region, ↓ range of motion ▪ If nerves involved ▫ Paresthesia, radiating pain, numbness



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Shows nerve impingement and disc abnormalities



OTHER DIANOSTICS



▪ Clinical exam ▫ Cervical compression test: lateral flexion of head causes pain in neck, shoulder on same side



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TREATMENT MEDICATIONS



▪ Pain management



SURGERY



▪ Alleviate neural impingement



OTHER INTERVENTIONS



▪ Braces ▪ Physical therapy to strengthen back muscles



NOTES



NOTES



TRAUMA COMPLICATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders following traumas such as fractures, penetrating trauma, crush injuries, lacerations, hemorrhage, etc. ▪ Affected tissue damage → tissue homeostasis disruption ▫ Compartment syndrome: ↑ tissue pressure → blood-flow disruption → tissue ischemia, necrosis ▫ Rhabdomyolysis: damaged tissue contents release into bloodstream



SIGNS & SYMPTOMS



DIAGNOSIS LAB RESULTS



▪ Complete blood count (CBC), metabolic panel, muscle enzymes, urinalysis



OTHER DIAGNOSTICS ▪ Asses injury mechanism



TREATMENT OTHER INTERVENTIONS ▪ Treat underlying cause



▪ Pain, bleeding, tenderness; limb-, lifethreatening conditions



COMPARTMENT SYNDROME osms.it/compartment-syndrome PATHOLOGY & CAUSES ▪ ↑ pressure in closed space compromises space’s blood supply ▪ Any body compartment can be affected (most commonly legs, arms)



TYPES Acute compartment syndrome ▪ Most commonly caused by fractures ▫ Other causes hemorrhage, crush injuries, vascular puncture, penetrating trauma, severe circumferential



burns, intravenous drug injection, revascularization procedures, poorfitting casts ▪ Most commonly affects leg, forearm; also foot, thigh, abdomen, gluteal region ▪ Fracture → hemorrhage, edema, necrotic debris accumulation → ↑ intracompartmental pressure exceeds perfusion pressure (10–30mmHg) → arteriolar collapse → compromised blood flow Chronic compartment syndrome ▪ Repetitive muscle use/exertion during vigorous exercise; most commonly affects leg



OSMOSIS.ORG 711



▪ Exercise → ↑ muscle size → ↑ intracompartmental pressure → fluid exudation into interstitial space → compromised blood flow



OTHER DIAGNOSTICS



Acute compartment syndrome ▪ Untreated → irreversible nerve damage (sensory deficits, paralysis); infection; tissue ischemia → necrosis; limb amputation ▪ Volkmann’s contracture ▫ Permanent affected-limb flexion contracture ▪ Rhabdomyolysis, kidney failure



Pressure measurement ▪ Acute compartment syndrome (usually not required ▫ Intracompartmental pressure > 25mmHg ▫ Delta pressure < 20–30mmHg (delta pressure = diastolic blood pressure ‒ measured compartment pressure) ▪ Chronic compartment syndrome ▫ Prior to exercise (≥ 15mmHg); after one minute of exercise (≥ 30mmHg); after five minutes of exercise (≥ 20mmHg) ▫ Diagnosis of exclusion



SIGNS & SYMPTOMS



TREATMENT



COMPLICATIONS



▪ Symptom location depends upon affected compartment Acute compartment syndrome ▪ Rapid signs, symptoms progression ▪ Early signs ▫ Severe deep pain exacerbated by movement, not relieved by analgesics; swelling, tense muscle compartment, paresthesias ▪ Late signs ▫ ↓ pulse/pulselessness, anesthesia, function loss, paralysis Chronic compartment syndrome ▪ Symptoms occur during physical activity, subside when activity stops ▫ Insidious pain, tense muscle compartment, numbness, tingling, cramping, muscle bulging, foot-drop



DIAGNOSIS LAB RESULTS ▪ Lab findings evident in later stages ▪ Acute compartment syndrome ▫ ↑ creatine kinase (CK) ▫ Myoglobinuria



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SURGERY



▪ Acute compartment syndrome ▫ Medical emergency: immediate management required ▫ Fasciotomy: all affected compartments → surgical decompression ▫ Escharotomy: burns ▫ Limb amputation: severe tissue necrosis ▪ Chronic compartment syndrome ▫ Fasciotomy/fasciectomy: moderate– severe cases



OTHER INTERVENTIONS



▪ Chronic compartment syndrome ▫ ↓ exercise volume, physical therapy



Chapter 120 Trauma Complications



Figure 120.1 Surgeons performing a fasciotomy on the lower leg of in an individual with compartment syndrome.



RHABDOMYOLYSIS osms.it/rhabdomyolysis PATHOLOGY & CAUSES ▪ Extensive muscle necrosis, muscle cell content release into bloodstream ▪ Muscle damage → ATP depletion → membrane cell pump dysfunction → ↑ intracellular Ca2+ due to ↓ efflux → Ca2+-dependent protease activation, hydroxylases, nucleases → cell death, muscle cell content release (myoglobin, CK, Ca2+)



CAUSES



▪ Trauma/compression ▫ Crush injury, prolonged immobilization (comatose individuals), acute compartment syndrome, hyperthermia, severe third-degree burns,



▪



▪ ▪ ▪ ▪



postoperative surgical trauma Metabolic/genetic factors ▫ Metabolic myopathies, glycogen storage diseases, mitochondrial disease Infections ▫ Influenza types A, B; HIV; coxsackievirus Medication ▫ Statins, colchicine, propofol Substance abuse ▫ Amphetamines, cocaine, alcohol Others ▫ Electrolyte disorders, exertional activity, snake venom, hyperkinetic states



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COMPLICATIONS



▪ Acute renal injury ▫ Massive myoglobin release exerts toxicity to renal tubules → acute tubular necrosis ▪ Acute compartment syndrome ▪ Hyperkalemia, hypocalcemia, metabolic acidosis ▪ Disseminated intravascular coagulation (DIC) ▪ Electrolyte imbalances → cardiac arrhythmias



TREATMENT OTHER INTERVENTIONS ▪ IV fluids, electrolyte-imbalance correction ▪ Kidney function monitoring ▪ Severe cases ▫ Dialysis/hemofiltration



SIGNS & SYMPTOMS ▪ Severity-dependent ▪ Non-specific symptoms ▫ Fever, nausea, dyspepsia, vomiting ▪ Muscle pain, weakness, affected muscle swelling ▪ Oliguria/anuria (acute renal injury) ▪ Dark urine discoloration



DIAGNOSIS LAB RESULTS



▪ ↑ CK ▫ Most sensitive, nonspecific indicator ▪ Myoglobinuria ▪ Hyperuricemia ▫ Blood urea nitrogen (BUN), creatinine ▪ ↑ Lactate dehydrogenase (LDH) ▪ Electrolyte imbalances ▫ Hyperkalemia, hypocalcemia (early signs)



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Figure 120.2 Urine of an individual with rhabdomyolysis.



NOTES



NOTES



UPPER LIMB INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Upper limb joint damage, dislocation ▪ Weakening/damaging of ligaments, tendons → distortion of normal anatomical joint structure, function loss/impairment



MRI ▪ Damaged ligaments and soft tissue Ultrasound ▪ Soft tissue damage ▪ Tendon dislocations



OTHER DIAGNOSTICS



CAUSES



▪ Trauma, overuse



SIGNS & SYMPTOMS ▪ Pain, swelling, numbness ▪ Reduced range of motion ▪ Visible/palpable malformations



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Dislocation ▪ Distorted articular spaces ▪ Fractures



▪ Physical examination ▫ Reduced range of motion ▫ Visible dislocation ▫ Swelling



TREATMENT MEDICATIONS



▪ Pain management ▫ Sedation, analgesia



SURGERY



▪ Joint reduction



OTHER INTERVENTIONS ▪ Rest, ice ▪ Physical rehabilitation



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DISLOCATED SHOULDER osms.it/dislocated-shoulder PATHOLOGY & CAUSES ▪ Humeral head detaches from glenoid fossa in glenohumeral joint ▪ Loose ligaments provide high mobility, but are prone to injury in abduction/external rotation



TYPES Anterior dislocation ▪ Most common ▪ Blow to extended, raised, outwardly turned arm → damaged inferior glenohumeral ligament



SIGNS & SYMPTOMS Shoulder feels unstable/like it’s “rolling out” Shoulder pain (can radiate down arm) Limited range of motion Visible displacement Injured/compressed axillary artery: hematoma/weak distal pulse ▪ Stretched axillary nerve: shoulder area numbness ▪ ▪ ▪ ▪ ▪



Posterior dislocation ▪ Strong muscle cramp/electric shock ▪ Associated with tuberosity, surgical neck fractures of humerus Inferior dislocation ▪ Uncommon ▪ Force applied to completely raised arm (e.g. individual falls, tries to grab onto something above) ▪ Highest incidence of axillary nerve, artery injuries



CAUSES



▪ Force from fall/blow → ligaments tear/ stretch → humeral head slips out of position



RISK FACTORS



▪ Previous dislocations ▪ Sports



COMPLICATIONS



▪ Axillary artery, nerve damage from injury/ while performing reduction



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Figure 121.1 An X-ray image of the shoulder demonstrating an anterior dislocation.



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Two views necessary ▫ Anteroposterior view (AP) ▫ Lateral view ▪ Anterior dislocation: humeral head is in front of glenoid



Chapter 121 Upper Limb Injury ▪ Posterior dislocation: humeral head is in place in AP view ▪ Fractured bones MRI ▪ Damaged ligaments (contrast enhancement for better visualisation) CT angiogram ▪ Arterial damage



TREATMENT ▪ Reduction ▫ Perform as soon as possible for easier reduction, less chance of complications ▫ e.g. Hill–Sachs lesion/compression fractures on humeral head ▪ Immobilisation, rest ▫ Age < 30 → three weeks ▫ Age > 30 → 7–10 days



Figure 121.2 An X-ray image of the left shoulder demonstrating a Hill–Sachs lesion. A Hill–Sachs lesion is a posterolateral compression fracture that occurs as a result of recurrent anterior dislocations of the shoulder.



NURSEMAID'S ELBOW osms.it/nursemaids-elbow PATHOLOGY & CAUSES ▪ Dislocation of radial head in elbow joint ▫ Pulled elbow/radial head subluxation



CAUSES



▪ Pulling extended arm makes annular ligament slip above radial head ▪ Lifting/swinging child ▪ Common in children < six years old



SIGNS & SYMPTOMS



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ When fracture suspected



TREATMENT OTHER INTERVENTIONS



▪ Reduction ▫ Supination, elbow flexion ▫ Hyperpronation (less painful)



▪ Child refuses to bend/use affected arm ▫ Fear of pain ▪ Holds affected arm in prone position, close to body ▪ Inability to supinate



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ROTATOR CUFF TEAR osms.it/rotator-cuff-tear PATHOLOGY & CAUSES ▪ One/more tendons of rotator cuff tear(s) ▫ Supraspinatus, infraspinatus, teres minor, subscapularis comprise the rotator cuff ▪ Most common shoulder problem ▫ Occurs in all age groups



TYPES By course ▪ Acute tears ▫ Strong force damages tendons (e.g. rowing, powerlifting) ▪ Chronic tears ▫ Prolonged repetitive motions (especially overhead moves) ▫ Tendon degeneration: aging, blood supplies worsen ▫ Tendons become irritated, inflamed while passing through narrowed gaps



▪ Weakness, instability, restricted range of motion ▪ Compressed nerves → numbness



DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Anteroposterior view ▫ Sclerosis, cyst formation, smaller gap between acromion, humerus ▪ Lateral view ▫ State of acromion ▪ Axillary view ▫ Humeral head position MRI ▪ Connective tissue visualization ▪ Size, location of damage ▪ Swelling



By amount of damage ▪ Partial thickness tears ▫ Damaged supraspinatus tendon ▪ Full thickness tears ▫ Damaged supraspinatus, infraspinatus, subscapularis, biceps tendon By exterior/interior factors ▪ Exterior factors ▫ Tendon impingement due to curved/ hooked acromion ▪ Interior factors ▫ Small repetitive injuries over prolonged period → tendon degeneration



SIGNS & SYMPTOMS ▪ “Arc of pain” (pain while lowering arm) ▪ Night pain



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Figure 121.3 An MRI scan of the shoulder in a non-orthogonal plane demonstrating a complete tear of the supraspinatus and infraspinatus tendons.



Chapter 121 Upper Limb Injury Ultrasound ▪ Evaluate tear extent ▪ Tendon dislocations



OTHER DIAGNOSTICS Supraspinatus injuries ▪ Active painful arc & drop arm test ▫ Fully raise arm, then steadily lower it back ▫ If pain occurs → positive test ▪ Jobe’s test (aka “empty can”) ▫ Individual raises straight arm 90°, flexes forward 30° with thumb pointing down → resists attempt to depress arm ▫ Pain without weakness → tendinopathy ▫ Pain with weakness → tendon tear Infraspinatus, teres minor injuries ▪ Test external rotation ▫ Individual attempts external rotation of arm, examiner provides resistance Subscapularis injuries ▪ Gerber’s lift-off test ▫ Place hand behind back → push backwards against resistance ▪ Supine Napoleon test ▫ Individual lays down, places hand on abdomen with elbow flexed 90° → attempts to raise elbow while examiner secures hand, shoulder



Impingement test ▪ Neer test ▫ Individual flexes pronated arm (with thumb pointing downwards) above head ▪ Hawkins test ▫ Individual raises arm 90° with halfflexed elbow → examiner attempts to internally rotate shoulder



TREATMENT MEDICATIONS



▪ Pain management ▫ NSAIDs



SURGERY



▪ Small tears → arthroscopically ▪ Large tears → open surgical repair



OTHER INTERVENTIONS



▪ Rest, ice ▫ Pain, inflammation management ▪ Physical therapy ▫ Restore range of motion ▪ Strengthen muscles that support joint ▪ Exercises for preserving neurologic control



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NOTES



NOTES



BREAST MASSES GENERALLY, WHAT ARE THEY? TREATMENT



PATHOLOGY & CAUSES ▪ Diverse breast tissue disorders; often in biologically-female individuals, often benign ▫ Young: ↑ benign masses ▫ Elderly: ↑ breast cancer



SURGERY



▪ Lumpectomy ▪ Mastectomy



CAUSES



▪ Hormonal stimulation ▪ Genetic predisposition



COMPLICATIONS



▪ Possibility that benign mass → breast cancer



SIGNS & SYMPTOMS ▪ Possibly asymptomatic ▪ Breast size/appearance change



DIAGNOSIS ▪ Suggestive physical findings, medical/ family history



DIAGNOSTIC IMAGING Mammogram MRI Ultrasound



LAB RESULTS



▪ Biopsy, histological analysis



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▪ Benign disorders may regress spontaneously



OTHER INTERVENTIONS



▪ Alternatives (e.g. cryoablation, radiation therapy)



Chapter 122 Breast Masses



BREAST CANCER osms.it/breast-cancer PATHOLOGY & CAUSES ▪ Diverse malignant breast lesions with different microscopic features, biologic behavior ▫ ↑ common non-skin malignancy in biologically-female individuals ▫ Rare in biologically-male individuals



TYPES Molecular subtypes ▪ Molecular subtypes classified by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) expression; protein Ki67 levels (controls cancer cell growth) ▫ Luminal A: ER, PR positive, HER2 negative, ↓ protein Ki67 levels ▫ Luminal B: ER, PR positive, HER2 negative or positive, ↑ protein Ki67 levels ▫ Triple-negative: ER, HER2, PR negative ▫ HER2 enriched: ER, PR negative, HER2 positive ▫ Normal-like: ER, PR positive, HER2 negative, ↓ protein Ki67 levels Most common types ▪ Ductal carcinoma in situ (DCIS) ▫ In ducts → possible invasive ductal carcinoma (usually in same breast) ▪ Lobular carcinoma in situ (LCIS) ▫ In lobules → ↑ cancer risk in either breast ▪ Invasive ductal carcinoma ▫ 70% of all invasive cancers ▫ Subtypes: tubular, medullary, mucinous, papillary, cribriform ▪ Invasive lobular carcinoma ▪ Inflammatory breast cancer ▫ Rare aggressive form ▫ Poor prognosis



Figure 122.1 The gross pathological appearance of breast cancer in a wide local excision specimen.



CAUSES



▪ Genetic aberrations ▪ Hormonal exposure ▪ Inherited susceptibility genes (familial, 10% of cases) ▫ Breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) (80–90% of singlegene familial breast cancers, 3% of all cancers)



RISK FACTORS



Breast cancer prior history ↑ age → ↑ risk Breast cancer in first-degree relatives Individuals who are biologically female Race/ethnicity ▫ Highest incidence in white people of Ashkenazi Jewish descent ▪ Hormonal influence ▫ Estrogen exposure (e.g., menopausal hormone therapy) ▫ Early menarche (< 11 years old) ▫ Late menopause



▪ ▪ ▪ ▪ ▪



OSMOSIS.ORG 721



▫ Nulliparity/ > 35 years old at first birth ▫ ↓ breastfeeding duration ▫ Obesity ▪ Toxin exposure ▫ Ionizing radiation ▫ Smoking ▫ ↑ alcohol consumption



Ultrasound ▪ Differentiate cystic/solid masses ▪ Provide procedure guidance ▪ Hypoechoic lesion ▫ Calcifications, shadowing, irregular margins



COMPLICATIONS



▪ Metastasis (bone, lung, liver, brain common) ▪ Treatment complications ▫ Lymph node resection → lymphedema ▫ Cytotoxic chemotherapy → infertility ▫ Chemotherapy, radiation therapy → cardiac disorders (e.g. cardiomyopathy) and/or myeloid neoplasms



SIGNS & SYMPTOMS ▪ Possibly asymptomatic (especially premalignant breast masses) ▪ Palpable mass (hard, nontender, irregular borders, immobile) ▪ Palpable lymph nodes ▫ Axillary, supraclavicular ▪ Skin dimpling (orange peel skin) ▪ Nipple retraction, discharge (usually bloody), eczema-like rash (Paget’s disease of breast) ▪ Inflammatory breast cancer ▫ Presentation mimics inflammation (tenderness, warmth, swelling, erythema) ▫ Orange peel skin over mass



Figure 122.2 An inverted nipple caused by a sub-areolar breast tumor.



DIAGNOSIS DIAGNOSTIC IMAGING Breast MRI ▪ High-risk individuals (with mammography) Mammogram ▪ Ill-defined, spiculated mass ▫ Clustered microcalcifications



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Figure 122.3 A mammogram of the breast demonstrating a well circumscribed tumor.



Chapter 122 Breast Masses



LAB RESULTS



▪ Core biopsy ▫ Histological analysis, tumor grading ▪ Immunohistochemistry analysis ▫ Detect estrogen/progesterone receptor expression; HER2 overexpression ▪ Sentinel lymph node biopsy



OTHER DIAGNOSTICS ▪ Suggestive physical findings, medical/ family history Figure 122.4 The histological appearance of breast carcinoma, no special type. This subtype can take many forms but in this instance there are cords of pleomorphic, atypical cells with open chromatin and prominent nucleoli.



TREATMENT SURGERY



▪ Lumpectomy/mastectomy ▫ Individual’s choice



OTHER INTERVENTIONS



▪ Radiation therapy ▪ Chemotherapy ▪ Adjuvant hormone therapy/ chemoprevention (some cancers)



Figure 122.5 A fungating tumor of the left breast. The tumor involves almost the entire organ and extends into the axilla where the overlying skin has ulcerated.



OSMOSIS.ORG 723



FIBROADENOMA osms.it/fibroadenoma PATHOLOGY & CAUSES ▪ Benign, estrogen-sensitive proliferative breast lesion (from stromal, epithelial components) ▫ ↑ occurence young people (< 35 years old) ▫ Most common benign breast neoplasm ▪ Cause unknown; possibly hormone presence ▫ Pregnancy, pre-menstruation → ↑ proliferation ▫ Regresses with age



TYPES ▪ Giant fibroadenomas ▫ >10cm/3.9in (phylloid tumors appear similar) ▪ Juvenile ▫ Young individuals (10–18 years of age), grow rapidly, ↑ glandularity, ↑ stromal cellularity ▪ Complex fibroadenomas ▫ Proliferative changes (e.g. sclerosing adenosis, calcifications/hyperplasia)



DIAGNOSIS DIAGNOSTIC IMAGING Breast ultrasound ▪ Well-defined, solid, hypoechoic lesion Mammogram ▪ Circumscribed, dense lesion, possible clustered calcifications



LAB RESULTS Biopsy ▪ Definitive diagnostic test ▫ Glandular, fibrous tissue ▪ Excludes breast cancer



OTHER DIAGNOSTICS ▪ Suggestive physical findings



COMPLICATIONS



▪ Size increases → possible infarction/ inflammation ▪ Mildly ↑ breast cancer risk (especially complex fibroadenomas)



SIGNS & SYMPTOMS ▪ Typical presentation: 2–3cm/0.79–1.2in average size, firm, well-circumscribed, round, palpable, mobile, painless (possibly painful during menstrual cycle) ▪ Often multiple, bilateral



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Figure 122.6 The histological appearance of a fibroadenoma. There is overgrowth of both the stroma and the glandular epithelium.



Chapter 122 Breast Masses



TREATMENT ▪ Therapy seldom required; often regress post-menopause



SURGERY



▪ Surgical excision



OTHER INTERVENTIONS ▪ Cryoablation



Figure 122.7 A fine needle aspirate of a fibroadenoma of the breast. Sheets of epithelial cells are arranged in a staghorn pattern.



FIBROCYSTIC BREAST CHANGES osms.it/fibrocystic-breast-changes PATHOLOGY & CAUSES ▪ Common benign breast disease ▪ Bilateral tenderness, multiple lumps related to cyclic ovarian hormonal stimulation ▫ AKA fibrocystic disease, mammary dysplasia, cystic mastitis ▫ Premenopausal individuals (< 35 years old) → ↑ common; 50% of reproductiveage biologically-female individuals ▫ Increased breast cancer risk not associated (non-proliferative breast lesions) ▪ Characteristic changes ▫ Cysts ▫ Adenosis ▫ Stromal fibrosis



TYPES



▪ Epithelial hyperplasia ▫ Cells in terminal ductal/lobular epithelium, atypical cells → ↑ carcinoma risk



COMPLICATIONS



▪ Some subtypes (sclerosing adenosis, atypical hyperplasia) → ↑ increased invasive carcinoma risk (both breasts)



SIGNS & SYMPTOMS ▪ Menstrual cycle-related clinical manifestations ▫ Bilateral breast pain, tenderness ▫ Multiple, smooth, well-defined, mobile lumps (“lumpy bumpy” breasts); usually upper outer quadrant



▪ Sclerosing adenosis ▫ Acini, stromal fibrosis, calcifications associated, slight ↑ cancer risk



OSMOSIS.ORG 725



TREATMENT



DIAGNOSIS DIAGNOSTIC IMAGING Mammogram ▪ Dense breasts with cysts Ultrasound ▪ Fluid-filled cysts



LAB RESULTS Aspiration ▪ If mass persistent ▪ Excludes tumor ▪ If clear fluid obtained, mass disappears → fibrocystic breast changes Biopsy ▪ Cysts ▫ Blue serous fluid (“blue dome” appearance), various sizes, calcifications common ▪ Fibrosis ▫ Due to chronic inflammation from cyst rupture, material release to stroma ▪ Adenosis ▫ ↑ acini per lobule



OTHER DIAGNOSTICS ▪ Suggestive physical findings



Figure 122.8 The histological appearance of fibricystic change of the breast. There are numerous small cysts surrounded by fibrous tissue. The cysts are lined with ductal epithelium.



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MEDICATIONS



▪ Conservative measures ▫ Oral contraceptives; analgesics (e.g., nonsteroidal anti-inflammatory agents (NSAIDs))



SURGERY



▪ Surgical intervention often unnecessary; resolves with menopause ▪ Surgical treatment ▫ Complex cysts, if biopsy results atypical/ malignancy revealed



OTHER INTERVENTIONS



▪ Conservative measure ▫ Caffeine elimination ▪ Conservative measures fail → therapeutic aspiration



Chapter 122 Breast Masses



INTRADUCTAL PAPILLOMA osms.it/intraductal-papilloma PATHOLOGY & CAUSES ▪ Rare benign fibroepithelial breast tumor arising from lactiferous duct epithelium



TYPES



▪ Central ▫ Develops near nipple, usually solitary, often arise near menopause ▪ Peripheral ▫ Often multiple, usually in younger individuals



RISK FACTORS



▪ Biologically female, 20–30 years old



COMPLICATIONS



Mammogram ▪ Excludes breast cancer ▪ Intraductal papilloma usually too small to detect Ultrasound ▪ Projections extending from duct wall within lumen; used to diagnose/guide surgical resection



LAB RESULTS Biopsy ▪ Fibrovascular intraductal projections lined by myoepithelial, epithelial cells



OTHER DIAGNOSTICS ▪ Suggestive physical findings



▪ Slightly ↑ breast cancer risk ▪ Peripheral ▫ ↑ risk ▪ ↑ age → ↑ risk



SIGNS & SYMPTOMS ▪ Intermittent bloody/serous nipple discharge (especially premenopausal) ▪ Breast feels full (relieved by discharge passage)



DIAGNOSIS DIAGNOSTIC IMAGING Galactography ▪ Contrast-enhanced mammogram; definitive test but invasive ▪ Filling lactiferous duct defect



Figure 122.9 Breast ductography demonstrating a solitary intraductal papilloma.



TREATMENT ▪ Small, incidental papillomas: treatment may be unnecessary



SURGERY



▪ Breast duct removal



OSMOSIS.ORG 727



Figure 122.10 The histological appearance of a papilloma of the breast. There are multiple infolded papillae giving a cribriform pattern. The papillae are lined by benign ductal epithelium.



PAGET'S DISEASE OF THE BREAST osms.it/pagets-disease-of-the-breast PATHOLOGY & CAUSES ▪ Rare cutaneous breast cancer manifestation ▫ Eczema-like skin changes in nipple, areola ▪ Pathogenesis ▫ Epidermotropic theory: underlying mammary carcinoma present (85–88% of cases) → malignant cells migrate through ductal system → nipple epidermis ▫ In situ transformation theory: nipple keratinocyte transformation → malignant cells (independent of other breast pathology)



SIGNS & SYMPTOMS ▪ Typical presentation: unilateral; nipple + adjacent areolar skin; scaly; itching, burning; erythematous



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▪ Less common: bloody nipple discharge, nipple inversion, pain ▪ Palpable mass in 50–60% of cases → worse prognosis



Figure 122.11 The clinical appearance of Paget’s disease of the breast.



Chapter 122 Breast Masses



DIAGNOSIS DIAGNOSTIC IMAGING Mammogram ▪ Identify associated mass, microcalcifications, tissue distortion



LAB RESULTS



▪ Ultrasound-guided mass core biopsy, histopathological analysis ▪ Nipple scrape cytology/full-thickness wedge/punch biopsy ▫ Malignant, intraepithelial adenocarcinoma cells (Paget cells) present



Figure 122.12 The histological appearance of Paget’s disease. There are tumor cells migrating upward toward the skin surface individually and in small groups.



OTHER DIAGNOSTICS ▪ Suggestive physical findings



TREATMENT SURGERY



▪ Mastectomy, breast-conserving surgery



OTHER INTERVENTIONS ▪ Whole breast radiotherapy



PHYLLODES TUMOR osms.it/phyllodes-tumor PATHOLOGY & CAUSES ▪ Rare fibroepithelial breast tumor ▫ Typical phyllodes (leaf-like) projections on pathologic examination ▫ AKA cystosarcoma phyllodes ▪ Generally benign, can become malignant sarcoma ▪ Arises from periductal breast stroma



▪ Associated with acquired chromosomal mutations; most commonly gains in chromosome 1q



COMPLICATIONS



▪ Local recurrence after excision ▪ Local hemorrhage, necrosis ▪ High-grade tumors can give distant hematogenous metastasis; lymphatic spread rare



RISK FACTORS



▪ Biologically female, 30–50 years old



OSMOSIS.ORG 729



SIGNS & SYMPTOMS ▪ Mass ▫ Large, palpable, firm, multinodular, wellcircumscribed, mobile, painless ▪ Slow-growing or develops rapidly over entire breast ▪ Overlying skin possibly shiny, stretched ▪ Possible bloody discharge



DIAGNOSIS DIAGNOSTIC IMAGING Breast MRI ▪ Well-circumscribed lesion, ↑ signal intensity on T1-weighted, ↓ signal intensity on T2weighted Mammogram ▪ Smooth, polylobulated mass, resembles fibroadenoma Ultrasound ▪ Solid, hypoechoic, well-circumscribed lesion; possible cystic areas within mass, microcalcifications absent



LAB RESULTS Core needle biopsy ▪ Histologic grading: ↑ cellularity, ↑ mitotic rate, nuclear polymorphism, fibrous stroma overgrowth, leaf-like lobulations, cysts ▫ Cellular pleomorphism indicates malignancy



OTHER DIAGNOSTICS ▪ Suggestive physical findings



TREATMENT SURGERY



▪ Treatment of choice: surgical removal (wide local excision)



OTHER INTERVENTIONS



▪ Large, high-risk/recurrent tumors: adjuvant radiotherapy/chemotherapy



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Figure 122.13 The histological appearance of a Phyllodes’ tumor. Whilst similar in appearance to a fibroadenoma, the stroma is more cellular and constitutes a larger component of the tumor



Chapter 122 Breast Masses



OSMOSIS.ORG 731



NOTES



NOTES



DISORDERS OF LABOR



PLACENTA ACCRETA osms.it/placenta-accreta PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ A type of abnormally developed, invasive placenta ▫ Normally a spontaneous, complete placenta separation from uterine wall (myometrium) ▫ Maternal placenta side (decidua) separates from myometrium at stratum basalis layer ▪ Absent/underdeveloped decidua occurs in placenta accreta → adherence of fetal chorionic villi directly to myometrium → placenta fails to fully separate after fetus is delivered ▫ Partial separation → profuse hemorrhage → hemorrhagic shock and coagulopathy ▫ If no separation → hemorrhage is induced when manual separation is attempted



▪ Placenta fails to spontaneously deliver after fetus’s birth ▫ Manual separation attempts unsuccessful, provoke increased bleeding ▪ Severe hemorrhage ▪ Boggy (soft, spongy) uterus unresponsive to uterotonics/uterine massage



TYPES



DIAGNOSTIC IMAGING



▪ Placenta accreta; placenta increta; placenta percreta (based on invasiveness) ▪ Placenta accreta also increases risk of preterm bleeding ▫ Association between placenta accreta, concurrent placenta previa



RISK FACTORS



▪ Previous uterine surgery ▫ Cesarean section (most common), myomectomy, curettage ▫ Scar tissue prevents normal placental implantation ▪ Previous placenta previa



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DIAGNOSIS ▪ Based on clinical presentation of hemorrhage post-delivery; severe hemorrhage after attempted manual placenta delivery ▪ Prenatal diagnosis allows planned management (e.g. cesarean birth, cesarean hysterectomy)



Ultrasound, color Doppler ▪ Evaluate alterations in intraplacental blood flow, status of placental-myometrial interface



LAB RESULTS



▪ Laboratory tests may show ↑ maternal serum alpha fetoprotein



Chapter 123 Disorders of Labor



TREATMENT MEDICATIONS



▪ Circulatory support ▫ Fluids, blood products



SURGERY



▪ Hysterectomy may be needed to control postpartum hemorrhage ▫ Most common life-saving intervention ▪ Cesarean hysterectomy (fetus delivery followed by uterus + placenta removal as one unit) may be planned preoperatively with invasive placenta evidence



Figure 123.1 A uterus removed following cesarian section demonstrating complate invasion through the uterine wall by the placenta, known as placenta percreta.



PLACENTA PREVIA osms.it/placenta-previa PATHOLOGY & CAUSES ▪ Placenta implants in lower uterine segment (placenta previa = placenta first) ▪ Implantation is in lower uterine segment, close to/covering uterine opening (cervical os) → as pregnancy progresses, uterine segment grows → disruption of uterine blood vessels → bleeding (usually after 20 weeks of gestation) ▪ Classified by placenta’s closeness to cervical os ▫ Complete: placenta completely covers cervical os ▫ Partial: placenta partially covers cervical os ▫ Marginal: placenta edge extends to within 2cm/0.79in of cervical os



CAUSES



RISK FACTORS



▪ Multiple placentas or placenta with a larger than normal surface area (e.g. multiple gestation) ▪ Previous cesarean section/any uterine surgery ▪ Multiparity ▪ Intrauterine fibroids ▪ Spontaneous/induced abortion ▪ Placenta accreta ▪ Maternal age ≥ 35 years old ▪ Smoking



COMPLICATIONS



▪ Maternal: hemorrhage ▫ Severity depends on placenta location ▫ Disseminated intravascular coagulation (DIC) if bleeding severe/prolonged ▪ Fetal: hypoxia, preterm birth



▪ Placenta implants lower in uterus when upper uterine endometrium is not well vascularized due to endometrial damage



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SIGNS & SYMPTOMS ▪ Bleeding ▫ Painless ▫ Bright red ▫ Intermittent/continuous ▫ Often increases during labor from uterine contractions, cervical dilation ▪ Uterine hyperactivity ▪ Electronic fetal monitoring tracings may show fetal heart rate deceleration, indicating hypoxia



DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ During routine prenatal ultrasound Transabdominal ultrasound ▪ When bleeding occurs during labor, determines placental location



TREATMENT MEDICATIONS



▪ Corticosteroids as indicated to enhance fetal lung maturity



SURGERY



▪ Emergent cesarean delivery if placenta obstructs delivery or hemorrhage is severe



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Figure 123.2 An MRI scan of the abdomen of a pregnant female demonstrating major placenta praevia. The internal cervical os is completely covered by the placenta. ▪ After delivery, measures to control bleeding include ▫ Hysterectomy/interventional radiology (e.g. uterine artery embolization)



OTHER INTERVENTIONS



▪ Manage maternal bleeding; support mother, fetus hemodynamic stability ▫ Transfusion of blood products ▫ IV fluids ▪ Continuous fetal heart rate monitoring



Chapter 123 Disorders of Labor



PLACENTAL ABRUPTION osms.it/placental-abruption PATHOLOGY & CAUSES ▪ Premature separation of all/section of otherwise normally implanted placenta from uterine wall after 20 weeks of gestation wall resulting in hemorrhage



TYPES



▪ Partial/complete: depending on separation degree ▪ Concealed: central separation may cause a pocket of blood to form, concealing bleeding between decidua basalis and uterine wall → hematoma promotes separation ▪ Apparent: bleeding is visualized



CAUSES



▪ Uterine artery degeneration in decidua basalis → diseased vessels rupture → hemorrhage → placenta separation



RISK FACTORS



Previous placental abruption Chronic hypertension Preeclampsia/chronic hypertension Multiparity Rapid uterine decompression (e.g. as with polyhydramnios/multiple gestation) ▪ Trauma (e.g. car crash, fall, domestic violence) ▪ Smoking ▪ Drugs: cocaine, methamphetamine ▪ ▪ ▪ ▪ ▪



SIGNS & SYMPTOMS ▪ Uterus ▫ Pain in abruption area ▫ Abdominal/back pain ▫ Irritability, tachysystole, tetany ▫ Mild to severe vaginal bleeding (evidence of consumptive coagulopathy if severe bleeding) ▪ Fetal hypoxia, bradycardia



DIAGNOSIS ▪ Ultrasound may show retroplacental blood collection ▪ Blood-stained amniotic fluid in vagina ▪ Abruption signs evidenced by fetal heart rate, uterine activity



DIAGNOSTIC IMAGING Electronic fetal monitoring ▪ Decelerations may indicate fetal hypoxia, bradycardia



COMPLICATIONS



▪ Maternal: hypovolemic shock, disseminated intravascular coagulation (DIC), end organ damage (e.g. renal failure, Sheehan syndrome (pituitary necrosis related to hypovolemia)) ▪ Fetal: hypoxia; asphyxia; premature birth, related sequelae; death



Figure 123.3 An ultrasound scan in pregnancy demonstrating a placental abruption. There is a crescent of avascular hypoechoic fluid between the placenta and the uterine wall.



OSMOSIS.ORG 735



TREATMENT MEDICATIONS



▪ Corticosteroids as indicated to enhance fetal lung maturity



SURGERY



▪ Emergent delivery ▫ Vaginal/cesarean, as indicated



OTHER INTERVENTIONS



▪ Expectant management for small abruptions ▪ For significant bleeding: support hemodynamic stability of mother, fetus ▪ Blood product transfusion ▪ IV fluids ▪ Continuous fetal heart rate monitoring



POSTPARTUM HEMORRHAGE osms.it/postpartum-hemorrhage PATHOLOGY & CAUSES ▪ Postpartum (post = after; partum = birth) hemorrhage (PPH) is excessive blood loss after giving birth ▪ Defined by estimated blood loss (EBL), mode of birth ▫ > 500mL after vaginal delivery ▫ > 1000mL after cesarean delivery



TYPES



▪ Primary/early: within 24 hours after delivery ▪ Secondary/late: after 24 hours, before six weeks postpartum



CAUSES Four Ts ▪ Tone: soft, boggy uterus (uterine atony) and ineffective uterine contractions that normally cause uterine involution (return of uterus to its pre-pregnancy state) and provide tourniquet-like action on major blood vessels → hemorrhage from placental attachment site ▫ Associated with uterine overdistension: multiple gestation or polyhydramnios (excessive myometrium stretching); uterine fatigue from prolonged labor; full bladder (interferes with contractions); medications (anesthetics, especially halothane)/preterm labor



736 OSMOSIS.ORG



drugs (magnesium sulfate, nifedipine, terbutaline) ▪ Trauma: damage to reproductive/genital structures (e.g. uterus, cervix, vagina, perineum) → hemorrhage ▫ Surgical incision: cesarean delivery or episiotomy ▫ Large fetus/fetal malpresentation/ shoulder dystocia (baby’s shoulder impacted against maternal pubic symphysis) → soft tissue damage during descent through vaginal canal ▫ Soft tissue laceration from instruments used in delivery (e.g. use of forceps, vacuum extraction), uterine rupture (lacerations may result in hematoma formation → hidden bleeding → interference with uterine involution → uterine atony → hemorrhage) ▪ Tissue: retained placental fragments, placenta accreta, excessive traction on umbilical cord → interferes with uterine contractions → uterine atony → hemorrhage from placental attachment site ▪ Thrombin: impaired clotting → hemorrhage ▫ Associated with clotting disorders (e.g. von Willebrand disease) ▫ Coagulopathy (e.g. disseminated intravascular coagulation) related to an obstetrical complication (e.g. eclampsia, placenta previa)



Chapter 123 Disorders of Labor



SIGNS & SYMPTOMS ▪ Excessive bleeding visualization ▪ Maternal physiological response to decreased circulating volume ▫ ↑ heart rate ▫ ↓ blood pressure ▫ ↓ pulse pressure ▫ ↓ oxygen saturation ▫ ↓ hematocrit ▫ Delayed capillary refill ▫ Shock signs usually appear when hemorrhage is advanced due to normally ↑ pregnancy blood volume ▪ Soft, “boggy” uterus ▪ Clinical presentation suggesting hematoma



DIAGNOSIS OTHER DIAGNOSTICS



▪ Based on clinical signs, symptoms ▪ Estimated blood loss



TREATMENT MEDICATIONS



▪ Uterotonics: stimulate uterine contractions ▫ Oxytocin ▫ Methylergonovine: ergot derivative ▫ Prostaglandins



SURGERY



▪ Laparoscopic arterial ligation ▪ Hysterectomy



OTHER INTERVENTIONS



▪ Maintain adequate circulating volume; clotting factors, as needed ▫ IV fluids ▫ Blood products ▪ Intrauterine packing/balloon tamponade ▪ Interventional radiology ▫ Uterine artery embolization ▪ Address underlying cause (e.g. repair lacerations, remove retained placental fragments, assess for hematoma; repair ruptured uterus) ▪ Fundal massage ▫ Massaging fundus (upper portion of uterus) often causes entire uterus to contract



OSMOSIS.ORG 737



PRETERM BIRTH osms.it/preterm-birth PATHOLOGY & CAUSES ▪ Birth is considered preterm when between 20–37 gestation weeks ▫ Moderate to late preterm: 32–37 weeks ▫ Very preterm: 28–32 weeks ▫ Extremely preterm: < 28 weeks ▪ Worldwide: approximately 15 million babies are born prematurely each year ▫ In the U.S., about 1 in 10 babies are born prematurely ▪ Maternal-fetal unit responds to one or more pathologic risk factors + gene-environment interaction influence → preterm labor, birth ▪ Pathologic processes activate major pathway components to labor, birth ▫ Cervical changes (ripening) include softening, thinning, shortening ▫ Enhanced uterine contractility (myometrial gap-junction formation → synchronized uterine contraction; ↑ oxytocin receptors) ▫ Fetal membrane-maternal decidua interface disruption → preterm premature rupture of membranes (PPROM)



RISK FACTORS Maternal ▪ Obstetric history: previous preterm birth, short interval between pregnancies, conception through assisted reproductive technology (ART)(e.g. in vitro fertilization), previous pregnancy termination, history of stillbirth ▪ Family history of preterm birth: associated genes include FSHR (follicle-stimulating hormone receptor), IGF1R (insulin-like growth factor 1 receptor)



738 OSMOSIS.ORG



▪ Obstetric disorders: preeclampsia, placenta previa, placental abruption, uterine or cervical anomalies (e.g. cervical insufficiency—cervix unable to sustain the pregnancy) ▪ Distended uterus: multiple gestation, polyhydramnios ▪ Infections: bacterial vaginosis, sexuallytransmitted infections, urinary tract infections, periodontal disease ▪ Concurrent medical diagnoses: diabetes, pulmonary disease, heart disease, anemia (hemoglobin < 10g/dL) ▪ Socioeconomic/personal factors: low income, lack of prenatal care, ethnic minority, maternal age < 18 or > 40; stressful working conditions, intimate partner violence ▪ Behavioral factors: smoking, substance abuse, poor nutrition, inadequate weight gain, BMI < 19.6 or > 30 Fetal ▪ Intrauterine growth restriction, genetic anomalies, multiple gestation, twin-to-twin transfusion



COMPLICATIONS Maternal ▪ Increased risk of hemorrhage, infection; complications from cesarean section Fetal ▪ Increased fetal/neonatal morbidity, mortality; low birth weight (less than 2.5kg/5.5lbs), lung immaturity, hypoxicischemic encephalopathy, cerebral palsy



Chapter 123 Disorders of Labor



SIGNS & SYMPTOMS ▪ Vaginal discharge before completed gestation ▫ Fluid or blood leak (bloody show) ▫ Ruptured membranes may present as a sudden gush of water ▪ Lower abdominal or pelvic pressure ▪ Low, dull back pain ▪ Onset of contractions every 10 minutes or less ▪ Electronic fetal monitoring may show fetal tachycardia/decelerations (drops in heart rate during contractions)



DIAGNOSIS ▪ Pelvic exam shows cervical changes ▫ Cervical shortening, softening, effacement (thinning) ▫ Opening of cervical os



DIAGNOSTIC IMAGING Transvaginal ultrasound ▪ Shows shortened cervix length



LAB RESULTS ▪ Fetal fibronectin (fFN) test ▫ Glycoprotein that acts like a “glue” between maternal decidua and fetal membrane ▫ Presence of fFN in cervicovaginal secretions indicates preterm labor, birth ▪ Cervical culture for Group B streptococcus if status unknown ▪ Bacterial infection that increases neonatal sepsis, pneumonia, meningitis risks



TREATMENT MEDICATIONS



▪ Tocolytic medications (drugs that interfere with myometrial contractions) may delay birth for up to 48 hours. Allows time for corticosteroids to affect fetal lung development, for transport to a higher level of care if needed ▫ Nifedipine: calcium channel blocker ▫ Indomethacin: prostaglandin inhibitor ▫ Terbutaline: beta 2-adrenergic ▫ Magnesium sulfate: reduces calcium influx into muscle cell, relaxing myometrium; may have fetal neuroprotective benefit (e.g. reducing cerebral palsy risk) ▪ Antibiotics ▫ If bacterial infection suspected/ confirmed ▪ Corticosteroids ▫ To enhance fetal lung maturity, other organ development ▫ Helpful if given between 24–34 gestation weeks



SURGERY



▪ Vaginal/cesarean birth as indicated



OTHER INTERVENTIONS



▪ Cervical cerclage ▫ Stitch application to keep cervix closed, if indicated ▪ Adequate hydration ▫ Dehydration may induce uterine irritability ▪ Lecithin/sphingomyelin (L/S) ratio in amniotic fluid: indication of fetal lung maturity; directes neonate treatment ▪ Continuous ante- and intrapartum surveillance of maternal and fetal status



OSMOSIS.ORG 739



NOTES



NOTES



FEMALE GENITOURINARY CANCERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Cancers arising in genitourinary organs of individuals who are biologically female



RISK FACTORS



▪ Genetic mutations, smoking, prolonged use of oral contraceptives, sexually transmitted infections (STIs) (e.g. human papillomavirus), immunodeficiency (e.g. HIV/AIDS)



COMPLICATIONS



▪ Bleeding, metastasis ▪ Tumors produce excess hormones → metabolic disorders ▪ Large tumors → compression/torsion of blood vessels → ischemia



SIGNS & SYMPTOMS ▪ Abnormal vaginal discharge, bleeding; pelvic pain; abdominal pain; dyspareunia



DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI, ultrasound ▪ Tumor visualisation, staging



LAB RESULTS



▪ Serum tumor markers ▫ ↑ carbohydrate antigen 125 (CA-125), Papanicolaou (Pap) test ▪ Biopsy (definitive diagnosis)



740 OSMOSIS.ORG



OTHER DIAGNOSTICS Staging ▪ Tumor, nodes, metastasis (TNM) system: 0–4 ▫ T: size, sites invaded (e.g. only uterus/ extrauterine invasion) ▫ N: degree of spread to regional lymph nodes ▫ M: presence of distant metastasis ▫ V: vascular invasion ▪ FIGO (International Federation of Gynecology and Obstetrics): stages ▫ Stage 0: carcinoma in situ (premalignant lesions) ▫ Stage I: lesions limited to primary ▫ Stage II: nearby organs/tissues affected ▫ Stage III: distant pelvic organs/tissues, nodes ▫ Stage IV: distant metastases out of the pelvis



TREATMENT SURGERY



▪ Tumor debulking, tumor, lymph node, organ resection



OTHER INTERVENTIONS ▪ Chemotherapy, radiotherapy



Chapter 124 Female Genitourinary Cancers



CERVICAL CANCER osms.it/cervical-cancer PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Cancer arising from cervix ▪ Mainly caused by two strands of human papillomavirus (HPV): 16, 18 ▪ HPV invades two kinds of cells ▫ Immature basal cells of squamous epithelium ▫ Cells of squamocolumnar junction ▪ HPV makes viral proteins E6, E7 → interfere with cell growth regulation ▪ E6, E7 inhibit tumor suppressor proteins (p53) → ↓ DNA repair/↑ cell turn over → ↑ mutations → cancer ▪ Precancerous cervical changes ▫ Cervical dysplasia, cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS)



▪ Usually asymptomatic in early stage ▪ Irregular/heavy vaginal bleeding, dyspareunia, postcoital bleeding, pelvic/ lower back pain ▪ Watery, mucoid, purulent vaginal discharge ▪ Hematuria, hematochezia



DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Lung metastasis Colposcopy ▪ Cervical lesions



TYPES Squamous cell carcinoma ▪ Most common (85–90%) Adenocarcinoma ▪ Glandular (10–15%)



RISK FACTORS



▪ HPV 16/18 infections, smoking, prolonged use of oral contraceptives, early sexual activity (< 21 years old), multiple sexual partners, STIs, other vaginal/vulvar cancers, immunodeficiency (e.g. HIV/AIDS)



COMPLICATIONS



▪ Hematogenous metastases (e.g. lungs, liver, bone)



Figure 124.1 An MRI scan in the sagittal plane of the abdomen and pelvis. There is carcinoma which has entirely replaced the cervix and invaded the uterus and vagina.



OSMOSIS.ORG 741



LAB RESULTS



▪ Pap test ▫ Abnormal cervical cytology ▪ Cervical biopsy (definitive diagnosis)



OTHER DIAGNOSTICS ▪ Staging ▫ TNM ▫ FIGO



TREATMENT SURGERY



▪ CIN ▫ Cryosurgery, laser ablation, loop electrosurgical excision procedure (LEEP)/large loops excision of transformation zone (LLETZ) ▪ Stage IA cancer ▫ Conization, hysterectomy ▪ Stage IB, IIA cancer ▫ Radical hysterectomy + bilateral pelvic lymphadenectomy ▪ Stage IVB, recurrent cancer ▫ Pelvic exenteration



Figure 124.2 A cervical smear stained with Papanicolaou stain demonstrating cervical squamous cell carcinoma. The squamous cells have large dark, irregular nuclei and orangeophilic cytoplasm.



OTHER INTERVENTIONS



▪ Stage IB, IIA cancer ▫ External beam radiation + brachytherapy ▪ Stage IIB, III, IVA cancer ▫ Radiation therapy, brachytherapy ▪ Stage IVB, recurrent cancer ▫ Radiation therapy, systemic chemotherapy, palliative care ▪ Prevention ▫ Pap test, HPV vaccine



Figure 124.3 The appearance of cervical intraepithelial neoplasia at colposcopy. The area of CIN turns “acetowhite” upon application of acetic acid.



Figure 124.4 The cytological appearance of a low grade cervical intraepithelial lesion. The abnormal cells have large, folded nuclei and perinuclear halos. Normal squamous cells are seen on the right for comparison.



742 OSMOSIS.ORG



Chapter 124 Female Genitourinary Cancers



CHORIOCARCINOMA osms.it/choriocarcinoma PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Highly malignant epithelial tumor arising from trophoblastic tissue (e.g. molar pregnancy, abortion, ectopic, preterm/term intrauterine pregnancy) ▪ Germ cell tumor; may arise in ovary/testis (in individuals who are biologically male) ▪ Histology ▫ Anaplastic cytotrophoblasts, syncytiotrophoblasts; no villi ▪ Altered paternal genomic imprinting → excessive expression of paternal genes → excessive proliferation of trophoblastic tissue → gestational trophoblastic disease (GTD) (e.g. choriocarcinoma) ▪ Excessive proliferation of syncytiotrophoblast → ↑ beta human chorionic gonadotropin (β-hCG) in plasma ▪ ↑ β-hCG → ovarian cysts



▪ Depends on metastasized organs ▫ Vagina: profuse vaginal bleeding, vulvar dark blue papules ▫ Lungs: chest pain, dyspnea, hemoptysis ▫ Brain, meninges: headache, dizziness ▫ Hepatic: jaundice, abdominal tenderness



TYPES Diploid ▪ Biparental chromosomes (e.g. after normal gestation) Aneuploid ▪ Only paternal chromosomes (e.g. postmolar)



RISK FACTORS



▪ Complete molar pregnancy; advanced maternal age (> 40); individuals of Asian, indigenous peoples of the Americas ancestry



Figure 124.5 The gross pathological appearance of the lungs containing metastatic choriocarcinoma.



COMPLICATIONS



▪ Highly vascularized tumor → profuse bleeding ▪ Hematogenous metastasis to other organs (e.g. lungs, brain, liver)



OSMOSIS.ORG 743



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI/chest X-ray ▪ Metastasis Pelvic ultrasound ▪ Infiltrative myometrial mass



LAB RESULTS



▪ ↑ serum quantitative β-hCG, liver enzymes ▪ Complete blood count (CBC) ▫ Anemia



OTHER DIAGNOSTICS ▪ Staging ▫ FIGO



Figure 124.7 A CT scan of the abdomen and pelvis in the coronal plane demonstrating a uterine choriocarcinoma.



TREATMENT SURGERY



▪ Hysterectomy, lung resection



OTHER INTERVENTIONS ▪ Chemotherapy, radiotherapy



744 OSMOSIS.ORG



Figure 124.6 The histological appearance of a choriocarcinoma. Malignant cytotrophoblasts are stained light pink whereas the syncitiotrophoblasts are stained a darker hue.



Chapter 124 Female Genitourinary Cancers



ENDOMETRIAL CANCER osms.it/endometrial-cancer PATHOLOGY & CAUSES ▪ Cancer arising from endometrium (uterine lining)



TYPES Endometrioid ▪ Result from excess estrogen ▪ ↑ estrogen → endometrial hyperplasia → endometrial intraepithelial neoplasia (EIN) → adenocarcinoma ▪ Related to gene mutations ▫ PIK3CA, CTNNB1, PTEN, ARID1A, KRAS ▪ No Tp53 mutations except in Grade III



DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Metastasis Ultrasound ▪ Endometrium > 5mm thick in postmenopausal individuals



LAB RESULTS



▪ Endometrial biopsy



Nonendometrioid ▪ Estrogen-independent ▪ Arising from endometrial atrophy/polyp ▪ Usually involves Tp53 gene mutation ▪ Two types: clear cell, serous ▪ Clear cell ▫ Precancerous lesions: clear cell intraepithelial neoplasia ▫ Hobnail cells ▫ Very aggressive (FIGO grade III) ▪ Serous ▫ Precancerous lesions: endometrial intraepithelial carcinoma (EIC) ▫ Presence of p53 mutations in EIC ▫ May arise after radiotherapy for cervical carcinoma



SIGNS & SYMPTOMS ▪ Postmenopausal vaginal bleeding, abnormal menstruation (frequent, long, heavy), lower abdominal pain, unusual vaginal discharge, pelvic cramping, dyspareunia



Figure 124.8 The gross pathological appearance of endometrial carcinoma of the lower uterine segment.



OSMOSIS.ORG 745



TREATMENT SURGERY



▪ Hysterectomy, pelvic/para-aortic lymphadenectomy



OTHER INTERVENTIONS



▪ Chemotherapy, radiotherapy, hormone therapy



Figure 124.9 The histological appearance of endometrioid endometrial carcinoma. This low-grade variant is composed of backto-back glandular structures with minimal underlying stroma.



GERM CELL OVARIAN TUMOR osms.it/germ-cell-ovarian-tumor PATHOLOGY & CAUSES ▪ Tumors that arise from primordial germ cells of ovaries, benign/malignant, produce β-hCG



TYPES Teratomas ▪ Contain all types of tissues (e.g. hair, teeth, neurons) ▪ Immature teratomas ▫ Specifically arise from neuroectoderm cells; usually malignant ▪ Mature cystic teratomas (AKA dermoid cysts) ▫ Arise from any germ layers; common in young individuals who are biologically female Yolk sac tumor (endodermal sinus tumor) ▪ Germ cells differentiate into yolk sac tissue ▪ Most common germ cell tumor in children ▪ Very aggressive ▪ Schiller–Duval Bodies: rings of cells around central blood vessels



746 OSMOSIS.ORG



Dysgerminoma ▪ Most common malignant ovarian tumor ▪ Germ cells turn into oocytes → grow uncontrollably → cancer ▪ Central nuclei surrounded by clear cytoplasm



RISK FACTORS



▪ Endometriosis, polycystic ovarian syndrome (PCOS) ▪ Genetic ▫ BRCA-1/BRCA-2 mutations ▪ Lynch syndrome (hereditary nonpolyposis colorectal cancer)



SIGNS & SYMPTOMS ▪ Sister Mary Joseph Nodule (umbilical metastasis) ▪ ↑ β-hCG ▫ Precocious puberty, unusual vaginal bleeding, pregnancy symptoms (e.g. breast tenderness, mood swing, nausea) ▪ Abdominal distension, bowel obstruction, abdominal/pelvic pain, dyspareunia



Chapter 124 Female Genitourinary Cancers



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Pelvic masses Pelvic ultrasound ▪ Cystic/solid pelvic masses



LAB RESULTS



▪ Serum tumor markers ▫ ↑ β-hCG, alpha fetoprotein (not always present with immature teratomas), lactate dehydrogenase (in dysgerminomas) ▪ Biopsy (definitive diagnosis)



TREATMENT SURGERY



▪ Resection of affected ovary ▪ Bilateral pelvic, para-aortic lymphadenectomy ▪ Omentectomy



OTHER INTERVENTIONS



Figure 124.10 The histological appearance of a mature cystic teratoma. There is a dermal component (upper section) and a neural component (lower section).



▪ Chemotherapy (if metastasized), radiotherapy



Figure 124.11 A mature cystic teratoma, the most common form of ovarian germ-cell tumor. This specimen contains mature dermal elements which give rise to the hair seen here.



OSMOSIS.ORG 747



KRUKENBERG TUMOR osms.it/krukenberg-tumor PATHOLOGY & CAUSES ▪ Ovarian cancer metastasized from another primary site ▪ Usually metastasizes from gastrointestinal (GI) tract/breast ▪ Likely spreads to ovaries by lymphatics ▪ Involves both ovaries ▪ Mucin-secreting signet ring cells



TREATMENT SURGERY



▪ Remove metastases



OTHER INTERVENTIONS ▪ Chemotherapy



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



Pelvic/abdominal pain Bloating Ascites Dyspareunia Vaginal bleeding



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Ovarian mass coexisting colic/gastric lesions



LAB RESULTS ▪ Biopsy (definitive diagnosis) ▫ Ovary



OTHER DIAGNOSTICS



▪ Laparotomy ▫ Ovarian mass + tumors in GI tract



748 OSMOSIS.ORG



Figure 124.12 The gross pathological appearance of a Krukenberg tumor. The ovary has been entirely replaced by metastasis.



Chapter 124 Female Genitourinary Cancers



SEX CORD-GONADAL STROMAL TUMOR osms.it/sex_cord-gonadal_stromal_tumor PATHOLOGY & CAUSES ▪ Arise from ovarian follicle cells, stromal/ connective tissue cells ▪ Benign/malignant



TYPES Granulosa-theca cell tumor ▪ Most common malignant stromal tumor in middle-aged individuals who are biologically female ▪ Causes estradiol overproduction → early puberty, uterine bleeding, breast tenderness ▪ Call–Exner bodies ▫ Tiny fluid pockets scattered in tissue



Figure 124.13 The gross pathological appearance of a Sertoli–Leydig cell tumor, a kind of sex cord stromal tumor. The cut surface is yellow and lobulated.



Sertoli-Leydig cell tumors ▪ Similar to testicular sertoli, Leydig cell tumors ▪ Made of primitive gonadal stroma → secretion of testosterone → hirsutism ▪ Reinke crystals (pink, rod-like) Fibroma ▪ Benign ▪ Made of fibroblasts ▪ Needle-like strands (elongated nuclei) under microscope ▪ Associated with ascites, pleural effusion ▪ Compress uterine round ligament → pulling sensation in groin



RISK FACTORS



Figure 124.14 The histological appearance of a Sertoli–Leydig cell tumor. There are two popualtions of cells. The Leydig cells have large amounts of eosinophilic cytoplasm, whereas the Sertoli cells have less cytoplasm which is pale in appearance.



▪ Endometriosis, PCOS ▪ Genetic ▫ BRCA-1/BRCA-2 mutations ▪ Lynch syndrome



OSMOSIS.ORG 749



SIGNS & SYMPTOMS ▪ Uterine bleeding, breast tenderness, early puberty (in young individuals who are biologically female), Sister Mary Joseph Nodule (umbilical metastasis), ascites, abdominal masses, bowel obstruction, abdominal distension, abdominal/pelvic pain, bloating, dyspareunia



DIAGNOSIS DIAGNOSTIC IMAGING



Figure 124.15 The gross pathology of an ovarian fibroma. The tumor has a homogenous, firm, cream-colored surface.



Pelvic ultrasound/CT scan/MRI ▪ Solid/cystic masses



LAB RESULTS



▪ Serum tumor markers ▫ ↑ β-hCG, neural cell adhesion molecule (NCAM) ▪ Biopsy (definitive diagnosis)



TREATMENT SURGERY



▪ If postmenopausal/childbearing completed ▫ Abdominal hysterectomy, bilateral salpingo-oophorectomy ▪ Fertility-sparing with one affected ovary ▫ Unilateral salpingo-oophorectomy for early-stage disease



OTHER INTERVENTIONS



▪ Chemotherapy (if metastasized) ▪ Radiotherapy



750 OSMOSIS.ORG



Figure 124.16 The histological appearance of an ovarian fibroma. The tumor is composed of spindles with interesecting bundles of collagen.



Chapter 124 Female Genitourinary Cancers



SURFACE EPITHELIAL-STROMAL TUMOR osms.it/surface_epithelial-stromal_tumor PATHOLOGY & CAUSES AKA ovarian adenocarcinoma Most common type of ovarian tumor Benign/malignant/borderline Originates from ovarian surface epithelium, fallopian tubes ▪ Mutation in epithelial cells → uncontrollable division → tumors ▪ ▪ ▪ ▪



TYPES Serous ▪ Benign/malignant/borderline ▪ Usually bilateral ▪ Serous cystadenoma if benign ▪ Serous cystadenocarcinoma if malignant ▪ Psammoma bodies → cystadenocarcinomas



Figure 124.17 The histological appearance of an ovarian, high-grade serous carcinoma. There is wild cellular and nuclear pleomorphism, marked atypia and psammomatous calcification.



Endometrioid ▪ Cyst filled with dark blood (chocolate color) ▪ AKA chocolate cysts ▪ Develop from ectopic endometrial cells Mucinous ▪ Usually unilateral ▪ Characterized by lining of tall columnar epithelial cells ▪ Mucinous cystadenoma if benign ▪ Mucinous cystadenocarcinoma if malignant ▪ Can cause pseudomyxoma peritonei ▪ Huge cystic masses (> 25kg/55lbs)



Figure 124.18 The gross pathological appearance of an ovarian mucinos neoplasm. The tumor is composed of innumerable mucin-filled cysts lined by mucin-producing epithelium.



OSMOSIS.ORG 751



RISK FACTORS



▪ Endometriosis, PCOS ▪ Genetic ▫ BRCA-1/BRCA-2 mutations ▪ Lynch syndrome



SIGNS & SYMPTOMS Figure 124.19 The histological appearance of a mucinous neoplasm of the ovary. There are multiple cystic spaces all of which are lined by columnar epithelium.



▪ Uterine bleeding, breast tenderness, early puberty, Sister Mary Joseph Nodule (umbilical metastasis), ascites, abdominal masses, bowel obstruction, abdominal distension, abdominal/pelvic pain, bloating, dyspareunia



DIAGNOSIS



Clear cell ▪ Large epithelial cells with clear cytoplasm ▪ Associated with endometrioid carcinoma of ovaries



DIAGNOSTIC IMAGING



Transitional/Brenner ▪ Resembles bladder epithelium (transitional cells) ▪ Can be associated with endometriosis ▪ Similar to cell carcinoma of endometrium



LAB RESULTS



Pelvic ultrasound, CT scan/MRI ▪ Cystic ovarian masses



▪ Serum tumor markers ▫ ↑ β-hCG ▪ Biopsy (definitive diagnosis)



TREATMENT SURGERY



▪ If postmenopausal/childbearing completed ▫ Abdominal hysterectomy, bilateral salpingo-oophorectomy ▪ Fertility-sparing with one affected ovary ▫ Unilateral salpingo-oophorectomy for early-stage disease



OTHER INTERVENTIONS Figure 124.20 The gross pathological appearance of a Brenner tumor. The tumor is sharply circumscribed, firm and has a pale tan to yellow cut surface.



752 OSMOSIS.ORG



▪ Chemotherapy (if metastasized) ▪ Radiotherapy ▪ Serum CA-125 levels (monitor response to therapy)



NOTES



NOTES



GENITOURINARY TRACT INFECTIONS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Infections of genital/urinary tract



CAUSES



▪ Mostly bacteria



RISK FACTORS



▪ Recent sexual activity ▪ High-risk sexual behavior ▪ Previous genitourinary tract infections



COMPLICATIONS ▪ Pelvic inflammatory disease, infertility, pyelonephritis, epididymitis, prostatitis, sepsis, abscesses



SIGNS & SYMPTOMS ▪ Abdominal pain, altered vaginal/urethral discharge, dysuria, fever



DIAGNOSIS LAB RESULTS ▪ Vaginal/urethral discharge microscopy ▪ Nucleic acid amplification tests (NAATs)



OTHER DIAGNOSTICS ▪ Clinical examination



TREATMENT MEDICATIONS



▪ Antibiotic therapy



PELVIC INFLAMMATORY DISEASE osms.it/pelvic-inflammatory-disease PATHOLOGY & CAUSES ▪ Infection, inflammation of upper genital tract (uterus, ovaries, fallopian tubes) in individuals who are biologically female ▪ Common pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, vaginal flora bacteria (e.g. Gardnerella vaginalis); often polymicrobial ▪ Bacterial vaginosis (alteration in vaginal flora) present in ⅔ of PID cases ▫ Anaerobic bacteria replace lactobacilli



in vagina → enzyme production → degradation of cervical mucus, antimicrobial agents → infections spread ▪ Associated syndromes ▫ Endometritis, salpingitis, oophoritis, peritonitis, perihepatitis (liver capsule inflammation), tubo-ovarian abscess ▪ Vaginal mucosa colonization → disruption of endocervical canal barrier → pathogens ascend to upper genital structures → inflammation



OSMOSIS.ORG 753



RISK FACTORS ▪ More common in individuals who are biologically female, < 25 years old, sexually active ▪ Multiple sexual partners ▪ Partner with sexually transmitted disease (STD) ▪ Personal history of PID/STD ▪ Unprotected sexual intercourse ▪ Cervix instrumentation (e.g. abortion)



COMPLICATIONS ▪ Recurrent PID, hydrosalpinx (fluid-filled fallopian tubes), pyosalpinx (infected fallopian tube filled with purulent matter), chronic pelvic pain, infertility, ectopic pregnancy, ovarian cancer



SIGNS & SYMPTOMS Acute symptomatic PID ▪ Bilateral lower abdominal/pelvic pain ▫ Abrupt onset during/after menstruation ▫ Constant, aching ▫ Worsens during sexual intercourse/ movement ▪ Abdominal/pelvic organ tenderness ▪ Feeling of pelvic fullness ▪ Intermenstrual/postcoital bleeding ▪ Dysuria ▪ Low-grade fever ▪ Rebound tenderness, fever, ↓ bowel sounds (severe) Chronic PID ▪ Low-grade fever, weight loss, abdominal pain Perihepatitis (Fitz-Hugh–Curtis syndrome) ▪ Right upper quadrant pain, tenderness



DIAGNOSIS DIAGNOSTIC IMAGING Pelvic/abdominal ultrasound ▪ Fluid-filled fallopian tubes with cogwheel sign (thickened loops on cross-section) ▪ Endometrium changes (e.g. wall thickening)



754 OSMOSIS.ORG



▪ Tubo-ovarian abscess (thick walls, multilocular cyst)



LAB RESULTS ▪ Vaginal discharge microscopy ▫ Saline microscopy, Gram stain ▫ ↑ leukocytes ▫ Clue cells (epithelial cells surrounded by bacteria) in bacterial vaginosis ▪ Nucleic acids amplification tests (NAATs) ▫ C. trachomatis, N. gonorrhoeae ▪ Tissue biopsy ▫ ↑ plasma cells, neutrophils (inflammation) ▪ Leukocytosis, ↑ C-reactive protein (CRP), ↑ erythrocyte sedimentation rate (severe)



OTHER DIAGNOSTICS ▪ Speculum exam ▫ Mucopurulent cervical discharge (positive swab test)



TREATMENT MEDICATIONS Broad-spectrum antibiotic therapy ▪ Inpatient (parenteral) ▫ Cefoxitin/cefotetan (cephalosporin) + doxycycline (tetracycline) ▫ Clindamycin (lincosamide) + gentamicin (aminoglycoside) ▪ Outpatient ▫ Ceftriaxone/cefoxitin (cephalosporin) + doxycycline (tetracycline) ▪ Pelvic abscess ▫ Clindamycin/metronidazole + doxycycline Antiemetic medication ▪ E.g. metoclopramide Antipyretic medication ▪ E.g. acetaminophen



OTHER INTERVENTIONS



▪ Prevention ▫ Barrier contraception (e.g. condoms) ▫ Abstinence



Chapter 125 Genitourinary Tract Infections



Figure 125.1 An MRI scan of the pelvis in the sagittal plane demonstrating a right-sided pyosalpinx.



URETHRITIS osms.it/urethritis PATHOLOGY & CAUSES ▪ Inflammation of urethra; more common in individuals who are biologically male with sexually transmitted diseases ▪ Common coinfection with other STDs ▪ Incubation period: 4–8 days



CAUSES ▪ Infectious urethritis (most common) ▫ Gonococcal: Neisseria gonorrhoeae ▫ Non-gonococcal: Chlamydia trachomatis (most common), Mycoplasma genitalium ▪ Non-infectious urethritis ▫ Chemical irritation (e.g. soaps, spermicides) ▫ Trauma



RISK FACTORS ▪ Individuals who are biologically male, young ▪ Multiple sexual partners ▪ Partner with sexually transmitted disease (STD) ▪ Unprotected sexual intercourse



COMPLICATIONS



▪ Reactive arthritis related to C. trachomatis, gonococcal conjunctivitis, epididymitis, prostatitis, penile lymphangitis, periurethral abscess



SIGNS & SYMPTOMS ▪ Sometimes asymptomatic ▪ Dysuria ▪ Urethral pruritus, discharge (mucoid, watery, purulent) ▪ Inflammation/edema of urethral meatus



OSMOSIS.ORG 755



DIAGNOSIS LAB RESULTS ▪ Diagnosis criteria (≥ one) ▫ Mucopurulent/purulent urethral discharge ▫ ≥ one leukocyte per oil immersion field in Gram stain of urethral discharge ▫ Positive leukocyte esterase, ≥ 10 leukocytes per high-power field (firstcatch urine) ▪ NAATs ▫ C. trachomatis, N. gonorrhoeae ▪ Urethral discharge microscopy (e.g. Gram stain)



OTHER DIAGNOSTICS ▪ Clinical examination ▫ Gonorrhoea: purulent discharge ▫ Chlamydia: isolated dysuria ▫ Herpes simplex virus (HSV): dysuria + painful genital ulcers



756 OSMOSIS.ORG



TREATMENT MEDICATIONS Antibiotic therapy ▪ Gonococcal urethritis ▫ Ceftriaxone (cephalosporin) + azithromycin (macrolide) ▪ Non-gonococcal urethritis ▫ Azithromycin or doxycycline (tetracycline) ▫ Azithromycin/moxifloxacin (persisent)



OTHER INTERVENTIONS



▪ Prevention ▫ Barrier contraception (e.g. condoms) ▫ Abstinence



NOTES



NOTES



INFERTILITY & FETAL LOSS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders that adversely affect the function of the female reproductive system fertility



SIGNS & SYMPTOMS ▪ See individual disorders



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Ultrasound



LAB RESULTS



▪ Serum hormonal levels



OTHER DIAGNOSTICS ▪ Obstetric history



TREATMENT ▪ See individual disorders



AMENORRHOEA osms.it/amenorrhoea PATHOLOGY & CAUSES ▪ Abnormal menstruation cessation/absence in biologically female people of reproductive age, not related to menopause/pregnancy/ lactation



TYPES



▪ Primary amenorrhoea ▫ Failure to reach menarche by age 15 years ▪ Secondary amenorrhoea ▫ Previously regular menses ceases for three months or longer



RISK FACTORS



▪ Hypothalamic-pituitary-gonadal axis does not induce cyclic changes in the endometrium ▫ Hypothalamic dysfunction (e.g. GnRH deficiency, traumatic injury, functional (stress, excessive exercise, eating disorders, systemic illness) ▫ Pituitary dysfunction (e.g. empty sella syndrome, pituitary tumor/infarct) ▫ Ovarian dysfunction (e.g. primary ovarian insufficiency (POI), Turner syndrome, FMR1 mutation) ▪ Psychogenic amenorrhea ▫ Pseudocyesis (false pregnancy)



OSMOSIS.ORG 757



▪ Outflow tract disorders ▫ E.g. Müllerian agenesis (Mayer– Rokitansky–Kuster–Hauser syndrome), intrauterine adhesions (Asherman syndrome) ▪ Other ▫ Polycystic ovary syndrome (PCOS) ▫ Hypo/hyperthyroidism ▫ Hormone receptor abnormalities ▫ Enzyme deficiencies



COMPLICATIONS



▪ Infertility ▪ Osteoporosis ▪ Psychological distress



SIGNS & SYMPTOMS ▪ Menses absent ▪ Clinical presentation of causative disorder



DIAGNOSIS ▪ Evaluate secondary sexual characteristics (Tanner staging) ▪ Discrepancy in Tanner stage and age may indicate constitutional puberty delay, Turner syndrome ▪ ↑ body mass index (BMI) + hyperandrogenism signs (acne, hirsutism) may indicate PCOS



DIAGNOSTIC IMAGING Pelvic ultrasound/hysteroscopy ▪ Detects structural abnormalities Head MRI ▪ Identifies pituitary anomalies



LAB RESULTS



▪ ↑ hGH indicates pregnancy ▪ ↑ serum prolactin indicates pituitary adenoma, prolactinoma ▪ Follicle stimulating hormone (FSH) ▫ ↑ level indicates Turner syndrome, primary ovarian insufficiency (POI)



758 OSMOSIS.ORG



▫ ↓ level indicates functional hypothalamic amenorrhea/hypothalamic-pituitary disorders ▪ ↓ luteinizing hormone level indicates functional hypothalamic amenorrhea/ hypothalamic-pituitary disorders ▪ ↓ estradiol indicates abnormal ovarian function ▪ ↑ free and total testosterone indicates PCOS, ovarian/adrenal tumor



OTHER DIAGNOSTICS



▪ Progesterone challenge test ▫ Oral medroxyprogesterone administered daily for 7–10 days → withdrawal bleeding when hormone stopped indicates adequate endogenous estrogen level, rules out outflow tract abnormality ▫ If no withdrawal bleeding, administer estrogen + progestin daily for 10 days → failure to bleed indicates abnormal endometrium ▪ Karyotype ▫ E.g. Turner syndrome (45,X), Müllerian agenesis (46,XX) ▪ Genetic testing ▫ Fragile X syndrome (FMR1) associated with primary ovarian insufficiency



TREATMENT MEDICATIONS



▪ Hypothalamic dysfunction ▫ Oral contraceptives if pregnancy not desired, gonadotropins if pregnancy desired ▪ Ovarian insufficiency ▫ Estrogen, progesterone replacement



SURGERY



▪ Tumor: surgical resection ▪ Surgically correct anatomic abnormalities preventing outflow



PSYCHOTHERAPY



▪ If functional hypothalamic dysfunction, address underlying cause (e.g. eating disorder)



Chapter 126 Infertility & Fetal Loss



OTHER INTERVENTIONS ▪ Specific treatments for causative morbidities (e.g. PCOS, thyroid disorders) ▪ Treat complications (e.g. estrogen replacement therapy, calcium + vitamin D supplements)



ECTOPIC PREGNANCY osms.it/ectopic-pregnancy PATHOLOGY & CAUSES TYPES



▪ Ectopic pregnancy ▫ Pregnancy in which fertilized ovum is implanted at site other than uterine endometrium ▪ Heterotopic pregnancy (rare) ▫ Concurrent ectopic pregnancy and intrauterine pregnancy



CAUSES



▪ Altered anatomy/function (e.g. impaired tubal motility)



▪ Inflammatory-induced tubal damage, distorted/blocked patency → disrupted blastocyst progress to endometrial implantation site ▪ Ectopic sites ▫ Fallopian tube (most common site, especially ampullary region) ▫ Cervical ▫ Abdominal ▫ Ovarian ▫ Interstitial/cornual (implantation where fallopian tube passes through myometrium) ▫ Uterine cesarean scar



OSMOSIS.ORG 759



RISK FACTORS ▪ ▪ ▪ ▪



▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪



Previous tubal pregnancy Cesarean section history Endometriosis Infection, pelvic inflammatory disease (e.g. salpingitis) ▫ Chlamydia: damages cilia lining fallopian tube ▫ Gonorrhea: causes clubbed fimbriae, blocked/tortuous tube Previous pelvic surgery Congenital anomalies Tumors Smoking (dose-dependant) Vaginal douching Risk increases with age Intrauterine device (IUD) use (past and present) Use of assisted reproductive technologies (ART) In utero diethylstilbestrol (DES) exposure



COMPLICATIONS



▪ Rupture of fallopian tube or other structures, leading to profound bleeding ▫ May be life-threatening ▪ Pregnancy loss ▪ Infertility ▪ A significant cause of pregnancy-related maternal mortality in first trimester



SIGNS & SYMPTOMS ▪ May be asymptomatic before rupture ▪ Common triad of symptoms ▫ Variable bleeding (spotting/intermittent/ hemorrhage) ▫ Lower abdominal pain/tenderness (abrupt/slow, continuous/intermittent) ▫ Menses absent ▪ Other symptoms ▫ Normal early pregnancy discomforts (e.g. nausea, breast tenderness) ▪ Symptoms of rupture (surgical emergency) ▫ Severe abdominal pain (may refer to shoulder with phrenic nerve irritation; rebound tenderness, guarding indicates peritoneal irritation) ▫ Hemodynamic instability (feeling faint, syncope; tachycardia; hypotension; diaphoresis)



DIAGNOSIS ▪ Pelvic examination ▫ Can identify source of bleeding ▪ Gentle adnexal palpation (light pressure to avoid rupture) ▫ Palpable mass, cervical motion, adnexal, abdominal tenderness



DIAGNOSTIC IMAGING



Figure 126.1 A ruptured cornual ectopic pregnancy following surgical removal. The fallopian tube (left) is distended at the junction with the cornu. The fetus is present on the right with an intact embryonic sac.



760 OSMOSIS.ORG



Ultrasound ▪ Combination of empty uterus on ultrasound with a positive pregnancy test can confirm diagnosis ▪ If hemodynamically unstable ▫ Abdominal Focused Assessment with Sonography for Trauma (FAST): detects peritoneal bleeding, indicates rupture ▪ If stable ▫ Transvaginal ultrasound (TVUS): locates anatomical pregnancy site



LAB RESULTS



▪ ↑ serum human chorionic gonadotropin indicates pregnancy



Chapter 126 Infertility & Fetal Loss



TREATMENT MEDICATIONS



▪ If unruptured ▫ Methotrexate: folic acid antagonist inhibits DNA synthesis, cellular replication



SURGERY



Figure 126.2 A Doppler ultrastound scan of the pelvis demonstrating the ring of fire sign in an individual with a tubal ectopic pregnancy.



▪ If ruptured, laparoscopic surgery ▫ Salpingectomy: fallopian tube removal (standard practice) ▫ Salpingostomy: tubal incision to remove tubal gestation only



OTHER INTERVENTIONS



▪ Stabilization measures if hemodynamic compromise is evident



MISCARRIAGE osms.it/miscarriage PATHOLOGY & CAUSES ▪ Loss of pregnancy < 20 gestation weeks ▫ AKA spontaneous abortion



TYPES



▪ Complete ▫ Spontaneous passage of all products of conception ▪ Incomplete (inevitable) ▫ Bleeding, partially dilated cervix, ruptured membranes, products of conception remain in utero ▪ Threatened ▫ Embryo/fetus jeopardized by bleeding, viable pregnancy, closed cervix ▪ Missed ▫ Intrauterine fetal death that is not expelled ▪ Recurrent ▫ History of ≥ three spontaneous pregnancy losses



RISK FACTORS



Prior miscarriage Multiparity Advanced maternal age Smoking, substance abuse (e.g. cocaine) Chromosomal abnormalities (e.g. aneuploidies) ▪ Structural uterine anomalies (e.g. cervical insufficiency, fibroids) ▪ Maternal infections ▫ Bacterial vaginosis ▫ Toxoplasmosis ▫ Coxsackie virus infection ▫ Paramyxovirus infection (measles, mumps) ▪ Maternal comorbidities ▫ Thrombophilia: ↑ decidual thrombosis risk ▫ Hypothyroidism: thyroid peroxidase autoantibodies → may impair thyroid function during pregnancy ▫ Diabetes mellitus: poor glycemic control ▪ ▪ ▪ ▪ ▪



OSMOSIS.ORG 761



(teratogenic effects of hyperglycemia; maternal vascular disease → uteroplacental insufficiency) ▫ Systemic lupus erythematosus: uteroplacental insufficiency, antiphospholipid antibodies, lupus anticoagulant ▫ Obesity: may be related to insulin resistance ▪ Trauma ▫ Iatrogenic: invasive intrauterine procedures (e.g. chorionic villus sampling, amniocentesis) ▫ Other injuries ▪ Idiopathic



762 OSMOSIS.ORG



COMPLICATIONS



▪ Vaginal blood/clots/fetal tissue passage ▪ Infection (e.g. septic abortion related to infection and retained products of conception) ▪ Disseminated intravascular coagulation (DIC) ▫ Missed abortion → retained products release chemical mediators → coagulopathy



Chapter 126 Infertility & Fetal Loss



SIGNS & SYMPTOMS ▪ Vaginal bleeding ▪ Cramping abdominal/suprapubic pain



DIAGNOSIS ▪ Internal digital examination ▫ Evaluates cervical dilation ▪ Vaginal speculum exam ▫ Determines cervical dilation, characteristics of blood or tissue



DIAGNOSTIC IMAGING Ultrasound ▪ TVUS ▫ < nine gestation weeks ▪ Transabdominal ▫ ≥ nine gestation weeks



LAB RESULTS



▪ Urine ▫ ↑ hCG confirms pregnancy ▪ Complete blood count ▫ Evaluates blood loss degree ▪ Blood type and Rh(D) testing ▫ Determines risk for isoimmunization



TREATMENT MEDICATIONS



▪ Inevitable/incomplete/missed abortion (nonviable pregnancy) ▫ If medically stable: medical evacuation (prostaglandin E1 analog, antiprogesterone); expectant management (allow for natural passage) ▪ Prophylaxis with Rho(D) immunoglobulin as indicated



SURGERY



▪ Inevitable/incomplete/missed abortion (nonviable pregnancy) ▫ If medically unstable: surgical evacuation (dilation and curettage/ vacuum extraction)



OTHER INTERVENTIONS



▪ Complete abortion ▫ No medical intervention ▪ Recurrent abortion ▫ Screening for possible causes ▪ Threatened abortion (viable pregnancy) ▫ Expectant management



MOLAR PREGNANCY osms.it/molar-pregnancy PATHOLOGY & CAUSES ▪ Benign abnormal trophoblastic growth, included in disease group called gestational trophoblastic disease (GTD) ▫ AKA hydatidiform mole (HM) ▪ Premalignant disease with potential to develop into gestational trophoblastic neoplasia (GTN), which includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, epithelioid



trophoblastic tumor



TYPES ▪ Classifications based on histopathology, karyotype Complete hydatidiform mole ▪ Single sperm fertilizes enucleated egg → paternal DNA duplication ▪ Usually diploid 46,XX/46,XY ▪ Contains paternal genetic material only



OSMOSIS.ORG 763



▪ No fetal cells present ▪ Potential to become invasive → malignant gestational trophoblastic disease (GTD) Partial hydatidiform mole ▪ One (normal) egg fertilized by two sperm ▪ Usually triploid 69,XXX/69,XXY/69XYY ▪ Contains maternal and extra paternal genetic material ▪ Some fetal cells evident (e.g. amnion, RBCs) ▪ Not usually associated with choriocarcinoma (< 5%)



CAUSES



▪ When nonviable fertilized ovum implants in uterus → paternal gene overexpression → trophoblastic proliferation, vesicular placental villi swelling → nonviable pregnancy



RISK FACTORS



▪ Obstetric history ▫ Previous molar pregnancy ▫ Spontaneous abortion ▫ Infertility ▪ Maternal age extremes (≤ 15 and > 35 years old) ▪ Low dietary carotene (vitamin A precursor) and animal fat is associated with partial mole



Figure 126.3 A transvaginal ultrasound scan demonstrating a mass within the uterus. The “bunch of grapes” sign is characteristic of a complete molar preganncy.



▪ ▪



▪ ▪



COMPLICATIONS



▪ Potential for malignancy and metastasis (pulmonary, CNS) ▪ Trophoblastic pulmonary emboli ▪ Complete mole (if diagnosed in second trimester) ▫ ↑ ↑ hCG levels → theca lutein cysts (multiloculated cysts due to ovarian hyperstimulation), hyperthyroidism, preeclampsia ▫ Anemia may also be present



SIGNS & SYMPTOMS ▪ Missed menses ▪ Enlarging uterus, feeling of pelvic pressure ▫ Partial mole: small or normal for gestational age



764 OSMOSIS.ORG



▪



▫ Complete mole: large for gestational age Hyperemesis gravidarum ▫ Associated with ↑ ↑ hCG First trimester uterine bleeding ▫ Evident when molar villi separate from underlying decidua ▫ Complete mole: dark, “prune juice”colored discharge (accumulated, oxidized blood) Spontaneous passage of “grape-like” molar vesicles (hydropic villi) Hyperthyroidism ▫ Tachycardia, warm skin, tremor, heat intolerance Preeclampsia ▫ ↑ blood pressure



DIAGNOSIS ▪ Bimanual examination ▫ Assess uterine size



DIAGNOSTIC IMAGING Transvaginal ultrasound ▪ Complete mole ▫ No embryo, fetus, or gestational sac visualized; absent fetal heartbeat ▫ Absence of amniotic fluid ▫ Numerous anechoic spaces contained



Chapter 126 Infertility & Fetal Loss in a central heterogeneous mass: snowstorm, bunch of grapes, or swiss cheese pattern ▫ Theca lutein cysts ▪ Incomplete mole ▫ A fetus may be identified ▫ Amniotic fluid is present ▫ Chorionic villi echogenicity ▫ Usually no theca lutein cysts Chest X-ray ▪ Screen for metastasis



LAB RESULTS



▪ ↑ ↑ serum hCG ▪ Blood type and Rh(D) testing ▫ Determines risk for isoimmunization ▪ Histopathologic analysis of evacuated material (definitive diagnosis) ▫ Hydropic swelling of chorionic villi (cluster of grapes tissue)



OTHER DIAGNOSTICS



▪ Monitoring hCG levels to assess malignant transformation



Figure 126.4 The histological appearance of a complete mole. The chorionic villi are expanded by loose fibrillar material (hydropic) and the overlying trophoblasts demonstrate marked atypical hyperplasia.



MEDICATIONS



▪ Actinomycin D ▫ Chemoprophylaxis for complete mole ▪ Rh(D) immune globulin if indicated



SURGERY



▪ Hysterectomy ▫ If ≥ 40 years old and/or do not wish further pregnancies



OTHER INTERVENTIONS



▪ Periodic (usually weekly) monitoring of hCG levels at regular intervals + reliable contraception until hCG is undetectable ▫ Persistent elevation indicates postmolar gestational trophoblastic neoplasia



Figure 126.5 A CT scan of the pelvis in the axial plane demonstrating a molar pregnancy. The uterine corpus is distended by heterogenously enhancing mass. There is no evidence of a fetus.



TREATMENT ▪ Uterine evacuation: suction and curettage



Figure 126.6 The histological appearance of a partial mole. In contrast to a complete mole, there will be both normal villi (right of image) and hydropic villi (left of image). Trophoblastic proliferation is minimal.



OSMOSIS.ORG 765



NOTES



NOTES



MALE GENITOURINARY CANCERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Male reproductive, urinary system cancers



CAUSES



▪ Depends on cancer type



RISK FACTORS



▪ Depends on cancer type ▫ Tobacco smoking, increased age, positive family history



COMPLICATIONS



▪ Metastasis, affected part function loss



SIGNS & SYMPTOMS ▪ Depends on cancer type ▫ Dysuria, painful ejaculation, back pain, hematuria/hematospermia, pelvic pain, weight loss, lower back/abdominal pain



DIAGNOSIS DIAGNOSTIC IMAGING ▪ CT scan/MRI/ultrasound ▪ Identify lesions



LAB RESULTS



▪ Serum tumor markers



766 OSMOSIS.ORG



OTHER DIAGNOSTICS ▪ History/physical exam



Biopsy ▪ Grading ▫ GX: grade cannot be assessed (undetermined grade) ▫ G1: well differentiated (low grade) ▫ G2: moderately differentiated (intermediate grade) ▫ G3: poorly differentiated (high grade) ▫ G4: undifferentiated (high grade) Staging ▪ Tumor, nodes, metastasis (TNM) system; scored 0–4 ▫ T: size, sites invaded (e.g. only testis/ extratesticular invasion) ▫ N: degree of spread to regional lymph nodes ▫ M: distant metastasis presence ▫ V: Vascular invasion



TREATMENT MEDICATIONS ▪ Chemotherapy



SURGERY



▪ See individual cancers



OTHER INTERVENTIONS ▪ Radiotherapy



Chapter 127 Male Genitourinary Cancers



PENILE CANCER osms.it/penile-cancer PATHOLOGY & CAUSES ▪ ▪ ▪ ▪



Malignant penis tumor Rare in high-income countries Initial lesions found on prepuce, glans Can invade corpora, shaft of penis → penile autoamputation



TYPES Squamous cell carcinoma (SCC) ▪ Most predominant; melanoma, small-cell carcinoma, Kaposi sarcoma, Meckel cell carcinoma, basal cell carcinoma, etc. ▪ Bowenoid papulosis ▫ SCC form in situ of penis ▪ Erythroplasia of Queyrat ▫ SCC of penis glans, presents as erythroplakia (red patch) Histologic subtypes of SCC ▪ Usual type ▫ Most predominant ▫ Involves corpus spongiosum ▫ Invades perineural, regional lymphovascular system ▪ Papillary carcinoma ▫ Involves superficial erectile tissues ▫ Not associated with human papillomavirus (HPV) ▫ Histology: papillomatosis, hyperkeratosis ▪ Warty tumors ▫ Associated with HPV infection ▫ Histology: irregular stroma with papillary fibrovascular core ▪ Basaloid carcinoma ▫ Associated with HPV ▫ Histology: necrosis, erectile tissue invasion



▪ Verrucous carcinoma ▫ Not aggressive (low metastatic ability) ▫ Histology: straight papillae, surface, interpapillary hyperkeratosis ▪ Sarcomatoid carcinoma ▫ Very rare ▫ Highly aggressive ▫ Histology: SCC, spindle cell carcinoma components



RISK FACTORS



▪ Infection ▫ HPV 16/18 infection, HIV, urinary tract infections (UTIs) ▪ Genital warts, poor hygiene, phimosis/ paraphimosis, tobacco smoking, smegma accumulation, increased age



COMPLICATIONS



▪ Metastasis ▫ Inguinal/femoral lymph nodes; liver, lung, bone, brain (rare) ▪ Penile autoamputation



SIGNS & SYMPTOMS ▪ Painless mass ▪ Ulcer/rash ▪ Penile pain/foul-smelling discharge/ bleeding ▪ Inguinal lymphadenopathy ▪ Penile skin color change (redness)



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI/ultrasound ▪ Regional lymph, distant metastasis assessment



OSMOSIS.ORG 767



OTHER DIAGNOSTICS



▪ Obvious suspicious penile lesions ▪ Biopsy ▫ Diagnosis, tumor grading ▪ Staging ▫ TNM



TREATMENT MEDICATIONS ▪ Chemotherapy



SURGERY



▪ Local excision in early stage ▪ Partial/total penectomy if glans/shaft invaded



Figure 127.1 The clinical appearance of a fungating penile tumor, likely a squamous-cell carcinoma. There is visible lymphadenopathy of the left superficial inguinal chain which almost certainly represents metastatic disease.



OTHER INTERVENTIONS ▪ Radiotherapy



PROSTATE CANCER osms.it/prostate-cancer PATHOLOGY & CAUSES ▪ Very common male cancer ▫ Arises in prostate gland ▪ Second leading cancer death cause in biologically-male individuals ▪ Usually associated with BRCA1/BRCA2 gene mutations ▪ Early cancer cells require androgens to survive ▪ Can later become androgen-independent ▪ Usually arise in prostate’s peripheral zone



TYPES Adenocarcinomas ▪ Most common ▪ Arise from glandular tissues; from luminal/ basal cells



768 OSMOSIS.ORG



Transitional cell cancer ▪ Arises from prostatic urethra transitional epithelium cells Small cell prostate cancer ▪ Arise from neuroendocrine cells



RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪



> 40 years old Black people of African descent ↑ risk Positive family history Smoking Obesity Animal-fat rich diet



COMPLICATIONS



▪ Bone osteolysis → hypercalcemia (rare) ▪ Metastasis ▫ Lymph nodes → more metastasis to distant organs (e.g. lungs)



Chapter 127 Male Genitourinary Cancers ▫ Bones (thoracic/lumbar spine, pelvis) → lower back pain, pathologic fractures → spinal cord compression (if spine involved) → neurological deficits (e.g. lower limb pain/weakness, bowel/ urinary bladder control loss, etc.) ▪ Nearby structure compression/invasion ▫ Urinary bladder/prostatic urethra (later stages) → difficulty urinating; bleeding; urination, ejaculation pain



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪



Urinary frequency/hesitancy/incontinence Dysuria Painful ejaculation Lower-back/bone pain Hematuria/hematospermia (rare) Neurological deficits (e.g. weakness/lack of lower limb sensation)



DIAGNOSIS Gleason score ▪ 2–4: low grade ▪ 5–7: moderate grade ▪ 8–10: high grade



Figure 127.2 The histological appearance of prostate adenocarcinoma. On the left the tumor forms vague gland like structures (Gleason 4) and on the right is composed of infiltrating single cells (Gleason 5).



DIAGNOSTIC IMAGING Ultrasound ▪ Hypoechoic areas in prostate → suggestive of cancer X-ray/CT scan/MRI ▪ Lesions in prostate, pelvic lymph nodes, bones ▫ Staging: TNM ▪ Bone scan ▫ Bone metastases presence



LAB RESULTS



▪ ↑ prostate specific antigen (PSA) serum levels ▪ ↑ alkaline phosphatase serum levels ▫ Suggestive of bone metastasis ▪ Biopsy used for Gleason scoring



OTHER DIAGNOSTICS



▪ Digital rectal exam (DRE) ▫ Asymmetric prostate enlargement



Figure 127.3 The histological appearance of prostate adenocarcinoma, Gleason grade 3. The tumor is composed of small, compressed glands with only a tiny amount of intervening stroma.



TREATMENT MEDICATIONS



▪ Anti-androgen therapy ▫ ↓ testosterone levels → ↓ cancer cell growth



OSMOSIS.ORG 769



SURGERY



▪ Prostatectomy ▪ Cryosurgery ▪ Orchidectomy ▫ ↓ testosterone levels → ↓ cancer cell growth



OTHER INTERVENTIONS



▪ Active surveillance (early stage) ▫ Regular biopsy, PSA monitoring ▪ Radiotherapy



Figure 127.4 An MRI scan of the pelvis in the axial plane demonstrating prostate adenocarcinoma invading the bladder and the rectum.



TESTICULAR CANCER osms.it/testicular-cancer PATHOLOGY & CAUSES ▪ Cancer develops in testicular cells ▫ Unilateral/bilateral ▫ Common in biologically-male individuals (15–35 years old) ▪ High cure rate (very high five year survival rate)



TYPES Germ cell tumors (GCT) ▪ Most common ▪ Seminomas ▫ Very poor prognosis ▫ Syncytiotrophoblastic/spermatocytic seminoma ▫ Histology: “fried egg”-like cells (clear cytoplasm, central nucleus) ▪ Non-seminomas germ cell tumors (NSGCT) ▫ Produce beta human chorionic gonadotropin (β-hCG)



770 OSMOSIS.ORG



▫ Yolk sac tumor (AKA endodermal sinus tumor) ▫ Histology: Schiller–Duval bodies (germ cells encircle blood vessel, resemble glomerulus) ▪ Embryonal carcinoma ▫ Histology: prominent nucleoli; necrotic areas; clear, empty-appearing nuclei ▪ Choriocarcinoma ▫ Histology: cytotrophoblasts, syncytiotrophoblasts, hemorrhagic areas ▪ Teratoma ▫ Histology: contains many tissue types (hair, teeth, neurons, etc.) Sex cord/gonadal stromal tumors ▪ Sertoli cells tumor ▫ Histology: dense fibrous stroma, abundant eosinophilic cytoplasm, cells have tubular arrangement ▪ Leydig cells tumors ▫ Histology: Reinke crystals (eosinophilic cytoplasmic inclusion bodies)



Chapter 127 Male Genitourinary Cancers



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



Painless/painful testis mass Lower abdominal pain, heaviness Previously atrophied testis → ↑ size Gynecomastia Metastasis evidence (e.g. dyspnea, hemoptysis, palpable lymph nodes, bone pain)



DIAGNOSIS DIAGNOSTIC IMAGING ▪ Tumor identification, TNM staging ▪ Orchidectomy ▫ Biopsy: diagnosis, tumor grading Chest X-ray ▪ Evaluate pulmonary metastasis CT scan ▪ Asses abdominal, pelvic metastasis Figure 127.5 The gross pathological appearance of a testicular seminoma. The tumor has entirely replaced the normal testicular parenchyma. ▪ Granulosa cell tumor ▫ Histology: Call–Exner bodies (fluid-filled eosinophilic spaces granulosa cells)



MRI ▪ If brain involvement is suspected Ultrasound ▪ Seminoma: smooth echogenic mass ▪ NSGCT: no defined borders, calcified cystic masses



CAUSES



▪ Unknown; chromosome 12p gene mutations usually present



RISK FACTORS



Cryptorchidism (undescended testis) Previous testicular malignancy Family history White individuals Congenital abnormality (hypospadias, inguinal hernias) ▪ Infection (mumps virus → orchitis) ▪ ▪ ▪ ▪ ▪



COMPLICATIONS



▪ Infertility ▪ Lungs, liver, bones, brain metastases



Figure 127.6 A scrotal MRI scan in the coronal plane demonstrating a tumor of the left testicle.



OSMOSIS.ORG 771



LAB RESULTS



▪ Serum tumor markers ▫ ↑ alpha fetoprotein (AFP): NSGCT ▫ Normal AFP: pure seminoma, choriocarcinoma ▫ β-hCG: NSGCT ▫ ↑ lactate dehydrogenase (LDH): GCT



TREATMENT MEDICATIONS



▪ Chemotherapy ▪ High-dose chemotherapy + stem cell transplantation



SURGERY



▪ Surgery ▫ Orchidectomy, affected lymph node removal



OTHER INTERVENTIONS



▪ Follow up/surveillance ▫ Regular AFP/β-hCG serum-level monitoring ▪ Radiotherapy for seminomas



772 OSMOSIS.ORG



Figure 127.7 The histological appearance of a testicular seminoma, the most common form of testicular cancer. The cells have a fried egg appearance with clear cytoplasm, well-defined nuclei with open chromatin and a well-defined cell border.



NOTES



NOTES



MATERNAL CONDITIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of disorders occurring during gestation which potentially have adverse maternal, fetal, neonatal health effects



DIAGNOSIS OTHER DIAGNOSTICS



▪ Preconception, prenatal, obstetric history ▪ Physical examination of mother; assessment of fetal well-being



SIGNS & SYMPTOMS ▪ See individual disorders



TREATMENT OTHER INTERVENTIONS



▪ Interventions focused on pregnancy maintenance, fetal viability, safe delivery, reduced neonatal complications



CERVICAL INCOMPETENCE osms.it/cervical-incompetence PATHOLOGY & CAUSES ▪ The inability of the cervix to retain pregnancy during second trimester → premature cervical os opening, fetal expulsion ▫ In absence of clinical contractions/labor ▪ Usually < 24 weeks of gestation



CAUSES



▪ Exact mechanism not well-understood ▫ Involves structural abnormality presence, factors such as infection, inflammatory processes; weaken cervix integrity



RISK FACTORS



▪ ▪ ▪ ▪ ▪ ▪



▫ Loop electrosurgical excision procedure (LEEP), cone biopsy Spontaneous/induced abortion history Previous forceps/vacuum-assisted birth Uterine anomalies Genetic predisposition Defective cervical collagen (e.g. Ehlers– Danlos syndrome) Idiopathic



COMPLICATIONS



▪ Premature membrane rupture, birth ▫ Fetal loss, morbidity related to prematurity ▪ Chorioamnionitis ▪ Cerclage procedure ▫ Cervical lacerations



▪ Prior cervical surgery



OSMOSIS.ORG 773



TREATMENT



SIGNS & SYMPTOMS ▪ Often asymptomatic until pregnancy is lost ▪ Mild symptoms ▫ Pelvic pressure, cramping, backache, vaginal discharge ▪ Signs of painless cervical changes ▫ Shortening, funneling at internal os; cervical canal dilation ▪ Bulging amniotic membranes ▪ Short duration from symptom onset → fetal loss



DIAGNOSIS DIAGNOSTIC IMAGING Serial transvaginal ultrasound ▪ Cervical shortening, funneling, dilation in the absence of significant uterine contractions ▫ Findings unexplained by other preterm birth causes



▪ Treatment aimed at reinforcing cervical structural integrity



MEDICATIONS



▪ Post-cerclage ▫ Indomethacin: enhances fetal lung development ▫ Progesterone: helps maintain pregnancy



SURGERY



▪ Cervical cerclage: concentric suture placement at cervical os (McDonald technique) ▫ 36–37 weeks of gestation → sutures removal ▪ Prior failed cervical cerclage → abdominal cerclage ▫ Circumferential Mersilene tape around uterine isthmus



OTHER DIAGNOSTICS ▪ History of recurrent (≥ two) consecutive pregnancy losses/extremely preterm births ( 35 years



COMPLICATIONS



▪ Status epilepticus (eclampticus), placental abruption, intrauterine asphyxia, maternal/ fetal death



Chapter 128 Maternal Conditions



DIAGNOSIS



SIGNS & SYMPTOMS Seizure ▪ May be preceded by certain signs/ symptoms ▫ May occur in asymptomatic individual ▫ Headache: persistent, frontal, occipital, thunderclap ▫ Visual disturbances: scotoma, cortical blindness, photophobia, blurred vision, visual field defect (e.g. homonymous hemianopsia) ▫ Right upper quadrant (epigastric) pain ▫ Ankle clonus Generalized tonic-clonic seizure onset ▪ Tonic phase ▫ Abrupt consciousness loss; extremities/ chest/back stiffening; possible cyanosis ▪ Clonic phase ▫ Muscle twitching/jerking; frothy/bloody sputum may be present ▪ Postictal phase ▫ Muscle movements stop ▪ Responsiveness resumes (usually) within 10–20 minutes; neurologic findings may include altered mental status, memory/ visual deficits, ↑ deep tendon reflexes Fetal seizure response ▪ Bradycardia → tachycardia + heart rate variability loss → maternal/fetal stabilization → improvement



▪ Clinical diagnosis based on new-onset of seizure in preeclamptic individual



DIAGNOSTIC IMAGING MRI ▪ Can visualize posterior reversible encephalopathy syndrome (PRES) ▪ Patchy T2/FLAIR hyperintensity in subcortical white matter; also in adjacent parietal, occipital lobes’ gray matter ▪ Posterior cerebral hemispheres show localized vasogenic edema



TREATMENT MEDICATIONS



▪ Antihypertensives ▪ Seizure prophylaxis ▫ Magnesium sulfate IV; diazepam/ lorazepam



SURGERY



▪ Prompt delivery ▫ Induced vaginal/cesarean (gestationdependent)



OTHER INTERVENTIONS ▪ Supplemental oxygen



GESTATIONAL DIABETES (GDM) osms.it/gestational-diabetes PATHOLOGY & CAUSES ▪ Glucose intolerance onset during pregnancy → maternal, fetal hyperglycemia ▫ Adverse fetal/neonatal effects depend on glycemic derangement degree/ duration



▪ Normal pregnancy: characterized by progressive insulin resistance, pancreatic β-cell hyperplasia ▫ Hyperplasia: influenced by chorionic somatomammotropin (hCS) AKA human placental lactogen (hPL) ▪ Gestational diabetes develops when insulin resistance overcomes pancreatic β-cell



OSMOSIS.ORG 777



ability to maintain normoglycemia ▪ Resistance begins in second trimester, peaks in third (fetal weight gain) ▫ Maternal hormonal, metabolic changes support steady glucose supply for fetal growth, cell proliferation, tissue development, differentiation. ▫ After fetus, placenta delivery → hCS no longer produced → ↓ pregnancyassociated insulin resistance ▪ Maternal hyperglycemia → fetal hyperglycemia → macrosomia (birth weight > 90th percentile on population-appropriate growth chart/> 4kg/8.82lbs) ▫ Hyperinsulinemia → ↓ surfactant production → impaired lung development ▫ ↑ fetal metabolic rate → ↑ oxygen consumption → fetal hypoxemia → metabolic acidosis ▫ ↑ erythropoiesis → polycythemia → hyperviscosity; iron redistribution secondary to accelerated erythropoiesis → ↓ iron available for developing organs → cardiomyopathy, altered neurodevelopment (reactive oxygen species → cardiac remodeling → transient hypertrophic cardiomyopathy)



RISK FACTORS



▪ Respiratory distress ▫ ↓ fetal surfactant development ▪ Hypoglycemia ▫ Hyperinsulinemia + placental glucose delivery loss ▪ Hyperbilirubinemia ▫ Polycythemia, excess red blood cell (RBC) breakdown ▪ ↑ stillbirth risk ▫ Often cardiomyopathy + ↓ ability to tolerate macrosomia-related difficult labor → failure to progress, shoulder dystocia → perinatal asphyxia ▪ ↑ obesity risk (later in life)



SIGNS & SYMPTOMS Maternal ▪ May be asymptomatic ▪ Severe hyperglycemia manifests with polyuria, polydipsia, polyphagia Neonatal (infant of diabetic mother) ▪ Low APGAR score ▪ Large for gestational age; > 4kg/8.82lbs ▪ Plethora ▪ Hypoglycemia (may be jittery on delivery)



DIAGNOSIS



▪ Polygenic influence; age > 25 years; nonwhite people of European descent; BMI > 25kg/m²; polycystic ovary syndrome; hypertension; multiple gestation; personal/ family glucose-intolerance history; previous macrosomic infant/unexplained fetal loss



DIAGNOSTIC IMAGING



COMPLICATIONS



Pulse oximetry ▪ Neonatal: ↓ oxygen saturation



Maternal ▪ ↑ risk of preeclampsia, polyhydramnios, developing type 2 diabetes mellitus Neotatal ▪ Macrosomia/large for gestational age (LGA) ▫ ↑ cesarean delivery risk; ↑ shoulder dystocia risk → ↑ maternal trauma risk (e.g. lacerations, hematoma); fetal birth trauma (brachial plexus injury, facial palsy, clavicular/humeral fractures, cephalohematoma, subdural hematoma)



778 OSMOSIS.ORG



Fetal ultrasound ▪ Prenatal: fetal size, weight estimation



LAB RESULTS Prenatal (maternal) ▪ Glucose tests: random capillary glucose, fasting glucose, hemoglobin A1c, oral glucose tolerance testing (OTT) ▪ Serum, urinary ketone bodies



Chapter 128 Maternal Conditions Postnatal ▪ Maternal: serial capillary glucose tests (hyperglycemia initially → resolving after placenta delivery) ▪ Neonatal: blood studies (↓ glucose; ↑ hematocrit; ↑ bilirubin; possible ↓ calcium, magnesium)



OTHER DIAGNOSTICS



▪ Postnatal: neonatal weight, gestational age assessment; physical examination



TREATMENT MEDICATIONS Prenatal ▪ A2 GDM (requires medical management) ▫ Insulin as required to reach blood glucose target (does not cross placenta) ▫ Oral antidiabetic agents (crosses placenta)



Postnatal ▪ Maternal: continue glucose medical management until normalization ▪ Neonatal: supplemental oxygen, oral/ intravenous glucose



SURGERY Prenatal ▪ Elective cesarean delivery (estimated fetal weight ≥4.5kg/9.92lbs)



OTHER INTERVENTIONS Prenatal ▪ Serial nonstress tests, amniotic fluid index (AMI) ▪ A1 GDM (maintains euglycemia via lifestyle modification) ▫ Labor induction: between 40+0–41+0 weeks of gestation ▪ A2 GDM (requires medical management) ▫ Labor induction: 39+0 weeks of gestation (39+0–39+6 if glucose is well-controlled)



GESTATIONAL HYPERTENSION osms.it/gestational-hypertension PATHOLOGY & CAUSES ▪ New hypertension onset; develops ≥ 20 weeks of gestation ▫ Systolic blood pressure (≥ 140mmHg)/ diastolic blood pressure (≥ 90mmHg) ▫ No proteinuria/new end-organ dysfunction evidence ▫ Usually resolves by postpartum week 12 ▫ Exact mechanism unclear



COMPLICATIONS



▪ Preeclampsia development



SIGNS & SYMPTOMS ▪ ↑ blood pressure (≥ 140mmHg)/diastolic blood pressure (≥ 90mmHg) ▪ Severe gestational hypertension (≥ 160mmHg)/diastolic blood pressure (≥ 110mmHg)



RISK FACTORS ▪ ↑ prevalence in primigravidas (first pregnancy) ▪ Genetic factors



OSMOSIS.ORG 779



DIAGNOSIS LAB RESULTS



▪ Urine dipstick ▫ Negative/trace protein amounts ▪ Normal platelet count ▪ Creatinine, hepatic transaminases ▫ Normal



OTHER DIAGNOSTICS



▪ Clinical exclusion diagnosis ▫ Established when preeclampsia eliminated as hypertension cause ▪ Focused history ▫ Cerebral/visual disturbance absence; epigastric/right upper quadrant pain absence



Figure 128.3 Histological section of the placenta from an individual with hypertension during pregnancy displaying hypertrophic decidual vasculopathy. There is hypertrophy of the smooth muscle layer and numerous perivascular inflammatory cells. This may also be seen in pre-eclampsia.



780 OSMOSIS.ORG



TREATMENT MEDICATIONS



▪ Antihypertensives, antenatal corticosteroids



OTHER INTERVENTIONS



▪ Delivery timed in accordance with individual status ▪ Ongoing maternal monitoring ▫ Blood pressure ▫ Proteinuria ▫ Platelet count, liver enzymes ▪ Ongoing fetal well-being monitoring ▫ Biophysical profile/nonstress test ▫ Measure amniotic fluid index (AFI) ▫ Uterine, umbilical artery doppler velocimetry ▫ Monitor fetal growth signs (placental insufficiency)



Chapter 128 Maternal Conditions



HYPEREMESIS GRAVIDARUM osms.it/hyperemesis-gravidarum PATHOLOGY & CAUSES



DIAGNOSIS



▪ Exaggerated, protracted nausea/vomiting in early pregnancy ▪ Incidence: 1 in 200 pregnancies (Western countries) ▪ Usually between week 4–8 of gestation ▪ May last ≥ 16 weeks



DIAGNOSTIC IMAGING



CAUSES



▪ ↑ Blood urea nitrogen (BUN), creatinine; urea/creatinine ratio > 25:1; ↓ potassium, sodium; ↑ hematocrit, pH ▪ Urinalysis ▫ ↑ specific gravity, ketones



▪ Multifactorial ▫ E.g. pregnancy-induced hormonal changes, pregnancy-related gastric motility ↓ + other individual factors



RISK FACTORS ▪ ▪ ▪ ▪ ▪



Previous hyperemesis gravidarum ↑ human chorionic gonadotropin (hCG) Multiple pregnancy, hydatidiform mole Biologically-female fetus Hyperthyroidism (may be hCG ↑ triggered)



COMPLICATIONS



▪ Dehydration, weight loss, electrolyte imbalance, metabolic alkalosis (HCl loss orally), ketosis, Mallory–Weiss esophageal tear (violent vomiting), intrauterine growth restriction (if prolonged)



SIGNS & SYMPTOMS ▪ Frequent, severe nausea; vomiting ▪ Dehydration ▫ Tachycardia, palpitations, hypotension, postural hypotension, dry mucous membranes, ↓ skin turgor ▪ ↑ smell sensitivity ▪ Malaise ▪ Weight loss ▪ Ketotic odor



Pelvic ultrasound ▪ Excludes molar pregnancy; identifies multiple gestation



LAB RESULTS



OTHER DIAGNOSTICS



▪ Excessive vomiting history ▫ Sufficient to cause clinically-evident dehydration



TREATMENT MEDICATIONS



▪ Antiemetics (off-label for pregnancy) ▪ Vitamin B6 ▫ ↓ nausea ▪ Fluid, electrolyte replacement



OTHER INTERVENTIONS



▪ Trigger avoidance ▫ Consume small, frequent meals ▫ Bland food (avoid spicy/greasy food)



OSMOSIS.ORG 781



INTRAUTERINE GROWTH RESTRICTION osms.it/intrauterine-growth-restriction PATHOLOGY & CAUSES ▪ Full fetal growth not accomplished during gestation → ↑ morbidity, mortality risk ▪ AKA fetal growth restriction



TYPES



▪ Symmetric ▫ Effects begin early in gestation ▫ Most commonly intrinsic factors (infection, chromosomal abnormality) ▫ Uniform effect (all organ systems) ▫ Body/head circumference, length, weight restricted proportionally ▪ Asymmetric ▫ Affects fetus in late second/third trimester ▫ Commonly ↓ nutrition delivery to fetus (limits glycogen, fat storage; brain sparing) ▫ Head circumference (normal), length (near normal), weight (significantly affected)



CAUSES



▪ Fetal factors ▫ Genetic (e.g. aneuploidy, single gene mutations) ▫ Infection (e.g. cytomegalovirus (CMV), toxoplasmosis; rubella) ▫ Multiple gestation (e.g. nutrientcompetition by > one fetus) ▪ Placental factors ▫ Ischemic placental disease (e.g. preeclampsia) ▫ Structural anomalies (e.g. single umbilical artery)



782 OSMOSIS.ORG



▪ Maternal factors ▫ Chronic disease (e.g. renal, cardiac, pulmonary disease) ▫ Substance use/abuse (e.g. alcohol, cigarettes, illicit drugs) ▫ Poor nutritional status/inadequate weight gain ▪ Environmental factors ▫ Teratogen exposure, pollution ▫ Certain maternal therapeutic medication



COMPLICATIONS



▪ Preterm birth, related sequelae (e.g. necrotizing enterocolitis, respiratory distress syndrome) ▪ Intrauterine asphyxia ▫ ↓ physiological reserve → poor response to temporary hypoxia secondary to uterine contractions ▫ ↑ meconium aspiration risk → pulmonary hypertension ▪ Impaired thermoregulation ▫ ↓ subcutaneous tissue + ↓ catecholamines (used in non-shivering thermogenesis via brown fat) → ↑ cold stress risk → hypoxia, hypoglycemia, metabolic acidosis ▪ Hypoglycemia ▫ ↓ glycogen, fat, protein reserves ▪ Polycythemia ▫ Chronic hypoxia ▪ Impaired immune function ▫ Inadequate nutrition-related ▪ Hypocalcemia ▫ ↑ serum phosphate load from tissue catabolism, ↓ nutrition, renal insufficiency ▪ ↑ mortality risk



Chapter 128 Maternal Conditions



SIGNS & SYMPTOMS ▪ General postnatal appearance ▫ Thin, loose skin; ↓ subcutaneous tissue, skeletal muscle; thin umbilical cord ▪ ↓ weight, length, head, chest circumference ▫ Asymmetric growth restriction (head circumference may be normal; will appear large relative to trunk, extremities)



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound biometry (prenatal) ▪ Correlate estimated date of confinement (EDC) with fetal parameters ▫ Sonographically-estimated fetal weight (SEFW) ▫ Head: biparietal diameter (BPD), head circumference (HC), transcerebellar diameter (TDC) ▫ Abdominal circumference (AC): AC/HC ratio ▫ Amniotic fluid index (AFI): oligohydramnios present if placental pathology Doppler velocimetry (prenatal) ▪ Measure circulatory status ▫ Vascular resistance, placental/cardiac function)



LAB RESULTS



▪ Blood studies (postnatal) ▫ ↓ capillary glucose level, serum calcium; ↑ hematocrit



OTHER DIAGNOSTICS ▪ Postnatal diagnostics



Ponderal index ▪ Low; asymmetric growth restriction especially ▪ Body weight:length ratio ▫ PI = [weight (in g) x 100] ÷ [length (in cm)]3 Ballard score ▪ Gestational age assessment ▫ Small for gestational age ▪ Includes weight, head, chest circumference; physical maturity, neuromuscular maturity indicators



TREATMENT MEDICATIONS



▪ Glucose ▫ Intravenous/oral/early feeding



OTHER INTERVENTIONS



▪ Maintain neutral thermal environment



OSMOSIS.ORG 783



MASTITIS osms.it/mastitis PATHOLOGY & CAUSES ▪ Localized infection: one/more mammary ducts, usually associated with lactation



LAB RESULTS



▪ Leukocytosis ▪ Breast milk culture ▫ Identifies causative microorganism



CAUSES



▪ Infectious ▫ Microorganism introduction: transferred from breastfeeding infant’s mouth/nose (commonly Staphylococcus aureus, Streptococcus spp.) ▪ Noninfectious ▫ Milk stasis: prolonged engorgement, infrequent/inefficient feedings, clogged ducts



RISK FACTORS



▪ Cracked/damaged nipples, poor hygiene, ineffective breastfeeding technique, impaired immunity, diabetes



COMPLICATIONS



▪ Infection progression, abscess formation



SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪



Localized firmness, redness, swelling, heat Palpable lump Breast pain Tender/enlarged axillary nodes Flu-like symptoms ▫ Fever, malaise, myalgias



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Identifies abscess presence



784 OSMOSIS.ORG



Figure 128.4 An ultrasound scan of the breast demonstrating a breast abscess, a complication of mastitis.



TREATMENT MEDICATIONS



▪ Analgesics ▪ Antibiotics (if conservative measures ineffective)



OTHER INTERVENTIONS



▪ Ice, cold compress application ▪ Continue breastfeeding/manual extraction ▪ Lactation consultant referral



Chapter 128 Maternal Conditions



OLIGOHYDRAMNIOS osms.it/oligohydramnios PATHOLOGY & CAUSES ▪ ↓ amniotic fluid volume surrounding fetus for gestational age ▫ Can adversely affect fetal development



CAUSES ▪ Amniotic fluid production, movement imbalance ▫ ↓ placental blood flow, ↓ fetal urine production, ↑ amniotic fluid loss → ↓ amniotic fluid volume ▫ ↓ fluid cushioning effect → ↑ umbilical cord compression risk ▫ Restricted fetal movement → ↓ musculoskeletal development ▫ Fetal thorax compression → ↓ pulmonary development ▫ ↓ amniotic fluid bacteriostatic effect → ↑ infection risk



RISK FACTORS Maternal ▪ Hypertensive disorders, diabetes, preeclampsia, abnormal placentation → uteroplacental insufficiency ▪ Premature rupture of membranes (PROM), amniotic fluid leak → fluid loss ▪ Maternal medications (e.g. ACE inhibitors, NSAIDs) ▪ Post-term pregnancy Fetal ▪ Renal/urinary tract anomalies (e.g. renal agenesis), restricted growth, fetal death → ↓ fetal urine production ▪ Congenital anomalies (e.g. aneuploidy, cardiac, preferential perfusion to brain at kidney’s expense)



COMPLICATIONS



▪ Amniotic band syndrome ▫ Adhesions between amnion, fetus → limb malformation, amputation ▪ Limb position defects (e.g. club foot) ▪ Pulmonary hypoplasia → respiratory distress ▪ Multiple anomalies (Potter sequence) ▫ Pulmonary hypoplasia, oligohydramnios, twisted skin/face, extremity malformation, renal agenesis ▪ Chorioamnionitis ▪ Low birth weight ▪ Meconium aspiration syndrome (MAS) ▪ ↑ fetal/neonatal mortality risk



SIGNS & SYMPTOMS ▪ Uterine size/fundal height less than expected for gestational age ▪ Easily palpated fetus ▪ ↓ fetal movement



DIAGNOSIS ▪ Targeted history, physical examination → identify specific cause



DIAGNOSTIC IMAGING Uterine ultrasound ▪ ↓ amniotic fluid index (AFI) ▫ < 5cm/1.97in total; single deepest pocket < 2cm/0.79in ▪ Amniotic fluid measurement in deepest pocket in each uterine quadrant ▪ Sum of each maximum vertical pocket = AFI



OSMOSIS.ORG 785



Fetal ultrasound + biophysical profile ▪ Detects fetal anomalies; assesses degree of fetal well-being



LAB RESULTS



▪ Amniotic fluid leak detection: nitrazine, fern tests, AmniSure



TREATMENT OTHER INTERVENTIONS ▪ ↑ intrauterine-fluid volume ▫ Maternal hydration ▫ Amnioinfusion



POLYHYDRAMNIOS osms.it/polyhydramnios PATHOLOGY & CAUSES ▪ Excessive amniotic fluid amount surrounding fetus for gestational age ▪ Can adversely affect fetal development



CAUSES ▪ Amniotic fluid production, movement imbalance ▪ ↑ placental blood flow ▪ ↑ fetal renal perfusion, urine production ▪ ↓ fetal amniotic fluid swallowing/absorption ▪ Idiopathic



RISK FACTORS Maternal ▪ Diabetes; chronic/gestational Fetal ▪ Gastrointestinal anomalies (e.g. duodenal, esophageal, intestinal atresia ) ▪ Central nervous system abnormalities ▪ High cardiac-output state ▪ Twin-twin transfusion syndrome ▪ Nonimmune hydrops ▪ Genetic ▫ Aneuploidy, trisomy 18 or 21



COMPLICATIONS Maternal ▪ Placental abruption, umbilical cord prolapse, postpartum uterine atony → hemorrhage, upward diaphragm pressure → respiratory distress Fetal ▪ Preterm birth, fetal anomalies



SIGNS & SYMPTOMS ▪ Uterine size/fundal height ↑ than expected for gestational age ▪ Difficulty palpating fetal parts



DIAGNOSIS DIAGNOSTIC IMAGING Uterine ultrasound ▪ AFI ≥ 24cm/9.44in ▪ Single deepest pocket ≥ 8cm/3.1in Fetal ultrasound + biophysical profile ▪ Detects fetal anomalies; assesses degree of fetal well-being



OTHER DIAGNOSTICS



▪ Focused history, physical examination → identify specific cause



786 OSMOSIS.ORG



Chapter 128 Maternal Conditions



TREATMENT ▪ Treatment determined by gestational age, amniotic fluid excess severity, symptom presence, cause



MEDICATIONS



▪ Indomethacin ▫ Severe polyhydramnios, preterm labor onset ▫ Fetal antidiuretic response via endogenous vasopressin production ▫ Short duration with monitoring → avoids ductus arteriosus constriction



SURGERY



▪ Severe polyhydramnios, preterm labor onset ▫ Amnioreduction (decompression amniocentesis) ▫ Amniotic fluid removal (amniocentesis)



Figure 128.5 A fetal ultrasound scan demonstrating polyhydramnios. There is a large hypoechoic region between the fetus and the maternal abdominal wall. There is also the double-bubble sign of duodenal atresia, which is the underlying cause in this case.



OTHER INTERVENTIONS



▪ Mild polyhydramnios ▫ Expectant management



PRE-ECLAMPSIA osms.it/pre-eclampsia PATHOLOGY & CAUSES ▪ New-onset hypertension, proteinuria/endorgan dysfunction > 20 weeks of gestation ▪ Preeclampsia (severe) characteristics ▫ ↑ ↑ blood pressure; thrombocytopenia; hepatic, renal abnormalities; cerebral/ visual dysfunction; pulmonary edema ▫ Often resolves days/weeks after delivery



CAUSES



▪ Abnormal placentation ▫ Abnormal spiral artery remodeling into shallow, narrow arteries instead of normally deeply implanted, large,



low-resistance arteries → placental, fetal hypoperfusion → gestational age progression → worsening hypoperfusion ▪ Ischemic placenta → release proinflammatory proteins into maternal circulation → generalized endothelial dysfunction → ↑ reactivity to circulating vasoconstrictors + ↓ endogenous vasodilators production + ↑ vascular permeability + abnormal procoagulant expression ▫ Hypertension ▫ Target-organ microangiopathy (kidneys, liver, brain)



OSMOSIS.ORG 787



▫ Intravascular fluid leakage into interstitium ▫ Microangiopathic intravascular hemolysis ▫ Placental thrombosis, sclerosis, infarction



RISK FACTORS



Positive preeclampsia family history Previous pregnancy preeclampsia Nulliparity Age > 40 Biologically-female individuals of AfricanAmerican descent ▪ Chronic disease (e.g. hypertension, diabetes, systemic lupus erythematosus, antiphospholipid syndrome) ▪ ↑ body mass index (BMI) ▪ Assistive reproductive technology use ▪ ▪ ▪ ▪ ▪



COMPLICATIONS Maternal ▪ Cerebral edema/hemorrhage; stroke; hepatic failure; renal failure; hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome; placental abruption; eclampsia; liver rupture; posterior reversible encephalopathy syndrome (PRES); death Fetal ▪ Intrauterine growth restriction, premature birth, fetal demise



SIGNS & SYMPTOMS ▪ Hypertension ▫ Vasoconstriction ▪ Epigastric pain ▫ Liver capsule swelling (advanced disease sign) ▪ Peripheral edema, dyspnea ▫ ↑ vascular permeability ▪ Oliguria, proteinuria ▫ ↓ glomerular filtration rate (GFR), glomerular damage ▪ Severe headache, altered mental status ▫ Cerebrovascular pathology



788 OSMOSIS.ORG



▪ Visual disturbances ▫ E.g. photopsia (flashes of light), scotoma (dark areas/gaps in visual field), blurred vision (retinal arteriolar spasm) ▪ Hyperreflexia, ankle clonus ▫ Neuromuscular irritability ▪ Sudden, rapid weight gain ▫ Fluid retention



DIAGNOSIS DIAGNOSTIC IMAGING Pulse oximetry ▪ ↓ oxygen saturation Ultrasound ▪ Fetal ▫ Intrauterine growth restriction, oligohydramnios ▪ Placenta ▫ Infarction, hematoma, cystic lesion ▪ Uterine, umbilical artery doppler studies ▫ ↑ flow resistance ECG ▪ ↓ left ventricular function; ↑ filling pressure



LAB RESULTS



▪ Proteinuria ▪ ↑ serum creatinine, liver transaminases, indirect bilirubin; ↓ platelet count ▪ Hyperuricemia ▪ Peripheral blood smear ▫ Schistocytes, helmet cells



OTHER DIAGNOSTICS ▪ Low fetal biophysical profile score



TREATMENT MEDICATIONS



▪ Antepartum ▫ Antenatal steroids: promote fetal lung development



Chapter 128 Maternal Conditions ▪ Intrapartum ▫ Intravenous magnesium sulfate: bolus, then continuous infusion (seizure prophylaxis) ▫ Intravenous antihypertensives: maintain normal blood pressure ▪ Postpartum ▫ Continue intravenous magnesium sulfate infusion until stable



SURGERY



▪ Antepartum ▫ Labor induction/cesarean delivery: progressive placental function deterioration, disease advancement (preeclampsia with severe pathological features)



OTHER INTERVENTIONS



▪ Antepartum ▫ Regular maternal status, fetal wellbeing assessments ▪ Intrapartum ▫ Electronic fetal monitoring ▫ Supplemental oxygen



OSMOSIS.ORG 789



NOTES



NOTES



OVARIAN & UTERINE DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Gynecological disorders; adversely affect reproductive function



SIGNS & SYMPTOMS ▪ Pelvic pain ▫ Focal/diffuse ▪ Disorder-specific



OTHER DIAGNOSTICS



▪ Obstetric, gynecologic history ▪ Physical examination



TREATMENT ▪ Considerations: desire to preserve fertility, menopausal/post-menopausal status, presence of malignancy



MEDICATIONS



DIAGNOSIS DIAGNOSTIC IMAGING



▪ Disorder-specific ▫ Hormonal



SURGERY ▪ Disorder-specific



Ultrasound, MRI ▪ See individual disorders



ENDOMETRIOSIS osms.it/endometriosis PATHOLOGY & CAUSES ▪ Inflammatory disorder characterized by ectopic endometrial-like tissue (endometrial glands, stroma) implantation, growth outside uterus ▪ Benign disorder with invasive, disseminating malignancy characteristics ▫ May regress during menopause Common locations ▪ Ovaries (most common); referred to as endometrioma/“chocolate cyst”



790 OSMOSIS.ORG



▫ Anterior/posterior cul-de-sac; fallopian tubes; posterior broad, round, uterosacral ligaments ▪ May also implant in non-reproductive sites (bowel, bladder, diaphragm, thorax, brain, skin)



CAUSES



▪ Implantation cause unclear ▫ Multifactorial process involves immune, endocrine, cellular, genetic factors



Chapter 129 Ovarian & Uterine Disorders ▪ Current theories ▫ Metastatic theory: lymphatic/ hematogenous spread, iatrogenic implantation, retrograde menstruation ▫ Metaplastic theory: metaplastic Müllerian remnants changes ▫ Induction theory: undifferentiated mesenchyme stimulated to form endometriotic tissue



TYPES



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Symptoms often related to implantation site ▫ Gynecological: dysmenorrhea, pelvic pain, dyspareunia, menorrhagia ▫ Bowel: constipation, hematochezia, obstruction ▫ Bladder: pain, dysuria, hematuria ▫ Thoracic: hemoptysis, bronchospasm



Pelvic ▪ Endometrial tissue within pelvic cavity ▫ Peritoneum, pelvic organs/rectouterine pouch Ovarian ▪ Ovarian cyst lined with endometrial tissue Deeply infiltrating endometriosis ▪ Endometrial tissue extension ≥ 5mm into retroperitoneal space; may exist in several regions



RISK FACTORS



▪ Nulliparity ▪ Prolonged endogenous, physiologic estrogen exposure ▫ Early menarche/late menopause, short menstrual cycles ▪ Menstrual flow obstruction ▪ In utero diethylstilbestrol (DES) exposure ▪ ↓ body mass index (BMI) ▪ ↑ dietary trans-fats ▪ Nucleotide polymorphisms (e.g. rs10965235 in CDKN2BAS gene at locus 9p21.3) ▪ Age ▫ Peak incidence: 25–29 years old



COMPLICATIONS



▪ Infertility ▪ Chronic pain ▪ Endometrioma ▫ ↑ ovarian rupture/perforation/torsion risk ▪ Pneumothorax, hemothorax (thoracic endometriosis) ▪ ↑ epithelial ovarian cancer (EOC) risk



Figure 129.1 An intraoperative photograph of a focus of endometriosis in the parietal peritoneum.



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Abdominal/transvaginal ultrasonography (TVUS) ▪ Endometrioma ▫ Visualization of homogeneous hypoechoic ovarian cyst containing diffuse low-level internal echoes (“ground-glass” echogenicity) ▪ Lesions found elsewhere ▫ Hypoechoic lesions, retroperitoneal tissue thickening; severe endometriosis may demonstrate “kissing ovaries” (ovaries joined behind rectouterine pouch)



OSMOSIS.ORG 791



MRI ▪ If ultrasound findings inconclusive ▪ Hemorrhagic “powder burn” areas appear bright on T1 ▪ Solid deep lesions ▫ T1 hyperintense, T2 hypointense ▪ Fibrotic adhesions ▫ Isointense to pelvic muscle on both T1, T2



TREATMENT ▪ No definitive treatment; management options depend on desire to preserve fertility



MEDICATIONS



Laparoscopy ▪ Ectopic endometrial tissue identification ▫ Irregularly-shaped reddish/reddish-blue lesions ▫ Whitish opacifications; occasional hemorrhagic blue-brown areas (“powder burns”) ▫ Nodules, cysts may be present ▫ Fibrous adhesions (severe disease)



▪ Combined norgestimate–ethinyl estradiol cyclic/continuous oral contraceptives ▫ ↓ dysmenorrhea, ↓ endometrioma volume ▪ Gonadotropin-hormone releasing (GnRH) antagonists ▫ Pituitary gonadotropin hormone suppressed → ↓ estrogen ▪ Pain management ▫ Nonsteroidal anti-inflammatory drugs (NSAIDs)



OTHER DIAGNOSTICS



SURGERY



▪ Pelvic exam ▫ Limited motion of ovaries, uterus (fixed uterus) ▫ Adnexal mass palpated; may be tender ▫ Nodules in posterior fornix



Figure 129.2 The histological appearance of endometriosis affecting the ovary. Ovarian stroma is seen on the left and an endometrial deposit on the right.



792 OSMOSIS.ORG



▪ Laparoscopic ectopic endometrial tissue removal ▪ Hysterectomy



Chapter 129 Ovarian & Uterine Disorders



OVARIAN CYST osms.it/ovarian-cyst PATHOLOGY & CAUSES ▪ Fluid-filled growth that develops in/on ovary ▫ Usually benign (occasionally malignant) ▪ Majority of cysts occur during reproductive years ▪ Size ▫ 1–10cm/0.4–3.9in ▪ Strenuous physical activity/sexual intercourse → rupture ▫ Contain components that irritate peritoneal cavity upon rupture (cystic serous/mucinous fluid/blood; sebaceous fluid, hair, fat, bone, cartilage from dermoid cysts)



TYPES Functional/physiologic ▪ Abnormally large ovarian components ▫ Follicular cyst ▫ Corpus luteum cyst ▫ Theca-lutein cyst (usually bilateral) Neoplastic ▪ Benign/malignant ▫ Polycystic ovaries ▫ Endometrioma ▫ Serous cystadenoma ▫ Mucinous cystadenoma ▫ Dermoid cyst (benign cystic teratoma)



RISK FACTORS



▪ Early menarche, obesity, infertility, fertility treatments, polycystic ovarian syndrome, hypothyroidism, hyperandrogenism, tamoxifen use, smoking (mucinous cysts)



Figure 129.3 The gross pathological appearance of a large, benign ovarian cyst. The internal lining of the cyst is smooth and would have contained serous fluid prior to opening.



COMPLICATIONS



▪ Rupture, hemorrhage, ovarian torsion



SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Pelvic pain/lower abdominal pressure sensation ▪ Dyspareunia Ruptured cyst ▪ Sudden severe, sharp pain onset ▪ Pain may be referred to shoulder/upper abdomen (due to subphrenic blood extravasation) ▪ Rebound tenderness/guarding may be present (due to peritoneal irritation) Hemorrhage ▪ Hemodynamic instability signs (e.g. hypotension, tachycardia)



OSMOSIS.ORG 793



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ TVUS/abdominal ▪ Provides mass characterization ▫ Generally round/oval anechoic mass; smooth, thin walls ▫ Different mass types have unique characteristics MRI ▪ If ultrasound indeterminate for surgical resection evaluation



OTHER DIAGNOSTICS



▪ Obstetric, gynecologic history



Pelvic examination ▪ Adnexal tenderness/palpable mass ▪ Usually unilateral, localized



TREATMENT ▪ Functional/physiologic cysts usually resolve spontaneously



MEDICATIONS



▪ Uncomplicated cyst rupture (hemodynamically stable) ▫ Pain management (e.g. NSAIDs)



SURGERY



Figure 129.4 An ultrasound scan of the pelvis in an individual with a hemorrhagic ovarian cyst. The ovary (outlined) contains a large hypoechoic area which has displaced most of the ovarian parenchyma.



LAB RESULTS ▪ Serum CA-125 (in menopausal, postmenopausal individuals) ▫ Assists in ruling out ovarian cancer Histopathological examination ▪ Ultrasound-guided aspiration ▪ Histology varies widely, depending on type (e.g. benign mucinous tumor—single layer of columnar epithelial cells with mucinous cytoplasm)



794 OSMOSIS.ORG



Laparoscopy/laparotomy ▪ Ongoing hemorrhage, hemodynamic instability, torsion/rupture risk ▪ Ovarian cystectomy ▫ Removal of abnormal tissue only ▪ Unilateral/bilateral oophorectomy ▫ Removal of entire ovary(ies); recommended for menopausal/ postmenopausal individuals, if malignancy confirmed



OTHER INTERVENTIONS ▪ Significant blood loss ▫ Inpatient care: fluid replacement; monitor complete blood count (CBC) ▪ Uncomplicated cyst rupture (hemodynamically stable) ▫ Expectant management



Chapter 129 Ovarian & Uterine Disorders



OVARIAN TORSION osms.it/ovarian-torsion PATHOLOGY & CAUSES ▪ Gynecological emergency caused by rotation of ovary on it’s vascular pedicle ▫ If the fallopian tube twists with the ovary, adnexal torsion occurs ▪ Blood supply from ovarian artery, uterine artery’s ovarian branch pass through mesovarium (suspends ovary between ovarian, suspensory ligaments) → ovarian torsion cuts off ovary’s blood supply → ischemia, infarction, hemorrhage, adnexal necrosis ▫ Venous, lymphatic drainage also impeded → ovarian edema



RISK FACTORS



▪ Ovarian enlargement (e.g. tumor, cyst) ▫ ↑ if > 5cm/2in, though can occur with normal ovary ▪ Strenuous exercise ▪ Sudden ↑ abdominal pressure ▪ Pregnancy ▪ Ovulation induction/hyperstimulation (infertility treatment) ▪ Most cases occur during reproductive years



DIAGNOSIS DIAGNOSTIC IMAGING Pelvic ultrasound ▪ Enlarged, edematous ovary; displaced follicles appear as “string of pearls” ▪ Ovary may be located anterior to uterus (rather than lateral) Doppler imaging ▪ ↓ blood flow to ovary ▪ “Whirlpool” sign ▫ Indicates coiled ovarian vessels ▫ Hypoechoic stripes indicate vascular pedicle twisting MRI ▪ If ultrasound equivocal ▪ Enlarged, edematous ovary, abnormal location; “whirlpool” sign



COMPLICATIONS



▪ Ovarian necrosis, peritonitis, pelvic adhesion formation, hemorrhage



SIGNS & SYMPTOMS ▪ Pelvic pain ▫ Unilateral, severe, sharp ▪ Nausea/vomiting ▪ Fever, ↑ heart rate (HR), ↑ blood pressure (BP) may indicate necrosis Figure 129.5 A CT scan of the abdomen and pelvis in the coronal plane demonstrating whirlpool sign in an individual with torsion of the right ovary.



OSMOSIS.ORG 795



OTHER DIAGNOSTICS



▪ Obstetric, gynecologic history



Physical examination ▪ Tender adnexal mass may be palpated ▪ Necrosis present → guarding, rebound tenderness



TREATMENT



Laparoscopic surgery ▪ Confirm torsion (direct visualization) → perform detorsion ▪ Determine ovary’s viability ▫ Preserve viable ovary (may be edematous/hemorrhagic) for premenopausal individuals ▫ Salpingo-oophorectomy (necrotic ovary) for postmenopausal individuals/ suspected malignancy



SURGERY



▪ Ovarian benign mass cystectomy



UTERINE FIBROID osms.it/uterine-fibroid PATHOLOGY & CAUSES ▪ Most common benign pelvic neoplasm in reproductive-age individuals ▫ AKA leiomyoma/myoma ▪ Arises from myometrial smooth muscle cells → forms firm, round smooth muscle, connective tissue tumors ▪ Hormone fluctuation sensitive: ↑ cyclically during menses; ↓ after menopause



Subserosal myoma ▪ FIGO: type 6, 7 ▪ Arise from serosal surface ▪ Pedunculated ▪ Growth may be intraligamentary (between broad ligament folds) Cervical myoma ▪ FIGO: type 8 ▪ Arise from cervix



TYPES



▪ International Federation of Gynecology and Obstetrics (FIGO) classification



Intramural myoma ▪ FIGO type: 3, 4, 5 ▪ Found within uterine wall Submucosal myoma ▪ Arise from cells just below endometrium, extend into uterine cavity ▪ FIGO type: 0, 1, 2 ▫ Type 0: completely within endometrial cavity ▫ Type 1: extend < 50% into myometrium ▫ Type 2: extend ≥ 50% within myometrium



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Figure 129.6 The gross pathological appearance of a uterine fibroid. The specimen has been bisected revealing a firm, whorled cut surface.



Chapter 129 Ovarian & Uterine Disorders



RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪



▪



▪ ▪ ▪



Family history Nulliparity Early menarche Prenatal exposure to diethylstilbestrol (DES) ↑ (body mass index) BMI Environmental exposures ▫ Phthalates, polychlorinated biphenyl, bisphenol A Dietary factors ▫ Insufficient vitamin D ▫ Significant red meat consumption ▫ Alcohol (especially beer) Hypertension history Physical/sexual abuse history ↑ risk in biologically-female individuals of African descent



COMPLICATIONS



▪ Surrounding structure pressure ▫ Constipation, urinary retention/ frequency ▪ ↑ bleeding → anemia ▪ Pedunculated fibroid torsion (surgical emergency)



Figure 129.7 An MRI scan of the pelvis in the sagittal plane. The uterine corpus is outlined. The many hypodense objects within it are uterine fibroids.



OTHER DIAGNOSTICS Physical examination ▪ Pelvic exam ▫ Lumpy, cobblestone uterus upon palpation



SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ Enlarged/distorted uterus ▪ Abnormal uterine bleeding (e.g. longer/ heavier periods) ▪ Pelvic pain/pressure ▪ Dysmenorrhea ▪ Dyspareunia



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Determines specific fibroid type (e.g. intramural) Transvaginal ultrasound ▪ Visualize fibroids



TREATMENT ▪ Depends on symptomatology degree ▫ Whether/not fertility preservation desired, menopausal status



MEDICATIONS



▪ GnRH agonists ▪ Endometrial atrophy inducement ▫ Oral estrogen-progestin contraceptives ▪ Menstruation suppression (medroxyprogesterone) ▪ Pain management (NSAIDs)



SURGERY



▪ Myomectomy (recurrence possible) ▪ Hysterectomy



OSMOSIS.ORG 797



▪ Endometrial ablation ▪ Laparoscopic myolysis ▫ Thermal, radiofrequency, cryoablation



OTHER INTERVENTIONS



▪ Mild cases: expectant management ▫ Annual pelvic exams ▪ Interventional radiology ▫ Uterine artery embolization



Figure 129.8 The histological appearance of a uterine leiomyoma. The tumor is composed of bundles of spindled smooth muscle cells with no atypia.



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NOTES



NOTES



PENILE, PROSTATE, & TESTICULAR DISORDERS



GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders affecting male genitourinary tract



SIGNS & SYMPTOMS ▪ See indiviudal disorders



DIAGNOSIS



LAB RESULTS



▪ Urinalysis, urine culture



TREATMENT ▪ Conservative measures ▫ E.g. decrease fluid intake for benign prostatic hyperplasia ▪ Pharmacological therapy ▪ Surgical therapy



DIAGNOSTIC IMAGING ▪ Ultrasound



BENIGN PROSTATIC HYPERPLASIA osms.it/benign-prostatic-hyperplasia PATHOLOGY & CAUSES ▪ Characterized by nodular prostatic hyperplasia ▪ Not premalignant ▪ Most common prostatic disease in biologically-male individuals > 50 years old



CAUSES



▪ Hyperplasia of prostatic epithelial, stromal cells → formation of nodules in periurethral (transition) zone → narrowing of urethral canal → urine flow constricted ▪ Testosterone, dihydrotestosterone (DHT), estrogens act on stromal, epithelial cells’ androgen receptors → hyperplasia,



inhibition of normal cell death ▪ Dysregulation of stromal growth factors → proliferation, hyperplasia of epithelium ▪ ↑ stem cells



RISK FACTORS



▪ ↑ age ▪ Family history of benign prostatic hyperplasia (BPH) ▪ Heart disease ▪ Beta-blocker use ▪ Obesity ▪ Diabetes ▪ Erectile dysfunction



OSMOSIS.ORG 799



COMPLICATIONS ▪ Chronic bladder outlet obstruction ▫ Bladder hypertrophy → formation of bladder diverticula ▫ Urinary retention → bladder calculi ▫ Residual urine can be infection source → recurrent UTIs ▫ Hydronephrosis → renal failure



SIGNS & SYMPTOMS ▪ Urinary ▫ Frequency ▫ Urgency ▫ Nocturia ▫ Dysuria ▫ Emptying bladder feels incomplete ▫ Difficulty starting, stopping urine flow ▫ Weak stream → small amounts of urine lost



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Evaluate bladder size, prostate size, degree of hydronephrosis Cystoscopy ▪ Reveal bladder diverticula/calculi before scheduled invasive treatment



Figure 130.1 An MRI scan of the abdomen and pelvis in the coronal plane demonstrating massive prostatic hypertrophy. The prostate extends past the pelvic brim and into the abdominal cavity.



LAB RESULTS



▪ Urinalysis ▫ Microscopic hematuria may be present ▫ Pyuria, bacteriuria in case of concomitant UTIs ▪ Urine culture ▫ Exclude UTIs ▪ Blood tests ▫ Often ↑ prostate specific antigen (PSA) ▫ Electrolytes, blood urea nitrogen (BUN), and creatinine to evaluate for renal impairment



OTHER DIAGNOSTICS



▪ Digital rectal examination ▫ Enlarged, nodular prostate



Figure 130.2 The histological appearance of benign prostatic hyperplasia. There is a nodule of hyerplastic stromal tissue surrounded by hyperplastic smooth muscle.



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Chapter 130 Penile, Prostate, & Testicular Disorders



TREATMENT MEDICATIONS ▪ Alpha-adrenergic receptor blockers (terazosin, tamsulosin) → decrease prostate, bladder, urethral muscle tone ▪ 5-alpha reductase inhibitors (finasteride) decrease DHT synthesis → reduce prostate gland size ▪ Phosphodiesterase-5 enzyme inhibitors (e.g., tadalafil) → induce smooth muscle relaxation



SURGERY



▪ Transurethral resection of prostate (TURP) ▪ Open prostatectomy



OTHER INTERVENTIONS



▪ Mild cases ▫ Conservative measures; e.g. decrease fluid intake before bedtime/going out; avoid caffeine, alcohol (mild diuretic effects)



CRYPTORCHIDISM osms.it/cryptorchidism PATHOLOGY & CAUSES ▪ Common congenital condition characterized by incomplete/partial descent of testis into scrotal sac ▪ AKA undescended testes ▪ Most cases resolve spontaneously during first year of life



CAUSES ▪ Testicles normally develop in abdomen, descend into scrotal sac before birth ▫ Malpositioned testis usually found in inguinal canal but can be anywhere in descent pathway ▪ Impaired spermatogenesis at temperatures >37°C/98.6°F ▪ Leydig cells remain unaffected → normal testosterone levels ▪ Usually unilateral; bilateral in ¼ of cases ▪ Associated conditions ▫ Malformations of genitourinary tract (e.g. hypospadias), inguinal hernia



RISK FACTORS



Prematurity ↓ birth weight Twining 1st trimester maternal exposure to estrogens ▪ Family history of undescended testes ▪ Genetic syndromes associated with cryptorchidism (e.g. Down syndrome, Klinefelter syndrome) ▪ Disorders of sexual development (e.g. gonadal dysgenesis, ambiguous genitalia) ▪ ▪ ▪ ▪



COMPLICATIONS



▪ Testicular atrophy, dysfunction → infertility ▪ When malpositioned in inguinal canal → prone to trauma, testicular torsion ▪ Left untreated/treatment delayed → germcell tumors, especially seminoma, high risk; contralateral testis also at risk



OSMOSIS.ORG 801



SIGNS & SYMPTOMS ▪ Asymptomatic ▪ One/both testes absent from scrotal sac ▪ Undescended testis can be palpable in abdomen



LAB RESULTS



▪ ↑ FSH ▪ ↑ LH ▪ Usually normal testosterone; ↓ in bilateral cryptorchidism



OTHER DIAGNOSTICS



▪ Physical examination ▫ Testis absent from scrotal sac



Figure 130.3 An MRI scan of the abdomen and pelvis in the coronal plane demonstrating bilateral undescended testes.



Figure 130.4 A CT scan of the pelvis in the axial plane demonstrating an undescended testicle in the right inguinal canal that has undergone malignant transformation.



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Used to localize testis



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TREATMENT SURGERY



▪ Treatment of choice ▫ Orchiopexy, preferably at 9–15 months ▫ Testis does not spontaneously descend → placed in scrotal sac



Chapter 130 Penile, Prostate, & Testicular Disorders



EPIDIDYMITIS osms.it/epididymitis PATHOLOGY & CAUSES ▪ Inflammation of epididymis ▫ Due to infectious/non-infectious etiologies ▪ AKA epididymo-orchitis when testicle involved



TYPES



Infectious Non-infectious Idiopathic Acute ▫ < six weeks ▪ Chronic ▫ > six weeks



▪ ▪ ▪ ▪



CAUSES Mechanism of disease ▪ Urinary tract infection → vas deferens/ lymphatics of spermatic cord → epididymitis ▪ Hematogenous spread (rarely) Infectious ▪ Children ▫ Gram negative pathogens (e.g. E. coli) ▪ Adults (35 years of age) ▫ Common urinary tract pathogens (e.g. E.coli, P. aeruginosa), tuberculosis Non-infectious ▪ Trauma ▪ Autoimmune diseases ▪ Vasculitis ▪ Medications (e.g. amiodarone) Idiopathic ▪ Cause unknown



RISK FACTORS ▪ ▪ ▪ ▪



Congenital abnormalities of urinary tract ↑ sexual activity Anal intercourse Urinary tract obstruction



COMPLICATIONS ▪ ▪ ▪ ▪ ▪ ▪



Hydrocele Abscess Fistulization Necrosis Chronic epididymitis Infertility



SIGNS & SYMPTOMS ▪ Gradual onset ▫ Scrotal pain usually unilateral; sometimes radiates to lower abdomen with/without swelling ▫ Fever, chills ▫ Lower urinary tract symptoms (e.g. frequency, urgency, dysuria) ▪ Less common ▫ Urethral discharge, hematuria, hematospermia ▪ Normal cremasteric reflex ▫ Cremasteric muscle contraction → ipsilateral elevation of testicle ▪ Prehn sign ▫ Elevating scrotum relieves pain ▪ Reactive hydrocele can be present



DIAGNOSIS DIAGNOSTIC IMAGING Color Doppler ▪ Enlarged, thickened epididymis with increased blood flow; excludes testicular torsion



OSMOSIS.ORG 803



LAB RESULTS ▪ ▪ ▪ ▪ ▪



Leukocytosis Pyuria, bacteriuria Positive urine culture Gram staining of urethral discharge Culture,nucleic acid amplification testing (NAAT) of first-catch urine/urethral swab specimens for C. trachomatis, N. gonorrhoeae



TREATMENT MEDICATIONS Infectious epididymitis ▪ Antimicrobial therapy ▪ Ceftriaxone, doxycycline to cover C. trachomatis, N. gonorrhoeae ▪ Ceftriaxone, quinolone for > 35 years old, individuals that have anal intercourse



SURGERY ▪ Performed when findings are equivocal, testicular torsion cannot be ruled out



OTHER INTERVENTIONS



Figure 130.5 An ultrasound scan of the scrotum demonstrating increased bloodflow in the epididymis, consistent with epididymitis.



Infectious, non-infectious epididymitis ▪ Rest ▪ Analgesia ▫ Hot or cold packs and/or analgesics (e.g. NSAIDs) ▪ Scrotal elevation Non-infectious epididymitis ▪ Treat underlying cause



HYPOSPADIAS & EPISPADIAS osmosis.org/learn/hypospadias osmosis.org/learn/epispadias PATHOLOGY & CAUSES ▪ Congenital malformations characterized by abnormal urethral opening found ventrally (hypospadias), dorsally (epispadias) ▪ Hypospadias more common



TYPES Hyposadias ▪ Glanular: least severe ▪ Midshaft: moderately severe ▪ Penoscrotal: most severe



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Epispadias ▪ Granular: least severe ▪ Penile: moderately severe ▪ Penopubic: most severe



CAUSES Hyposadias ▪ Urethral folds along penile urethra do not close properly → abnormal opening along penile shaft’s ventral surface Epispadias ▪ Genital tubercle grows in posterior direction



Chapter 130 Penile, Prostate, & Testicular Disorders instead of cranial direction → opening along penis’ dorsal surface



RISK FACTORS ▪ Family history of hypospadias/epispadias ▪ Genetic factors causing hormonal disturbances ▪ ↓ androgens ▪ Maternal age > 35 years old ▪ Maternal exposure to environmental toxins (e.g., pesticides on fruits and vegetables)



COMPLICATIONS



▪ Constriction of abnormal opening → urinary tract obstruction ▪ High risk of ascending urinary tract infections ▪ If orifices are situated near base of penis → abnormal ejaculation and insemination → infertility ▪ Psychosocial problems



SIGNS & SYMPTOMS ▪ Depends on location of abnormal urethral opening ▪ Difficulty urinating/incontinence



Figure 130.6 The appearance of subcoronal hypospadias.



DIAGNOSIS DIAGNOSTIC IMAGING Excretory urogram ▪ Series of X-rays used to visualize substances passing through kidneys, bladder, urethra



OTHER DIAGNOSTICS ▪ Clinical examination of newborn infants to reveal abnormal urethral opening



TREATMENT MEDICATIONS ▪ Hormone therapy for additional problems (e.g. low androgen levels → micropenis)



SURGERY ▪ Reconstruction of urethra within first two years of life ▪ Infants with hypospadias should not undergo circumcision → foreskin may be useful for reconstruction



Figure 130.7 A male neonate with epispadias due to non closure of the urethral plate during development. There is also congenital malformation of the external genitalia.



OSMOSIS.ORG 805



ERECTILE DYSFUNCTION osms.it/erectile-dysfunction PATHOLOGY & CAUSES



SIGNS & SYMPTOMS



▪ Sexual arousal disorder characterized by inability to obtain, maintain erection during sexual intercourse ▪ AKA impotence



▪ Inability to achieve erection suitable for penetration ▪ ↓ libido ▪ ↓ erection rigidity ▪ Inability to achieve orgasm and/or ejaculation ▪ Early ejaculation ▪ ↓ peripheral pulses ▪ ↓ sensation ▪ Small testicles ▪ Penile abnormalities (e.g. Peyronie’s disease, hypospadias) ▪ Nocturnal erections present in psychogenic erectile dysfunction (ED), absent in organic ED



CAUSES ▪ Cardiovascular disease/peripheral artery disease → abnormal penile vasculature ▪ Drug side effects ▫ Antihypertensives, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, nicotine, ethanol, betablockers, statins ▪ Psychogenic ▫ Performance anxiety, depression ▪ Neurological problems ▫ Prostatectomy surgery trauma, multiple sclerosis ▪ Penile disorders ▫ Peyronie’s disease, priapism



RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪



↑ age Hypertension Smoking Hyperlipidemia Diabetes Alcohol/drug abuse Hypogonadism (↓ testosterone levels)



COMPLICATIONS ▪ ▪ ▪ ▪



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↓ sexual activity Inability to satisfy sexual partner(s) Psychosocial problems Infertility



DIAGNOSIS DIAGNOSTIC IMAGING Duplex ultrasound ▪ Measures blood flow before and after injection of vasodilators



LAB RESULTS Hormonal blood tests ▪ ↓ serum testosterone → hypogonadism ▪ Luteinizing hormone (LH) ▫ ↑ LH along with ↓ testosterone → testicular deficit ▫ ↓ LH along with ↓ testosterone → CNS deficit ▫ ↓ prolactin → pituitary dysfunction Other blood tests ▪ Detect risk factors for cardiovascular disease (e.g. glucose, lipids)



Chapter 130 Penile, Prostate, & Testicular Disorders



OTHER DIAGNOSTICS



▪ Nocturnal penile tumescence testing to detect nocturnal erections ▪ Intracavernosal injection of prostaglandin E1 ▫ If adequate vasculature → erection in several minutes ▪ Detailed medical, drug history ▪ Physical examination ▪ Psychological testing



release → penile smooth muscles relax → ↑ penile blood flow → erection ▪ Intracavernosal injections of vasodilators agents ▪ Hormonal replacement (e.g. androgens) in individuals with hypogonadism



SURGERY



▪ Revascularization ▪ Implantation of prosthetic devices



PSYCHOTHERAPY



TREATMENT



▪ Reduce performance anxiety



MEDICATIONS



▪ First line ▫ Phosphodiesterase (PDE) type 5 inhibitors (e.g. sildenafil citrate) ▫ 30–60 minutes before sexual intercourse ▫ Mechanism of action: inhibitions PDE5 → ↑ cGMP levels → ↑ nitric oxide



OTHER INTERVENTIONS ▪ External facilitating devices (e.g. vacuum/ constriction devices) help obtain, maintain erection ▪ Treat underlying causes



ORCHITIS osms.it/orchitis PATHOLOGY & CAUSES ▪ Inflammation of testicle secondary to infection ▪ May occur with epididymitis (epididymoorchitis)



CAUSES



SIGNS & SYMPTOMS ▪ Unilateral/bilateral testicular tenderness, pain, scrotal swelling ▪ Fever ▪ Reactive hydrocele ▪ Inguinal lymphadenopathy



▪ Most cases of isolated orchitis seen in children with viral mumps infection ▪ Viral causes may also include coxsackie B virus ▪ May also be caused by bacterial infections ▫ E.g. E. coli



DIAGNOSTIC IMAGING



COMPLICATIONS



LAB RESULTS



▪ Atrophy ▪ Infertility ▪ Reactive hydrocele



DIAGNOSIS Color Doppler ultrasound ▪ Exclude testicular torsion



▪ Serum immunofluorescence antibody testing → establish diagnosis



OSMOSIS.ORG 807



OTHER DIAGNOSTICS ▪ Suggestive clinical findings of mumps/other infections



TREATMENT OTHER INTERVENTIONS ▪ Usually resolves spontaneously after 3–10 days ▪ Conservative measures (e.g. rest, analgesics)



Figure 130.8 The histological appearance of the testicular parenchyma in a case of suppurative orchitis. The seminiferous tubules have been almost completely destroyed and there is a massive neutrophilic infiltrate.



PRIAPISM osms.it/priapism PATHOLOGY & CAUSES ▪ Involuntary, persistent erection unrelated to sexual stimulation, unrelieved by ejaculation ▪ Urologic emergency



TYPES Low flow (ischemic) ▪ Decreased venous outflow; most common High flow (nonischemic) ▪ Increased arterial inflow



CAUSES ▪ Often idiopathic/secondary Low flow ▪ Hypercoagulable state (e.g. sickle cell anemia, thalassemia) ▪ Neurologic disease (e.g. spinal cord stenosis) ▪ Metastatic disease (e.g. prostate cancer, bladder cancer) ▪ Medications relaxing smooth muscles (e.g.



808 OSMOSIS.ORG



prostaglandin, hydralazine) High flow ▪ Penile/perineum trauma → rupture of cavernous artery rupture → fistulas between cavernosal artery, corpus cavernosum



COMPLICATIONS



▪ Hypoxic damage → penile necrosis ▪ Erectile dysfunction ▪ Corporeal fibrosis → loss of penile length



SIGNS & SYMPTOMS ▪ Persistent erection usually lasting 30 minutes to three hours Low flow ▪ Usually painful ▪ Rigid erection ▪ Corporeal aspiration → dark blood



Chapter 130 Penile, Prostate, & Testicular Disorders High flow ▪ Not painful ▪ May be episodic ▪ Trauma evidence



TREATMENT MEDICATIONS Low flow ▪ Intracavernosal injection of sympathomimetic agent ▫ Phenylephrine → pure alpha agonist effects



DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Differentiate low/high flow priapism, reveal fistulas CT scan ▪ Detect malignancies



LAB RESULTS ▪ Penile blood gas measurement ▫ Low flow: increased pCO2, decreased pO2, pH less than 7.0 ▪ Complete blood count (CBC) ▫ Detect sickle cell anemia ▪ Selective angiography ▫ Identify exact location of fistulas



SURGERY Low flow ▪ If other measures fail → surgical decompression High flow ▪ Identification, obliteration of fistulas with selective arterial embolization



OTHER INTERVENTIONS Low flow ▪ Treat underlying condition ▪ Corporal aspiration with/without saline irrigation



PROSTATITIS osms.it/prostatitis PATHOLOGY & CAUSES ▪ Prostate gland inflammation; usually → Gram-negative bacterial infection



TYPES Acute bacterial prostatitis ▪ Usually occurs in younger individuals ▪ More serious condition Chronic bacterial prostatitis ▪ Can be bacterial/abacterial ▪ Usually occurs in individuals aged 40–70 years ▪ Chronic bacterial is the most common form



of prostatitis Granulomatous prostatitis ▪ Infectious ▪ Bladder injections of Bacillus Calmette– Guérin (BCG) for treatment of bladder cancer (most common cause) ▪ Fungi in immunocompromised individuals ▪ Noninfectious ▪ Reaction to secretions from prostatic ducts and acini ▪ Acute granulomatous prostatitis ▫ Older adults: Gram bacteria—E.coli (most common), Klebsiella, Proteus, Pseudomonas, Enterobacter, Serratia ▫ Enterococci



OSMOSIS.ORG 809



▫ Staphylococci ▫ Young adults: Chlamydia trachomatis, Neisseria gonorrhoeae ▪ Chronic granulomatous prostatitis ▫ Infectious: same causes as acute granulomatous prostatitis ▫ Noninfectious: chemical irritation; secondary to previous infections, nerve problems



CAUSES ▪ ▪ ▪ ▪



Ascending urinary tract infection Spread from rectum (direct/via lymphatics) Hematogenous (rare) May follow catheterization, cystoscopy, urethral dilation, prostate resection procedures



COMPLICATIONS



▪ Urinary retention ▪ Recurrent exacerbations in chronic prostatitis are common ▪ Prostatic abscess; usually in immunocompromised individuals ▪ Urosepsis; can be fatal ▪ Pyelonephritis ▪ Infertility



SIGNS & SYMPTOMS Acute ▪ Fever, chills ▪ Malaise ▪ Urinary symptoms ▫ Frequency, urgency, dysuria ▪ Perineal/low back pain ▪ Digital rectal exam ▫ Boggy, warm, tender, enlarged prostate Chronic ▪ Can be asymptomatic ▪ Intermittent urinary symptoms ▪ History of recurrent UTIs ▪ Perineal/low back pain; suprapubic discomfort ▪ Digital rectal examination ▫ Enlarged, nontender prostate



DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan/cystoscopy ▪ For individuals with significant voiding dysfunction/suspected abscesses/ neoplasms



LAB RESULTS



Figure 130.9 The histological appearance of acute prostatitis. There are neutrophils present within the lumina of the prostatic glands.



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▪ Urinalysis ▫ ↑ WBCs in acute ▪ Prostatic secretion ▫ ↑ WBCs in acute and chronic ▪ Urine cultures ▫ Positive in acute, chronic bacterial prostatitis ▫ Negative in chronic abacterial ▪ Blood tests ▫ CBC, blood cultures if clinical findings suggestive of bacteremia ▫ Blood urea nitrogen, creatinine levels for individuals with urinary retention/ obstruction ▫ Serum prostate-specific antigen (PSA) may be elevated



Chapter 130 Penile, Prostate, & Testicular Disorders



TREATMENT MEDICATIONS Acute ▪ Antimicrobial therapy ▫ IV broad-spectrum penicillin, third generation cephalosporin, aminoglycoside, quinolone ▫ PO antibiotics (TMP/SMX or quinolone, doxycycline) ▪ Urinary retention ▫ Alpha-blocking agents/suprapubic catheterization



OTHER INTERVENTIONS Acute ▪ Increase fluid intake ▪ Drain abscesses ▪ Prostatic massage should be avoided to prevent hematogenous spread (sepsis)



Chronic ▪ Antimicrobial therapy ▫ Prolonged course, usually with quinolone ▪ Chronic prostatitis difficult to treat because antibiotics penetrate prostate gland poorly → recurrences common



Figure 130.10 An MRI scan of the pelvis in the coronal plane demonstrating a large prostatic abscess secondary to prostatitis.



TESTICULAR TORSION osms.it/testicular-torsion PATHOLOGY & CAUSES ▪ Vascular disorder of testis characterized by rotation of testicle around spermatic cord ▪ Can lead to testicular infarction ▪ Urologic emergency ▪ Rotation of testicle → thick walled arteries remain patent while thin walled veins become obstructed → congestion → hemorrhagic infarction



RISK FACTORS



▪ Typically occurs in young adolescents; can also occur in neonates/older individuals



▪ Usually → testes’ congenital failure to strongly attach to scrotum ▪ Occasionally → trauma; also → during sleep



COMPLICATIONS ▪ If left untreated/surgery delayed beyond six hours → testicle may not be salvageable → infertility ▪ Recurrent torsions ▪ Contralateral testicle also → torsion risk ▪ Infection ▪ Orchiectomy → cosmetic malformation → psychosocial problems



OSMOSIS.ORG 811



SIGNS & SYMPTOMS ▪ Sudden onset of acute, severe pain ▪ Swollen, tender, erythematous scrotum ▪ High riding testis ▫ Moves to a higher scrotal position ▪ Absent cremasteric reflex ▪ Nontender cord



DIAGNOSIS



TREATMENT SURGERY



▪ Immediate surgical detorsion → best within six hours from onset of symptoms ▪ Orchiopexy of testis to scrotum → prevent recurrence ▫ Orchiopexy of contralateral testis also indicated ▪ If testicle non-salvageable → orchiectomy



DIAGNOSTIC IMAGING ▪ Unnecessary if clinical findings are strongly suggestive; surgical detorsion should not be delayed Color Doppler ultrasound ▪ Absent or decreased blood flow in affected testicle Contrast enhanced MRI ▪ Torsion knot or whirlpool patterns; highly sensitive and specific



LAB RESULTS



▪ Can help exclude alternate diagnosis (e.g. orchiepididymitis)



Figure 130.11 A Doppler ultrasound of the testicles demonstrating complete absence of blood flow on the right side, consistent with testicular torsion.



VARICOCELE osms.it/varicocele PATHOLOGY & CAUSES ▪ Common testicular disorder of young adults characterized by dilatation of pampiniform venous plexus, internal spermatic vein ▪ Most common cause of scrotal enlargement in young adults ▪ Impaired venous drainage → ↑ venous pressure → vein dilatation



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▪ Usually left-sided (> 80%) due to ↑ flow resistance from left testicular vein drainage into left renal vein; right testicular vein drains directly to inferior vena cava (↓ flow resistance)



TYPES Large ▪ Easily identified by inspection as distention



Chapter 130 Penile, Prostate, & Testicular Disorders Moderate ▪ Identified by palpation as “bag of worms” Small ▪ Identified only by bearing down → ↑ abdominal pressure → impeding drainage → ↑ varicocele size



TREATMENT SURGERY



▪ Indicated if varicocele associated with discomfort/pain, testicular atrophy, infertility ▪ Surgical ligation/embolization



CAUSES



▪ Idiopathic ▪ Retroperitoneal pathology (e.g. renal cell carcinoma) → can invade renal vein → leftsided varicocele



COMPLICATIONS ▪ Significant impairments in sperm production, quality due to ↑ heat, ↑ pressure, ↓ oxygen, release of toxins ▫ ↓ sperm concentration ▫ ↓ motility ▫ Abnormal morphology of spermatozoa ▪ Testicular damage, atrophy, poor sperm production, quality → infertility ▪ Contralateral testicle can also be affected



Figure 130.12 A Doppler ultrasound of the scrotum demonstrating avid flow within the spermatic cord; an appearance typical of a varicocele.



SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Symptomatic ▫ Scrotal heaviness or scrotal pain



DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Characteristic reverse blood flow Ultrasound/ CT scan ▪ May be useful in right-sided varicocele → reveals retroperitoneal pathology



LAB RESULTS



Figure 130.13 The clinical appearance of a varicocele of the right scrotum. There are dilated veins visible on the scrotal surface.



▪ Semen analysis ▫ Impairment in semen parameters (e.g. concentration, motility, morphology)



OSMOSIS.ORG 813



NOTES



NOTES



PERINATAL INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Infections during pregnancy, birth ▫ Teratogenic/other adverse effects on fetus, neonate ▫ Congenital infections cross placenta, infect fetus in utero ▫ Neonatal infections shortly before, during, after delivery



RISK FACTORS



▪ Maternal infection



COMPLICATIONS



▪ Premature birth; intrauterine growth restriction; tissue damage, related sequelae



SIGNS & SYMPTOMS ▪ Self-limiting to life-threatening conditions



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DIAGNOSIS ▪ Maternal prenatal, delivery history; neonatal physical examination ▪ Imaging



LAB RESULTS



▪ Culture, serology testing



TREATMENT ▪ Address complications



MEDICATIONS ▪ Antimicrobials



Chapter 131 Perinatal Infections



CONGENITAL CYTOMEGALOVIRUS INFECTION osms.it/congenital-CMV-infection PATHOLOGY & CAUSES ▪ Clinical syndrome affects developing fetus, neonate ▫ Caused by Cytomegalovirus (CMV) perinatal infection ▫ Herpesvirus family ▪ Enveloped, double-stranded linear DNA, icosahedral viral capsid ▫ Toxoplasmosis, other (syphilis, Varicella zoster, parvovirus B19), rubella, CMV, herpes (TORCH) infection ▫ Tends to become latent, reactivate ▪ Highly-prevalent virus; not very contagious ▫ Infects all ages ▫ Approx. one-third of children are infected with CMV by age five ▫ > half of adults are infected by age 40 ▪ Virus spreads to fetus transplacentally/may be acquired via maternal genital contact during delivery/through breastmilk Maternal infection ▪ Direct infectious body-fluid contact (e.g. saliva, urine, sexually transmitted); blood transfusions; transplanted organs; household contact, close contact with young infected children (e.g. daycare centers) ▫ Usually asymptomatic in adults



RISK FACTORS



▪ Maternal infection



COMPLICATIONS



▪ Fetal/neonatal ▫ Sensorineural hearing loss (SNHL), chorioretinitis, microcephaly, neurodevelopmental disability, seizure, anemia (hemolytic), pneumonitis, dental irregularity



Figure 131.1 Histological sections of chorionic villi demonstrating nuclear inclusions seen in congenital cytomegalovirus infection.



SIGNS & SYMPTOMS ▪ Birth ▫ May be asymptomatic ▪ Small for gestational age, petechial rash, “Blueberry muffin” rash, hypotonia, weak suck, hepatosplenomegaly, jaundice



DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Neuroimaging ▫ Intracranial calcification, ventriculomegaly, white matter disease, periventricular leukomalacia, corpus callosum dysgenesis, cerebellar hypoplasia Auditory brainstem response (ABR) ▪ Hearing deficit



OSMOSIS.ORG 815



Ultrasound ▪ Suggestive prenatal fetal diagnostic findings ▫ Growth restriction, ventriculomegaly, microcephaly, periventricular calcification, hepatic calcification, hydrops/ascites, echogenic bowel



LAB RESULTS



TREATMENT ▪ Address complications



MEDICATIONS



▪ Antiviral therapy ▫ Intravenous (IV) ganciclovir/oral (PO) valganciclovir



▪ Maternal prenatal, delivery history; positive maternal CMV immunoglobulin G (IgG), CMV immunoglobulin M (IgM) antibody; neonatal examination



Microbe identification ▪ Positive culture (urine, saliva) ▪ Polymerase chain reaction (PCR) (blood, urine, saliva) ▪ CMV antigens (pp65) in peripheral leukocytes Blood studies ▪ ↑ liver transaminases ▪ ↑ direct, indirect serum bilirubin ▪ ↓ white blood cells (WBCs), ↓ platelets, ↓ red blood cells (RBCs)



Figure 131.2 Retinal photograph demonstrating the necrotizing retinitis of CMV infection. The retinitis will typically spread in a “brush fire” pattern.



CONGENITAL RUBELLA SYNDROME osms.it/congenital-rubella-syndrome PATHOLOGY & CAUSES ▪ Syndrome caused by fetal rubella virus infection ▫ Enveloped, positive-sense, singlestranded RNA virus ▫ Rubivirus in Togaviridae family ▫ Humans are only natural hosts Maternal infection ▪ Occurs through droplet inhalation/ direct infectious nasopharyngeal secretion contact → maternal viremia → hematogenous transplacental spread to fetus → persistent fetal infection



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throughout gestation → virus-induced impaired cellular division, direct cytopathic effects ▪ Maternal–fetal transmission, congenital defect risk varies in accordance with maternal infection timing ▫ ↑ ↑ risk: inoculation occurs during first ten gestational weeks ▫ ↑ risk: cardiac, eye defects if inoculation occurs before eight gestational weeks ▫ ↑ risk: hearing deficits if inoculation occurs up to 18 gestational weeks ▫ ↓ risk: inoculation occurs after 18–20 gestational weeks



Chapter 131 Perinatal Infections



RISK FACTORS



▪ Maternal non-immunized status, infection



COMPLICATIONS



▪ Fetal growth restriction ▪ Hemolytic anemia, thrombocytopenia



Neurological, sensory defects ▪ Sensorineural hearing loss ▪ Cataracts, congenital glaucoma, pigmentary retinopathy, microphthalmia ▪ Microcephaly, meningoencephalitis, intellectual disability Congenital heart defects ▪ Patent ductus arteriosus ▪ Pulmonary artery stenosis ▪ Coarctation of aorta Vascular defects ▪ Intimal fibromuscular proliferation, arterial sclerosis, systemi345c hypertension (related to renal disease) ▪ May result in adult coronary, cerebral, peripheral vascular disease Late complications ▪ Diabetes, thyroid disease, growth hormone deficiency, progressive rubella panencephalitis



SIGNS & SYMPTOMS ▪ “Blueberry muffin” rash ▫ Purpuric rash indicates cutaneous hematopoiesis ▪ Small for gestational age; low birth weight ▪ Hepatosplenomegaly ▪ Jaundice ▪ Complications present (e.g. cataracts, heart defects)



DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Head ▫ Periventricular calcifications; demyelination ▪ Long bones ▫ Radiolucent bone lesions; irregular, alternating longitudinal light, dark bands of density (“celery stalk” appearance)



LAB RESULTS Viral identification ▪ Nasopharyngeal swabs, blood/cord blood, placenta, urine, cerebrospinal fluid (CSF) ▫ PCR/culture: rubella-specific IgM (usually present at birth); persistent IgG Prenatal diagnosis ▪ Viral isolation from amniotic fluid



OTHER DIAGNOSTICS Maternal prenatal history ▪ Rubella exposure ▪ Neonatal exam Figure 131.3 Bilateral cataracts in a newborn baby as a consequence of congenital rubella infection.



TREATMENT ▪ No specific treatment ▪ Address complications Prevention ▪ Maternal MMR vaccination before conception



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CONGENITAL SYPHILIS osms.it/congenital-syphilis PATHOLOGY & CAUSES ▪ Congenital infection caused by Treponema pallidum (spirochete bacterium causes syphilis) Maternal infection ▪ Sexually ▫ Direct infectious lesion contact → enters via microscopic abrasions → crosses placenta easily → fetal spirochetemia → widespread dissemination (almost all fetal organs) → congenital syphilis



RISK FACTORS



▪ Maternal infection → vertical (transplacental) → fetal transmission



COMPLICATIONS ▪ ▪ ▪ ▪



▪ ▪



▪



▪



▪



Stillbirth Premature birth Nonimmune hydrops Neurological ▫ Sensorineural hearing loss, intellectual disability, seizures Hematologic ▫ Hemolytic anemia, thrombocytopenia Renal ▫ Nephrotic syndrome (immune complex mediated) Ophthalmologic ▫ Chorioretinitis, uveitis, cataract, glaucoma, optic atrophy Gastrointestinal ▫ Necrotizing enterocolitis, ileus, malabsorption Skeletal ▫ Long-bone abnormalities, pathologic fractures



Treatment-related complications ▪ Benzathine penicillin G ▫ Jarisch–Herxheimer reaction: release



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of endotoxin-like compounds during penicillin-mediated lysis of T. pallidum → fever/chills, hypotension



SIGNS & SYMPTOMS Early congenital syphilis ▪ General ▫ Low birthweight, fever, hepatomegaly, jaundice, lymphadenopathy, painrelated ↓ extremity movement (pseudoparalysis) ▪ Mucocutaneous ▫ Vesicular (pemphigus syphiliticus)/ maculopapular rash ▫ Contagious, wart-like lesions (condylomata lata) ▫ Syphilitic rhinitis (“snuffles”) ▪ Umbilical cord ▫ Necrotizing funisitis (“barber-pole” appearance) Late congenital syphilis ▪ Onset after two years old ▪ Facial features ▫ Frontal bossing, saddle nose, short maxilla, protuberant mandible ▪ Sensory ▫ Impaired vision/hearing ▪ Oropharynx ▫ Hutchinson teeth (widely-spaced; notched incisors); mulberry molars (small, defective molars; cusps covered with globular enamel growths) ▪ Cutaneous ▫ Gummas ▪ Skeletal ▫ Anterior tibia bowing (saber shins), Higouménakis’ sign (sternoclavicular portion of clavicle enlargement), painless arthritis (Clutton’s joints), scaphoid scapula



Chapter 131 Perinatal Infections



LAB RESULTS



▪ T. pallidum identification ▫ Dark field microscopy ▫ Direct fluorescent antibody (DFA) staining (nasal secretions, placenta, umbilical cord, autopsy tissue) ▫ Reactive venereal disease research laboratory (VDRL), rapid plasma reagin (RPR) ▪ Blood studies ▫ ↓ platelets, ↑ ↓ WBCs ▪ CSF analysis ▫ Reactive VDRL, pleocytosis, ↑ protein, T. pallidum DNA presence (identified by PCR)



TREATMENT Figure 131.4 A newborn baby with a saddle nose malformation and snuffles, both of which are signs of congenital syphilis infection.



DIAGNOSIS DIAGNOSTIC IMAGING Long-bone radiographs ▪ Multiple anomalies ▫ E.g. metaphyseal lucent bands, metaphyseal “sawtooth” serration (Wegener sign), “moth-eaten” appearance



MEDICATIONS



▪ Intramuscular (IM) benzathine penicillin G



Prevention ▪ Screening at first prenatal visit ▫ IM benzathine penicillin G



OTHER INTERVENTIONS Prevention ▪ Characteristic fetal congenital infection features detectable via ultrasound ▫ 18–22 weeks of gestation



Chest X-ray ▫ Diffuse infiltrate/opacification of both lung fields (“pneumonia alba”)



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GROUP B STREPTOCOCCUS (GBS) INFECTION osms.it/group-b-strep-infection PATHOLOGY & CAUSES ▪ Serious neonatal infection caused by Streptococcus agalactiae ▫ Gram-positive, encapsulated diplococcus ▫ Commonly colonizes maternal gastrointestinal, genital tracts ▫ Produces complete (beta hemolysis) on blood agar plates ▪ Acquired via intra-amniotic infection, ascending infection after amniotic membrane rupture/during birth canal passage Classification ▪ GBS onset timing ▫ Early-onset GBS: presents between 24 hours to six days post-delivery (most common) ▫ Late-onset GBS: 4–5 weeks postdelivery ▫ Late, late-onset GBS: presents in infants > three months (most common in infants with immunodeficiency history/born < 28 gestational weeks)



RISK FACTORS



▪ Biologically-female individuals of African descent



COMPLICATIONS



Bacteremia Sepsis; septic shock Pulmonary hypertension (PPHN) Focal infections ▫ Meningitis, pneumonia, endocarditis septic arthritis, osteomyelitis, cellulitis, adenitis ▪ ↑ preterm infant mortality



▪ ▪ ▪ ▪



SIGNS & SYMPTOMS ▪ Lethargy/irritability; poor feeding ▪ Temperature instability ▪ Respiratory symptoms ▫ E.g. tachypnea, grunting, retractions, apnea, hypoxemia/↓ oxygen saturation ▪ Hypotension ▪ Bulging fontanel, nuchal rigidity (GBS meningitis) ▪ ↓ extremity movement/pain with manipulation GBS bone/joint infection



DIAGNOSIS



▪ GBS-positive intrapartum nucleic acid amplification test (NAAT) ▪ Chorioamnionitis ▪ Preterm labor ▪ Premature membrane rupture ≥ 18 hours



DIAGNOSTIC IMAGING



Maternal presentation ▪ Delivery time ▫ Intrapartum fever ≥ 38°C/100.4°F ▫ Delivery < 37+0 gestational weeks ▫ GBS bacteriuria in current pregnancy



LAB RESULTS



Demographic risk factors ▪ Young maternal age



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Chest X-ray ▪ Diffuse alveolar infiltrates, pleural effusion indicate GBS pneumonia



Neonatal blood studies ▪ ↑ ↓ absolute neutrophil count ▪ ↓ platelet count ▪ Positive blood culture



Chapter 131 Perinatal Infections ▪ ↑ C-reactive protein (CRP) Neonatal CSF analysis ▪ ↑ protein level, WBC count ▪ ↓ glucose level ▪ Positive Gram stain, culture results Urinalysis ▪ Gram stain, culture ▫ Presence of nitrates, leukocyte esterase, bacteria



TREATMENT MEDICATIONS



▪ Antibiotics ▫ Penicillin G, ampicillin, nafcillin



Prevention ▪ Vaginal-rectal culture: 35–37 gestational weeks ▫ If positive culture →intrapartum antibiotic prophylaxis ▫ Penicillin, ampicillin, cefazolin



Figure 131.5 Algorithm for GBS screening and prophylaxis.



OSMOSIS.ORG 821



Figure 131.6 Group B streptococcus colonies cultured on blood agar.



NEONATAL CONJUNCTIVITIS osms.it/neonatal-conjunctivitis PATHOLOGY & CAUSES ▪ Clinical infection manifestation occurs within first four weeks of life, AKA ophthalmia neonatorum ▫ Most commonly caused by Neisseria gonorrhoeae/Chlamydia trachomatis (coinfection with both microbes common) ▫ Rarely, herpetic conjunctivitis caused by herpes simplex virus (HSV) ▫ Staphylococcus, Streptococcus may also be implicated in some conjunctival infections



COMPLICATIONS ▪ ▪ ▪ ▪



Corneal ulceration, scarring Vision impairment, blindness Systemic sequelae of infection HSV: keratitis, keratouveitis



SIGNS & SYMPTOMS ▪ Eyelid swelling, watery/mucopurulent discharge, chemosis, micropannus (granulation tissue membrane)



Transmission ▪ Primarily via exposure to mother’s infected genital flora during vaginal birth ▪ Ascending infection in case of premature membrane rupture



RISK FACTORS



▪ Maternal infection Figure 131.7 The clinical appearance of severe neonatal conjunctivitis.



822 OSMOSIS.ORG



Chapter 131 Perinatal Infections



DIAGNOSIS LAB RESUTS Microbe identification ▪ Conjunctival, nasopharyngeal specimens ▫ Culture ▫ Gram stain ▫ Nucleic acid amplification test (NAAT) ▫ Polymerase chain reaction (PCR) ▫ Direct fluorescent antibody (DFA), enzyme immunoassay (EIA) tests ▫ HSV: Giemsa stain, PCR CBC ▪ ↑ eosinophil count



TREATMENT ▪ Antibiotics ▫ Gonococcal disease: IV/IM ceftriaxone ▫ Chlamydial disease: oral erythromycin, azithromycin ▫ HSV: acyclovir Prevention ▪ Gonococcal conjunctivitis ▫ Routine neonatal prophylaxis with erythromycin 0.5% ointment



OTHER INTERVENTIONS



▪ Treat neonate’s mother, sexual partner ▪ Maternal prenatal screening



OTHER DIAGNOSTICS



▪ Maternal history ▪ No prenatal care; untreated C. trachomatis/N. gonorrhoeae infection; neonatal examination



NEONATAL HERPES SIMPLEX osms.it/neonatal-herpes-simplex PATHOLOGY & CAUSES ▪ Uncommon, serious neonatal infection caused by herpes simplex virus (HSV-1, HSV-2) ▪ Enveloped, double-stranded DNA virus ▫ HSV-2: most neonatal cases ▫ TORCH infection Transmission ▪ Intrauterine/transplacentally is rare ▪ Intrapartum: ascending infection from maternal genitals during delivery/mother’s infected genital flora exposure ▫ Most maternal HSV infections are clinically inapparent ▪ Postnatal via close contact



Inoculation ▪ 2–21 day incubation ▪ Skin, eyes, mouth (SEM) disease ▪ Central nervous system (CNS) disease ▪ Disseminated disease ▫ Multiple organs (e.g. lungs, liver, adrenal, CNS, skin, eye, mouth)



RISK FACTORS Maternal infection ▪ ↑ transmission risk with vaginal delivery, prolonged membrane rupture, delivery instruments that disrupt fetal skin barrier



COMPLICATIONS



▪ Recurring skin lesions throughout childhood



OSMOSIS.ORG 823



▪ CNS HSV ▫ Meningoencephalitis ▪ Disseminated HSV ▫ Hepatitis, disseminated intravascular coagulation (DIC), hemorrhagic pneumonitis ▫ High mortality



SIGNS & SYMPTOMS ▪ May be asymptomatic initially ▪ SEM ▫ Mucosal vesiculopustular eruption ▪ CNS HSV ▫ Temperature instability, irritability/ lethargy, bulging fontanelle, seizure ▪ Disseminated HSV ▫ Temperature instability, lethargy, poor feeding, jaundice, hepatosplenomegaly, respiratory distress



DIAGNOSIS LAB RESULTS ▪ Microbe identification ▫ Culture (blood, CSF, urine, mucous membrane fluid) ▫ PCR ▪ CNS analysis ▫ CSF ↑ protein, ↑mononuclear pleocytosis ▪ Lesion analysis ▫ Multinucleated giant cells visualized with Giemsa/Wright stain



TREATMENT MEDICATIONS ▪ IV acyclovir



OTHER INTERVENTIONS



▪ Also treat mother, mother’s partner



Figure 131.8 A neonate with herpes simplex vesicles on the scalp.



824 OSMOSIS.ORG



Chapter 131 Perinatal Infections



NEONATAL MENINGITIS osms.it/neonatal-meningitis PATHOLOGY & CAUSES ▪ Severe neurological infection complication ▫ High morbidity, mortality rate ▫ Most often occurs during first week of life ▫ Bacterial, viral, fungal infections ▪ Usually caused by variety of bacteria (e.g. GBS, E. coli, S. pneumoniae, Enterococcus, coagulase-negative staphylococci, S. aureus, L. monocytogenes, H. influenzae)



RISK FACTORS



▪ Premature birth, low birthweight, maternal infection, sepsis



COMPLICATIONS



▪ Cerebral edema/abscess, hydrocephalus, intraventricular hemorrhage, encephalomalacia, cerebral palsy, seizure disorder, auditory/visual sensory deficits



ventriculitis, extracerebral fluid collections MRI/CT scan ▪ Detects cerebral edema, infarction/abscess area, CSF obstruction, encephalomalacia, atrophic tissue (cortical, white matter)



LAB RESULTS ▪ Microbe identification ▫ CSF ▫ Gram stain, culture, PCR, NAAT ▫ Blood culture (may be negative) ▫ Urine culture ▪ Blood studies ▫ ↑↓ WBC count, left shift, ↓ platelets ▪ CSF ▫ ↑ WBCs, ↑ protein, ↓ glucose



SIGNS & SYMPTOMS General ▪ Temperature instability, lethargy, poor feeding, vomiting, diarrhea Neurological ▪ Irritability, hypotonia, tremors, seizures, full/ bulging fontanelle; may have nuchal rigidity Respiratory ▪ Tachypnea, retractions nasal flaring, grunting, apnea



DIAGNOSIS



Figure 131.9 A sample of cerebrospinal fluid from a neonate with meningitis. There are neutrophils present, denoting an acute inflammatory process as well as cocci arranged in groups and pairs. Culture grew Staphylococcus capitis.



DIAGNOSTIC IMAGING Cranial sonography ▪ Assess ventricular size ▫ Detect ventricular hemorrhage,



OSMOSIS.ORG 825



TREATMENT MEDICATIONS



▪ Antimicrobials ▫ usually ampicillin + gentamicin + thirdgeneration cephalosporin ▪ Anticonvulsants ▪ IV fluids, vasopressors



NEONATAL SEPSIS osms.it/neonatal-sepsis PATHOLOGY & CAUSES ▪ Serious infection; presents within neonate’s first 30 days; characterized by bacteremia/ meningitis ▪ Characterized by onset ▫ Early-onset sepsis: occurs with first 3–7 days ▫ Late-onset sepsis: occurs between 7–30 days ▪ May be bacterial (most common), viral, fungal (more common in preterm infants) → vertical transmission before/during labor/ delivery



RISK FACTORS



Low birthweight Preterm birth Low Apgar score at five minutes Prolonged membrane rupture Chorioamnionitis Maternal GBS colonization (inadequate intrapartum treatment) ▪ Inborn metabolism errors ▪ Maternal age ≤ 20 ▪ ▪ ▪ ▪ ▪ ▪



COMPLICATIONS



▪ Meningitis, pneumonia, multi-organ failure, necrotizing enterocolitis (NEC), high mortality rate



826 OSMOSIS.ORG



SIGNS & SYMPTOMS ▪ May be initially nonspecific ▪ Fever, temperature instability General signs ▪ Lethargy, irritability, poor suck, hypotonia Respiratory distress signs ▪ Tachypnea, grunting, nasal flaring, retractions, apneic periods, cyanosis Hemodynamic instability ▪ Tachycardia/bradycardia, prolonged capillary refill time, hypotension, pallor



DIAGNOSIS ▪ Maternal, intrapartum, neonatal history ▪ Compatible clinical presentation



LAB RESULTS



▪ Blood, CSF culture ▫ Identify causative microbe ▪ CBC ▫ Neutropenia (due to small neutrophil storage pool) ▪ CSF analysis ▫ ↑ WBCs; protein, glucose may also be ↑



Chapter 131 Perinatal Infections



TREATMENT MEDICATIONS ▪ Antibiotics ▪ Vasopressors



OTHER INTERVENTIONS



▪ Supplemental oxygen, mechanical ventilation ▪ IV fluids



TOXOPLASMOSIS osms.it/toxoplasmosis PATHOLOGY & CAUSES ▪ Congenital infection ▫ Caused by protozoa Toxoplasma gondii ▫ TORCH infection ▪ Obligate intracellular parasite ▪ Transplacental transmission to fetus Biphasic life cycle ▪ Sexual cycle ▫ Occurs exclusively in felines (definitive host) ▪ Asexual cycle ▫ Occurs in other animals, including humans Maternal infection routes ▪ Cats consume infective form (cysts) from prey (e.g. intermediate hosts—rodents, birds) → replication within intestines → oocyst formation → fecal excretion → maternal infection via cat fecal exposure (soil, litter box) ▪ Wild game/animals bred for human consumption (e.g. cattle) may ingest environmental oocytes → infection → maternal consumption of raw/undercooked meat, contaminated water/vegetables → maternal infection



RISK FACTORS



▪ Maternal infection ▫ Primary infection during pregnancy/ reactivation in immunocompromised host



COMPLICATIONS



▪ ↑ congenital effect severity when infection occurs early in gestation ▫ Classic triad: chorioretinitis, hydrocephalus, intracranial calcification ▫ Sensorineural hearing loss, microcephaly, intellectual disability, motor/cerebellar dysfunction, growth delay, seizure, pneumonitis, anemia, thrombocytopenia



SIGNS & SYMPTOMS Subclinical infection ▪ Routine assessment reveals no anomalies ▪ Focused examination may reveal infection signs (e.g. ophthalmologic, CNS imaging) Clinically apparent disease ▪ During neonatal period/first few months of life ▫ May be mild/severe, CNS/ocular complications, purpuric rash (“blueberry muffin” rash), fever, jaundice, hepatosplenomegaly, lymphadenopathy, microphthalmia, hypotonia Late infancy, childhood, adolescence ▪ Undiagnosed/untreated infection emergence/relapse ▫ Complication developments (e.g. chorioretinitis, neurosensory hearing loss) ▫ Growth delay, endocrine abnormalities secondary to hypothalamic, pituitary dysfunction



OSMOSIS.ORG 827



DIAGNOSIS DIAGNOSTIC IMAGING ABR ▪ Sensorineural hearing loss CT scan ▪ Neuroimaging ▫ Intracranial calcifications, hydrocephalus (ventriculomegaly), cortical atrophy



LAB RESULTS Confirmatory diagnostics ▪ With any of following ▫ Positive IgG with positive IgM (after five days of life), IgA (after ten days of life) + confirmed maternal serology ▫ Positive CSF PCR + confirmed maternal T. gondii infection during pregnancy, characteristic neonatal clinical findings ▫ Positive IgG beyond 12 months of age demonstrates anti-Toxoplasma IgG persistence Ophthalmic examination ▪ Chorioretinitis Neurologic examination ▪ Lumbar puncture ▫ ↑ protein, mononuclear pleocytosis Blood studies ▪ CBC ▫ ↓ RBCs ↓ platelets, ↑ eosinophils ▪ Liver function tests ▫ Possible ↑ aspartate aminotransferase; alanine aminotransferase; total, direct bilirubin Cytologic placental examination ▪ T. gondii cyst/tachyzoite presence



828 OSMOSIS.ORG



Figure 131.10 Retinal photograph demonstrating the characteristic “headlight in the fog” appearance of toxoplasma retinitis.



TREATMENT MEDICATIONS Neonatal treatment ▪ Antiparasitic therapy ▫ Pyrimethamine + sulfadiazine + folinic acid ▪ Prednisone if ↑ CSF protein Prevention ▪ Maternal antiparasitic therapy ▫ Positive amniotic fluid PCR before 18 gestational weeks ▪ Pyrimethamine + sulfadiazine plus folinic acid until delivery



PATHOLOGY VOLUME 1 INDEX 22q11.2 deletion syndrome, 45 abdominal aorta, 15, 109, 142–143 abdominal aortic aneurysm, 15–16, 18, 816 abdominal cavity, 16, 317, 322, 325, 346, 352–353 abdominal guarding, 236, 264 abdominal mesenchymal desmoid tumors, 209 abduction, 503, 674 ablate, 22, 24, 37, 111–112, 115, 118, 121, 131, 133, 135–136, 138, 140, 184, 193, 218, 249, 609, 617, 660, 773 abruptio placentae, 390 abscess, 22, 86, 260, 263–265, 301, 338–339, 343, 347–348, 356, 500–502, 507–508, 514, 576, 579, 583, 592, 594, 681, 684, 819, 855, 950–951, 953–954 absence seizure, 577–580 abusive head trauma, 614 acalculous cholecystitis, 198, 200 acamprosate, 749 acanthamoeba, 590, 597, 602 accessory nerve, 675 ace, 3, 35, 57, 60–61, 79, 82, 495, 499, 764, 766, 783–784, 788, 791, 800, 825, 835–837, 842, 864, 914, 941 ace inhibitors, 3, 60–61, 82, 495, 764, 788, 791, 836–837, 842, 914 acetaminophen, 581, 624, 643, 676, 678, 685, 955 acetylcholine, 556, 612, 661–664, 862 achalasia, 215–217, 244 achalasia cardiae, 215 achlorhydria, 231–232 acidosis, 51, 122, 125, 129, 276, 278, 280, 352, 583, 643, 764, 796, 800, 813, 823–824, 865, 868, 893, 900–901, 903 acne, 164 acoustic nerve, 626–627 acoustic nerve neuritis, 626 acoustic neuroma, 554, 626 acquired methemoglobinemia, 413 acrocyanosis, 426 acromegaly, 667 acuity, visual, 600, 605 acupuncture, 621 acute abdomen, 220, 236, 352 acute bacterial endocarditis, 86 acute cholecystitis, 197–198 acute coronary syndromes, 1, 3, 5 acute disseminated, 537–538 acute fulminant episodes, 638 acute gastritis, 231 acute hepatitis, 124 acute intermittent porphyria, 447–448 acute kidney injury, 762, 764, 786, 816 acute leukemia, 377, 412 acute lymphoblastic leukemia, 395, 453 acute lymphoid leukemia, 394–396 acute monocytic leukemia, 396 acute motor axonal neuropathy, 678 acute myelogenous leukemia, 373 acute myeloid leukemia, 394–397 acute myocardial infarction, 490, 499 acute otitis media, 568–569, 954 acute pericarditis, 98–100, 102–104 acute proliferative, 826



2



OSMOSIS.ORG



acute promyelocytic leukemia, 389, 396 acute renal failure, 97, 347, 830, 832 acute respiratory distress, 347, 867 acute respiratory distress syndrome, 347, 867 acute rheumatic fever, 92–94, 954 acute sensorimotor axonal neuropathy, 678 acute tubular injury, 816 acute tubular necrosis, 767–768, 816, 865 acyanotic defects, 6–7, 9, 11, 13 acyclovir, 506, 512 add, 412, 817 addisonian crisis, 501, 795 adenine, 413, 954 adenitis, 952–953 adenocarcinoma, 212, 217–218, 222, 232, 238, 240, 242–244, 246, 252–253, 389, 776–778, 923, 926, 928–930 adenoid, 944 adenoma, 207–209, 307–308, 684 adenomatous polyps, 207, 209–211 adenosine deaminase, 370 adenosine triphosphate, 487, 618 adenoviral conjunctivitis, 589 adenovirus, 568, 589, 879, 891, 948, 953 adh, 808, 810, 931 adhd, 651, 711, 849 adjuvant chemotherapy, 467 adrenal crisis, 123 adrenal gland, 248, 302 adrenaline, 494 adt-kd-ren, 785 adtkd, 785–786 adtkd due to ren mutations, 785 adult inclusion conjunctivitis, 588–589 adult pkd, 790 adult primary brain tumors, 464–465, 467, 469, 471 adult t cell lymphoma, 407 afap, 209 affective disorder, 704 afp, 247–248 afterload, 41, 55, 58, 60, 66, 824, 913–914 age-related macular degeneration, 598–600 agenesis, 517–518, 521, 792–793, 837, 876 agent orange, 398, 439 ageusia, 552–553 agnosia, 549, 562, 687 agoraphobia, 690 aha, 55, 425 aid, 89–90,142, 160–161, 339, 341, 361, 566, 624, 627, 684, 698–699, 761, 920 aidp, 678 aiha, 425–427 airway obstruction, 58, 338, 874, 878, 891, 899–900, 944, 946–947, 950–951, 954–955 aki, 762, 816–817, 822 akinesia, 642, 644–645 akinetic, 644 alanine aminotransferase, 204 albumin, 122, 205, 286, 289–290, 293, 298, 312, 352, 439, 766–767, 794–796, 798, 835, 841, 843, 908, 913



albuminuria, 436 alcohol, 2, 34, 41, 45, 48, 51, 58, 60–61, 80, 82, 117, 133–134, 139, 183, 218, 224, 231, 242, 244, 248, 250, 252, 276, 291–292, 297, 299, 309–310, 314, 316, 325, 347–348, 350, 409, 411, 432, 435, 440, 447–450, 475, 485, 492–493, 496, 515, 517, 576–577, 583, 599–600, 614, 617–618, 639, 642, 666, 744, 749–750, 778, 783, 806, 814, 831, 862, 870, 881, 927, 944 alcohol abuse, 133, 347, 614, 783, 881 alcohol use disorder, 749, 806, 814 alcoholic fatty liver, 292, 309 alcoholic hepatitis, 299 alcoholic liver disease, 291 aldosterone, 9, 57, 60–61, 80, 298, 766, 790, 810, 823, 863 alkaline phosphatase, 204, 241, 246, 249, 251, 280, 290, 297, 349, 377, 939 alkalosis, 122, 269, 573, 580, 795, 803, 814, 868, 870–871, 894, 917 allergen, 889 allergic bronchopulmonary aspergillosis, 894 allergic conjunctivitis, 589 allergic contact dermatitis, 566 allergic granulomatosis, 166 allergic reaction, 123 allergic rhinitis, 617, 953 allergy, 124, 166, 337, 477, 522, 565–566, 568, 675, 889, 940, 944, 948–949, 952 alpha 1-antitrypsin, 297, 308, 887–888 alpha thalassemia, 418–419 alpha-fetoprotein, 247, 249, 523, 650 als, 632–634 alt, 196, 204, 290, 292–293, 298, 304–306, 310 altitude sickness, 870 alveolar hypoxia, 919 alzheimer disease, 555–556, 562 aman, 678 amaurosis fugax, 167, 498 amenorrhea, 940 amino acid, 818 aminoglycosides, 665, 767, 816 aminotransferase, 57, 63, 204 amitriptyline, 229, 620–621 aml, 373–374, 378–379, 381, 395–398 amnesia, 547, 549, 557, 562, 579, 581, 584, 613, 696, 698–699, 749, 872 amniocentesis, 321, 325, 429, 518, 659, 903 ampulla of vater, 240 amputation, 105–106, 108, 457 ams, 870 amsan, 678 amygdala, 549 amyloidosis, 28, 38–39, 55–56, 59–60, 192, 439–440, 442 amyotrophic lateral sclerosis, 632, 634 ana, 258, 290 anaerobic, 124, 165, 330 anal atresia, 319, 366 anal fissure, 355 anal fistula, 356



Pathology Volume 1 Index analgesia, 301, 335, 358, 436, 569, 598, 602, 613, 618, 621, 778, 820, 823, 871, 924, 948, 955 anaphylactic shock, 124 anaphylaxis, 391 anastomosis, 10 androgen, 372 anemia, 56, 66, 73, 83–84, 87, 108, 124, 158, 172, 207–209, 211–213, 222, 226, 228, 231–232, 242, 253, 255, 258, 260–261, 311, 315, 327, 330–331, 363, 368–372, 378, 390, 394–395, 397–398, 400, 409–412, 415–419, 421–427, 429–437, 439–440, 442, 459, 462, 483, 646, 763–764, 785–786, 830, 835, 894, 920, 939–940 anemia of chronic disease, 421 anesthesia, 269, 483, 680, 682 aneuploidy, 517 aneurysm, 2, 15–19, 65, 97, 108, 167, 171, 174, 474, 485, 488, 492–495, 554, 628, 630, 684, 816 angelman syndrome, 579 anger, 581, 703, 714, 726, 756, 759 angina, 4–5, 41–42, 64, 66–67, 109, 174, 338, 363, 416, 925, 930 angina pectoris, 41, 363 angiogenesis, 467, 609, 845 angiogram, 9, 51, 165, 171, 173, 175, 864, 916 angiomyolipoma, 658, 844–846 angiopathy, 485, 556 angioplasty, 10, 106, 109, 153–154, 156, 175, 295, 495, 863–864 angiosarcoma, 157–158, 453, 920 angiotensin, 9, 35, 57, 80, 82, 84, 124, 499, 620, 764, 766, 783, 790–791, 800, 825, 835–836, 863–864, 914, 941 angiotensin converting enzyme, 57, 80, 783, 800, 825, 835, 864, 941 angle glaucoma, 601, 604 anhidrosis, 474, 930 anhydrosis, 474 anisocytosis, 374, 410, 412, 417, 419, 433 ankle, 106–107, 177, 289, 666, 940 ankylosing, 65, 597 ankylosing spondylitis, 597 anorexia, 62, 87, 108, 123, 142, 187, 190, 197, 199–200, 237, 242, 246–247, 251, 264, 304–306, 346, 351–352, 416, 475, 709–710, 796, 803, 826 anorexia nervosa, 142, 187, 190, 475, 709–710 anosmia, 470, 939 anosognosia, 557, 686 antacids, 223, 235, 795, 814 anterior pituitary, 938 anterior uveitis, 597, 938, 940 anterograde amnesia, 557, 562, 696, 749 anteroposterior, 772 anti-gbm antibody disease, 828 anti-infective, 956 antiarrhythmic, 128, 135, 137 antibiotics, 46, 88, 91, 94, 190, 194, 196, 206, 255, 257, 265–266, 277–278, 281, 299, 301, 312, 317, 330–332, 334, 336, 338–343, 348, 351–352, 413, 441, 452, 476–477, 506, 508, 510–511, 567, 569–570, 589, 594, 624, 626–627, 768, 787, 803, 830,



855, 857, 868, 882, 885, 892–893, 895, 897, 901, 905, 948, 951–952, 955 anticholinergic, 340, 342, 646, 782, 862 anticoagulant, 1, 70–71, 89, 133, 138, 176, 180, 182, 295, 383, 385–388, 453, 499, 835, 921, 933 anticonvulsant, 98, 481, 516, 522, 572, 577, 580, 620–621, 629–630, 656 antidepressant, 84, 185, 190, 221–222, 229, 504, 561, 620–621, 647, 689, 691–692, 695, 699–700, 703–704, 710, 717–719, 724, 726, 728–729, 735, 761, 862 antidiarrheals, 257–258 antidiuretic hormone, 298, 505, 808, 931 antiemetic, 225, 229, 413, 449, 476–478, 481, 627, 647, 871 antifungal, 334, 340, 567 antigen, 87, 89, 93, 173, 211, 232, 241, 290, 292–293, 304, 346, 425–426, 530, 537, 589, 663, 678, 838, 841, 938 antihistamine, 190, 222, 476–478, 481, 564, 569, 647, 955 antihypertensive, 60, 109, 495, 563, 620, 686, 864 antimalarials, 427 antineoplastics, 187 antinuclear antibody, 314, 908 antioxidant, 598, 600, 632 antiphospholipid syndrome, 179, 384 antipsychotic, 190, 504, 647, 698, 701– 702, 716, 726, 733, 735–737 antisocial personality disorder, 713, 724–725 anton-babinski syndrome, 686 antrum, 231–232, 235, 253 anxiety, 133, 221, 447–448, 453, 494, 504, 516, 541, 560, 574, 621, 644, 689–695, 699, 703, 708–711, 715–717, 722–723, 729, 739–741, 743–744, 748–749, 751–752, 754, 756, 759–761, 796, 913, 947 aorta, 6, 9–10, 15–16, 18–20, 44–49, 51, 80, 105, 109, 142–144, 155, 167, 370, 474, 488, 490 aortic aneurysm, 15–16, 18, 97, 108, 167, 174, 816 aortic arch, 9, 19, 155, 167, 174–175 aortic dissection, 19–20, 65, 81, 83, 100, 104, 155, 167 aortic insufficiency, 65 aortic regurgitation, 19–20, 60, 65–66, 93, 167, 174 aortic stenosis, 59–60, 66, 93 aortic valve, 16, 18, 22, 55, 65–67, 69–70, 76, 174, 213 aortoplasty, 10 ap, 111, 773 apathy, 470, 557, 560, 634 apc, 207–209, 211, 386 apgar score, 900 aphasia, 466, 486, 498, 533, 547–548, 550, 560, 562, 619 aphonia, 947 aphthous ulcers, 334–335 aplasia, 369, 371, 410, 423, 462 aplastic anemia, 423–424, 433 apnea, 58, 137, 279, 370, 498, 514, 743, 877, 880, 883, 903, 920, 943–945,



949 apoptosis, 209, 320, 402, 405, 411, 418, 434, 487, 538, 556, 558, 560, 635, 649, 785, 816, 829, 924 appendectomy, 265, 322 appendicitis, 263–264 appendix, 238, 264–265, 322 apraxia, 146, 555, 557, 562, 649 aqueduct, 478, 514, 519 arbovirus, 505 ards, 124, 347, 867, 869 armd, 598–600 arnold-chiari malformation, 514–515, 522, 524 arrhythmia, 21, 29, 33–34, 36, 56, 59–60, 70–72, 84–85, 90–91, 102, 111, 114, 121, 166, 171, 187–188, 302, 412, 419, 459, 494, 545, 562, 635, 642, 676, 679, 749, 764, 795–796, 798–799, 801, 803–804, 806, 814, 938, 945 arterial blood gas, 414, 886, 905, 917 arterial pressure, 83–84, 101, 126, 628, 919 arteriogram, 863–864 arteriole, 107, 289, 816, 836 arteriolosclerosis, 15, 107, 485, 767 arteriosclerosis, 81, 107–108, 836 arteriovenous malformation, 147, 485–486, 494 arthralgia, 93, 173, 302, 306, 939 arthritis, 65, 89, 92–93, 95, 98–99, 164, 170, 255–256, 260, 421, 590, 646, 667, 763, 820, 908, 939–940, 948, 954 asbestos, 250, 846, 923–924 asbestosis, 936 ascaris, 203 ascending aorta, 18–19 ascending cholangitis, 195–196, 204, 296, 790 aschoff bodies, 92 ascites, 62, 102, 205, 248, 251, 259, 284, 289, 291, 294, 298–299, 310–313, 315, 349–352, 357, 418, 429–430, 433, 766, 920 ascorbic acid, 413–414 asd, 6–7, 44, 712 aso, 93, 954 asperger syndrome, 712 aspergillosis, 891, 894 aspergillus, 16, 566, 590 asphyxia, 338, 902 aspirate, 29, 194, 216, 244, 254, 339, 341, 373–374, 377, 380–381, 461–462, 486, 489, 491, 495, 504, 539, 568, 608, 634–636, 640, 649, 868, 899–900, 902, 909, 924, 928, 941, 947, 956 aspiration pneumonia, 244, 489, 504, 539 aspirin, 3, 42, 94, 104, 172, 218, 235, 242, 374, 380–381, 385, 458, 482, 490–491, 499, 574–575, 620, 626, 643, 889, 918, 949, 955 asplenia, 283, 377, 451–452 ast, 196, 204, 290, 292–293, 298, 304, 310 asthenia, 251 asthma, 166, 222, 377, 870, 886, 889, 891, 905, 910, 949, 954 astrocytoma, 465, 533–534



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asystole, 24, 28, 130 at, 3–6, 13, 17, 22, 32, 42–45, 48, 61, 65–66, 70–71, 81, 83–84, 86–87, 99, 109, 121, 123, 128, 131, 133, 136–137, 146, 148–151, 159–160, 181, 183, 192, 197, 207, 209, 216–217, 219, 224, 226, 229, 235, 240, 244–245, 251, 253, 260, 264, 269, 278, 284, 294, 315–319, 325, 329, 344, 347, 360–361, 364–365, 370–371, 379, 386–388, 392, 395–396, 399–400, 406, 408, 413–414, 430–431, 442, 449, 452, 456, 470, 478, 483, 501–502, 512, 523, 532, 537, 543, 550, 557–558, 561, 565, 599–601, 605, 607, 612, 614, 619, 622–623, 626, 633–635, 644, 647, 649, 651, 653, 657, 667–669, 673–674, 681, 684, 705, 715, 721–723, 734–737, 740, 746, 751, 759, 769–771, 774, 777–778, 781, 783, 786, 789, 792, 796, 804, 836, 841–842, 864–865, 869–871, 875, 887–888, 892–893, 896, 910, 913, 920, 923, 931, 939, 941, 944, 956 ataxia, 36, 232, 330, 417, 442, 467, 486, 489, 504, 513, 515–516, 529, 531, 533, 537, 541, 572–573, 626, 638, 640–641, 649–650, 749, 870 ataxia-telangiectasia, 531, 649 atelectasis, 872, 879–880, 895, 899–900, 903, 907 atheroma, 488 atherosclerosis, 1, 15, 41, 80–81, 105, 108–109, 153, 155, 165, 280, 384, 475, 485, 487, 491, 498, 562, 863, 921 ati, 816 atonic, 578–579 atonic seizures, 579 atopic dermatitis, 566, 889 atp, 314, 434, 487–488, 612, 618, 801 atresia, 44, 76, 283–284, 296, 319–321, 366, 517, 623, 874, 956–957 atrial arrhythmia, 111 atrial bigeminy, 118–119 atrial fibrillation, 134 atrial myxoma, 29–30, 488 atrial septal defect, 6–8, 44, 370 atrial septum, 52 atrial tachycardia, 28 atrial trigeminy, 118 atrioventricular, 21–24, 111–112, 114, 118, 133, 139, 192, 796 atrioventricular node, 21–22, 111–112 atrium, 7–8, 30–31, 36, 44, 50–51, 59–62, 64, 68–73, 75–76, 102, 134, 136, 913, 920, 933 atrophic gastritis, 231–233, 238, 252 atropine, 21, 23 attention deficit hyperactivity, 711 attention deficit hyperactivity disorder, 711 attenuated fap, 209 atypical anorexia nervosa, 709 atypical antipsychotics, 701–702 atypical hemolytic uremic syndrome, 829–830 audiogram, 569, 622, 624, 627 audiometry, 479, 481, 570 aura, 488, 581, 584, 616, 618–619, 621



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auricle, 564, 623 autism spectrum disorder, 712 autoantibody, 425–426, 459–460, 661, 664–665 autoimmune disorder, 205, 256, 328, 426, 662–663 autoimmune hemolytic, 398, 425 autoimmune hemolytic anemia, 398, 425 autoimmune hepatitis, 293–294, 297, 299 autoimmune thrombocytopenic purpura, 457 autoimmunity, 231, 293, 313, 398 autologous, 441–442 autonomic diseases, 473, 475 autonomic nervous system, 123, 473, 520, 541, 559, 662, 904 autosomal dominant polycystic kidney disease, 791 autosomal dominant trait, 36 autosomal recessive fap, 209 av, 6, 22–23, 82, 111–112, 118, 120, 133, 137–140 av node, 111, 118, 120, 139–140 av reentrant tachycardia, 112 avm, 146–147, 688 avnrt, 139–140 avoidant personality disorder, 729–730, 732 avulsion, 668 awake bruxism, 743–744 axon, 473, 612, 677 azotemia, 762–764, 766–768, 816, 863 b cell, 328, 395, 398, 405, 407 b cell acute lymphoblastic leukemia, 395 b cell lymphomas, 405 b-all, 395 b-cell lymphoma, 407–408 b-type natriuretic peptide, 57 ba, 588 bacillus, 332 back pain, 220, 225, 428, 483, 507, 522, 525, 529, 628, 631, 680, 682 bacteremia, 87, 594, 954 bacteria, 15, 86, 162, 195–196, 198, 200, 260, 275, 278, 300, 330, 336–337, 341–342, 352, 355, 389, 452, 500, 509–510, 565, 568, 590, 602, 640, 818, 830, 853–854, 856, 891, 894, 947, 950, 952–953 bacterial conjunctivitis, 588–589 bacterial epiglottitis, 947 bacterial infections, 394–395, 397–398, 856, 883 bacterial keratitis, 590–591 bacterial meningitis, 511–512 bacterial peritonitis, 298, 311–312, 351–352 bacterial rhinosinusitis, 591 bacterial tracheitis, 878–879 bacteroides fragilis, 15 balance disorders, 476–477, 479, 481 balloon angioplasty, 10, 154, 295, 495 balloon tamponade, 312 barbiturates, 448 bariatric surgery, 409 barium enema, 209, 257, 267, 281 barium sulfate, 220 barium swallow, 215–217, 221, 227, 245, 312, 331, 363, 366 barrett’s esophagus, 217–219 basal cell, 31, 223



basal cell carcinoma, 31 basal ganglia, 93, 375, 485, 504, 644, 646, 798 basaloid carcinoma, 926 basement membrane, 259, 449, 603, 767, 826, 828, 832, 836, 838, 840–842 beck’s triad, 100–101 becker’s muscular dystrophy, 544 beckwith-wiedemann syndrome, 325, 851 bedwetting, 747 behcet’s disease, 164, 181 behcets, 164 belching, 204 bell’s palsy, 552–553, 590 benign chronic conditions, 638 benign prostatic hyperplasia, 764 benzodiazepines, 481, 504, 516, 583, 627, 638–639, 643, 689–697, 731–732, 744 berger disease, 170, 831 beriberi, 34, 573 bernard-soulier syndrome, 444 beta blockers, 1, 22, 37, 42, 60–61, 67, 73, 79, 84, 118, 121, 133, 135, 138–139, 150, 193, 312, 481, 598, 620, 638–639, 730, 766 beta-lactamase, 339 biceps, 668 bicuspid, 16, 65, 67, 69–70, 86–87, 213 bilateral bundle branch block, 24 bilateral renal agenesis, 792, 876 bilateral temporal lobe disorder, 549 bile, 194–201, 203–206, 217, 229, 240, 245–246, 248, 256, 258, 283–284, 286, 296–299, 307–309, 313–314, 330, 351–352, 899 biliary atresia, 283–284, 296 biliary cirrhosis, 296, 313–314 biliary colic, 197 biliary tract diseases, 194–195, 197, 199, 201, 203, 205 bilirubin, 57, 63, 203–206, 241, 246, 265, 283–287, 289–290, 296, 298, 304, 309, 314, 348–349, 410, 418–419, 425–426, 428, 430–431, 433–434, 436, 460, 939 bilirubin stones, 203 binge-eating/purging anorexia nervosa, 709 binocular vision, 498 biofeedback, 621 bipolar disorder, 701–702 bipolar i disorder, 701 bipolar ii disorder, 702 bitemporal hemianopsia, 684 biventricular heart failure, 55–56 bladder, 265, 319, 473, 507, 514, 516, 522, 525, 682, 706, 746–747, 756, 765, 769–771, 773–783, 788, 819, 824, 853–854, 856, 859–862 bladder cancer, 776–777, 779 bladder exstrophy, 769–771, 776, 783 bladder pathology, 776, 781 blast, 400, 910 blast crisis, 400 blastoma, 850, 874 bleeding diathesis, 483, 486 blepharitis, 586–587, 595 blepharospasm, 590, 642 blind, 83, 164, 167, 319, 489, 588, 598, 601, 604, 609, 619, 685–686, 927, 940



Pathology Volume 1 Index blocker, beta, 35 blood cell, 208, 226, 369–370, 372, 410, 415–416, 419, 433, 436, 459, 576, 643, 767, 830 blood clot, 176, 482, 484, 493, 495, 497, 502, 672, 771–772, 933 blood coagulation, 162, 181 blood culture, 87, 125, 279, 339, 878, 948, 951 blood group, 429 blood test, 213, 325, 440, 835 blood transfusion, 373, 417, 427, 767 blood urea nitrogen, 57, 108, 122, 124, 762, 764, 783, 815, 863 blood-brain barrier, 509 bmi, 309, 673, 709, 783, 819, 947 bnp, 57, 59, 61, 63, 102 bochdalek hernia, 362 body dysmorphic disorder, 718 body focused repetitive disorders, 718 bone density, 313 bone marrow, 370–375, 377, 380–381, 394–402, 404, 406–407, 409, 411–412, 419, 422–424, 432–433, 439, 441, 608, 709, 939 bone marrow aspiration, 373–374, 377, 380–381, 608 bone marrow biopsy, 371, 381, 400, 423–424, 439, 441 bone marrow transplant, 399, 424 bony outgrowth, 623 borderline personality disorder, 724, 726 bordetella pertussis, 377 borrelia burgdorferi, 90–91 botox, 217, 716 botulinum toxin, 221, 639, 862 bowel, 143–144, 199–200, 207, 210, 213, 230, 238, 240, 242, 255–257, 259–261, 263, 265, 267–270, 273–282, 318, 321–322, 325, 327, 330, 346, 351–353, 355, 357, 362–363, 384, 407, 410, 473, 507, 514, 516, 522, 525, 574, 682, 706, 774, 819, 895 bph, 764 bra, 792 brachial artery, 798, 806, 813 brachial plexus, 668, 670, 672–673, 675, 930 bradycardia, 21–23, 25, 27–28, 188, 190, 614, 665, 679, 796, 900, 943–944 bradykinesia, 638, 644–646 bradypnea, 899 brain abscess, 500–502, 576, 579, 583, 592 brain herniation, 494, 629 brain ischemia, 482–483, 485, 487, 489, 491, 493, 495, 497, 499, 628 brain stem, 640, 927 brain tumor, 527, 531, 550, 781 brca, 251, 649 breast, 29, 95, 157–158, 181, 213, 649, 749 breast cancer, 29, 95 breastfeeding, 904 broca’s aphasia, 547–548 bronchi, 878, 883, 889, 891–892, 894 bronchiectasis, 501, 886–887, 891–892, 894–895, 936 bronchiole, 928 bronchiolitis, 879–880



bronchitis, 751, 886–887, 893, 898 bronchodilators, 187, 892–893, 895, 897 bronchopulmonary dysplasia, 877, 903 bronchoscope, 924 bronchoscopy, 161, 244, 942, 958 bronchospasm, 665 bronchus, 892, 924, 931 brown pigmented gallstone, 203 brown-sequard syndrome, 680 brugada syndrome, 127–129 bruise, 158, 160 bruit, 66, 81, 106, 109, 146–147, 248, 864 bruxism, 743–744 bss, 444, 680–681 buccal mucosa, 250 budd-chiari syndrome, 294, 311, 379 bulbar als, 633 bulbar conjunctiva, 649 bulimia, 217, 224, 416, 710 bulimia nervosa, 710 bullous, 251, 601 bullous pemphigoid, 251 bun, 57, 124, 762–764, 766, 768, 783– 784, 815, 817, 863–865 bundle branch block, 24, 26–27, 118, 120, 128–129, 917–918 bundle of kent, 114 burkitt lymphoma, 160, 405 burn, 171, 231, 235, 377, 390, 602, 760, 766, 797, 867–868, 913, 947 bypass, 10, 17, 106, 109, 111, 137, 153–154, 175, 280, 305, 863–864 c-anca, 168–169, 832 c-reactive protein, 87, 93, 104, 109, 162, 196, 261, 271, 422, 882, 947 ca, 213, 241, 246, 251, 577, 626, 643, 762–764, 766 cabg, 131, 154 cachexia, 62, 102, 242, 251 cad, 59, 185 caffeine, 73, 217, 231, 276, 475, 621, 638–639, 644, 646–647, 744 calcinosis, 813, 824 calcitonin, 618, 794, 796–797 calcium stones, 818–819, 824 campylobacter jejuni, 678 cancer, 29, 86, 95, 98, 100, 142, 200, 204–205, 210, 213, 216–217, 231, 242, 244–245, 250–252, 298, 302, 349, 377, 390, 419, 421, 423, 452, 502, 526, 548, 550, 616, 649, 662–663, 681, 748, 756, 771, 776–779, 784, 840, 844–847, 849, 851, 859, 875, 908, 923–924, 926, 931, 933, 938 candida, 16, 86, 339, 566, 587, 590, 940, 948 candida albicans, 86, 339, 566, 587 candidiasis, 161, 250, 339–340, 597, 897 canker sores, 334, 743 cannabis, 229, 750–752 cannabis dependence, 750, 752 cannabis use disorder, 750 cannula, 181, 880 capillary hemangioma, 150 caps, 703 caput medusae, 289, 311–312 carcinoembryonic antigen, 211, 241, 346 carcinogenic, 231 carcinoid syndrome, 75, 238–239 carcinoid tumor, 238–239, 784, 928



carcinoma, 29, 31, 205, 218, 223, 226, 231, 242, 244, 248–251, 253, 260, 290–291, 293, 298, 304–305, 310, 365, 377, 380, 448–449, 586, 624, 658, 661, 776, 778–780, 844, 846–848, 887, 923–924, 926–932 carcinoma in situ, 780, 923 cardiac arrest, 131, 482, 629, 642, 801, 803, 805 cardiac catheterization, 13, 51, 59, 67, 76, 101, 131, 251, 280 cardiac index, 57 cardiac muscle, 90, 120 cardiac output, 38–39, 55, 57, 60, 66, 80, 100, 102, 104, 111, 124, 130, 192, 280, 416, 475, 488 cardiac steal syndrome, 154 cardiac tamponade, 20, 98, 100–101, 104, 122, 129, 462 cardiac tumors, 29, 31, 76 cardiogenic shock, 44, 56–57, 66, 90, 122, 124–125 cardiomyopathy, 33–39, 41, 55–56, 59–60, 62, 102, 130, 192, 302, 419, 436, 545–546, 573, 640, 749, 919, 941 cardiopulmonary, 57, 127, 131, 194, 280, 904, 911, 947 cardiopulmonary bypass, 280 cardiopulmonary resuscitation, 127, 131, 904 cardiospasm, 215 cardioversion, 111–112, 115, 130, 134–135, 138, 185, 188, 193 cardioverter, 33, 37, 61, 188, 191 caries, 336 carotid, 18, 109, 111, 140, 155, 167, 474, 490–492, 499, 502–503, 562, 616 carotid artery, 18, 109, 167, 474, 492, 502–503, 562 carotid endarterectomy, 109, 491, 499 carpal tunnel, 667–668 cartilage, 874, 893 cataplexy, 745 cataract, 315, 597–598, 600–601, 606, 653 catatonic, 642, 733, 735–737 catecholamines, 124, 660 catheter, 22, 75, 79, 84, 86, 111–112, 115, 118, 121, 133, 135, 138, 140, 147, 181, 193, 356, 498, 629, 765, 772, 779, 782, 854, 856, 909, 911, 920, 933, 956 cauda equina syndrome, 680–682, 859 caudal, 876 caudal regression syndrome, 876 cauterization, 225 cavernous hemangioma, 147–148 cavernous sinus, 469, 500, 502–503, 592, 616, 684, 952 cavernous sinus meningiomas, 469 cavernous sinus thrombosis, 500, 502, 592, 952 cavity, 16, 97, 101, 151, 219–220, 250, 269, 272, 316–317, 322, 325, 334, 336, 339, 346, 351–354, 360–363, 377, 453, 489, 568, 766, 877, 897, 906, 910, 924–926, 946, 949, 953 cecal, 281–282 cecal volvulus, 281–282 celiac disease, 258, 328–329, 410, 416 celiac sprue, 259



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5



cell cycle, 371, 538, 648–649 cellulitis, 96, 151, 338, 567, 591, 594, 881, 950–952, 954 central hypothyroidism, 655 central nervous system, 87, 89, 375, 435, 464, 480, 537, 626, 640, 649, 781, 796, 861 central pontine myelinolysis, 538–539, 811 central vision, 599–600, 604 cephalosporins, 352, 508, 955 cerebellar, 479–480, 489, 500, 504, 514–515, 517–518, 533, 629–630, 650 cerebellar astrocytoma, 533 cerebellopontine angle meningiomas, 470 cerebral, 15–16, 83, 109, 147, 166, 289, 386, 433, 442, 475, 485, 488–492, 494, 498, 500–505, 507, 509–513, 515, 522, 538, 548, 550, 556, 562, 575, 581, 583, 612, 614–615, 628–630, 633, 644, 653, 656, 685–687, 790, 809–811, 870, 904, 933 cerebral aneurysm, 16 cerebral cavernous malformations, 147 cerebral edema, 488, 490–491, 500, 509–510, 512, 575, 612, 628–629, 809, 870, 933 cerebral hemisphere, 581, 630 cerebral palsy, 515 cerebral ventricle, 615 cerebroatrophic hyperammonemia, 520 cerebrospinal malformations, 513, 515, 517, 519, 521, 523, 525 cerebrovascular disease, 105, 108, 556, 576, 578, 583 cerebrum, 684 cerumen impaction, 623 cervical, 171, 213, 219–220, 226–227, 300–301, 363, 404, 474, 614, 618, 639, 645, 672, 681, 926, 930–931, 953–955 cervical rib, 474, 672 ces, 586, 680–682 chagas disease, 28, 34, 90, 216 chalazion, 586–587, 595 charcot’s triad, 196 charcot-marie-tooth disease, 676–678 cheek, 498, 743 cheilopalatoschisis, 360 cheiloschisis, 360 chemoprevention, 218 chemotherapy, 34, 158, 161, 210, 218, 237, 241, 243, 245–247, 249–251, 254, 339, 341, 378, 394, 396–397, 399, 402, 423, 441–442, 461, 463–464, 467, 472, 500, 502, 527, 530, 532–533, 608, 652, 779, 844, 847, 849, 851, 924–925, 928, 930, 932–933 chest pain, 3, 5–6, 9, 19, 28–30, 35–36, 41–42, 58, 64, 66, 83, 89–90, 92, 98, 123, 133–134, 139, 146, 154, 168, 172, 179, 185, 192, 216, 220–222, 259, 301, 375, 461–462, 641, 692, 872, 881, 907, 910, 912, 915, 917, 920, 928, 939–940, 945 chest x-ray, 8–9, 11, 13, 20, 33, 37, 43–44, 48, 50–51, 57–59, 61–62, 66, 69, 71–73, 83, 90, 103, 166, 169, 171, 220, 366, 461–462, 614, 673, 868,



6



OSMOSIS.ORG



877, 879, 885–886, 888, 892–893, 895, 897, 899–900, 903, 905–907, 910, 913, 917, 920, 924–925, 930, 933 chiari malformation, 514–515, 522, 524 chiari malformation type ii, 514 child abuse, 615 childbirth, 11, 32, 44–45, 51, 149–150, 278, 284, 308, 316–319, 325, 360–361, 364, 370–371, 384, 418, 446, 509, 513, 515, 523, 609, 614, 670, 769, 781, 783, 789–790, 792, 849, 860, 880, 899, 904–905, 943 childhood, 170, 247, 479, 498, 526–527, 529, 531–533, 535, 546, 607, 609, 635, 698, 712–713, 786, 831 childhood disintegrative disorder, 712 childhood primary brain tumors, 526–527, 529, 531, 533, 535 chl, 403 chlamydia, 300, 355, 588–589, 856, 953 chlamydia trachomatis, 300, 588 choana, 956–957 choanal atresia, 956–957 chocolate, 217–218, 224, 229, 413, 819 choking, 366, 692, 957 cholangiocarcinoma, 205, 240–241, 248 cholangiogram, 206, 284 cholangitis, 194–196, 198, 200, 204–206, 240, 245, 260, 283–284, 296, 298, 313, 375, 790 cholecystectomy, 194, 196–197, 199, 201, 205, 246, 297 cholecystitis, 194, 197–201, 204, 273 choledocholithiasis, 195, 203 cholelithiasis, 198, 200, 203–204, 245, 256, 296, 426 cholescintigraphy, 199, 201 cholestasis, 201, 241, 246, 283, 286, 290, 296–297, 308, 314, 791 cholestatic hepatitis, 306 cholestatic liver disease, 296, 309 cholesteatomas, 624 cholesterol, 1–2, 70–71, 110, 198, 200, 203–204, 296, 314, 485, 488, 499, 528, 791, 835, 842, 863, 908 cholesterol stones, 198, 200, 203–204 cholesterol, hdl, 314 cholesterol, ldl, 488 chordoma, 684 chorea, 93, 642 chorionic villus sampling, 429, 659 chorioretinitis, 587–588 christmas disease, 392 chromophobe carcinoma, 846 chromosome, 209, 302, 371, 377, 391– 392, 400, 438, 440, 465, 469, 607, 632, 635, 640, 649–650, 652, 656, 658, 685, 846, 848–850, 887, 894 chronic bronchitis, 886–887, 893, 898 chronic gastritis, 231, 233, 235 chronic hepatitis, 297–298, 887 chronic kidney disease, 80, 433, 762–763, 765, 767, 786–788, 800, 813, 831, 837, 845, 920 chronic lymphocytic leukemia, 399, 457 chronic lymphoid leukemia, 394, 398–399 chronic myelogenous leukemia, 377, 400 chronic myeloid leukemia, 394, 400 chronic obstructive pulmonary disease, 235, 923



chronic patency, 565 chronic suppurative otitis media, 568–570 chronic venous insufficiency, 177 churg-strauss syndrome, 166–167 ciliary dysfunction, 565 ciliary dyskinesia, 565, 891, 949 circle of willis, 15, 488, 492–493 circulation, 6–7, 45, 48, 50, 55, 58, 60, 62, 64–65, 69–71, 76, 105–106, 109, 126, 142, 151, 154, 248, 276, 280, 296, 312, 314, 384, 389, 410–411, 421, 429, 487, 492, 498, 597, 599, 629–630, 863, 913, 919–920 circumlocution, 550 cirrhosis, 102, 124, 205, 240, 248, 283–284, 289–294, 296–299, 302, 304–305, 308–315, 352, 384, 419, 449, 749, 797, 810, 887–888, 894, 907 classic fap, 209 classic trigeminal neuralgia, 554 claudication, 9, 105–106, 109, 156, 165, 167 clavicle, 672 clear cell carcinoma, 846 cleft lip, 360–361, 568 cleft lip & palate, 360 cleft palate, 360, 370, 517 clitoris, 770 cll, 398 clonic seizures, 578–580 clonorchis sinensis, 203 closed angle glaucoma, 601, 604 clp, 360 club foot, 522, 525 cluster headache, 616 cns demyelinating disorders, 536–537, 539, 541, 543 coagulation, 124–125, 162, 181, 228, 236, 284, 289, 293, 347, 358, 383, 385–389, 391–393, 396, 442, 642, 672, 816, 830, 865, 868, 887 coarctation of the aorta, 6, 9–10, 80, 370 cobalamin, 231–232, 327, 409 cocaine, 2, 19, 34, 56, 117, 130, 185, 192, 475, 485, 488, 492–493, 498, 521, 576, 752–754, 788, 920 cocaine dependence, 752 coenzyme, 620 cognition, 315, 351–352, 375, 489, 497, 510, 519, 522, 542, 555, 557–560, 562–563, 612–613, 621, 644, 648–650, 658, 678, 689–697, 699, 701–705, 708–710, 714, 716–719, 731, 733–734, 736–737, 740–742, 748–749, 755, 759–761 cognitive behavioral therapy, 689–695, 701–705, 708–710, 714, 716–719, 731, 755 colchicine, 99, 104 cold agglutinin syndrome, 426 colectomy, 208, 210–212, 243, 261 colic, 197, 230, 322, 765, 787, 801, 819 colitis, 86, 205, 207, 255–256, 258–262, 267, 276–278, 377, 433 colitis, crohn’s, 205 collagen, 15, 19, 87, 92, 97, 102, 162, 258, 273, 297, 310, 349, 381, 393, 402–403, 828, 832, 891, 896, 908, 936 colon, 29, 207, 209–213, 238, 243,



Pathology Volume 1 Index 256–258, 265–266, 270, 276–278, 282, 318–320, 322, 330, 356, 359 colon cancer, 210 colonic adenomas, 207 colonoscopy, 208–209, 211–213, 242, 267, 277, 282, 327, 417, 453 colony-stimulating factor, 372, 423 color blindness, 685 colorectal, 86, 207–209, 211–213, 242 colorectal cancer, 242 colorectal polyp conditions, 207, 209, 211, 213 colostomy, 319 colporrhaphy, 859 coma, 123, 311, 413, 459, 486, 494, 497–498, 505, 537, 539, 572, 574, 613–614, 619, 629, 642, 763, 795–796, 805, 809–810, 910 common bile duct, 195, 198, 200, 203, 245, 284, 297 common cold, 565, 953–955 community-acquired pneumonia, 881 complete blood count, 87, 103, 124, 162, 290, 327, 341, 351, 373, 409, 412, 415, 421, 425, 438, 444, 455, 572, 592, 791, 878, 946 complete heart block, 22, 24, 938 complex febrile seizure, 580 complication, 3, 16, 56, 83, 92, 257, 261, 266, 311, 345, 366, 370, 389, 477, 483, 496, 545–546, 568, 776, 815, 824, 826 compulsive disorder, 93, 692, 709, 719, 731 compulsive personality disorder, 729, 731 concussion, 611–613 conduct disorders, 713 conductive hearing loss, 565–567, 569–570, 623 congenital aganglionic megacolon, 318 congenital anemia, 368–369, 371 congenital asplenia, 452 congenital defect, 94, 774, 854 congenital diaphragmatic, 362, 876 congenital disorders, 769, 771, 773, 775 congenital heart disease, 13, 21–22, 24, 56, 69, 88, 371, 501, 880 congenital kidney conditions, 783, 785, 787, 789, 791, 793 congenital malformation, 73–74, 316–317, 319–321, 323, 325, 360–361, 363, 365–367, 521, 626, 771, 837, 874–875, 877, 956–957 congenital methemoglobinemia, 413 congenital myopathies, 544–545 congenital pulmonary airway, 874–875 congenital rubella syndrome, 11, 73–74 congestive heart failure, 13, 39, 46, 84, 709, 763, 766, 810, 907 conjunctiva, 588–589, 598, 607, 649 conjunctivitis, 164, 171, 588–590, 954 connective tissue, 16, 19, 64, 68, 72, 97– 98, 100, 102, 266, 284, 297–298, 507, 784, 788, 919 connective tissue disease, 97, 100, 919 connective tissue disorders, 16, 19, 64, 68, 72, 98, 102, 266 constipation, 207, 212–213, 238, 242, 263–267, 269, 271, 274–276, 281, 318–319, 323, 355, 357–359, 440, 448, 541, 559, 619, 635–636, 644,



662, 697, 705–706, 796, 803–804, 850, 859 constrictive pericarditis, 98, 102, 104, 311 contact dermatitis, 566 continuous positive airway pressure, 880, 903, 914, 945 contraceptive, 179, 181, 204, 286–287, 296, 307, 386, 388, 434, 446, 448, 704, 760, 915 contusion, 613–614 convulsive status epilepticus, 583 copd, 58, 133, 235, 887–888, 893, 896, 910, 919–920, 923 coprolalia, 716 copropraxia, 716 cor pulmonale, 55, 58, 117, 886, 892–893, 896, 915, 919, 938, 945 corn, 248, 310 cornea, 315, 586, 589–591, 597–598, 602, 604–605, 683 corneal ulcer, 598, 602 coronal plane, 18, 151, 198, 270, 273, 392, 399, 404, 407, 466, 469, 522, 630, 772, 791, 793, 854, 895, 908, 911, 914, 925, 931–932, 952 coronary artery, 2, 4, 24, 28, 41, 55, 60, 81, 105, 133–134, 154, 171, 185 coronary artery disease, 24, 28, 41, 55, 60, 81, 133–134, 185 coronary heart disease, 108 coronary steal syndrome, 153–154 coronavirus, 953 corpus, 231, 517–518, 521–522, 541 corrigan pulse, 65 cortex, 80, 489, 500–501, 503–505, 507, 509, 511, 522, 548, 556, 558, 600, 616, 618, 629, 644, 656, 683, 686–687, 696, 790, 846, 865–866 cortical blindness, 489, 686 cortical cataract, 601 cortical disorders, 547, 549, 551 corticosteroid, 500, 502, 566–567, 569, 590, 597, 668, 673, 843 cortisol, 80, 744, 847, 931 corynebacterium diphtheriae, 883, 953 coryza, 954 costal margin, 199–200, 251 cough, 13, 60, 82, 146, 161, 168, 172, 222, 227, 259, 271, 436, 461–462, 526, 633, 828, 860, 870, 872, 878–881, 883, 885–887, 892–894, 896, 913, 915, 925, 928, 930, 932, 935–936, 939, 948, 951, 954–955 counseling, 370, 641, 659, 897 cox, 218 coxiella burnetii, 86 cranial, 166–167, 469, 479, 483, 497, 502–503, 507, 509, 514, 529, 552–554, 590, 592, 613–614, 616–617, 628–629, 633, 639, 678, 683, 938, 940 cranial dystonia, 639 cranial nerve injury, 552–553 cranial nerves, 469, 497, 502–503, 552, 592, 633, 678, 938 craniopharyngioma, 528–529, 684 craniosynostosis, 514, 956 craniotomy, 484, 486, 495, 497, 507–508 creatine kinase, 90, 544–546, 643 crepitus, 279 creutzfeldt-jakob disease, 500, 503



crigler-najjar syndrome, 285–286 crohn’s disease, 207, 255–257, 259–260, 263, 597 crossed straight leg raising test, 671 croup, 878, 883–884 crouzon syndrome, 623 crp, 87, 89, 103–104, 109, 162, 166, 171–172, 196, 261, 271, 304–306, 422, 882, 885, 947 cruveilhier-baumgarten murmur, 289 cryoglobulinemia, 442 crypt, 231, 261–262, 328–329 cryptococcus neoformans, 501 cryptorchidism, 849 csf, 372, 377, 396, 424, 466, 493–496, 504–505, 510, 514, 519, 525, 527, 530, 532, 535–538, 541–542, 547, 549, 572, 628, 631, 676, 679 ct scan, 7, 10, 12, 17–18, 20, 29–31, 83, 96, 101–102, 141–142, 144, 146–148, 151, 157, 166, 194, 197–198, 204, 208–209, 211, 213, 220, 227, 234, 236, 238–239, 241, 243–244, 246–248, 250–251, 253, 263–265, 267–268, 270, 272–275, 277, 280–281, 290–291, 295, 301, 307, 310–311, 313, 316–317, 319, 322–324, 334, 336, 338–339, 341, 345–346, 348–349, 351, 353–354, 360–361, 365–366, 397, 399, 402, 404, 407, 437, 440, 442, 451–452, 454, 461–464, 466, 468–471, 476, 480, 482, 484, 486–487, 489–490, 494–495, 497, 500–503, 505, 508, 513–514, 516, 519, 523, 526, 528, 530–531, 533, 535–537, 539, 547–550, 552, 554–555, 557, 562, 565, 569, 572–573, 576, 578–579, 581, 583–585, 592, 594, 610, 613–614, 616–617, 628, 630–631, 648, 655–656, 659, 661, 663–664, 673, 684, 687–688, 697, 762, 765, 770, 772, 780, 783–785, 787, 791, 793, 819–820, 822, 844, 846–847, 850–851, 854–855, 863–866, 868, 874–877, 880, 886, 888, 892, 895, 906, 908, 910–914, 922, 924–925, 927, 930–933, 935–937, 941, 945, 949, 951–952, 956–957 curettage, 587, 595 cushing’s syndrome, 80, 931 cutaneous, 106, 157, 238–239, 248, 261, 384, 393, 447, 449, 618–619, 652–653, 939 cyanosis, 6, 9, 43–45, 48–51, 146, 220, 338, 362, 366, 380, 413–414, 868, 875, 877, 880, 893, 899–900, 903, 905, 910, 913, 920, 936, 943, 947, 949, 956 cyanotic, 43, 45, 47–49, 51, 53, 165, 672 cyanotic defects, 43, 45, 47, 49, 51, 53 cyclic vomiting syndrome, 229 cyclooxygenase, 80, 210, 213, 218, 231 cyclophosphamide, 56, 164, 168–169, 172–173, 446, 538, 542, 778, 828, 832, 835, 839, 842, 942 cyclosporine, 164, 261, 458, 800, 842, 942 cyst, 263, 346, 365, 514, 524, 532–533, 658, 684, 688, 787, 790, 876 cystectomy, 777 cystic fibrosis, 894



OSMOSIS.ORG



7



cystic hygroma, 151 cystic kidney disease, 785 cystine, 818–819 cystinuria, 818 cystitis, 853, 856 cystocele, 859 cystoscope, 777 cystoscopy, 776, 779 cytomegalovirus, 308, 370, 457, 466, 477, 587, 597, 626, 678, 798, 953 cytoplasm, 31, 206, 249, 307, 375, 377, 403, 409, 441, 465, 468, 470, 846, 926, 929, 932 d-dimer, 124–125, 176, 301, 830, 916–917 dacryocystitis, 589, 591, 594 dactylitis, 435, 940 dander, 889 dandy-walker syndrome, 517 danlos syndrome, 16, 68, 266, 342, 492–493, 514 ddx, 248 deafness, 371, 411, 470, 486, 510, 623, 677 decompression sickness, 871 decongestant, 566, 955 decubitus, 144, 351, 353, 907 deep chalazion, 586 deep vein thrombosis, 179, 379–380, 383, 385, 387–388, 489, 915, 917 deficiency, 385, 387–388, 416, 427, 434, 887 deformation, 952 degeneration, 16, 28, 68, 72, 75, 215, 232, 309–310, 314, 479, 544–546, 561, 598–600, 605–606, 626, 632–635, 644, 678 degenerative joint disease, 302 deglutition, 633 degradation, 309, 328, 330, 386, 389–390, 427, 460, 494, 556, 600, 635, 661, 889, 894 dehydrogenase deficiency, 427 delirium, 351–352, 572, 642, 697, 749 delirium tremens, 749 delusions, 697, 733–737 dementia, 232, 315, 489, 496, 503–504, 513, 519, 555–563, 612, 633, 642, 644, 696–697, 795 demyelinating disorders, 536–537, 539, 541, 543, 554, 676–677, 679 demyelination, 410, 538, 552 denervation, 188, 634, 640 dental caries disease, 336 denture stomatitis, 339 dependent personality disorder, 729, 732 depersonalization/derealization disorder, 698–699 depression, 1–3, 5, 42, 70, 72, 99, 103, 315, 504, 541, 558–559, 612, 614, 618, 621, 644, 657, 696, 698–700, 708–711, 715–716, 735, 739, 741, 743–744, 748–749, 751–752, 754, 759–760, 796, 803, 956 derealization disorder, 698–699 dermabrasion, 658 dermatitis, 177, 183, 328–329, 566, 889 dermatitis herpetiformis, 328 dermatome, 670 dermatomyositis, 462 descending aorta, 9, 20



8



OSMOSIS.ORG



desmoplasia, 238 desquamation, 171 developmental delay, 712 developmental disorder, 711–712, 716, 943 dextro, 51, 53 dextrocardia, 283, 876 dextrose, 491, 767, 802, 809 diabetes, 1–2, 41, 45, 51, 56, 59–60, 64, 69–70, 105–108, 134, 137, 155, 213, 234, 242, 251, 291, 307, 309–310, 336, 349, 375, 411, 419, 473, 475, 488, 491, 498–500, 502, 521–522, 528, 552, 555, 562, 566, 600, 603, 606, 640–641, 646, 662, 666, 685, 710, 739, 741, 768, 781, 796, 800, 803, 806, 808–809, 814, 836, 854, 856, 859, 863, 897, 902, 905, 940–941, 945, 947 diabetes insipidus, 375, 528, 796, 808– 809, 940–941 diabetes mellitus, 1–2, 60, 64, 107, 134, 242, 251, 309, 336, 349, 473, 475, 488, 522, 552, 600, 603, 640, 710, 739, 741, 781, 856, 859, 947 diabetic nephropathy, 763, 835–836 diabetic retinopathy, 598, 603, 606, 685 dialysis, 351–352, 391, 764, 783, 789, 791–792, 794, 796, 802, 813, 828, 832, 845–846, 853, 855, 907 diamond-blackfan anemia, 368–369 diaphragmatic hernia, 362 diarrhea, 84, 160, 207, 209, 211–213, 229–230, 232, 238–239, 242, 248, 255–256, 258–261, 264–265, 267, 270, 275–276, 306, 327–332, 351–352, 355, 357–358, 409, 619, 659, 754, 763, 766, 801, 803, 806, 808, 810, 829–830, 927 diastolic heart failure, 36, 39, 59 diathesis, 483, 486 dic, 347, 385, 388–390, 396, 816, 830 differential diagnosis, 577, 666, 830 diffuse cortical necrosis, 865 diffuse esophageal spasm, 221 diffuse large b cell lymphoma, 398, 405, 407–408 digeorge syndrome, 45, 48 digital rectal exam, 243, 318 digitalis, 803 dilated cardiomyopathy, 34–35, 545–546, 749 dilatory dysfunction, 565–566 diphyllobothrium latum, 410 diplopia, 462, 494, 503, 531, 539, 631, 664, 684, 687 direct inguinal hernia, 271–273 dislocation, 601, 669 disorder, 19, 93, 98, 139, 187, 205, 221, 223, 229, 256, 268, 275–276, 278, 285–287, 328–329, 371, 375, 379, 384, 387, 391, 393, 422, 426, 432, 438, 444–445, 455, 475, 478, 515, 520, 542, 549, 559, 576–577, 579, 581, 584, 639–640, 644–645, 649–652, 655–656, 658, 662–663, 667, 671, 675, 690–692, 694–695, 698–699, 701–704, 707–713, 716, 718–719, 721–737, 739–743, 749–750, 752, 754–756, 759–761, 769, 773, 784, 787, 806, 809, 814,



818, 842, 848–850, 874, 887, 889, 894, 902, 943, 954 disruptive, impulse control, and, 713 disseminated intravascular, 279, 347, 385, 387–389, 396, 642, 816, 830, 865 disseminated intravascular coagulation, 347, 387–389, 396, 642, 816, 830, 865 dissociation, 192, 434, 560, 581, 676, 679, 759 dissociative amnesia, 698–699 dissociative disorders, 696–699 dissociative identity disorder, 698–699 distributive shock, 122–124, 824 ditp, 457–458 diuresis, 60, 806, 809, 813, 817, 908 diuretic, 39, 46, 58–61, 63, 70–71, 79, 82, 84, 102, 295, 299, 312, 478, 482, 484, 486, 495, 497, 499, 527, 538, 626–627, 629–631, 668, 709–710, 766–767, 783, 787, 794–796, 800, 802–803, 805–806, 809–810, 813, 817, 824–825, 835, 837, 842, 862, 868, 870, 914, 921 diurnal, 706, 743 diverticula, 227, 265–267, 773 diverticulitis, 244, 263, 265, 267, 323 diverticulosis, 266 diverticulum, 227, 238, 265–266, 274, 323–324 dizziness, 29–30, 45, 109, 130, 185, 192, 226, 374, 380–381, 413, 475, 480, 482, 489, 498, 531, 584, 613, 619, 687, 690, 692–693, 870, 940 dlb, 555–556 dmd, 34, 545 dna, 207, 229, 237, 290, 304, 371, 378, 386, 407, 409–410, 446, 452, 465, 545–546, 560, 649, 849, 877, 924 dna repair, 371, 649 dorsum, 106, 450 dot, 599 down syndrome, 48, 151, 318, 320, 325, 395–396, 556, 568, 623 downregulation, 748–750, 752, 754, 756 dr, 598, 603–604 dressler’s syndrome, 2, 97–98, 103 drug-induced, 337, 457, 626 drug-induced immune thrombocytopenia, 457 drusen, 599–600 dry beriberi, 573 dry eyes, 939–940 dry mouth, 343, 662, 766 dubin-johnson syndrome, 286 duchenne muscular dystrophy, 34, 545–546 ductus, 6, 11–12, 44, 49–52, 902 ductus arteriosus, 6, 11–12, 44, 49–52, 902 dumping syndrome, 230 duodenal adenomas, 209 duodenal intestinal atresia, 320–321 duodenal ulcer, 351, 353 duodenitis, 197 duodenum, 16, 143–144, 194–195, 210–211, 218, 230, 235, 245, 283, 296, 316, 320–322, 328, 333, 346 dupuytren’s contracture, 289, 298 dura mater, 483, 496, 502, 507, 512 duroziez’s sign, 66 dvt, 176–177, 179–181, 383–384, 386



Pathology Volume 1 Index dysarthria, 361, 489, 537, 539, 541, 633, 640–642, 664, 679 dyscalculia, 715 dysesthesia, 514, 522, 524, 552 dysgraphia, 715 dyskinesia, 565, 638, 645, 891, 949 dyslexia, 715 dyslipidemia, 41–42, 108, 488, 556 dyspareunia, 741 dyspepsia, 253 dysphagia, 69, 71, 216, 218, 220–222, 226, 244–245, 253, 338, 340, 363, 365–366, 462, 489, 504, 539, 633, 635, 640, 642, 649–650, 664, 933, 939, 947 dysphonia, 220, 361, 633, 642 dysplasia, 80, 130, 207–208, 217–218, 223, 231, 244, 423, 492, 514, 517, 521–522, 651, 677, 769, 863, 877, 903 dyspnea, 3–7, 9, 13, 22, 28–30, 35–36, 39, 41, 45, 48, 50, 57–60, 64, 66–67, 71, 79, 81, 83, 92, 100, 102, 104, 128, 130, 133–134, 146, 161, 168, 172, 179, 220, 226, 259, 362, 365, 380, 409, 412–413, 415–417, 421–423, 433, 436, 456, 461–462, 573, 628, 633, 641, 657, 828, 867–868, 870, 872, 878–881, 886, 889, 892, 894, 896, 899, 907, 910, 912–913, 915, 920, 925, 930, 932–933, 935–936, 939, 941, 951 dyspnoea, 21, 375 dyspraxia, 557 dystocia, 668, 670 dystonia, 433, 639, 644–645, 649 dystrophinopathies, 544 dysuria, 265, 448, 765, 779, 787, 819, 853, 856 e. coli, 195, 198, 200, 203, 300, 331, 352, 507, 509, 566, 829–830, 853, 856 ear, 341, 476–478, 480, 501, 507, 517, 553, 564–571, 591, 622–624, 626–627, 659, 927, 954, 956 ear infection, 501, 626 ear pathology, 564–565, 567, 569, 571 ear, external, 570 ear, middle, 564 eardrum, 564, 566, 569–570 early dumping syndrome, 230 eating disorders, 416, 709 ebv, 340, 377, 402, 406, 505, 926 ecchymosis, 423, 496 ecg, 2–3, 5, 9, 11, 13, 17, 20–26, 28, 33, 37, 39, 42–44, 46, 49–50, 57, 61, 63, 70–72, 91, 97, 99, 101, 103–104, 112–120, 122, 125, 128–130, 132–134, 136–137, 139–140, 153–154, 171, 185–186, 188–192, 211, 490, 494, 794, 796, 799, 801–803, 805–806, 899–900, 912, 917–918, 920, 942 echocardiography, 8, 37, 43, 48, 50, 57–59, 61, 63, 66, 69, 71–72, 76, 99, 101, 124,171, 370 echolalia, 716 echopraxia, 716 echovirus, 953 eclampsia, 80, 576–577, 579, 583, 865 ect, 701, 939 ectopic, 117–118, 120–121, 188, 192,



247, 263, 323–324, 521, 684, 844, 847, 924 eczema, 375 eeg, 504, 506, 572, 574, 577–579, 582–584 ef, 55, 57, 59 effacement, 490, 531, 628, 837, 842–843 effusion, pleural, 430 egd, 209, 215, 298 ehec, 829 ehlers-danlos syndrome, 16, 68, 266, 493, 514 ejaculation, 742 ejaculatory, 741 ejection click, 45, 66, 74, 76 ejection fraction, 35, 37, 55, 59–60, 66, 137 ekc, 589–590 ekg, 801 el escorial criteria, 633 elbow, 92, 669, 674 electric shock, 541 electrocardiogram, 42, 66–67, 93, 113, 127–128, 130–131, 137–138, 190, 641 electroconvulsive therapy, 643, 696, 701 electroencephalogram, 572, 577 electrolyte, 23, 108, 117–118, 120, 130, 139, 185, 187–188, 190–192, 228–229, 269–270, 276, 280, 330, 364, 576, 579, 643, 697, 708–709, 762–763, 766, 783, 808–809, 877 electrolyte imbalances, 23, 117–118, 120, 130, 187, 192, 576, 579, 643, 766, 783 electromyogram, 641, 661, 663 electron microscope, 825, 835, 837 electron microscopy, 333, 826, 828, 831, 841–843 electrophoresis, 419, 436, 460 elephantiasis, 95 elimination disorders, 705 elisa, 271, 305, 456, 830 embolism, 8, 24, 29, 56, 58–59, 69, 71, 86, 122, 124, 129, 133, 179, 181–182, 276, 280, 383, 385, 488–489, 838, 871, 907–908, 912, 915–918 embolization, 147, 180, 225, 484, 562, 658, 844, 846 embolus, 105, 488, 490–491, 766, 915–916, 918 embryonic development, 874 emesis, 144, 235, 269 emg, 632, 634, 636, 666–667, 670, 676, 678–679 emphysema, 220, 872, 886–888, 896–898 empyema, 502, 592, 907–908 encephalitis, 505–506, 508, 549, 576, 579–580, 583 encephalomyelitis, 505, 537 encephalopathy, 83, 205, 284–285, 289, 294, 298–299, 311, 313, 351–352, 503, 537, 549, 572–576, 579, 583, 612, 628, 642, 686, 749, 763, 887–888 encopresis, 705 end-stage renal disease, 842, 845, 907 endarterectomy, 106, 109, 156, 491, 499 endocardium, 38, 85–86, 89 endocrine disorders, 84 endocrinology, 372 endometriosis, 263, 273, 351–352



endometrium, 92 endophthalmitis, 590, 592, 601 endoscopy, 161, 208–209, 211–213, 216, 220–222, 225, 227–228, 230, 234, 236, 238–239, 255, 257–258, 261, 298, 311, 331, 350, 565, 927, 949, 956 endothelial, 66, 74, 79, 86, 107–108, 149–151, 157–158, 160, 162, 168, 170, 176, 389, 433, 436, 459, 467–468, 538, 598, 654–655, 781, 816, 829–830, 876, 915, 919 enophthalmos, 474, 670 enoxaparin, 5 enterobacter, 195, 331, 853 enterococcus, 86, 195, 853 enterocolitis, 278–279, 318 enteropathy, 259, 328 enterovirus, 505, 511 enucleation, 608 enuresis, 705–706, 746–747 enzyme-linked immunosorbent assay, 271, 305 eosinophil, 124 eosinophilia, 166, 232, 768 ependymoma, 529–530 epicardium, 85 epidemic keratoconjunctivitis, 589 epidermis, 567 epididymis, 939 epidural, 483–484, 500–501, 507–508, 592, 614, 681 epidural abscess, 501, 507, 681 epidural hematoma, 483–484 epigastrium, 322 epiglottis, 883, 947, 957–958 epiglottitis, 947 epilepsy, 146, 496, 510, 515, 576–584, 655, 658, 716 epileptic seizure, 576, 578 epinephrine, 130, 188, 225, 803, 884 epiphysis, 419 episiotomy, 740 epispadias, 769–770, 783 epistaxis, 374, 380–381, 391–395, 397–398, 438, 442, 445–446, 455, 458–459, 927, 939 epithelial, 200, 205, 207, 231, 240, 242, 252, 259, 307, 416, 461–462, 528, 530, 591, 601, 767–768, 815–817, 841, 845–846, 850–851, 879, 883, 889, 894, 905, 923, 949 epo, 379–380, 783, 844 epstein-barr virus, 377, 540, 926, 953 erb-duchenne palsy, 668 erectile dysfunction, 433, 436, 473, 742 erythema, 92–93, 96, 171, 173, 232, 256, 260–261, 268, 272, 277, 279, 289, 567, 586, 590, 594–595, 597, 939–941, 954 erythema nodosum, 173, 256, 260–261, 939–941 erythroblastosis, 429 erythroblastosis fetalis, 429 erythrocyte, 87, 93, 103, 162, 258, 261, 370, 411–412, 417, 419, 421–423, 432, 437, 768, 917 erythromycin, 190 erythroplakia, 250 erythropoietin, 370, 379, 421–422, 658, 763–764, 783–784, 786, 844, 847,



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870 escherichia coli, 829, 853 esophageal, 197, 215–227, 244–245, 289, 294, 298, 311–313, 315, 319, 363, 366–367, 416, 433, 874, 887, 908, 933 esophageal achalasia, 215 esophageal aperistalsis, 215 esophageal cancer, 216, 244 esophageal disease, 215, 217, 219, 221, 223, 225, 227 esophageal varices, 289, 298, 311–313, 315, 433, 887 esophageal web, 226, 244, 363 esophagitis, 217, 219, 222–223, 229, 244 esophagogastroduodenoscopy, 209, 215, 218, 226, 253, 298 esophagram, 220 essential thrombocythemia, 374, 381 essential thrombocytosis, 374 essential tremor, 639 estrogen, 147, 176, 181, 204, 296, 307, 450, 492, 741, 744, 856, 860, 915–917 euphoria, 619, 735 eustachian tube, 564–565, 568, 623 eustachian tube dysfunction, 564–565, 568, 623 exanthem, 954 excess vitamin d, 795 excoriation disorder, 718 exertional dyspnea, 48, 60, 66, 433 exocrine, 251, 302, 349, 411, 938, 940 exogenous, 755, 816, 903 exon, 635–636 exostoses, 623 external auditory canal atresia, 623 external ear, 567, 624 external jugular vein, 63 extrahepatic cholestasis, 296 extrahepatic metastasis, 248 extraorbital extension, 592 extrasphincteric, 356 exudative armd, 599–600 eye, 164, 256, 275, 315, 469, 474–475, 477, 489, 494, 503, 517, 541, 553, 559, 585, 587, 589–593, 595, 597–602, 604–606, 608, 613, 619, 641, 648–649, 652–653, 665, 670, 685, 688, 745, 943 eye infections, 585, 587, 589, 591, 593, 595, 597 eyelid, 462, 534, 553, 578, 586–587, 589, 594–595, 602, 617, 657, 664, 670 facial nerve, 340, 479, 552–553, 798, 806, 813 factitious disorder, 707, 761 factitious disorder by proxy, 707 factitious disorder imposed on another, 707 factor v leiden, 176, 181, 276, 386, 915 factor viii, 391–393, 497 failure to equalize, 565 failure to thrive, 6–7, 9, 13, 44–45, 48, 50, 328, 330, 760 failure, heart, 85 fainting, 28, 576 false (pseudo-) diverticulum, 266 false lumen, 19–20 false negative, 305 false positive, 384 familial adenomatous, 209–210, 242, 247



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familial adenomatous polyposis, 209–210, 242, 247 familial hemiplegic migraine, 618 fanconi anemia, 368, 371, 410, 423 fap, 209–210 fascia, 219, 271, 950 fasciitis, 954 fatty acids, 291, 309, 797 favism, 427–428 fcjd, 503 febrile, 576, 580–581, 774 febrile seizure, 580 fecal incontinence, 358, 483, 557, 769 fecal occult blood test, 213 fecalith, 264 feces, 356, 705 female sexual interest/ arousal disorder, 740 femoral, 9, 15, 49, 66, 105, 165, 179, 268 femoral artery, 66, 105, 165, 268 femoral hernia, 268 femoral vein, 268 fenestration, 631 ferritin, 208–209, 211–213, 292, 302, 417, 419, 422 fertile, 204, 631 fetal development, 45, 320, 418, 769, 784 fetal distress, 900 fetal hemoglobin, 370 fetal movement, 877 fetus, 320, 389–390, 429, 771, 900 fgf, 876 fhm, 618 fiber, 218, 356 fibrillation, 130, 134 fibrin, 162, 389 fibrinogen, 390 field effect, 778 filariasis, 95 fine needle aspiration, 254, 461, 924, 928 fish, 377, 400, 410, 440, 849 fish tapeworm, 410 fistula, 256, 265, 356, 366 fitz-hugh-curtis syndrome, 300 flatulence, 204 flexion, 674, 784 floaters, 587 flow cytometry, 433, 445–446, 458, 941 flu, 948 fluorescence in situ hybridization, 849 fluoroscopy, 220, 363–364, 366 focal (partial) seizures, 578 focal aware seizure, 578–579, 581 focal impaired awareness seizure, 578–579, 581 focal segmental glomerulosclerosis, 837 focal seizure, 581 folate, 226, 253, 331, 360–361, 409–410, 431, 434, 522 foley catheter, 765 folic acid, 420, 427–428, 432–433, 435–436 follicle, 938 follicle-stimulating hormone, 938 follicular lymphoma, 405 fontanelle, 516, 531, 614 food poisoning, 224 foramen, 45, 50–51, 365, 470, 488, 514–515, 530, 629, 671, 872 foramen magnum, 470, 514–515, 629 foramen magnum meningiomas, 470



foramen ovale, 45, 51, 488 forearm, 96, 164, 441, 667, 669, 673 foregut tumors, 238 foreskin, 770, 856 foster-kennedy syndrome, 469 fourth ventricle, 514, 517–518, 529, 531–532 fracture, 123, 338, 390, 482–484, 501–502, 521, 591, 612, 614, 626, 629, 651, 669, 916 frank-starling, 55 free radical, 314, 626 friedreich’s ataxia, 36, 638, 640 frontal lobe, 471, 495, 502, 560 frontotemporal dementia, 555, 560 frontotemporal lobar dementia, 633 ftld, 633–634 functional asplenia, 452 fundic gland polyps, 209 fundoplication, 224 fundus, 230, 232, 245, 601 fungal keratitis, 590 fungal meningitis, 512 fungus, 892 furosemide, 11, 626, 631, 813, 825, 835, 842 furuncle, 502 fusiform, 15 g6pd, 427–428 g-dif, 252, 254 g-int, 252, 254 galactosemia, 298, 600 gallbladder, 194–195, 197–201, 203–205, 240, 245–246, 251, 283–287, 297, 301 gallbladder attack, 197 gallbladder cancer, 200, 204, 245 gallium, 941 gallstone, 197, 203, 269–270, 297, 425, 434 gallstone ileus, 269 gamma knife, 617 ganglion, 215–216, 474, 604, 616–617 gangrene, 106, 165, 179, 456 gardner’s syndrome, 210 gardnerella vaginalis, 300 gas, 60, 62, 105, 144, 157, 269, 275–276, 278–279, 329–330, 351, 353, 364, 414, 568, 606, 867–869, 871–872, 886, 896, 900, 905–906, 910, 913, 917, 919, 935–936, 953–955 gastrectomy, 409 gastric, 187, 209, 216, 219, 222–223, 228–236, 252–253, 279, 294, 321, 323–324, 330, 364, 366, 380, 410, 416, 433, 565, 635–636, 640, 643, 868 gastric atrophy, 231, 416 gastric cancer, 252 gastric carcinoma, 231, 253 gastric disease, 228–229, 231, 233, 235 gastric dumping syndrome, 230 gastric emptying study, 230 gastric ulcer, 231, 236 gastritis, 223, 231–233, 235, 238, 252 gastroenteritis, 270, 275, 763 gastroesophageal reflux, 222 gastroesophageal reflux disease, 222 gastrointestinal cancers, 237, 239, 241, 243, 245, 247, 249, 251, 253 gastrointestinal disorders, 278



Pathology Volume 1 Index gastrointestinal tract, 161, 270, 278, 316, 327, 360, 885 gastroparesis, 234 gastroschisis, 316–317 gastrostomy, 636 gene deletion, 848 gene expression, 531 gene mapping, 400 gene marker, 532 generalized anxiety, 691–692 generalized anxiety disorder, 691 generalized seizures, 578–579 genetic counseling, 370, 659 genetic disorders, 45, 65, 240, 360, 915, 952 genetic mutations, 34, 36, 147, 151, 207, 251, 283, 418, 438, 440, 576, 638, 676–677, 806, 823, 846, 850–851, 902 genital, 164, 740 genitalia, 682, 770, 849 genito-pelvic pain and/or penetration disorder, 740 genitourinary, 238, 392, 436, 445–446, 848–849, 956 genome, 648, 659 genotype, 250 gerd, 222, 244 germ cell, 534, 684 germ cell tumor, 684 german measles, 45 gestation, 297, 316, 363, 430, 773, 784, 876, 900 gestational diabetes, 45 gi tract, 160, 212, 238, 259–260, 352, 407, 417, 763, 810, 813–814 giant cell arteritis, 155, 167–168, 488 gilbert’s syndrome, 287 gingiva, 161, 250, 341 gingivitis, 337–338, 341, 375 glanzmann’s thrombasthenia, 445 glaucoma, 370, 597–598, 601, 603–605, 609, 655, 659, 685, 849 gliadin, 328 glial cell, 465, 534 glial cell tumors, 534 glioblastoma multiforme, 465–466 glioma, 209, 651, 653 gliosis, 561, 632 globe pathology, 598 globus, 574, 646 globus pallidus, 574, 646 glomerulonephritis, 85, 87, 168, 172, 763, 767–768, 825–828, 832, 835, 838, 840–843, 954 glomerulosclerosis, 763–764, 835, 837 glomus tumors, 159 glossitis, 226, 232, 363, 416 glottis, 219 glucocorticoid, 99, 222, 441, 458, 460, 538, 543, 545–546, 589, 600, 617, 794, 796, 895 glucose, 107, 109, 230, 302, 307, 330, 413, 419, 427–428, 466, 487, 490, 501, 505, 511, 549, 556, 573, 576, 579, 584, 598, 604, 612, 763, 767, 802, 809, 836, 901, 903, 905, 908, 924, 931 glucose-6-phosphate, 413, 427–428 glucose-6-phosphate dehydrogenase, 413, 427



gluten, 328 gluten-sensitive enteropathy, 328 glycogen storage disease, 247, 291, 307 glycogen storage disease type i, 307 gonadotropin, 247 goodpasture’s syndrome, 767, 825, 832, 828–829 gorlin syndrome, 531 gout, 377, 379, 785–786, 819 gouty arthritis, 820 graft, 10, 17, 154, 423–424, 624 grand mal seizure, 584 granulation, 2, 345, 377, 496, 507, 564, 568–569 granulocyte, 372, 377, 423 granuloma, 93, 256–257, 294, 941 granulomatosis with polyangiitis, 168–169, 172 graves disease, 462 gray matter, 488, 504 gross hematuria, 820 group a streptococcus, 93, 568, 826, 953 group b streptococcus, 452, 509 group therapy, 491, 728–731, 733, 735–737, 761 growth factor, 108, 210, 349, 465, 467, 598, 654, 763, 876, 927, 938 growth hormone, 504, 521, 655 guanine, 655 guillain-barré syndrome, 676, 678 gynecomastia, 289 h. pylori, 231–233, 235, 252, 406 hakim’s syndrome, 519 halitosis, 222, 227, 342, 951 hamartoma, 31, 656, 845 hamartomatous polyps, 207 hard palate, 161, 250, 361 hashimoto’s thyroiditis, 293, 662 hav, 305 hb, 418 hbs beta thalassemia, 435 hbsa, 435 hbsc, 435 hbsd, 435 hbse, 435 hbso, 435 hbss, 435 hbv, 173, 304–305 hcg, 535 hcm, 36 hcv, 173, 305 hdl, 41, 108, 314, 498 head injury, 477, 493, 507, 611–615 headache, 21, 28, 79, 81, 83, 146, 164, 167, 229, 374, 380–381, 413, 417, 433, 442, 459, 464, 466, 474, 483, 485–486, 494, 496–497, 500–501, 503, 505, 507, 510–511, 526, 528–529, 531, 533–534, 537, 592, 604, 611, 613, 616–622, 628, 631, 653, 684, 689, 691, 826, 870–872, 927, 940, 945, 949, 952, 954 headache, cluster, 616 hearing aids, 624, 627, 698 hearing loss, 187, 442, 476–481, 498, 564–570, 622–623, 625–627, 653, 659 heart attack, 64, 748, 752, 756 heart block, 21–25, 27, 85, 111, 938 heart failure, 2, 6, 9, 11, 13, 22, 29, 33–34, 36, 39, 43–44, 46, 55–57, 59–66,



69–76, 83–85, 88, 90–91, 93, 97, 102, 104, 108, 131, 133–134, 136–137, 145–146, 166, 179, 311, 412, 416, 418–419, 436, 544–545, 573, 640, 709, 763, 766, 790, 798, 810, 816, 868, 907–908, 913, 919–920, 938, 945 heart murmur, 38, 72 heart transplant, 33, 35, 37, 39, 44, 58, 61, 91, 94 heart valve, 64–65, 67, 69, 71, 73, 75, 77, 84, 86–87, 94 heart valve disease, 64–65, 67, 69, 71, 73, 75, 77, 84 heartburn, 144, 216–218, 222, 804 helicobacter pylori, 217 hemangioblastoma, 467–468 hemangioma, 147–150, 485 hemarthrosis, 391–392 hematemesis, 218, 225, 232, 236, 253, 289, 311, 416 hematocrit, 108, 122, 124, 220, 225, 280, 370, 380, 410, 416, 423, 426, 430, 436, 460, 766 hematoma, 269, 392, 454, 483–486, 496–497, 514, 614–615, 681 hematopoiesis, 247, 369–370, 373, 378–379, 419, 432, 439 hematuria, 89, 142, 168–170, 172, 391, 416, 436, 445–446, 458, 762, 765, 767–768, 776–777, 779, 784, 786–787, 790, 815, 820, 822, 824–826, 828, 830–832, 838, 840, 844, 847, 850, 854, 856, 863, 865 hemianopia, 528, 619, 687 hemiparesis, 156, 489, 496–497, 548, 655, 680–681 hemiplegia, 19, 498 hemithorax, 362 hemochromatosis, 28, 34, 38–39, 60, 248, 297–298, 302–303, 411–412, 449 hemodialysis, 87, 276, 280, 304–305, 762, 764–765, 768, 796, 802, 805, 863, 866 hemoglobin, 108, 220, 225, 277, 302, 370–371, 380, 410–419, 422–423, 425–428, 430–431, 433, 435–436, 460, 870, 913 hemoglobin a, 435 hemoglobin f, 436 hemoglobin s, 435 hemoglobinuria, 73, 423, 425–426, 428, 432–434, 816 hemolysis, 203, 286–287, 377, 390, 410, 412, 417–419, 425–437, 442, 459–460, 801, 813 hemolytic anemia, 73, 83, 315, 390, 398, 425, 427, 432, 434–435, 459, 830 hemolytic anemias, 302 hemolytic-uremic syndrome, 816, 829 hemophilia, 391–392 hemophilia a, 391 hemophilia b, 392 hemoptysis, 146, 168, 172, 828, 881, 892, 894, 915, 917, 923, 928, 930, 932, 939 hemorrhage, 2, 16, 39, 60, 84, 87, 122, 146–147, 166, 174, 232, 247, 269, 277, 279–280, 345, 347–348, 377, 389, 391, 416, 423, 429–430, 442, 444, 446, 456, 458, 467, 480,



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485–487, 492–495, 507, 515, 533, 547–548, 550, 556, 587, 599, 603–604, 611–615, 628–630, 752, 766–767, 844–845, 872, 903, 917 hemorrhagic shock, 124, 614 hemorrhagic stroke, 16, 435, 482, 490, 687–688 hemorrhoid, 357–358 henoch-schönlein purpura, 162, 170, 832 heparin, 3, 5, 70–71, 89, 176, 180, 182, 385, 387, 455–457, 486, 499, 835, 842, 917–918 heparin-induced, 455–456 heparin-induced thrombocytopenia, 455 hepatic, 50, 148–150, 199, 201, 238–240, 247–248, 259, 284, 286–287, 289, 291–292, 294–299, 307–310, 312–313, 375, 377, 384, 386, 411, 433, 573, 576, 579, 583, 790, 810, 818, 887–888, 939–940 hepatic duct, 240 hepatic encephalopathy, 284, 289, 299, 573, 583, 887–888 hepatitis, 124, 173, 240, 248, 250, 290– 294, 297–299, 304–306, 308, 423, 442, 449, 457, 768, 840–842, 887 hepatitis a, 290, 292, 308 hepatitis b, 173, 248, 290, 292, 297–299, 304, 840–842 hepatitis c, 173, 250, 290–292, 297, 305, 449, 457, 840, 842 hepatitis d, 248, 290 hepatitis e, 306 hepatoblastoma, 209, 247 hepatocellular adenoma, 307–308 hepatocellular cancer, 419 hepatocellular carcinoma, 29, 205, 248–249, 291, 293, 298, 304–305, 310, 380, 448–449, 887 hepatocellular cholestasis, 296 hepatolenticular degeneration, 314 hepatomegaly, 6, 57–58, 90, 240, 251, 289–291, 294, 304–306, 308, 310, 400, 418, 433, 442, 913, 919, 940 hepatorenal syndrome, 294 hepatosplenomegaly, 62, 64, 102, 205, 286, 293, 315, 375, 380, 394–395, 397–398, 412, 419 hereditary chronic pancreatitis, 349 hereditary hemochromatosis, 248, 297 hereditary hemorrhagic telangiectasia, 146 hereditary spherocytosis, 431–432 heritable, 607 heritable retinoblastoma, 607 hernia, 217, 222, 224, 244, 263, 268–269, 271–273, 280, 316, 354, 362–363, 769, 876 herniation, 266, 322, 325, 362, 464, 466–467, 469, 479, 483, 488, 494, 496, 507, 510, 614–615, 629–630, 671, 681–682, 769, 810 heroin, 837 herpes, 335, 355, 423, 474, 480, 505, 549, 552, 587, 590, 602, 626, 781–782, 798, 953 herpes simplex encephalopathy, 549 herpes simplex virus, 505, 587, 953 herpes zoster, 474, 480, 552, 590 heterochromia iridis, 474 heterogenous dementia, 562 heterozygous, 388, 434–435, 848, 887



12



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hev, 306 hfpef, 55, 57, 59–60 hfref, 55, 60 hhv, 160 hiatal hernia, 217, 222, 244 hib, 511, 947 high blood pressure, 2, 28, 69–71, 80–81, 105, 107, 137, 213, 659, 790, 792, 850, 931 hill’s sign, 65 hindgut tumors, 238 hippocampus, 549, 557–558, 696 hirschsprung’s disease, 281, 318 histamine, 238, 380, 745, 889, 920 histiocytosis, 375–376, 936–937 histiocytosis x, 375, 937 histrionic personality disorder, 724, 727 hit, 309, 455–456 hitt, 455 hiv, 90, 142, 157, 160–161, 173, 291, 305, 338–339, 341–342, 388, 402–404, 423, 442, 449, 457, 473, 500, 505, 616, 678, 763, 837, 919–920, 953 hiv infection, 338, 388, 473, 919 hiv/aids, 142, 161, 339, 341, 920 hla, 205, 232, 293, 328, 445–446, 540, 828, 841 hodgkin’s lymphoma, 403–405, 453, 662 holosystolic, 11, 13, 35, 48, 69, 76 holosystolic murmur, 13, 35, 48, 69, 76 holter monitor, 28, 117–118, 121, 562 homocysteine, 232, 410 homonymous hemianopsia, 485–486, 489, 629, 688 hookworm, 416 hormone replacement therapy, 522 hormone secretion, 763, 810, 847, 924 hormone, thyroid, 938 hormone, thyroid-stimulating, 938 horner’s syndrome, 474, 670, 923, 930 horseshoe kidney, 370, 783–785, 819 hpv, 250, 355, 778 hs, 109 hsv, 505–506, 511–512, 552, 587, 589–590, 597 ht, 238, 904 human herpesvirus 8, 160, 466 human papillomavirus, 250, 355, 778 human t-lymphotropic virus, 407 humor, 591, 597, 604–605, 731 hyaline arteriolosclerosis, 15, 107, 485 hydrocele, 272 hydrocephalus, 371, 464, 466–467, 469, 479, 485, 493–495, 505, 510, 514, 516–519, 522–523, 528–529, 531, 534, 628, 655, 657 hydrogen breath test, 230 hydronephrosis, 764–765, 771–774, 784, 819–820, 876 hydrops fetalis, 418–419, 429–430, 875 hyperactivity, 93, 494, 651, 711–712, 735, 849 hyperacute bacterial conjunctivitis, 588 hyperacute conjunctivitis, 590 hyperaldosteronism, 80, 803 hyperbaric oxygen therapy, 348, 491, 502, 872 hyperbilirubinemia, 249, 251, 283, 285–287, 429–432, 521 hypercalcemia, 117, 248, 347, 439–441, 579, 794–797, 799, 806, 847, 939



hypercalciuria, 439, 787, 795–796, 818, 824, 939 hypercapnia, 893, 905, 910, 943–944 hypercholesterolemia, 313 hypercoagulable disorders, 383, 385, 387 hypercoagulable state, 384, 386 hyperemesis gravidarum, 224 hyperglycemia, 482, 488, 490, 579, 603, 809, 836, 856 hyperhidrosis, 473 hyperkalemia, 22, 129–130, 786, 800–803, 805, 865 hyperlipidemia, 16, 64, 105, 310, 313, 562, 599, 835, 837, 840, 842–843 hypermagnesemia, 804–805, 807 hypernatremia, 808–809, 811 hyperopia, 604 hyperparathyroidism, 763, 795–796, 798, 813–814, 819 hyperphosphatemia, 797, 812–813 hyperpigmentation, 160, 176–177, 332 hyperplasia, 107, 223, 232, 264, 274, 328, 358, 412, 419, 461, 684, 764, 771, 893–894 hyperplastic arteriolosclerosis, 107 hyperprolactinemia, 521, 741 hypersensitivity, 90, 92, 275, 537, 540, 604, 619, 621, 662–663, 730, 743, 767–768, 826, 828, 838, 889, 891, 927, 931, 936 hypersensitivity pneumonitis, 936 hypersomnia, 528 hypertension, 9, 11, 13–14, 16, 19, 24, 34, 41, 45, 50, 55–56, 58–60, 64–65, 69–72, 75, 79–81, 83, 107–109, 120, 134, 136, 142, 168, 174, 205, 225, 235, 283–284, 289, 294, 298, 309, 311–312, 314–315, 338, 357, 362–363, 379–380, 384, 436, 447–448, 456, 482, 485–486, 488, 490–494, 498, 556, 562, 597, 599, 603–604, 628, 631, 650, 679, 763, 766, 768, 774, 790–792, 796, 816, 825–826, 832, 836, 838, 840, 846–847, 850, 854, 863–864, 887, 893–894, 896, 899–900, 912–913, 917, 919–922, 938, 945 hypertension, pulmonary, 136 hyperthermia, 642–643, 752 hyperthyroid, 56, 133–134, 137, 139 hypertonic solution, 431 hypertriglyceridemia, 310, 347, 810 hypertrophic cardiomyopathy, 36–37, 41, 130, 640 hypertrophic pyloric stenosis, 364 hypertrophy, 9, 11, 13, 36–37, 41, 44, 46, 48–50, 56, 58–59, 61–62, 65–67, 69, 71, 73–75, 81, 209–210, 357, 364, 488, 546, 655, 763, 772–773, 792, 859, 886, 892–894, 896, 899, 919–920, 953 hyperuricemia, 379, 785–786, 819 hyperventilation, 575, 578, 580, 629–630, 870, 896, 917, 944 hypervitaminosis, 795 hypnotics, 222, 697 hypo, 79, 373, 644, 938 hypoactive sexual desire disorder, 741 hypocalcemia, 187, 190, 192, 763, 794– 795, 797–799, 804, 806, 813 hypocoagulable disorders, 389, 391, 393



Pathology Volume 1 Index hypoglycemia, 129, 230, 248, 302, 499, 505, 521, 572, 575–576, 579, 903 hypogonadism, 940 hypokalemia, 117, 129–130, 187, 190, 192, 800–801, 803, 806, 814, 824 hypomagnesemia, 117, 187, 190, 192, 797–799, 803–807 hypomania, 700 hyponatremia, 259, 298, 494, 499, 538, 579, 808–811 hypoparathyroidism, 796–798, 813 hypophosphatemia, 812–814 hypopituitarism, 502, 521, 528, 940 hypoplasia, 362, 423, 478, 517–518, 521, 773, 792, 875–877 hypoplastic left heart syndrome, 43–44 hypopyon, 590, 597, 602 hypospadias, 769, 783, 849 hyposplenism, 435, 452 hypotension, 9, 16, 19, 57, 66, 79, 81, 83–84, 100, 122–125, 139, 187, 196, 225, 276, 280, 307, 453, 475, 496, 559, 644, 679, 709, 766, 798, 809, 903 hypothalamus, 474, 616–617, 642, 750 hypothermia, 129 hypothyroidism, 100, 655, 810, 940, 944 hypotonia, 635 hypoventilation, 58, 679, 920, 957 hypovolemia, 84, 129, 269, 280, 352, 475, 766, 809–811, 820, 824 hypovolemic shock, 122–124, 453 hypoxemia, 57, 124–125, 179, 194, 417, 436, 630, 867, 870, 880, 893–894, 896, 900, 902, 905, 915, 917, 936, 943–944, 957 hypoxia, 11, 107, 129, 149, 179, 185, 278, 280, 360, 380, 390, 410, 412–413, 417, 419, 421–422, 429, 467, 485, 487, 516, 576, 578, 614, 655, 658, 816, 878, 880, 883, 891–893, 900, 903, 905, 919 hysterectomy, 446 iatrogenic, 21–22, 24, 104, 160, 230, 234, 351, 353, 501, 503, 507, 570, 685, 805, 809, 815, 910 ibd, 263, 355 ibs, 275 ibuprofen, 581, 620, 624, 685 icjd, 503 icterus, 304–306, 431, 434 id, 34 idiopathic, 21–22, 34, 65, 79, 98, 100, 102, 104, 117, 234, 258, 274, 308, 334, 347, 349, 373, 378, 384, 423, 429, 435, 457, 478, 498, 513, 519, 552, 576, 578, 628, 631, 638, 644, 646, 666, 675, 740, 832, 840–841, 876, 919, 936–937 idiopathic intracranial, 628, 631 idiopathic pulmonary fibrosis, 936 iga, 170, 328, 330, 425, 438–440, 650, 767, 825, 828, 831–832 iga nephropathy, 170, 767, 825, 831 igd, 438 ige, 589, 768 igg, 172, 290, 292, 304, 328, 349, 425– 426, 429–430, 438–440, 455, 457, 459, 549, 650, 679, 826, 828–829, 831, 840 igm, 206, 290, 304, 306, 314, 341, 406,



425–426, 438–439, 442, 549, 826, 828, 831, 837 igm mgus, 438–439 il, 168, 421–422, 439, 537, 540, 847, 867, 889, 896, 941 ileum, 238–239, 256, 270, 278, 320, 323 ileus, 269, 278, 280, 322, 351–353, 679, 803 iliac, 15, 105–106, 183, 264 im, 620 imagery, 746 immune response, 256, 332, 337, 429, 505, 709, 883, 953–954 immune system, 90, 161–162, 164, 173, 264, 278, 296, 304–305, 391, 483, 831, 847, 885 immune thrombocytopenia, 445, 457 immune thrombocytopenic purpura, 457 immunization, 451, 511, 843 immunocompromised, 86, 160–161, 270, 500–501, 507, 510, 585, 589–590, 595, 854, 882 immunoglobulin e, 589 immunoglobulin g, 349, 679 immunohistochemistry, 332, 375 immunosuppression, 98, 161, 250, 293, 338–339, 341, 370, 501–502, 505, 568, 842 immunotherapy, 399, 665, 924 imperforate anus, 283, 319, 371 impetigo, 826 impotence, 559 in situ hybridization, 400, 440, 849 incontinence, 228, 232, 258, 260, 319, 358, 483, 519, 541–542, 557, 559, 581, 584, 643, 653, 680, 682, 765, 769, 781–782, 856, 858–861 increased intracranial pressure, 501, 514, 526, 628–629, 631 indigestion, 3, 346 indirect inguinal hernia, 271–273 infant, 48–49, 150, 296, 361, 614, 657, 669, 884, 900, 903–904, 957 infant respiratory distress syndrome, 900 infarct, 2–3, 488, 555, 916, 918 infarction, 2–3, 5, 17, 20, 24, 29, 55–56, 62, 69, 75, 83–85, 97, 100, 102–103, 108, 117, 120, 129–131, 137, 154, 166, 171, 179, 185, 187, 192, 213, 235, 274, 276, 280–281, 316, 379, 384, 435–436, 452, 456, 480, 486–488, 490, 498–499, 515, 619, 630, 683, 686, 907–908 infected mucocele, 591 infections, 7, 13, 21, 46, 50, 85, 87–94, 97, 102, 160, 170, 203, 215, 229, 261, 278, 283, 294, 336, 338, 345, 355, 366, 371, 377–378, 390, 394–395, 397–398, 400, 407, 416, 423–424, 426–427, 431–434, 439–441, 443, 451, 457, 476, 500–501, 503, 505–507, 509, 511, 515, 536–537, 540, 542, 555, 580, 585, 587, 589, 591, 593–595, 597, 600, 623–624, 626, 650, 697, 745, 751, 776–777, 781, 787, 792, 819, 829, 831, 835, 842, 853–857, 861, 868, 875, 878–879, 881, 883, 885, 889, 891, 893–895, 927, 938, 944, 949–950, 952, 955 infectious mononucleosis, 453



infective, 85, 215, 488, 827, 878 infective endocarditis, 16, 65, 69–70, 73–76, 85–86, 88–89, 213 inferior quadrantanopia, 687 infertility, 894, 939 inflammation, 85 inflammatory bowel disease, 255 infratentorial herniation, 483, 496, 629 inguinal, 268, 271–273, 407, 651, 769 inguinal canal, 272 inguinal hernias, 271–272 inheritance, 159, 209, 211–212, 252, 285–287, 411, 418, 436, 444–445, 503, 534, 544, 618, 620, 639–640, 677, 848 inner ear, 476–478, 565, 622, 626 inotropic agents, 46, 766 inotropy, 55 inr, 241, 290, 830 insomnia, 435, 534, 647, 691, 744, 756, 796, 945 insulin, 230, 242, 309–310, 490, 562, 649, 708, 800, 802–803, 814, 902, 938 intention tremor, 541, 639 interferon, 150, 164, 256, 299, 304–305, 328, 374, 380–381, 421, 540, 847 interleukin, 421, 439, 847, 889 intermediate uveitis, 597 intermittent bundle branch block, 24 intermittent claudication, 105 internal jugular vein, 151, 502 interstitial lung disease, 649, 920, 942 interventricular septum, 14, 36–37 intervertebral disc, 682 intestinal adhesions, 273, 281 intestinal atresia, 283, 320–321 intestinal gas, 364 intestinal malrotation, 274, 281, 322 intestinal obstruction, 143, 212, 256, 265, 268, 272, 275, 281, 320 intestine, 198, 200, 230, 260, 266–267, 269–270, 274–275, 280, 296, 302, 316, 318, 320, 322–323, 328, 330, 332, 346, 362 intracerebral hemorrhage, 391, 485, 487 intracranial epidural abscess, 507 intracranial epidural hematoma, 483 intracranial hemorrhage, 87, 423, 611–612, 614, 903 intraepithelial, 232, 238, 258–259, 314 intrahepatic, 206, 240–241, 295, 311–313 intraocular, 590, 592, 597, 600–601, 604, 606–607, 655–656 intraocular lens, 601 intraocular pressure, 592, 597, 604, 655–656 intraperitoneal, 272, 280, 300, 353 intrathecal chemotherapy, 396 intrauterine, 149, 316–317, 320, 325, 360, 429–430, 436, 515, 865, 901–902, 904 intrauterine growth restriction, 429, 436, 515, 904 intravenous immunoglobulin, 172, 430, 542, 676 intraventricular, 485, 629 intron, 641 intubate, 126 intussusception, 213, 238, 263, 269, 274, 280, 323 ipsilateral, 470, 489, 494, 497, 617, 629,



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680–681, 687, 930 iris, 315, 596–598, 604–605, 651, 848 iritis, 164, 596 iron, 38, 208–209, 211–213, 226, 232, 242, 292, 302–303, 305–306, 310, 363, 370, 378, 409, 411–413, 415–417, 419–422, 425, 430, 433–436, 446, 449–450, 640, 643, 646–647, 764 iron-deficiency anemia, 416 irritable bowel syndrome, 263, 275 ischemia, 2, 4–5, 11, 15, 19, 21–22, 24, 36, 41–42, 56, 84–85, 89, 100, 105–106, 124–125, 130, 137, 141, 146, 154–155, 162, 165, 173–174, 185, 192, 198, 200, 238, 264, 269, 273–274, 276–277, 280–282, 294, 374, 381, 390, 435–436, 456–457, 459, 480, 482–483, 485, 487–493, 495, 497–499, 501–502, 507, 513, 552, 562, 576, 579, 603, 605, 614, 628–629, 655, 667, 672, 803, 816, 865, 933 ischemic colitis, 276–278, 377 ischemic stroke, 83, 482–483, 485, 487, 490, 498–499, 576 ishihara plates, 685 itching, 314, 355–357, 380, 541, 589, 647, 872 itp, 457–458 jaundice, 147, 194, 196, 199–200, 204–205, 211, 240, 246, 248, 251, 283–287, 289, 291, 293–294, 296, 299, 304–306, 308, 310–311, 313, 315, 351–352, 410, 412, 419, 425–426, 428, 431, 433–435, 521, 830, 887 jaw, 3–5, 41, 161, 167, 211, 221, 336, 406, 664, 743 jeghers syndrome, 213 jejunal, 320–321, 330–331 jejunostomy, 221 jejunum, 320 jervell and lange-nielsen syndrome, 187 jugular, 6, 57–58, 63, 76, 101–102, 104, 151, 340, 502, 766, 913, 919–920, 954 juvenile myoclonic epilepsy, 582 juvenile polyposis syndrome, 212 juvenile polyps, 212 kaposi sarcoma, 160–161 kawasaki disease, 171, 953 kegel exercises, 359, 861–862 kehr’s sign, 453 keratin, 528–529 keratitis, 552, 589–591, 602 keratoconjunctivitis, 589–590 keratoplasty, 590 kernicterus, 283, 285, 428–429, 516 ketoacidosis, 377, 814 ketogenic diet, 658, 803 kidney, 79–80, 83, 89, 108, 142, 170, 172, 266, 283, 293–294, 315, 362, 370, 421, 433, 441–442, 448, 456, 490, 492–493, 762–767, 769, 771–774, 776, 779, 783–793, 795–798, 800, 803, 809–810, 812–825, 828–829, 831–832, 835–838, 840–847, 849–850, 853–857, 863–865, 870, 920, 939 kidney cancer, 784



14



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kidney disorders, 763, 815, 817, 819, 821, 823 kidney stone, 764, 771, 776, 784, 790, 792, 795–796, 813, 818, 820, 854 kidney transplant, 783, 789, 791–792, 828, 832, 855 klebsiella, 195, 331, 352, 452, 853, 885 klebsiella pneumoniae, 452, 885 klinefelter syndrome, 520 klumpke paralysis, 670 klüver-bucy syndrome, 547, 549 knee, 92, 144, 181, 391–392, 494, 510, 915 kyphoscoliosis, 58, 640 l-dopa, 642, 645 labia, 770 labor, 151, 614, 669–670, 900, 905 labyrinthitis, 477, 480, 626 laceration, 224 lacrimal, 552, 589, 591, 941 lacrimation, 238, 479, 553–554, 587, 589, 595, 617 lactase, 329–330 lactation, 410, 416, 684 lactobacillus, 336 lactose intolerance, 329 lafora disease, 582 lambert-eaton myasthenic syndrome, 661–662 laminectomy, 484, 508, 682 langerhans cell histiocytosis, 375–376, 936 laparoscopy, 251, 301 laparotomy, 279, 281, 351, 353–354 laplace, 15, 17, 266 large cell carcinoma, 923 large intestine, 260, 266–267, 320 laryngeal, 150, 462, 883, 923, 930, 933, 939, 957 laryngitis, 222, 948 laryngomalacia, 957–958 laryngoscopy, 250, 879, 947–948, 958 lasix, 63 late dumping syndrome, 230 lateral ventricle, 519 lateral x-ray, 319 latex allergy, 522 laxative, 276, 299, 705–706, 709–710, 813 lbbb, 24–25 ldl, 41, 108, 485, 488, 498 lead poisoning, 415, 417, 447 learning disability, 650, 715 left bundle branch block, 24, 26, 120 left heart, 43–44, 60, 63, 102, 919 left heart failure, 60 left ventricle, 7, 24, 36, 44, 46, 49, 51, 55, 60, 65, 69, 71–72, 120, 124, 187, 913, 919, 932 left-sided heart failure, 44, 55, 62, 69 lems, 661–662 lens, 589–591, 595, 597–598, 600–602, 604, 683, 688 leptomeninges, 653 lesion, 151, 158, 160, 218, 241, 248, 257, 470, 474–475, 477, 489, 501, 522, 525–526, 530, 533, 539, 554, 586, 590–591, 628–629, 648, 651, 655, 657, 670, 673, 681, 687–688, 835, 864, 924, 957 leukemia, 29, 370–371, 373, 377, 389, 394–400, 407, 412, 453, 457, 819, 840



leukemias, 378, 394–399, 401, 649 leukemoid reaction, 377 leukocyte, 166, 199, 201, 370, 377, 445–446, 768, 841, 853–854, 856 leukocyte count, 166, 199, 201 leukocytosis, 87, 93, 103, 124, 220, 265, 277, 280, 341, 352, 377, 400, 422, 446, 452, 592, 594, 643, 854, 879, 882, 885 leukopenia, 311, 410, 440, 939 leukoplakia, 250 levo, 51, 53 levodopa, 645–646 lewy body dementia, 555, 558–559, 642 li-fraumeni syndrome, 247, 465, 531 libido, 739, 945 libman-sacks endocarditis, 85, 89 ligament, 143–144, 268, 271, 341, 667–668, 671, 777 ligand, 559 lightheadedness, 21–22, 84, 104, 111–112, 114, 117–118, 120, 128, 133–134, 187, 190, 459, 480, 699, 920 lip, 360–361, 416, 568, 578–579, 581, 684 lipid, 1, 80, 109, 291–292, 309, 410, 466, 487, 586, 810, 835 lipoma, 525 lipoprotein, 498 lisch nodules, 651 listeria, 256, 505 listeria monocytogenes, 505 lithium, 617, 642, 700–702, 728, 795, 823–824 lithotripsy, 196, 205, 765, 820 livedo reticularis, 173, 384, 768 liver, 50, 56, 58, 124, 147–149, 157, 194, 198–201, 203–206, 209–211, 238, 240–241, 243, 246–249, 251, 253, 283–316, 353, 362, 375, 379, 383, 385, 387–388, 390, 394–395, 397–398, 404, 410, 419–421, 425, 434, 442, 459, 573–576, 607, 643, 645, 658, 749, 766, 791, 818, 845, 850, 887–888, 907, 913, 917, 919, 923, 939 liver biopsy, 206, 284, 286, 288, 290, 295, 298, 302–303, 309–310, 314, 888 liver cavernous hemangioma, 147 liver cellular dysfunction, 289, 298 liver diseases, 289, 291, 293, 295, 297–299, 301, 303, 305, 307, 309, 311, 313, 315 liver transplantation, 293, 295 lobar, 485–486, 633, 882 lobe, 147, 247, 295, 308, 466, 471, 495, 502, 506, 549, 560–561, 581, 683, 686–687, 874, 876, 882, 913, 916, 923, 929, 931–932, 938 lobectomy, 549, 924 local therapy, 942 long qt syndrome, 130, 187 loop diuretics, 39, 63, 495, 626, 631, 794, 796, 802, 805, 809, 824 losing enteropathy, 259 lou gehrig’s disease, 632, 634 low blood pressure, 38, 122, 125, 419, 786 lower gastrointestinal congenital malformations, 316–317, 319, 321, 323, 325 lower respiratory tract congenital malformations, 874–875, 877



Pathology Volume 1 Index lower respiratory tract infection, 878 lqts, 187–188, 190–191 ludwig’s angina, 338 lumbar, 440, 483, 494–496, 500–501, 505, 508, 511, 519, 522, 527, 532, 535, 537, 580, 608, 631, 671 lumbar puncture, 483, 494–496, 500–501, 505, 508, 511, 519, 527, 532, 535, 537, 580, 608, 631 lung, 29, 36, 38, 45, 51, 56, 58–59, 61, 69, 71, 134, 166, 168–169, 172, 179, 239, 244, 362, 377, 390, 636, 640–641, 649, 657–658, 661–663, 828, 847, 867–868, 874–877, 880–881, 883, 886–889, 891–893, 895–897, 902–903, 905–908, 910, 913, 915, 918–921, 923–924, 926, 928–933, 935–937, 939, 941–942 lung cancer, 29, 662–663, 923–924, 931, 933 lung transplant, 59, 888, 897, 921, 935, 937 lupus, 65, 89–91, 98, 384, 423, 445, 452, 457, 459, 462, 483, 492, 579, 763, 768, 824–825, 832, 835, 838–840, 842, 940 lupus anticoagulant syndrome, 384 lupus erythematosus, 65, 89–91, 98, 384, 423, 445, 452, 457, 459, 462, 483, 579, 768, 824–825, 832, 838, 842 lupus nephritis, 763, 835, 838–839 lyme disease, 22, 90, 552, 633 lymph, 95–96, 151, 157, 161, 171, 237–238, 240, 248, 250, 253, 259, 375, 394–395, 397–399, 402, 404, 406–408, 440, 777, 846, 851, 853, 856, 923–924, 926, 933, 940–941, 948, 951, 953 lymph node, 96, 171, 238, 399, 402, 404, 407–408, 851, 924, 951 lymphadenopathy, 171, 244, 251, 332, 338, 375, 394–395, 397–398, 400, 404, 407, 442, 566–567, 589–590, 594, 938–939, 941, 953–955 lymphangioma, 150–152 lymphangioma circumscriptum, 150–151 lymphatic, 95–96, 104, 150–152, 238, 259, 264, 300, 607, 907–908 lymphatic system, 95 lymphedema, 95, 151, 157, 160 lymphedema tarda, 95 lymphocyte, 329, 404–405, 649 lymphocytic, 90, 223, 258–259, 328, 344, 377, 399, 402, 457, 506, 508, 908 lymphocytosis, 232, 399, 505, 549 lymphoid, 264, 274, 394–396, 398–399, 406, 457 lymphoid tissue, 406 lymphoma, 29, 160, 398, 402–408, 442, 453, 505, 662, 684, 771, 840, 843, 908 lymphoplasmacytic lymphoma, 406, 442 lymphoproliferative disorders, 662 lysis, 301, 405, 431–432, 458, 486, 493, 797, 801, 804, 813, 816–817 m protein, 438–439 macrocephaly, 146, 517 macrocytic, 330, 368–369, 371, 409, 411–412 macrocytic anemia, 409, 411 macroglobulinemia, 406, 439, 442–443



macroglossia, 851 macrolides, 955 macrophage, 332, 372, 426, 938 macroscopic, 275, 298, 462 macrosomia, 668, 670 macula, 599–600 macular, 587, 598–601, 603, 687 macular degeneration, 598–600 magnesium, 188, 191, 620, 794, 796, 799, 803–807, 814, 818, 820 major depressive disorder, 692, 702 malabsorption, 207, 230–231, 256–257, 284, 296, 316, 327–331, 333, 349, 409–410, 797, 806 malabsorption conditions, 327, 329, 331, 333 malaise, 162, 174, 211, 240, 246, 253, 270, 291, 301, 304–306, 310, 334, 338, 505, 507, 826, 846–847, 853, 885, 948, 954 malaria, 453, 505 male hypoactive sexual desire disorder, 741 malformation, 6, 73–74, 146–147, 308, 320, 325, 365–366, 474, 482, 513–518, 521–522, 524, 568, 623, 626, 655, 688, 771, 788, 837, 856, 874–876, 957 malignant peripheral nerve sheath tumor, 651 malignant tumors, 535, 658, 795, 923 malleolus, 177 malleus, 564, 569 mallory-weiss tear, 224–225, 229 malnutrition, 143, 211, 259, 291, 318, 320, 322, 334, 337, 339, 341, 538, 556, 806, 881, 913, 953 mandible, 254 mania, 700 manic, 700–702, 704, 735 mantle cell lymphoma, 406, 408 mao, 646 maoi, 475 marfan syndrome, 16, 65, 68, 266, 514 marginal zone lymphoma, 406 marrow, 25, 369–375, 377, 380–381, 394–402, 404, 406–407, 409, 411–412, 419, 422–424, 432–433, 439, 441, 608, 709, 939 massage, 111, 140, 343, 675 mast cell, 589 mastectomy, 95, 157 mastitis, 940 mastoid, 568, 622, 624 mastoiditis, 501, 507, 569, 623 mcv, 208–209, 211–213, 370, 378, 410, 412, 416, 418–419, 422, 426, 431, 436 md, 547 mean cell hemoglobin, 431 measles, 45, 426, 537 meckel’s diverticulum, 238, 274, 323–324 meconium, 269, 318, 320, 895, 899–902 meconium aspiration, 899, 902 mediastinum, 20, 219–220, 461–463, 923 medulla, 514, 750, 790, 822, 866 medulla oblongata, 514 medulloblastoma, 531–532 megacolon, 260–261, 318–319 megakaryocyte, 400, 457 megaloblastic anemia, 331, 409, 411, 431, 434



melanin, 213 melanoma, 29, 907 melatonin, 534–535, 744 melena, 213, 225, 232, 236, 253, 311, 323 membrane, 107, 259, 286, 292, 296–297, 315, 333, 335, 351–352, 363, 417, 425, 427, 431–432, 449, 452, 487, 493, 496, 530, 556, 564–570, 588, 599, 603, 606, 612, 624, 640, 652, 663, 764, 767, 769, 773, 808, 826, 828, 832, 836, 838, 840–842, 869, 889, 903, 923 membrane attack complex, 826, 841 membranoproliferative, 835, 840 membranous glomerulonephritis, 835, 838, 841–842 memory, 147, 154, 409, 466, 471, 489, 503–504, 513, 547, 549, 555, 557, 559–560, 562, 613, 696–699, 733, 736–737, 746, 760 meniere’s disease, 478, 480 meningeal, 394–395, 397–398, 466, 469, 483, 494, 505, 510, 618 meninges, 469, 494, 507, 509, 512, 522–523, 627 meningioma, 469–470, 626, 653–654, 684 meningitis, 477, 494, 502, 505, 509, 511–512, 516, 519, 522, 569, 580, 592, 626, 829, 881, 885, 938, 952, 954 meningocele, 523, 525 meningococcal meningitis, 511 menopause, 108, 183, 302, 860 menorrhagia, 393, 442, 445–446, 458 menstrual cycle, 703, 940 menstruation, 448, 709–710 merrf, 582 mesenteric ischemia, 173, 280 mesentery, 210, 281, 322 mesothelioma, 908, 924–926 metabolic acidosis, 122, 125, 276, 278, 280, 643, 764, 800, 824, 865, 903 metabolic alkalosis, 269, 795, 803 metabolic disease, 97 metabolic syndrome, 60, 105, 108, 307, 309 metabolism, 124, 258, 276, 280, 287, 289–290, 330, 347, 406, 466, 556, 573, 612, 630, 646, 656, 658, 763 metaplastic gastritis, 231 metastasis, 157–159, 237–238, 240, 242, 244, 247–248, 250–251, 253, 402, 527, 531, 608, 777–778, 844, 846–847, 850–851, 923–924, 928, 931 methadone, 755 methemoglobin, 413–414, 428, 484, 486, 497 methemoglobinemia, 413 methotrexate, 257, 410 metrorrhagia, 446 meulengracht disease, 287 mgus, 438–439, 442 mhc, 328, 422 microangiopathic hemolytic anemia, 73, 83, 390, 459, 830 microangiopathy, 384, 459, 767, 830, 920 microcephaly, 371, 568 microcytic, 330, 411–412, 415–419, 422, 835 microcytic anemia, 415



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micropenis, 521 microscopic colitis, 258 microscopic polyangiitis, 172, 816, 832 microtia, 623 micturition, 781, 858 middle ear, 564–565, 568, 570, 591, 623–624, 659, 954 midgut tumors, 238 midgut volvulus, 281–282, 364 migraine, 480, 488, 616, 618–619 migraine aura, 619 migraine with aura, 618–619 migraine without aura, 618 mild traumatic brain injury, 612 mineralocorticoid, 57 mini-mental state examination, 555 minimal change disease, 835, 843 miosis, 474, 486, 617, 670, 930 missense mutation, 36, 544 mitochondria, 291–292, 378, 411, 574, 642, 677 mitochondrial, 229, 309, 313, 411, 487, 632, 640, 649, 676 mitochondrial dna, 229, 649 mitochondrial inheritance, 411 mitotic, 31, 238, 395, 470–471 mitral regurgitation, 2, 68–70, 76, 93, 134, 545 mitral stenosis, 70, 84, 93 mitral valve, 28, 35–36, 38, 44–45, 68–73, 86–89, 92, 94, 134, 488, 499, 790, 920 mitral valve prolapse, 68, 72–73, 87, 134, 790 mkd, 785–786 mmr, 537 mmse, 555, 557, 559, 561 mobitz i, 22–23 mobitz ii, 22–24 moca, 555, 557, 559, 561 monoclonal, 394–396, 398, 400, 405, 427, 433, 438–440, 458, 460, 464, 654, 816, 847, 880, 927 monoclonal antibody, 405, 427, 433, 458, 460, 880 monomorphic ventricular tachycardia, 186 mononeuritis, 166 mononeuritis multiplex, 166 mononucleosis, 453 monosodium urate, 818 monro-kellie hypothesis, 628 montreal cognitive assessment, 555 mood disorders, 694, 718 moraxella catarrhalis, 878, 948 morgagni hernia, 362 morning sickness, 224 morphine, 1, 3, 63, 914 morsier syndrome, 521 motor neuron disease, 560, 632–633, 635, 637 motor tics, 716 mountain sickness, 870 movement disorders, 315, 504, 539, 547, 638–639, 641, 643, 645, 647 mpnst, 651 mrna, 636 mrsa, 86, 885 ms, 22, 25, 115, 540, 542, 781, 861 msafp, 317, 325 mucin-1 kidney disease, 785 mucocele, 591



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mucocutaneous lymph node, 171 mucosa, 198, 200, 213–214, 216–217, 222, 224–225, 227–228, 231–233, 235, 242–243, 250, 252, 256–258, 260, 266, 276–277, 280, 323–324, 335, 339, 355–356, 363, 390, 406, 569, 879, 950, 953–954 mucositis, 171 mucous, 43, 161, 250, 255, 260, 269, 357–358, 375, 568, 588, 766, 809, 893, 953, 956 mucus, 168, 198, 200, 231, 274–275, 300, 357, 365, 565, 591, 874, 879, 886–887, 889, 891–894, 924, 949 multi-infarct dementia, 555 multicystic dysplastic kidney, 783, 788–789 multifactorial inheritance, 620 multiple myeloma, 438–441, 488, 810, 816 multiple sclerosis, 473, 480, 540–542, 579, 626, 685, 781 mumps, 340–342, 345, 347, 477, 511, 537 mumps virus, 477 munchausen syndrome, 707 munchausen syndrome by proxy, 707 murphy’s sign, 199–200 muscle relaxants, 634, 744 muscular dystrophy, 22, 34, 544–546, 675 mutant, 38, 187, 386 mutation, 36, 127, 151, 159, 187–188, 207, 209, 211, 252, 256, 283, 285–287, 314, 349, 369, 371, 374, 379–381, 385–386, 388, 391–392, 395, 398, 402, 407, 418, 427, 432, 434–435, 446, 448, 452, 459–460, 465, 469, 471, 479, 513, 520–521, 524, 531, 544–545, 557, 618, 632, 635, 644, 648–650, 652–653, 655–658, 661, 790, 798, 823, 840, 844–845, 848, 850, 887, 894–895 mutism, 642 myalgia, 172 myasthenia gravis, 462, 661, 663–665 mycobacterium tuberculosis, 174, 377 mycoplasma, 300, 426, 537, 678, 879, 953 mycoplasma pneumoniae, 537, 879 mycosis fungoides, 407 mydriasis, 475, 494, 628–629 myelin, 232, 536–538, 540, 542, 561, 676–678, 781, 810 myelitis, 542–543 myelodysplastic syndrome, 371, 378–379, 410–411, 445 myelofibrosis, 381 myelogenous, 370–371, 373, 377, 396, 400 myeloid, 375, 394–397, 400 myeloid leukemia, 394–397, 400 myeloma, 438–441, 488, 810, 816 myelomeningocele, 514, 523 myocardial infarction, 2–3, 5, 17, 20, 24, 29, 55, 69, 75, 83–84, 100, 103, 108, 117, 120, 130–131, 137, 154, 171, 185, 187, 235, 276, 379, 384, 436, 456, 490, 499 myocardial ischemia, 21–22, 100, 192, 490 myocarditis, 22, 24, 34, 55–56, 85, 90–91, 93, 117, 332 myocardium, 3, 30, 33–34, 36–37, 39, 75, 85, 89–92, 419 myoclonic seizure, 582, 578–579 myoclonus, 504, 572, 582



myoglobin, 816 myomectomy, 37 myometrium, 92 myopathy, 287, 411 myopericarditis, 98 myopia, 606, 609 myringotomy, 569 myxedema, 97, 104, 907 myxoma, 29–31, 488 myxopapillary ependymoma, 529 nadir, 39 nafl, 309–310 narcissistic personality disorder, 724, 728 narcolepsy, 745 narcotic, 697 nares, 361, 423, 940 nasal decongestant, 955 nasal passage, 570, 950, 956 nasal polyp, 894, 949–950 nasal septum, 753 nash, 309–310 nasogastric, 144, 224, 270, 279, 360, 363, 366, 952 nasopharyngeal carcinoma, 926–927 nasopharynx, 168, 509, 564, 568, 623, 684, 926, 947, 950, 952 natriuresis, 60 natriuretic, 57, 60, 102, 124 ncse, 583 nd, 122, 606 nearsightedness, 601 necrotizing enterocolitis, 278 necrotizing fasciitis, 954 necrotizing ulcerative periodontitis, 341 necrotizing vasculitis, 168, 172 needle biopsy, 250, 845, 851 neisseria, 300, 433, 452, 477, 509, 588, 856, 953 neisseria gonorrhoeae, 300, 588, 856 neisseria meningitidis, 433, 452, 509, 588 nematode, 95 neologism, 550 neonatal, 305–306, 308, 387–388, 428–432, 434–436, 514, 661, 664, 668, 895, 900–902 neonatal hepatitis, 308 neonatal jaundice, 428, 435 neonatal respiratory distress, 902 neonate, 319, 321, 789, 809, 900, 903 neoplasia, 238, 263, 318, 441, 461, 463, 469 neoplasm, 195, 251, 269, 374, 439, 442, 513, 565, 589, 656, 772, 930 neoplastic, 212, 379, 394–398, 400, 402–403, 405–407, 439, 441–442, 468, 534, 653, 662 nephrectomy, 660, 849, 851–852, 855 nephritic syndrome, 825–829, 831–833, 838, 840 nephritis, 763, 767–768, 822, 831, 835, 838–839, 939 nephroblastoma, 849–850 nephrogenic diabetes insipidus, 796, 808 nephrolithiasis, 818, 824, 939 nephrology, 370, 372 nephron, 788, 797, 813, 816, 827–828, 837, 850, 865 nephropathy, 81, 170, 763, 767, 822, 825, 831–832, 835–836 nephrotic syndrome, 388, 810, 831, 835, 837, 839–841, 843, 850–851, 907,



Pathology Volume 1 Index 913, 915 nephrotoxic, 767, 806 nerve cell, 612 nerve compression, 473, 628, 666, 923 nervous system infections, 500–501, 503, 505, 507, 509, 511 neural tube defect, 514, 517, 522 neuralgia, 554, 671 neurectomy, 554 neuritis, 164, 541, 592, 626, 675, 685 neuroblastoma, 474–475, 926 neurocutaneous disorders, 648–649, 651, 653, 655, 657, 659 neurodevelopmental disorders, 517, 711, 713, 715 neuroendocrine tumors, 232, 461 neurofibromatosis, 650, 652 neurofibromatosis type i, 650 neurofibromatosis type ii, 652 neurogenic, 123, 494, 514, 516, 522, 525, 618, 636, 672, 781, 819 neurogenic bladder, 514, 516, 522, 525, 781 neuroleptic malignant syndrome, 642, 645 neuroma, 554, 626, 668 neuromuscular junction diseases, 634, 661 neuron, 474–475, 552, 556, 560, 612, 632–637, 644, 662, 677, 681, 806 neuronal ceroid lipofuscinosis, 582 neuropathic pain, 666 neuropathy, 166, 232, 234, 330, 384, 447–448, 473, 475, 554, 573, 592, 646, 677–678 neurotransmitter, 556, 646, 700, 702, 704, 711–712, 763 neutropenia, 371, 378, 394–395, 397–398, 423, 439–440 neutrophil, 168, 172, 231–232, 260, 352, 371, 377, 379, 423, 427, 592, 854, 856, 867 newborn screening, 428, 895 nf, 439, 465, 469, 479, 529, 533, 650–653 nfi, 650 nicotine, 638–639, 644, 756–757 nidus, 146, 586 night sweats, 160, 174, 301, 404, 847 night terror, 746 nipple, 911 nitrates, 1, 42, 58, 61, 216, 221, 252, 356, 413, 766, 856 nitrogen narcosis, 871 nitroglycerin, 3, 42, 486, 914 nocturia, 39, 60, 787, 854, 945 nocturnal enuresis, 746 nodular lymphocyte predominant hodgkin’s lymphoma, 404–405 nodular sclerosis hodgkin’s lymphoma, 403 non-alcoholic fatty liver, 309 non-alcoholic fatty liver disease, 309 non-alcoholic steatohepatitis, 309 non-bizarre delusions, 734 non-hodgkin’s lymphoma, 404–405, 407, 453 non-igm mgus, 438 non-urothelial bladder cancers, 776 noncompensatory pause, 118 nonconvulsive status epilepticus, 583 nonexudative armd, 599–600 noninfectious (nonallergic) conjunctivitis, 589 nonproliferative dr, 603–604



nonsyndromic, 655 nontropical sprue, 328 noonan syndrome, 74, 151, 514 normal pressure hydrocephalus, 519 normal tension glaucoma, 604 normocytic anemia, 421, 423, 425, 427, 429, 431, 433, 435, 437 norovirus, 270 norwalk virus, 271 nosocomial, 86, 885 nosocomial pneumonia, 885 nostril, 956 nph, 519 nsaid, 56, 80, 94, 102, 104, 210, 218, 228, 231, 233, 236, 242, 258, 334, 458, 613, 618, 620–621, 671, 676, 678, 763, 767, 786, 800, 816, 842–843, 942, 948, 955 nstemi, 2–3 nuchal, 151, 394–395, 397–398, 505, 510 nuclear medicine, 462 nucleotide, 256, 655 nucleus, 206, 291, 379, 403, 412, 470, 600, 616, 618, 646 nup, 341 nutcracker syndrome, 142–143 nyctalopia, 685 nystagmus, 477, 480–481, 489, 514, 521–522, 531, 533–534, 537, 541, 573, 608, 613, 641, 649, 749, 849 obesity, 2, 41, 56, 58–60, 80, 95, 105, 134, 155, 176–177, 179, 183, 197, 204, 217, 222, 240, 242, 245, 248, 251–252, 266, 268, 271, 291, 307, 309, 325, 440, 469, 498, 502, 515, 522, 599, 646, 667–668, 819, 836–837, 846, 848–849, 860, 915–916, 944 obsessive-compulsive, 93, 692, 694, 717, 719, 729, 731 obsessive-compulsive disorder, 93, 692, 694, 717, 719 obstruction, intestinal, 273 obstructive lung disease, 886–887, 889, 891, 893, 895, 897 obstructive shock, 122–124 obstructive sleep apnea, 58, 498, 743, 944–945 obturator sign, 264 occiput, 397 occlude, 623 occult, 213, 242–243, 272, 416, 423, 525 occult spinal dysraphism sequence, 525 occupational therapy, 518, 652, 658, 670, 674, 676, 678, 699 ocular cavernous hemangioma, 147 oculomotor nerve, 467, 492, 494 oculosympathetic paresis, 474 of infancy, 149 olfactory groove meningiomas, 470 oligodendrocyte, 537 oligodendroglioma, 471–472 oligohydramnios, 772–773, 790–792, 876–877, 900 oligonucleotide, 636 oliguria, 79, 83, 108, 763, 766–768, 801, 815–816, 826, 832, 838, 840, 865 omentum, 268 omphalocele, 322, 325 omphalomesenteric duct, 323 onchocerciasis, 587



oncogene, 318, 438, 440 open angle glaucoma, 604 ophthalmic, 167, 210–211, 498, 500, 503, 522, 589, 591, 594, 604, 616, 655, 657 ophthalmic artery, 167, 498 ophthalmic vein, 503 ophthalmopathy, 590 opioid, 644, 754–755, 760 opioid dependence, 754 opioid use disorder, 754–755 opisthotonos, 642 opportunistic infection, 339 optic glioma, 651 optic nerve, 470, 521, 535, 592, 604, 607–608, 631, 683, 685 optic nerve meningiomas, 470 optic neuritis, 164, 541, 592, 685 optic pathway glioma, 651 oral cancer, 250 oral candidiasis, 161, 250, 339–340, 897 oral contraceptive, 204, 434 oral disease, 334–335, 337, 339, 341, 343 orbital cellulitis, 591, 594 orgasm, 742 orgasmic dysfunction, 742 oropharynx, 250, 944 orthopnea, 29–30, 39, 57, 59–60, 907, 913, 920 orthostatic hypotension, 84, 475, 559, 644, 766 osler, 87, 146 osmotic demyelination syndrome, 538 osseous, 957 osteoarthropathy, 298, 924 osteoblast, 795 osteodystrophy, 108, 763, 813 osteomalacia, 814 osteomas, 210–211, 623 osteomyelitis, 336, 340, 507–508 osteopathy, 941 osteopenia, 798 osteopetrosis, 514, 823 osteoporosis, 313, 419, 436, 651, 795, 798, 897 otalgia, 569 otitis, 360, 477, 507, 564–570, 580, 623, 954 otitis externa, 564, 566–567, 623 otitis media, 360, 477, 507, 564–565, 568–570, 623, 954 otitis media with effusion, 568–570 otosclerosis, 624 outer ear, 564, 566–567 ovary, 263 overgrowth syndrome, 330 overriding aorta, 48 oximetry, 46, 125, 414, 899–900, 905, 944 oxymetholone, 372 p-anca, 166, 172, 206, 832 pa, 907 pacemaker, 21–23, 28, 58, 69, 71, 75–76, 120, 185, 188, 191–192 pacemaker, implantable, 191 pain management, 20, 205, 281, 301, 348, 350, 436, 527, 554, 671, 676, 678–679, 924 pain, chest, 123 palate, 161, 250, 360–361, 370, 517, 568, 945 palatoschisis, 360



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palilalia, 716 palpitations, 6–7, 21, 28, 36, 45, 72–73, 108, 111–112, 114, 117–118, 120, 128, 133–134, 137, 139, 185, 187, 190, 230, 412, 416, 448, 475, 641, 748–749, 940 palsy, 340, 489, 492, 515, 529, 552–553, 590, 633, 668, 670, 674–675, 940–941 panacinar emphysema, 896 pancoast tumor, 474, 930, 933 pancolitis, 276 pancreas, 209, 251, 296, 302, 345–349, 389–390, 419, 459, 640, 658, 756 pancreatic, 142, 181, 194, 204, 213, 232, 251–252, 323, 345–350, 409, 411, 659–660, 894 pancreatic cancer, 251, 349 pancreatic pseudocyst, 345–346, 349 pancreatitis, 194, 197, 251, 263, 273, 327, 330, 341, 345, 347–350, 459, 749, 797, 868, 894, 907–908 pancytopenia, 371, 423, 433 pandas, 92–93, 954 panic, 690, 692 panic disorder, 690, 692 panniculitis, 251 panuveitis, 596 papillary carcinoma, 846 papillary cystadenoma, 254 papillary cystadenoma lymphomatosum, 254 papillary muscle, 2–3, 69, 75 papillary renal cell carcinoma, 848 papillary tumor, 534 papilledema, 83, 469, 501, 510, 529, 531, 628, 631 papilloma, 250 papillomatosis, 240 papillomavirus, 250, 355, 778 papule, 164 paracentesis, 298, 312, 351–352, 430 paracetamol, 613, 620–621, 630 paradoxical embolism, 8 paralysis, 106, 123, 146, 269, 447, 483, 494, 507, 514, 522, 524–525, 534, 541, 553, 565, 579, 584, 592, 669–670, 672, 681, 684, 745, 801, 803, 805, 872, 923 paralytic ileus, 803 paraneoplastic syndrome, 248, 377, 850 paranoid personality disorder, 721, 723 paraplegia, 232, 682 parasagittal meningiomas, 470 parasite, 90, 95, 261, 269, 500, 505, 509, 590 parathyroid gland, 795, 806 parathyroid hormone, 763, 794–797, 804, 812–814, 924 parenchyma, 61, 201, 251, 289, 297–298, 303, 313, 348, 454, 482, 490, 494, 505, 640, 655, 683, 774, 791, 874, 886, 935–936 parenteral nutrition, 204, 279, 346 paresis, 109, 474, 479, 486, 489, 498, 513, 515–516, 524–525, 579, 584 paresthesia, 106, 440, 479, 503, 666–667, 672, 674, 676, 679, 682, 805, 872, 927, 930 parietal pericardium, 92 parinaud’s syndrome, 534



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parkinson’s disease, 84, 473, 475, 559, 612, 638, 642, 644–646, 781–782, 861 parotid gland, 254, 340–341, 709–710 parotitis, 338, 340–341, 940 paroxysmal cold hemoglobinuria, 426 paroxysmal nocturnal, 39, 57, 64, 423, 432, 913 parturition, 149 parvovirus, 431, 434, 626 parvovirus b 19, 431, 434, 626 patau syndrome, 360 patellar, 682 patent ductus arteriosus, 6, 11–12, 50, 902 paterson-brown-kelly syndrome, 226 pathognomonic, 148, 328, 332, 405 patulous dysfunction, 565–566 pauci-immune glomerulonephritis, 172 pba, 633–634 pcs, 612 pd, 638, 861 pda, 6, 9, 11, 44 peg, 221, 269 penetrance, 72, 209, 212, 369, 385, 624, 894 penetration disorder, 740 penicillin, 94, 98, 315, 332, 512, 767, 853, 857, 952, 955 penis, 181, 770, 849 peptic ulcer, 235, 353, 416 peptic ulcer disease, 353 percutaneous, 3, 8, 11, 151, 153, 246–247, 249, 251, 314, 430, 617, 765, 845, 851, 864 percutaneous umbilical blood sampling, 430 perforated eardrum, 564, 570 peri, 881 perianal, 213, 256, 356–358, 682 pericardial, 2, 19, 57, 97–104, 125, 134, 137, 171, 192, 259, 429–430, 938 pericardial disease, 97, 99, 101, 103, 938 pericardial effusion, 98–101, 103–104, 125, 429–430 pericardial friction rub, 98 pericardial tamponade, 2, 19 pericarditis, 2, 90, 92, 97–100, 102–104, 311, 332, 763, 950 pericardium, 92, 97–98, 100–104, 924 perihepatitis, 300 perinatal, 11, 278, 283, 515, 576, 578, 614, 899–901, 903–905 perinatal acute respiratory disease, 899, 901, 903, 905 perineal, 740, 777, 779 perineum, 682 periodontal, 165, 250, 337, 341–342 periodontal disease, 250, 337 periodontitis, 337, 341 periorbital, 496, 503, 594, 952 periosteal, 939 peripheral artery disease, 105–109 peripheral nervous system, 646, 649, 666, 676 peripheral neuropathy, 166, 573, 646 peripheral vascular disease, 756 peristalsis, 215–216, 269, 274, 364, 819, 900 peritoneal dialysis, 351–352, 391, 764, 796, 907 peritoneal pathology, 351, 353 peritoneum, 240, 253, 264, 271, 301, 325,



352, 453–454 peritonitis, 198–200, 236, 242, 264–265, 269, 273–274, 276, 281, 298, 311–312, 320, 323, 346, 351–353, 895 peritonsillar abscess, 950–951 pernicious anemia, 231–232, 409, 462 persistent truncus arteriosus, 43, 45–47 personality disorder, 713, 721–732 personality disorders: cluster a, 720–721, 723 personality disorders: cluster b, 724–725, 727 personality disorders: cluster c, 729, 731 pertussis, 377 pervasive developmental disorder, 712 pes cavus, 641, 677 pet scan, 404, 407, 941 petechiae, 390, 394–395, 397–398, 400, 423, 438, 445–446, 455, 458–459 petit mal seizures, 577 peutz, 213–214 peutz-jeghers syndrome, 213 pft, 661, 663, 888 ph, 218, 220, 222, 329, 336, 567, 787, 818, 823–824, 870, 908, 917 phalen maneuver, 667 pharyngeal pouch, 227 pharyngitis, 92, 880, 950, 953–955 pharyngoesophageal diverticulum, 227 pharynx, 227, 339, 570, 945–946, 954 phd, 176 phenotype, 420, 652 pheochromocytoma, 658 philadelphia chromosome, 400 phlebotomy, 303, 380, 412, 447, 450 phobia, 693 phosphate, 413, 427–428, 787, 796, 798, 812–814, 818–819, 822 phosphorylation, 574, 640 photodynamic therapy, 218, 600 photophobia, 229, 492, 494, 510, 519, 587, 589–590, 595, 597, 602, 621, 849, 940 photosensitivity, 447, 505 phototherapy, 286, 428, 430, 432, 435 physical & sexual abuse, 759 physical therapy, 521, 523, 525, 542, 545–546, 553, 636, 641, 646, 650, 652, 668–669, 673–675, 741 pia mater, 493 pica, 416, 489 pick bodies, 560–561 pick cells, 561 pick disease, 549, 555, 560–561 pid, 263, 300 pigmented stones, 203 piles, 312 pilocytic astrocytoma, 533–534 piloerection, 581 pineal gland, 535 pineal parenchymal cell tumors, 534 pinealoblastoma, 607 pinealoma, 534, 684 pinna, 552, 564, 566, 622 piriformis muscle, 671 piriformis syndrome, 671 pituitary gland, 375 pjs, 213 pkd, 790 placenta, 429



Pathology Volume 1 Index placental abruption, 865 plantar, 677 plaque, 2, 5, 15, 41, 105, 108–110, 155, 160, 175, 336–338, 342, 482, 488, 492, 504, 541, 556–557 plasma cell, 232, 438–439, 441, 443 plasma cell dyscrasias, 438–439, 441, 443 plasmacytoma, 441, 926 plasmapheresis, 286, 442, 542, 661, 663, 665, 676, 679, 768, 828, 832 platelet count, 171, 372, 389–393, 423– 424, 438, 445–446, 452, 455–456, 458, 460, 486 platelet disorders, 444–445 pleomorphic, 252, 533 pleura, 103, 219, 892, 906–907, 909, 911, 913, 923–924 pleural effusion, 35, 102–103, 151, 219–220, 430, 868, 882, 906–908, 913, 919 pleural space, 906–911 pleurodesis, 658, 909, 911 plummer, 226, 250, 363 plummer-vinson syndrome, 226, 250, 363 pneumococcus, 882 pneumocystis jirovecii, 597 pneumomediastinum, 878, 900 pneumonia, 124, 222, 244, 394–395, 397–398, 440, 489, 502, 504, 539, 633, 635–636, 656, 679, 697, 829, 867–868, 878, 881–883, 885, 891–892, 923, 930, 936–937, 954 pneumonitis, 277, 366, 899, 936 pneumoperitoneum, 277, 279, 320, 351, 353–354 pneumothorax, 122, 124, 129, 220, 375, 657–658, 875, 877–878, 891, 894, 896, 900, 906, 910–911 pns, 649, 666, 676–679 pns demyelinating disorders, 676–677, 679 point mutation, 435, 635 poisoning, 224, 415, 417, 447, 555, 759, 767, 798 polio, 505 polyarteritis nodosa, 173–174 polyarticular, 940 polycystic kidney disease, 493, 763–764, 783–784, 790–791 polycythemia, 294, 379–380, 467, 488, 490, 847, 893 polycythemia vera, 294, 379–380, 488, 490 polydipsia, 796, 803, 810 polyhydramnios, 320–321, 362 polymerase chain reaction, 271, 505, 549, 597, 878, 954 polymyalgia rheumatica, 167 polymyositis, 462 polyp, 207–209, 211–214, 242, 274, 949–950 polypectomy, 208, 212–213, 243 polyposis, 207–210, 212, 242, 247, 939 polysomnography, 943, 945 popliteal, 15, 105, 179 porphyria, 447–450, 473 porphyria cutanea tarda, 447, 449 port, 655 portal hypertension, 205, 283–284, 289, 294, 298, 311–312, 314, 357, 384, 766, 791, 887, 919 portal vein, 181, 225, 298, 311–312, 380,



384, 791 positron emission tomography, 243, 402, 466, 547 post-streptococcal glomerulonephritis, 825 postconcussive syndrome, 612 postductal coarctation, 9 posterior subcapsular cataract, 601 posterior uveitis, 587, 596–597 posteroanterior, 907 postherpetic trigeminal neuropathy, 554 postmyocardial infarction syndrome, 103 postpartum, 187, 318, 383, 387–388, 446, 475, 552, 916 postpartum hemorrhage, 446 postprandial, 222–223, 280 postrenal azotemia, 762, 764 poststreptococcal glomerulonephritis, 767, 826, 832 poststreptococcal reactive arthritis, 92–93 posttraumatic stress disorder, 759–760 postural hypotension, 809 potassium, 122, 187, 417, 538, 612, 618, 663, 787, 800–803, 806, 820, 824–825 ppms, 540 pre-excitation disorders, 111, 113, 115 precocious puberty, 247, 534 preductal coarctation, 9 preeclampsia, 80, 377, 384, 389, 436, 804, 900 preload, 1, 42, 55, 59–60, 69, 75–76, 122–123, 129, 824, 914, 921 premalignant, 217, 222, 226, 250, 438 premature atrial contraction, 118–119, 136 premature birth, 384, 513, 609, 614, 880, 904 premature contraction, 117, 119, 121 premature ejaculation, 742 premature ventricular, 70, 72, 118, 120–121, 185, 192, 806 premature ventricular complexes, 192 premature ventricular contraction, 118, 120 premenstrual dysphoric disorder, 703 prenatal care, 904 prenatal diagnosis, 657, 659 prerenal azotemia, 762, 766, 863 pres, 686 presbycusis, 626 preterm birth, 515 priapism, 436 primary biliary cholangitis, 298, 313 primary biliary cirrhosis, 313–314 primary ciliary dyskinesia, 891, 949 primary itp, 457 primary lateral sclerosis, 633 primary progressive multiple sclerosis, 540 primary rls, 646 primary sclerosing cholangitis, 205–206, 240, 245, 260 prinzmetal’s angina, 4 prion, 503–504 prms, 540 probability, 188, 916 probable migraine, 618 probiotic, 276 progesterone, 744 prognosis, 125, 157–160, 166, 206, 362, 375, 402–404, 482, 485, 526, 531, 633, 689, 776, 846, 874, 923, 925–926, 931 progressive bulbar palsy, 633



progressive chronic syndromes, 638 progressive motor atrophy, 633 progressive myoclonus epilepsy, 582 progressive-relapsing multiple sclerosis, 540 prolactin, 938 prolapsed uterus, 859 proliferative dr, 603 promoter, 287, 405–406 proprioception, 641, 677, 681 prostaglandin, 10–11, 44, 49, 52, 231, 605 prostate, 389–390, 765, 770–772, 779, 854, 859, 939 prostatitis, 771 prosthetic valve endocarditis, 86 prosthetics, 336 protease, 347, 385, 459, 887 protease inhibitor, 347, 385, 887 protein c, 176, 179, 386–388 protein c deficiency, 387 protein losing enteropathy, 259 protein s deficiency, 388 proteinuria, 108, 168, 172, 259, 440, 762, 786, 789, 822–823, 825–826, 828, 830–831, 835, 837–838, 840–843, 863, 865, 940 prothrombin, 125, 179, 205, 241, 293, 298, 389–392, 486, 572, 575 prothrombin time, 125, 241, 293, 298, 389–392, 486, 572, 575 protozoa, 505, 602 provoked seizures, 576–577 pruritus, 176–177, 183, 205, 240, 290, 296, 304–306, 308, 313, 380, 567, 763 psc, 205–206, 240 pseudoachalasia syndrome, 253 pseudoaneurysm, 2, 175 pseudobulbar affect, 633 pseudomembranous colitis, 259 pseudomonas aeruginosa, 15, 590, 623, 885, 894 pseudotumor cerebri, 631 pseudoxanthoma elasticum, 492 psilocybin, 576 psoas, 264, 392, 507 psoas sign, 264 psoriasis, 566 psychosis, 290, 315, 504, 557, 572, 644, 749 psychotherapy, 491, 621, 652, 658, 689–695, 697, 699–710, 712–713, 716–733, 735–737, 739–742, 747–749, 751, 753, 755, 757, 759–761 ptosis, 462, 474, 494, 664–665, 670, 930 puberty, 213, 247, 534 pubis, 770–771 pubs, 430 pulmonary artery, 8, 41, 44–47, 50–51, 57, 59, 124, 894, 915, 919–920, 922 pulmonary edema, 35, 57–58, 60–62, 64–65, 83, 85, 122, 124, 494–495, 867, 870–871, 903, 913–915, 919 pulmonary embolism, 24, 58–59, 122, 124, 129, 133, 179, 181–182, 385, 907–908, 915–918 pulmonary embolus, 916, 918 pulmonary fibrosis, 936 pulmonary function test, 166, 661, 886 pulmonary hypertension, 13–14, 24, 41,



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45, 59, 69–71, 75, 362–363, 384, 893–894, 899–900, 912, 917, 919–922, 938, 945 pulmonary hypoplasia, 362, 773, 792, 875–877 pulmonary infarction, 179, 907 pulmonary valve, 73–74, 916 pulmonary vascular disease, 912–913, 915, 917, 919, 921 pulmonary vein, 50, 913 pulmonic regurgitation, 48, 73, 93 pulse, 9, 11, 36, 39, 45–46, 57, 65, 67, 106, 124–125, 127, 129–130, 154, 156, 167, 174, 181, 410, 416, 629, 673, 832, 899–900, 905, 944 pulseless electrical activity, 129 pupil, 66, 483, 485, 489, 503, 604, 607, 609, 670 purging anorexia nervosa, 709 purine, 818 purpura, 162, 166, 170, 172–173, 387–388, 390, 438, 445–446, 455, 457–459, 816, 830, 832 purulent, 100, 102, 169, 300, 340–341, 566, 589, 595, 954 pus, 264, 343, 353, 356, 507, 512, 568– 569, 602, 854, 879, 907, 950 pvc, 120, 157 pyelonephritis, 767–768, 774, 819, 822, 853–856 pyloric stenosis, 364 pylorus, 364 pyoderma gangrenosum, 256 pyridoxine, 412, 579 pyuria, 822, 853–854, 856 q fever, 86 qrs complex, 25, 39, 101, 104, 112, 115, 120–121, 185, 187, 190, 193, 796, 801, 805 quadrantanopia, 498, 619, 687 quadriparesis, 536, 539 quadriplegia, 467, 486, 676, 679 quinidine, 190, 457, 626, 665 quinine, 634, 685 quinolones, 190, 352 rabies, 505 radiation therapy, 157, 218, 237, 249, 376, 378, 394, 396, 399, 402, 461, 467, 472, 479, 652, 660, 924, 927, 932–933 radiculopathy, 671 radioactive tracer, 199, 201 radiograph, 10, 35, 49, 52, 99, 103, 122, 261, 282, 321, 354, 364, 771, 820, 868, 871, 880–882, 891, 895, 900, 903, 907, 914, 918 radiology, 847 radiolucent, 203, 773, 819 radionuclide scan, 452 radiopaque, 194, 203, 819, 905 radiosensitive, 926 radiotherapy, 211, 463, 470, 479, 529–530, 532, 534–535, 627, 654, 844, 847, 849 range of motion, 669, 678 rapidly progressive, 503–504, 544, 826, 832, 838 rash, 86, 89, 92, 171, 238, 306, 328, 375, 439, 511, 768, 872, 927, 954 rate-related bundle branch block, 24 rathke’s cleft, 528



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raynaud phenomenon, 165, 426, 442 rbbb, 24–25 reactive arthritis, 92–93, 954 recalcitrant chalazia, 587 recalcitrant conjunctivitis, 589 recombinant, 391–392, 446, 488, 495, 917 rectal, 207–213, 242–243, 260, 267, 275, 280, 294, 318, 355, 357–359, 442, 706, 765, 769, 853, 856, 894 rectal prolapse, 212, 358–359, 894 rectus abdominis, 271 recurrent laryngeal nerve, 462, 923 recurring chalazion, 586 red blood cell, 208, 369–370, 415–416, 419, 433, 459, 830 red cell, 168–169, 172, 378, 419, 422, 427, 431, 434, 549 red cell distribution width, 378, 419, 422, 431 reed-sternberg cells, 402–405 refeeding syndrome, 708–710, 814 reflux, 222, 774 refractory itp, 457 regional enteritis, 256 regurgitation, 2, 19–20, 34–35, 45, 48, 59–60, 62, 65–66, 68–73, 75–77, 87, 89, 92–93, 134, 167, 174, 215–216, 221–222, 227, 244, 322, 545 rehabilitation, 61, 476–477, 481, 542, 733, 735–737, 893, 897 rehydrate, 794, 796 rela fusion-positive ependymoma, 529 relapsing-remitting multiple sclerosis, 540 relaxant, 643 rem, 559, 745–746, 943 remission, 370, 396, 617, 736, 841 renal, 15, 17, 56, 60, 80–82, 97, 104, 107– 108, 124, 137, 142, 166, 168, 170, 173–174, 183, 259, 305, 315, 319, 347, 352, 366, 370–371, 377, 380, 383–385, 411, 419, 426, 428, 433, 436, 439–440, 459–460, 576, 642, 646, 656–659, 762–767, 771–772, 774, 778, 780, 783–793, 795–797, 802–806, 808, 813, 815–820, 822–824, 826, 828, 830–832, 835–838, 840, 842, 844–849, 851, 853–854, 856, 858–861, 863–866, 876–877, 907, 914, 917, 939–941 renal agenesis, 792–793, 876 renal artery stenosis, 81, 174, 764, 766, 784, 863 renal azotemia, 762, 767 renal calculi, 787, 940–941 renal cancer, 844–845, 847, 849, 851 renal capsule, 838, 865 renal cell carcinoma, 377, 844, 846–848 renal failure, 56, 97, 104, 107, 347, 352, 383, 385, 428, 440, 642, 646, 656, 762, 783, 785–786, 790, 792, 795–797, 802, 804–805, 819, 826, 828, 830, 832, 837, 840, 864 renal fusion, 784 renal osteodystrophy, 108, 763 renal papillary necrosis, 822 renal pelvis, 771, 774, 778, 780, 820, 854 renal transplant, 846 renal tubular acidosis, 823 renal vein thrombosis, 142, 838 rendu, 146



renin inhibitors, 800 renovascular hypertension, 80–81, 83, 763 reperfusion, 3, 117, 120, 198, 276, 280, 485, 488 reperfusion injury, 198, 276, 488 repetitive stress injury, 667 resistance, pulmonary, 124 respiratory acidosis, 800, 868, 893 respiratory alkalosis, 580, 803, 814, 868, 870–871, 917 respiratory disorders, 867 respiratory distress syndrome, 347, 867, 900, 902 respiratory failure, 278, 448, 514, 539, 545, 633, 661–662, 664, 676, 801, 805, 868, 883–884, 894, 896, 936, 945 respiratory syncytial virus, 568, 879, 881 respiratory tumors, 923, 925, 927, 929, 931, 933 restless leg syndrome, 183, 638, 646 restricting anorexia nervosa, 709 restrictive cardiomyopathy, 38–39, 55, 59, 102, 941 restrictive lung disease, 636, 640–641, 935–937, 939, 941 reticulocyte, 371, 378, 410, 412, 419, 422–423, 433, 460 reticulocyte count, 371, 378, 410, 412, 422–423, 433, 460 retina, 88, 467, 587, 591, 596, 598–600, 603, 606, 608–609, 659, 683 retinal detachment, 436, 601, 603–606, 609–610, 659 retinoblastoma, 607–608 retinopathy, 81–83, 436, 442, 598, 603, 606, 609, 685, 768, 903 retinopathy of prematurity, 606, 609 retrograde amnesia, 557, 696, 749 retropharyngeal & peritonsillar, 950 rett syndrome, 520 reverse transcriptase, 304 reye syndrome, 292, 574–575 rf, 258, 290 rh incompatibility, 429 rhabdomyolysis, 642, 795, 797, 801, 804, 813–814 rhabdomyoma, 29, 31–32, 657 rheumatic fever, 65, 69–70, 72, 85, 92–94, 97, 954 rheumatic heart disease, 66–67, 69, 73–76, 92–94, 134, 954 rheumatoid arthritis, 65, 89, 98, 590, 646, 667, 763, 908, 948 rheumatoid factor, 87, 258, 290, 908 rhinitis, 617, 889, 953 rhinorrhea, 483, 496, 554, 953 rhinovirus, 948, 953 rib, 9, 474, 614, 672 rickets, 814 rickettsiosis, 442 right heart, 8, 24, 44, 48, 57, 62–63, 896, 919–920 right heart failure, 62–63, 919 right ventricle, 7–8, 24, 48–49, 51, 55, 58, 73–75, 120, 893, 920 right ventricular hypertrophy, 13, 44, 48–50, 58–59, 69, 74, 892 right-sided heart failure, 55, 69, 71, 73–74, 76, 311, 919 ring sideroblasts, 378 rinne, 564, 566–567, 569–570, 622, 624,



Pathology Volume 1 Index 627 rinne test, 566–567, 569–570 rls, 638, 646 rna, 290, 305–306, 378, 633 rods, 397 rokatansky-aschoff sinus, 200 romano-ward syndrome, 187 romberg’s test, 477 rome iv, 229, 275 rosacea, 586–587, 590 rotavirus, 270–271 roth spots, 87 rotor syndrome, 287 roundworm, 90 rovsing’s sign, 264 rrms, 540, 542 rsv, 879–881, 883, 953 rubella, 11, 48, 51, 73–74, 308, 477, 517, 537, 626 rubella virus, 477 rubor, 106 run-on speech, 550 runny nose, 754 ruptured spleen, 453 rv, 7, 48, 58, 62–63, 886, 895 sa node, 28, 118, 120 saccular, 15, 18, 492–493, 554, 684 saccular aneurysm, 15, 492, 554, 684 sacral, 671 sacrum, 359 sagittal, 10, 31, 325, 365, 376, 483, 495, 515, 518–519, 524–525, 528, 532, 539, 541, 543, 682, 811, 927, 945 sagittal sinus, 483 sah, 493–494 saline, 275, 486, 491, 566, 629, 766, 809, 811, 813, 895, 901, 949, 955 salivary gland, 254, 336, 340, 591 salmonella, 15, 245, 452 salt, 56, 58–60, 286, 475, 809–810, 820, 825, 894, 932, 955 saphenous vein, 183 sarcoidosis, 28, 34, 38–39, 55, 59, 311, 340, 587, 840, 920, 938–942 sarcoma, 157, 160–161, 397, 465 saturated fat, 1, 835, 842 scapula, 199–200, 675 scapula alata, 675 scarlet fever, 954 schistosomiasis, 311 schizoaffective disorder, 735 schizoid, 720, 722–723 schizoid personality disorder, 722 schizophrenia, 720, 722–723, 733, 735–737, 751 schizophreniform disorder, 737 schizotypal personality disorder, 723 schonlein, 170, 832 schwann cell, 479 schwannoma, 479, 554, 652–653, 671 schwartz score, 188 sciatic nerve, 671 sciatica, 671, 680, 682 scintigraphy, 234, 284, 853 scjd, 503 sclera, 315, 598, 606–607 scleroderma, 98, 222, 449, 767, 840 sclerosing cholangitis, 205–206, 240, 245, 260, 375 sclerosis, 31, 205, 222, 403–404, 465, 469, 473, 480, 540–542, 554, 562, 579,



601, 626, 632–634, 656–657, 685, 763, 781, 832, 836–837, 845, 861 sclerotherapy, 148, 151, 184, 312, 358 scoliosis, 143, 516, 522, 524–525, 544–545, scrotum, 183, 396 sdh, 496–497 seasonal affective disorder, 704 sebaceous gland, 595 seborrhea, 586, 595 second degree atrioventricular block, 22, 24 second-impact syndrome, 612 secondary itp, 457 secondary progressive multiple sclerosis, 540 secondary rls, 646 sedatives, 229, 504, 744, 944 sedimentation rate, 87, 93, 103, 162, 258, 261, 422, 917 seidel sign, 591 seizure, 83, 311, 413, 448, 495, 516–517, 520–523, 529, 533, 547, 557, 572, 576–584, 611–612, 614, 619, 650, 653, 656–658, 687, 809–810 seizure disorders, 584 sella turcica, 469, 684 sella turcica vicinity, 469 semen, 304 sensorineural hearing loss, 187, 479, 564, 569, 622, 626 separation anxiety disorder, 694 sepsis, 85, 125–126, 194, 196, 198, 200, 219, 231, 264, 269, 274, 276, 278, 296, 338, 340, 377, 389, 394–395, 397–398, 423, 459, 507, 516, 592, 797, 814, 867, 878, septic, 87, 123–126, 181, 196, 278, 319, 340, 502, 507, 853, 856, 865, 868, 954 septic shock, 123–126, 196, 278, 319, 507, 853, 856, 865, 868 septicemia, 878 septo-optic dysplasia, 521 septum, 2, 14, 24, 36–38, 52, 102, 521–522, 594, 753, 920 sequencing, 371, 446, 659 serotonin, 238, 456, 618, 620, 647, 689, 699–700, 702, 704, 710, 717–719, 730, 745, 749, 761, 904, 919–920 serotype, 829 serrated polyps, 207 serum sickness, 424 sexual abuse, 698, 759–760 sexual dysfunction, 302, 536, 541–542, 680, 682, 739, 741 sexually transmitted infections, 355, 856 shaken baby syndrome, 496, 611, 614 shock, 9, 44, 56–57, 66, 84, 90, 111, 122–126, 131, 134, 196, 205, 220, 231, 276, 278, 280, 319, 347, 390, 429, 451, 453, 507, 541, 554, 614, 629, 766, 781, 798, 816, 824, 853, 856, 865, 868, 916, 954 shock treatment, 126 shock, cardiogenic, 122 shoulder, 197, 204, 220, 296, 300, 451, 453, 474, 621, 668–670, 675 shunt, 6–8, 11, 13, 48–49, 155, 177, 295, 312, 495–496, 501, 514, 518–519, 535, 791, 872, 875, 896 siadh, 505, 538, 810–811, 924, 931



sialadenitis, 342–344 sibling, 274, 651 sick sinus syndrome, 28 sickle cell disease, 437, 452, 485, 488, 493, 837 sickle-cell anemia, 435 sideroblastic anemia, 411–412 sideropenic dysphagia, 226, 363 sigmoid, 265–266, 281–282, 356, 359, 483 sigmoid volvulus, 281–282 sigmoidoscopy, 209, 211–212, 242, 267, 282 silver, 381 simple febrile seizure, 580 single-stripe sign, 277 sinoatrial node, 21, 28 sinus, 28, 50, 91, 104, 111, 116, 131, 134–136, 140, 188, 200, 365, 469, 483, 500, 502–503, 569, 592, 594, 616, 684, 917–918, 939, 949, 952, 956 sinus arrest, 28 sinus bradycardia, 28 sinus node, 28, 131, 134 sinus rhythm, 116, 134–136 sinus tachycardia, 91, 104, 917–918 sinusitis, 168–169, 342, 500–503, 507, 594, 894, 949, 952, 954 sjogren’s syndrome, 342–343 skeletal, 32, 436, 440, 504, 635, 642–643, 663, 676, 678, 763, 770, 872 skeletal muscle, 32, 504, 635, 642–643 skin biopsy, 166, 449 skin lesions, 164, 172–173, 375, 449–450, 506, 648–649, 653, 656–658 skull, 440–441, 469, 474, 482–484, 496, 501–502, 507, 612, 614, 626, 628–629, 927 sle, 89–90, 384, 459, 824 sleep, 58, 93, 137, 146, 187, 436, 498, 514, 520, 557, 559, 569, 574, 635, 639, 644, 647, 701, 703, 743–747, 760–761, 870, 904, 920, 939, 943–945, 949, 951, 953 sleep apnea, 58, 137, 498, 514, 743, 920, 944–945, 949 sleep bruxism, 743–744 sleep disturbances, 520, 644 sleep-related respiratory disease, 943, 945 slow-fast avnrt, 140 small bowel bacterial overgrowth, 330 small bowel ischemia & infarction, 280 small cell carcinoma, 924, 932 small intestine, 198, 200, 270, 274, 280, 296, 316, 322, 328, 330, 346, 362 small-cell lung cancer, 662–663, 931 smooth muscle, 4, 19, 82, 107–108, 151, 215, 221, 266, 275, 293, 433, 492–493, 798, 859, 919, 921 snellen chart, 585, 591, 597 snoring, 943–945, 951 snowman sign, 50 social anxiety disorder, 694–695 sodium, 28, 60–61, 80, 82, 124, 127, 187–188, 223, 258, 312, 417, 478, 487, 521, 538–539, 612, 766, 787, 800, 803, 808–810, 816, 818, 863, 894 soft palate, 361, 945 soft tissue, 267, 334, 336, 567, 940, 956



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somatic, 252, 442, 552, 607, 662, 734, 761 somatic symptom disorder, 761 somatostatin, 239 spasm, 215, 221, 227, 275–276, 433, 798, 806, 813, 819, 889 spasticity, 232, 515–517, 634 speech therapy, 516, 548, 561 spermatic cord, 271 sphincter, 215–217, 221–224, 347, 355–356, 364, 536, 542, 860–861, 900 sphygmomanometer, 79, 83–84 spider nevi, 289 spina bifida, 522 spinal column, 474, 522, 671 spinal cord, 84, 232, 402, 407, 440, 466–467, 470–471, 507, 509, 514, 522–526, 529, 536, 540–543, 614, 629, 640, 659, 668, 680–681, 770, 781, 859 spinal cord injury, 84, 680–681, 859 spinal disc herniation, 671 spinal disorders, 671 spinal epidural abscess, 507 spinal epidural hematoma, 483–484 spinal hemiparaplegia, 681 spinal muscular atrophy, 635–636 spinal nerve, 507, 671, 676, 679 spinal shock, 781 spinal stenosis, 671, 681 spine, 144, 146, 264, 440, 524–525, 537, 543, 651, 671, 679–682, 784 spirochete, 174, 505 spleen, 87, 205, 210, 291, 311–312, 375, 379, 390, 394–395, 397–399, 404–406, 425, 427, 434, 440, 451–454, 504 spleen pathology, 451, 453 splenectomy, 420, 427, 432, 435, 451– 452, 454, 457–458 splenic marginal zone lymphoma, 406 splenomegaly, 226, 248, 284, 289, 294, 298, 311, 313, 374, 380–381, 399–400, 410, 425, 431, 434, 442, 453, 940 spms, 540 spondylitis, 65, 597 spongiform encephalopathy, 503 spontaneous bacterial peritonitis, 298, 311–312, 351–352 sprue, 259, 328, 331 sputum, 60, 878, 882, 885–886, 889, 892, 896, 913, 924–925 squamous cell, 223, 226, 240, 244, 250, 528, 624, 776, 778, 923, 926–927, 929–931 squamous cell carcinoma, 244, 250, 624, 776, 778, 923, 926–929, 931 staph, 90 staphylococcus, 86, 342, 501–502, 507, 588, 590–591, 594–595, 623, 853, 878, 891, 894, 947, 950, 953 staphylococcus aureus, 86, 342, 501–502, 507, 588, 590–591, 891, 894, 947, 953 staphylococcus epidermidis, 86, 595 staphylococcus saprophyticus, 853 statin, 1, 3, 42, 70–71, 287, 310, 499, 563 status epilepticus, 579, 583–584 std, 760 steal syndrome, 153–155



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stem cell, 370–373, 378–379, 402, 424, 432–433, 441–442 stem cell transplantation, 441–442 stemi, 2–3 stenosis, 48, 50, 55, 59–60, 62, 65–67, 70–71, 74, 76–77, 81, 84, 92–93, 109, 142, 146, 155, 162, 165, 169, 174–175, 195, 205, 319–320, 349, 364, 488, 498–499, 514, 671, 681, 764, 766, 784, 816, 819, 863–864, 919–920 stent, 10, 17, 106, 142, 154, 196, 491, 493, 765, 772, 821 stereotactic, 249, 468, 470, 479, 486, 526, 535, 654, 660 steroid, 370, 424, 567, 587, 598, 602, 668 stethoscope, 289, 553 stomatitis, 226, 335, 339, 953 stool, 205, 222, 232, 242–243, 260, 265, 267, 271, 274–275, 277, 285, 304–306, 316–318, 329, 355–356, 358, 423, 449, 706, 899 strabismus, 370, 608–609, 649 straight leg raise test, 671 strain, 260, 493, 525, 668, 917, 919–920 strep, 90, 92, 954 strep throat, 92, 954 streptococcus, 86, 92–94, 300, 336, 338, 342, 452, 477, 501–502, 509, 568, 588, 590, 594, 826, 829, 878, 893, 947, 950, 953–954 streptococcus pneumoniae, 452, 477, 509, 588, 590, 594, 829, 878, 893, 947 streptococcus pyogenes, 950, 953 streptococcus viridans, 338, 342 stress incontinence, 860–861 stricture, 196, 219, 222, 224, 256, 265, 269, 276, 416 stroke, 16, 19, 36, 55, 72, 81, 83, 85, 89, 101, 108, 135, 147, 164, 174, 185, 374, 384, 435, 482–483, 485, 487–490, 498–499, 502, 516, 547–550, 576, 672, 685, 687–688, 749, 752, 756, 781, 830, 861 stroke volume, 36, 55, 101, 185 struvite stones, 818 sturge-weber syndrome, 655 stye, 586, 595 subacute bacterial endocarditis, 86 subarachnoid, 16, 146, 166, 458, 485, 492–495, 508–509, 607, 614–615 subarachnoid hemorrhage, 16, 146, 458, 492–493, 495, 615 subclavian steal syndrome, 153, 155 subcutaneous, 92–93, 96, 165–166, 181, 183, 220, 376, 429, 620, 653, 939–941 subdural hematoma, 496–497, 614 subependymoma, 529 subglottis, 939 sublingual, 42, 254, 338, 342 sudden cardiac death, 21, 29, 33, 36, 114, 127, 129, 131, 185, 190, 192, 938 sudden infant death, 904 sudden infant death syndrome, 904 sudden unexpected death in epilepsy, 579 sudep, 579 sulcus, 337, 910 sulfonamide, 377, 423, 457 superior quadrantanopia, 687 superior vena cava syndrome, 16, 933



supraglottis, 939 supratentorial herniation, 483, 629 supraventricular tachycardia, 133, 135, 137, 139 surfactant, 362, 867, 899, 902–903, 905 sv, 55, 59 sweat, 473, 803, 892, 894–895 sweat chloride test, 895 sweat gland, 473 sweat test, 892 sweating, 13, 448, 474, 581, 643–644, 670, 692, 748–749, 754, 784, 808, 913 swimmer’s ear, 566, 623 sydenham’s chorea, 93 sympathetic nervous system, 123, 494, 642 symphysis pubis, 770–771 symptomatic multiple myeloma, 440 synapse, 474, 557 syncope, 6, 16, 19, 21–22, 28–30, 36, 64, 66–67, 79, 84, 111–112, 114, 128, 133, 139, 154, 156, 174, 185, 187, 190, 192, 473, 475, 559, 662, 915, 920 syndrome of inappropriate, 505, 538, 810, 923 syndrome of inappropriate antidiuretic, 810, 923 syndromes, 1, 3, 5, 72, 130, 141, 143, 153, 155, 192, 207–208, 378, 410–411, 418, 461–462, 489, 531, 582, 618, 638, 788, 835, 843–844, 847, 850–851, 923, 931, 956 syphilis, 15–16, 65, 384, 505, 587, 597, 626, 781–782, 842 syringomyelia, 514, 517, 524 systemic lupus erythematosus, 65, 89–91, 384, 423, 445, 452, 457, 459, 462, 483, 579, 768, 824–825, 832, 842 systemic sclerosis, 222 systolic, 9, 34, 45, 50, 55, 58–60, 62, 65–67, 69, 72–74, 80, 84, 125, 475, 490, 672, 919 t cell, 395, 405, 407, 457, 649, 942 t cell acute lymphoblastic leukemia, 395 t cell lymphoma, 407, 505 t-all, 395 tabes dorsalis, 781 tachycardia, 28, 50, 57, 90–91, 100–101, 103–104, 112–114, 120, 124–125, 127–129, 131, 133, 135, 137, 139, 185–187, 189, 191–193, 225, 269–270, 307, 351–352, 362, 370, 419, 426, 429, 447, 453, 456, 473, 475, 482, 494, 573, 643, 766, 809, 824, 868, 880–881, 903, 910, 913, 916–920 tachypnea, 50–51, 57, 125, 220, 362, 416, 429, 453, 643, 867–868, 875, 880–881, 883, 899–900, 903, 905, 912, 915–916, 947 takayasu arteritis, 174–175 takayasu disease, 155 tapeworm, 410 tarsal conjunctiva, 588 taussig, 155 tb, 511 teeth, 211, 336–337, 341–342, 375, 554, 591, 710, 743, 952 telangiectasia, 146, 177, 531, 649–650



Pathology Volume 1 Index temporal arteritis, 167 temporal lobe, 466, 471, 506, 549, 560, 687 temporomandibular joint, 743 tendonitis, 667 tenesmus, 242, 260 tension, 122, 129, 604, 616, 620, 691, 740, 902, 910–911 tension headache, 616, 620 tension pneumothorax, 122, 129, 910–911 teratoma, 876 testicle, 142, 183–184, 272 testosterone, 741 tetany, 798–799, 806, 813 tethered spinal cord syndrome, 525 tetracycline, 233, 292, 665, 823, 909 tetralogy of fallot, 13, 43, 48–49, 73–74 thalamus, 485, 489, 498, 504, 547, 616, 618, 644 thalassemia, 415, 418–420, 435 thalassemia major, 419–420 thalidomide, 378, 441 therapeutic, 96, 185, 222, 236, 412, 433, 456, 817, 909 thiamine, 34, 299, 410, 573, 576, 579, 696, 749 thiazide diuretics, 787, 795, 803, 806, 824 thiazides, 190 third degree atrioventricular block, 22 third ventricle, 514 thoracentesis, 430, 906, 908 thoracic aorta, 15 thoracic aortic aneurysm, 15–16, 18 thoracic duct, 908 thoracic outlet syndrome, 672 thoracotomy, 936 thrombi, 87, 107, 134, 176, 459, 672, 915 thrombin, 89, 179, 385, 446 thromboangiitis obliterans, 165 thrombocythemia, 374, 381 thrombocytopenia, 169–170, 277, 311, 371, 378, 384, 394–395, 397–398, 400, 410, 423, 439–440, 444–445, 455–457, 459, 496, 830 thrombocytosis, 171, 374, 452, 499 thromboembolism, 2, 176, 251, 385–388, 390, 426, 436, 439, 456, 672, 835, 917 thrombolytics, 683, 917 thrombophilia, 176, 383, 386–388, 502, 915 thrombophlebitis, 165, 181, 183, 340, 384, 954 thrombosis, 5, 16–17, 42, 86–87, 129, 142, 147, 174, 177, 179–180, 253, 264, 276, 280, 294, 311, 357, 374, 379–381, 383–390, 432–433, 455–456, 482, 488–489, 492–493, 498, 500, 502, 515, 569, 592, 655, 672, 816, 835, 838, 915, 917–919, 952 thrombotic thrombocytopenic, 459, 816, 830 thrombotic thrombocytopenic purpura, 459, 816, 830 thrombus, 2, 69, 71, 151, 165, 175, 177, 179–181, 295, 488, 490, 492, 499, 503, 830, 915 thrush, 339 thunderclap headache, 494 thymoma, 461–463, 661, 664–665



thymus, 394–395, 397–398, 461–463, 649, 663–664 thymus neoplasia, 461, 463 thyroglossal duct cyst, 365 thyroid cancer, 213 thyroid gland, 365 thyroid hormone, 795 thyroid-stimulating hormone, 133–134, 137, 938 thyroiditis, 293, 662 tia, 498–499 tic, 93, 554, 716 tic disorder, 93 tic douloureux, 554 tinel’s sign, 667 tinnitus, 476–480, 569–570, 613, 619, 622, 626, 631, 653, 659, 927 tma, 459 tobacco, 165, 250, 316, 325, 448–449, 466, 617–618, 685, 756 tobacco use disorder, 756 todd paralysis, 584 tongue, 171, 250, 335, 338, 416, 498, 552, 554, 584, 639, 645, 743, 954 tonic seizures, 578–579 tonic-clonic seizure, 578–581, 584 tonometry, 604 tonsil, 479, 514, 955 tonsillectomy, 951, 955 tonsillitis, 950, 955 torsades des pointes, 190 torticollis, 618, 645 total anomalous pulmonary, 50 total parenteral nutrition, 204, 279, 346 tourette syndrome, 716 toxemia, 390 toxic shock syndrome, 954 toxicology, 185, 490 toxoplasma gondii, 90–91, 501 toxoplasmosis, 587, 597, 626 tpn, 279, 346 trachea, 366, 878, 883, 900, 910 tracheoesophageal fistula, 366 tracheostomy, 339, 634, 869 trachoma, 588 traction, 496, 566, 606, 670, 936 transfusion, 286, 373, 417, 419, 422, 427–428, 430, 434–435, 446, 767 transient acquired neonatal myasthenia, 661 transient aplastic crisis, 431, 434 transient ischemic attack, 108, 384, 435, 498 transitional cell carcinoma, 776, 778–780 translocation, 396, 405–406, 438, 440, 471, 649 transplant, 33, 35, 37, 39, 44, 58–59, 61, 91, 94, 160, 176–177, 206, 249, 284, 286, 290, 305–306, 309, 370, 372–373, 375, 378, 399, 402, 424, 433, 783, 789, 791–792, 828, 832, 846, 855, 888, 897, 921, 935, 937 transposition of the great, 51–53 transudate, 568 transurethral resection, 777, 779 transverse, 143, 227, 483, 542–543, 667–668 transverse myelitis, 542–543 trauma- and abuse-related disorders, 761 traumatic brain injury, 548, 550, 612–613 treadmill, 188



tremor, 311, 541, 559, 572, 638–639, 641–642, 644–646 treponema pallidum, 953 trichomona, 300 trichomonas vaginalis, 300 trichotillomania, 718 tricuspid insufficiency, 75 tricuspid regurgitation, 62, 75 tricuspid stenosis, 76 tricuspid valve, 59, 75–77, 87 trigeminal nerve, 479, 554 trigeminal neuralgia, 554 triglyceride, 284, 291 trimester, 11, 34, 321, 374, 552, 876 trisomies, 247, 600 trisomy 13, 21, 320–321, 325, 556, 784 tropical sprue, 259, 331 troponin, 3, 5, 90, 103, 124, 153, 494 true aneurysms, 15 true diverticulum, 266, 323 truncus arteriosus, 43, 45–47 trypanosoma, 90–91, 216 trypanosoma cruzi, 91 tsh, 134, 137 ttp, 459–460, 816, 830 tubercle, 268 tuberculosis, 102, 174, 294, 300, 377, 587, 597, 822, 891, 908, 910, 923, 941 tuberous sclerosis, 31, 465, 656–657, 845 tubes, 279, 300, 565–566, 569–570, 623, 893, 939, 952 tubule, 767, 795, 813–814, 816, 823, 846, 865 tumor marker, 243, 251 tumor necrosis factor, 335, 378, 421, 597, 867, 942 tumor suppressor gene, 207, 469, 532, 648, 658, 844–845 tunica intima, 15, 19, 108, 173 tunica media, 15, 19, 107, 492 turner syndrome, 9, 95, 151, 685, 784 tympanic membrane, 564–565, 567–570, 624 tympanic membrane perforation, 565, 569, 624 tympanoplasty, 571 tympanostomy tubes, 566, 569 tympany, 269, 281 type i, 22–23, 128, 238, 240, 285–286, 307, 387–388, 393, 432, 449, 462, 469, 514, 533, 618, 650, 652, 767–768, 800, 803, 832, 836, 840–841, 872, 876 type ii, 22–23, 128, 238, 240, 285–286, 387–388, 393, 432, 449, 462, 479, 514, 529, 618, 652–654, 662–663, 828, 832, 836, 840–841, 867, 872, 876, 931 type ii hypersensitivity, 662–663, 828, 931 type iii, 238, 388, 393, 432, 462, 618, 826, 832, 838, 840–841, 927 type iii hypersensitivity, 826, 838, 927 type iv, 240, 462, 537, 540, 768, 828 type iv hypersensitivity, 537 ukd, 785–786 ulcer, 105–106, 164, 231, 235–236, 250, 256, 260, 277, 351, 353, 416, 522, 589–591, 598, 602, 954 ulceration, 149, 165, 172, 213, 228, 235, 358, 568, 590–591, 878 ulcerative colitis, 86, 205, 207, 255–256,



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259–262 ulcerative keratitis, 602 ulnar, 159, 673–674 ulnar claw, 673–674 ulnar nerve, 673–674 umbilical cord, 325, 446, 900 umbilicus, 144, 264, 316, 325, 770, 777 undetermined significance, 438 unilateral hemianopia, 687 unilateral renal agenesis, 792 unresectable, 251 unstable angina, 5, 42 unverricht-lundborg disease, 582 upper gastrointestinal congenital malformations, 360–361, 363, 365, 367 upper gi series, 222 upper respiratory tract, 168, 477, 566, 594, 831, 946–947, 949–953, 955–957 upper respiratory tract congenital malformations, 956–957 upper respiratory tract infections, 831, 950, 952 ura, 792 urachus, 776 urate, 785, 818 urea, 57, 108, 122, 124, 605, 762–764, 766, 783, 805, 815, 818, 829, 863, 877 uremia, 108, 231, 377, 762–763, 825 uremic syndrome, 97–98, 816, 825, 829–830 ureter, 142, 765, 771–772, 774, 778, 780, 819, 824 ureterocele, 771 urethra, 764, 769–770, 773, 778, 780, 849, 853, 856, 860 urethral strictures, 859 urethritis, 771, 853, 856 urge incontinence, 781–782, 861 uric acid, 816, 818–819 uric acid stones, 818–819 urinalysis, 83, 125, 173, 436, 576, 765, 786, 789, 791, 815, 817, 824, 858–861 urinary incontinence, 228, 232, 519, 541, 559, 858–859, 861 urinary tract, 440, 765, 771, 774, 776–778, 781, 787, 815, 819, 854, 856, 861, 956 urinary tract disorders, 819 urinary tract infection, 765, 787 urine ph, 787 urogenital, 370, 681 urography, 772 uromodulin kidney disease, 785 urothelial carcinoma, 780 urothelial cell carcinoma, 778 uterine prolapse, 769 uterus, 300, 756, 771, 859, 939 uti, 256, 765, 774, 822, 853–854, 856 utility, 664 uv, 600, 602 uvea, 938 uveitis, 164, 255–256, 260, 587, 596–597, 604, 938, 940 uvula, 360 vaccination, 341, 452, 537, 893 vaccine, 271, 304–305, 452, 882–883, 895, 937, 947 vacterl, 319, 366, 371



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vacterl association, 366 vagina, 256, 265, 300, 319, 770 vaginitis, 740 vagus nerve, 111, 658 valgus, 673 valsalva maneuver, 72, 111, 140, 268, 272, 473, 514 valvular incompetence, 183 variant angina, 4 varicella, 426, 505, 574, 589, 626 varicella zoster virus, 589 varicocele, 142, 183–184, 847 varicose veins, 177–178, 183–184 vascular bed, 919 vascular compression syndromes, 141, 143 vascular dementia, 555, 562 vascular disorders, 576, 579–582, 584 vascular endothelial growth factor, 467, 654, 876 vascular malformations, 145, 147, 149, 151, 496 vascular renal disease, 863, 865 vascular steal syndromes, 153, 155 vascular tumors, 157, 159, 161, 846 vasculitis, 19, 80, 162–175, 181, 483, 485–486, 510, 562, 920 vasoconstriction, 9, 60, 80, 124, 276, 280, 433, 474–475, 494–495, 753, 863, 896, 919 vasodilation, 1, 9, 82, 628, 630, 766, 889, 921 vasodilator, 42, 80, 154 vasomotor, 230, 374, 642 vasopressin, 124, 521 vasopressors, 63, 276 vasospasm, 4, 276, 280, 433, 493, 865 vasospastic angina, 4 vcjd, 503 venereal, 384 venereal disease, 384 venlafaxine, 620–621 venous dysfunction, 176–177, 179, 181, 183 venous return, 36, 50, 72, 274 vent, 911 ventilation, 58, 61, 126, 279, 353, 363, 643, 664, 679, 867, 869–870, 894, 896, 899, 901, 903, 906–907, 914–915, 917, 920, 935–936 ventilator, 539, 633–634, 636, 885 ventral, 685 ventricular arrhythmia, 192 ventricular hypertrophy, 9, 11, 13, 37, 44, 46, 48–50, 58–59, 66–67, 69, 71, 73–75, 81, 892 ventricular septal defect, 6–7, 13–14, 48, 51, 872 ventricular septum, 2, 24 ventricular tachycardia, 90, 120, 127–129, 131, 185–187, 189, 191–193 vertebra, 681 vertebral artery, 155, 498 vertebral column, 770 vertical transmission, 305 vertigo, 146, 154, 229–230, 442, 475–478, 480, 482, 514, 529, 569, 613, 618, 626, 659 vesicoureteral reflux, 774 vesicular, 375, 875 vessels, 11–12, 43, 48, 51–52, 61, 82, 86, 90, 105, 107–108, 142, 147, 149,



151, 154–155, 157, 159, 162, 167–168, 172–175, 177, 183, 198, 200, 232, 264, 266, 271–272, 289, 295, 316, 322, 348, 380, 389, 459, 483, 485, 488, 496, 510, 529–530, 540, 556, 566, 588, 591, 599, 603, 607, 609, 614, 618, 620, 628, 649, 655, 672, 790, 829, 835, 845–846, 863, 872, 879, 881, 896, 899, 912, 919, 930, 933, 936 vestibular, 476–481, 554, 626–627, 652–654 vestibular schwannoma, 479, 554, 652–653 vestibular system, 480 vestigial, 264 vinson syndrome, 226, 250, 363 viral conjunctivitis, 590 viral hepatitis, 240, 292, 305–306 viral infection, 264, 270, 309, 477–478, 505, 509, 553, 565–566, 568, 879–880, 883, 953 virchow’s triad, 176, 179, 181, 915 visceral pericardium, 92 vision disorders, 489, 683, 685, 687 visual acuity, 589–592, 595, 597–598, 600–603, 606, 940 vitamin a, 602 vitamin b, 410, 579 vitamin c, 337, 414, 417 vitamin d, 330, 540, 542, 545–546, 763, 794–799, 813–814, 939 vitamin e, 558 vitamin k, 284, 385, 387, 486, 497, 917 vitiligo, 662 vocal tics, 716 volvulus, 273, 280–282, 322–323, 325, 364 von gierke’s disease, 307 von hippel-lindau (vhl) disease, 467, 846 von hippel-lindau disease, 147, 467, 658 von recklinghausen disease, 650 vsd, 6, 13–14, 48–49, 51 vulva, 939 vulvodynia, 740 wagr syndrome, 848, 850 wagro, 848 waldenstrom macroglobulinemia, 406, 443 warfarin, 70–71, 135, 176, 180, 385, 387, 457, 491, 499, 517, 917 warthin’s tumor, 254 water on the brain, 517 wbc, 89, 196, 304–306, 396, 398, 436, 505, 511 weber, 146, 564, 566–567, 569–570, 622, 624, 627, 655–656 weber syndrome, 655–656 weber test, 566–567, 569–570 wegener’s granulomatosis, 168, 832 wenckebach, 22–23 wernicke’s aphasia, 547, 550 wernicke-korsakoff syndrome, 572–573, 696 west nile virus, 505, 587 western blot, 545–546 wet beriberi, 34, 573 wheezing, 222, 238–239, 436, 880, 886–887, 889, 892–893, 923, 930, 932, 939 whipple’s disease, 332–333 white blood cell, 370, 436, 643



Pathology Volume 1 Index white blood cell count, 643 white matter, 465, 536–538, 562–563, 612, 657 wilms tumor, 784, 844, 848–852 wilson disease, 299, 314, 600 wine stain, 655 winged scapula, 675 withdrawal symptoms, 748–749, 751, 753, 755–756 wolff-parkinson-white syndrome, 114–116, 130 womb, 44, 792 x chromosome, 391–392 x-linked recessive, 391, 544, 685 xanthelasma, 313 xanthine stones, 818 xanthinuria, 818 xanthoma, 313 xerophthalmia, 479, 602 xerostomia, 339, 479, 766, 927 yawn, 565 yeast, 341 zenker’s diverticulum, 227 zinc, 315, 411, 956



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