Skin Cancer Guide: Actinic Keratoses, BCC, SCC, Melanoma

Disease
Clinical Variants
Defining Characteristics
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Actinic Keratoses (AK)
Hypertrophic AK (thickened), pigmented AK, actinic chelitis (lips)
small, raised scaly spots on chronically sun-exposed skin; scattered, thick erythematous patches
UV induced mutations in p53 cause unrestrained growth and damage to repair genes prevents tumor rejection
sun exposure immunosuppression genetic conditions
skin type I, age > 70, field disease on upper limbs/ head/ neck
Histology? Surface changes at epidermis
cryosurgery, topicals (5-FU, imiquimod, PDT w/ photosensitizer ALA, chemical peel, reduction of immunosuppressants to safe levels
Most common precursor to SCC
Nodular (can be pigmented in darker pts) Basal Cell Carcinoma (BCC) Superficial (more scaly, less thick) Morpheaform (scarring, loss of pigment; MORE AGGRESSIVE)
UVB causes direct DNA damage to p53 and overexpression of originate from keratinocytes from epidermis or follicular bcl-2, which prevents apoptosis; carcinoma of follicular epithelium; unlikely to metastasize; most common skin cancer keratinocytes & found above clavicle
Chronic UVB exposure, immunosuppression, inherited conditions (Gorlin Goltz basal cell nevus syndrome, XP), chronic arsenism, patch mutations, previous BCC
750,000 new cases/yr, growing incidence among younger ages (30-40s)
male, older age, fair complexion, tendency to burn, outdoor occupation
Clinical
surgical excision, Moh's, PDT w/ ALA, radiation tx (for non-operable), topical tx for field dz (5-FU, imiquimod), reduction of immunosuppressants to safe levels
Basal Cell Nevus Syndrome (BCNS)
N/A
TONS of BCCs as child, megaloblastomas, palmar pits, bifid ribs, frontal bossing of scalp
Deficiency in patch (negative regulator of Shh) causes constitutive action of positive regulator (Shh), increasing incidence of BCC Shh binds and inhibits patch; without patch, smoothened causes increased transcription of GLI-1,2,3, causing increased cell proliferation Chronic UVB exp Originates from interfollicular keratinocytes following direct DNA chem carcinogens damage to p53 from UVB; SCC make VEGF so highly genetic disorders angiogenic immunosuppression HPV Apoptosis loss possibly due to ROS resistance of SCC chronic inflam (leg ulcers, DLE, Genetic predisposition for loss of p53 (XP, HPV) osteomyelitis)
Vismodegib (targets Shh to decrease tumor size; but still residual tumor so perhaps development of resistance)
Loss of taste (and ultimately anorexia) is a side effect of tx
Squamous Cell Carcinoma (SCC)
Worrisome when recurrent, location on forehead / temple/ ear/ lip, large size (>2cm), poor differentiation, invasion (in-transit met to lymphatic channels), perineural invasion
Asymptomatic until fast growing --> painful, grows faster than BCC, ulceration/ verruca-like, common in transplant pts, metastatic potential
250,000 new cases/yr; growing incidence among younger ages (30-40s)
Heart/lung transplant recipients Chronic lymphocytic leukemia XP
surgical excision, Moh's, PDT w/ ALA, radiation tx (for non-operable), topical tx for field dz (5-FU, imiquimod, cryosurgery), reduction of immunosuppressants to safe levels
genetic mutations (MC1R mutations- red hair & predispose to B-raf mut; familial loss of p16) less common than other skin cancers (BCC>SCC>>MM) SSMM (common, pagetoid - migration to place not typically found, trunk of men, legs of female; regression = loss of pigment/scarring) - NM (no radial growth- often ulcerated, rapidly growing, can lack pigment; trunk of men, invades through dermal/epidermal jx); - LMM (sun exposed areas; slowest growth rate and longest radial growth stage); usually appears as growing freckle, freckle in unusual place, or freckle that crosses anatomic boundaries - ALM (palms, soles, subungal; Hutchinson's sign, melanonychia striata, abnl nail) Malignant tumor arising spontaneously from melanocytes in basal epidermis or from dysplastic nevi; dysplastic nevi then undergoes radial growth where it becomes invasive until able to grow vertically; once vertical growth phase reached, the tumor has high metastatic potential young adults FH of MM or DN UV light rptd childhood sunburns # (>50) & size (>5mm) of nevi CN PMH of MM high SES Skin types 1&2 latitude DNA repair defects immunosuppression NM in middle-aged men; LMM in older pts w/ chronic UVB exposure & age spots; ALM more common in dark/Asian pts uniform pigmentation, symmetrical shape, sharply demarcated borders, wide distribution and colors Dysplastic nevus syndrome (DN) - multiple benign with characteristics of precursor melanoma: irregular family members w/ melanoma and multiple DN growth, variation in color/size, multiple asymmetric lesions in pt (also have only one copy of p16)
Superficial spreading melanoma (SSMM) Nodular melanoma (NM) Malignant Melanoma (MM) "know your ABCDEs" Lentigo maligna melanoma (LMM) Acral lentiginous melanoma (ALM) - hands, feet, mouth, genitals Mucosal melanoma (very rare!)
ALM can sometimes occur in conjuction with 4% of cancer cases, but vitiligo (autoimmune more than 75% of skin dz); associated with cancer deaths; 5th & mutations in C-kit 7th most common Associated with oxidative damage from UVA cancers in men & Melanoma in sunwomen; 70,000 new protected areas can Staging depends on Breslow's depth, ulceration, # mitotic cases/yr; primarily result from mutations in figures, lymphatic/ vasculature entry younger adults; b-raf or N-ras increased incidence B-raf mutation --> loss of PTEN --> activation of oncogene Akt - oncogenes due to recreational -> transformation of radial/noninvasive melanoma to habits vertical/invasive MM LACK MUTATIONS IN p53 N-ras mutation --> activation of oncogene Akt
Evaluation includes history, TBSE, LN exam, CXR, routine labs, & MRI brain/CT of chest (for late-stage) HIGH risk for metastasis Histology? Sun exposure signs (loss of elastin fibers, solar Surgical removal/ excisional bx elastosis - abnl elastin in upper dermis) Sentinel LN bx to stage metastasis Excisional (or incisional punch) bx for Breslow's depth to LNs (used for melanomas >1.0mm in depth) Braf inhibitors (PLX4032) prolongs survival but not curative later detection and higher stage associated with higher mortality Pts with p16 mutations have increased risk of pancreatic cancer too!
Benign Nevi
Arise from melanocytes
Dysplastic Nevi
can be sporadic or familial
b-raf mutations
Congenital Nevi
Giant Melanocytic Nevus
Present at birth or within first year of life; important to monitor changes in size/color/symmetry
Relative risk for melanoma depends on size of CN
N-ras mutations
Prophylactic removal during teen years; staged surgical removals if large New tx include mimics of photolyases (enzymes in other organisms that repair CPDs) Histology? Endothelial swelling, decreased langerhans, neutrophil recruitment, apoptotic keratinocytes (bright pink) areas of hyperplasia (thickened stratum corneum, epidermis, dermis)
Xeroderma pigmentosum (XP)
N/A
marked increase in skin malignancies at young age, photosensitivity, impaired DNA damage repair systems
Defective NER (nucleotide excision repair); accumulation of oxidative and DNA damage Determined by total UVB energy absorbed (ind of duration)
At least 10 DNA repair defects Failed or incomplete repair of thymine dimers --> mutations in p53 (higher risk for nonmelanoma skin cancers)
High rate of MM, SCC, freckles
Sunburn
N/A
Inflammation, erythema
Inflammation (cytokines, histamine, prostaglandins, serotonin) cause redness; increased adhesion protein expression --> immune cell recruitment Change in existing melanin (immediate pigment darkening caused by redistribution of melanin - IPD, persistent pigment darkening- PPD)
Major risk factor for nonmelanoma and melanoma skin cancers
Sun tan
N/A New melanin (delayed tanning) formed when keratinocytes release MSH in response to UVR; MSH binds MC1R on melanocytes --> increased melanin production and proliferation mutations in filaggrin (which binds to keratin) causes bundling/collapsing of keratin fibers
Ichthyosis
N/A
Inherited disease causing generalized scaling and thickened skin
Excess stratum corneum due to altered epidermal differentiation
Psoriasis
Localized scaly plaques, can be raised; less prone to infections (abundant AMPs)
Excess stratum corneum from low epidermal turnover
Disease
Epidermolysis bullosa (EB) (General)
Clinical Variants
blisters on hands and feet
Pathogenesis
Inherited disorder w/ defects in cellular attachments, causing epidermis to no longer stick to dermis Superficial blistering within the epidermis caused by disorganization of keratin intermediate filament network
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Less severe bc blistering in higher skin layers EB Simplex Dominant mutation causes complete disruption of the keratin more superficial (but painful blisters), non-scarring, localized to polymer (even if you have one nl K14) hands/ feet/ extremities, no mucus membrane involvement Recessive mutation causes truncated protein or loss of protein but not as problematic Very serious bc blistering in middle skin layers Junctional Generalized blisters at birth, periorificial granulation tissue, nail shedding/dystrophy, denuded areas, enamel defects, growth retardation, anemia, epithelial blistering of mucosal membranes (Resp, GI, GU) Subepidermal blistering w/ scarring Dystrophic (Recessive-RDEB or DominantDDEB) milia (cysts on newborns) that scar upon healing, Subepidermal blistering absent/dystrophic nails, Mitten deformities (fusion of finger scar tissue (RDEB)); mucosal surfaces involved, malnutrition, growth retardation, anemia Autoimmune-mediated blistering disease caused by antibody deposition against collagen VII blistering disease where epidermis is lifting off of basement membrane; usually on lower extremities of older patients Itchy, tense blisters (do not break easily!), Autoimmune blistering disorder where antibodies are directed at hemidesmosomes (sub-basal) so loss of epidermal attachment to basement membrane Blistering in the lamina lucida
Genetic defects w/ keratin (arginine at position G of alpha-helix heptad is mutated)
Histology? Cytolytic fracture / cleavage plane below the nuclei of basal cells --> aggregation of keratin fibers
premature stop codon in laminin 5 genes sometimes defects w/ collagen 17 or B4/a6 integrins Can be lethal in early childhood
Premature stop codon in collagen VII genes
Severe scarring
Epidermolysis bullosa acquisita Bullous pemphigoid (BP) Bullous pemphigoid
Autoantibodies against Collagen VII Histology? Subepidermal blister (white space btwn epidermis & dermis) (sub-basal split), healthy epidermis, +eosinophils (pink) Dx confirmed w/ immunofluorescent Abs binding to basement membrane Histology? Subepidermal blister (white space btwn epidermis & dermis) (sub-basal split), healthy epidermis, +eosinophils (pink) Dx confirmed w/ immunofluorescent Abs
Significant scarring
Autoantibodies against BPAG1 and/or BPAG2
Mucus membrane pemphigoid
red line along gingivial sulcus (white picket fence), no scarring
Autoimmune blistering disorder where antibodies are directed at hemidesmosomes (sub-basal) so loss of epidermal attachment to basement membrane Severe inflammation of the eye causes thick & fibrous scarring that fuses with the eye conjunctiva as symblepharon
Autoantibodies against BPAG2, laminins, integrins
Ocular cicatricial pemphigoid Pemphigus Pemphigus vulgaris
severe ocular disease, symblepharon (fibrous bands where eyelid fuses to conjunctiva) Inter-epidermal blisters, jagged & flaccid blisters w/ positive Nikolsky sign (easy to deform w/ slight pressure), hyperpigmentation in healing areas, not too much scarring, severe nail disease, oral lesions
Possible blindness as skin covers cornea if no aggressive treatment Histology? Basal epidermis still attached to BM, and rete ridges still visible but huge white space above represents blister (suprabasal split) Chicken wire appearance w/ direct immunofluorescence Immunosuppressants, corticosteroids; new therapies (tyrosine kinase inhibitors to increase resistance to pemphigus IgG) Immunosuppressants, corticosteroids
Autoimmune blistering disorder where antibodies (IgG) are Autoantibodies against attacking intra-epidermal (suprabasal) proteins of desmosome, desmoglein 3 and/or resulting in compromised cell-cell adhesion [basal layer splits desmoglein 1 from spinous layer]
side effects of steroids; high fatality w/o tx
Pemphigus foliaceus Ectodermal Dysplasia N/A
Albinism Vitiligo Keloid Panniculitis onychomycosis Dermatitis
N/A N/A N/A N/A N/A General Acute dermatitis (eczema) Chronic dermatitis Subacute dermatitis
Autoimmune blistering disoder where antibodies (IgG) attack Autoantibodies against intra-epidermal (suprabasal) proteins of the desmosome, resulting in compromised cell-cell adhesion [basal layer splits desmoglein 1 from spinous layer] Mutation in Loss of desmosomal cadherin organization and mediation of desomosomal Fragility syndrome subsequent adhesion cytoplasmic plaque protein (plakophilin) Tyrosinase mutation causes inability of melanocytes to produce Hypopigmentation melanin Hypopigmentation - usually splotchy; symmetrical involvement of Autoimmune destruction of melanocytes produces decreased body parts or absent melanocytes Exuberant scar usually from trauma Excessive collagen in the dermis Inflammation of subcutaneous adipose tissue Yellowing, hyperkeratosis of nails; possible presence of debris Tinea unguium (see Fungal infection of nail under nails Dermatophytosis) Edematous epidermis causes skin to become swollen, raised, Inflammation of skin inflamed --> erythema and itchiness severe inflammation and edema causes edema fluid to leak oozing, crusted vesicles (poison ivy) from skin surface --> oozing & crusting Lichenification Lichenification and spongiosis with crusting on surface Hypersensitive, twitchy skin - overreaction to various stimuli, causes skin to turn red--> white when scratched; same "twitchiness" also seen in lung/nasal membranes Abnormal cytoskeleton? Mutation in filaggrin causes abnl barrier fx so increased dryness; mutation also causes chronic, pruritic dermatitis that waxes & wanes; face & extensor bundling/collapsing of keratin fibers extremities of infants; flexural surfaces of older children/adults; lichenification and linear excoriations can be present (chronic); Aberrant inflammatory response? abundance of TH2 cells in xerosis, dermatographism dermal inflammatory infiltrate Hygiene hypothesis? overreaction upon antigen exposure due to "too clean" of environment Probably all of these! Abnormal circulation in skin comprises the skin barrier, causing dryness and inflammation --> itch --> LSC & SD Xerosis, erythema, red-brown discoloration from hemosiderin OLD theory - SD caused by stasis and hypoxia, but pts actually deposits and degraded extravasated RBCs, dilated superficial have high flow rate and oxygen veins; often involves medial ankle, possible lipodermatosclerosis (hard feeling from underlying fat Abnormal microcirculation - increased permeability of dermal necrosis); hypopigmentation, ulceration capillaries allows leakage of fibrinogen, which polymerizes to fibrin to form fibrin cuff around capillaries --> ultimately inflammation May or may not have underlying primary dermatitis; skin itches Lichenification of skin, very pruritic beginning chronic scatching cycle that causes the skin to lichenify Itching, redness, erythematous papules; possible spongiosis and 1. edema --> crusted vesicles; 2. Allergic - patient becomes sensitized from previous allergen exposure (no rash at first exposure); upon re-exposure to Diaper dermatitis (irritant, also caused by Candida), poison ivy ACD - due to oleoresin in Rhus group of plants); nickel ACD antigen, there is a delayed-hypersensitivity reaction neomycin ACD; formaldehyde ACD variation of dandruff, can be on scalp/face 1. irritant - not allergic, but burned/inflamed by substance (occur in anyone exposed) 2. Allergic - allergy response (poison ivy, does not occur in everybody) Once child outgrows AD, can have asthma/ allergies later; higher prev in developed countries suggest environmental factor
side effects of steroids
Histology? Melanocytes present (just not making melanin!) Histology? No melanocytes seen African American race Histology? Dermis has taken over! Histology? KOH prep or PAS stain reveals hyphae Histology? Epidermal spongiosis (intercellular edema; white) Histology? Spongiosis causing fluid-filled vesicles (subcorneal vesicles) Histology? Acanthosis of epidermis (thickening) Histology? Marked acanthosis, elongation of rete ridges, spongiosis Complications due to abnl barrier function of skin or abnl immune response? Secondary infections of AD skin with S. aureus, MRSA, HSV (tingling, stinging at lesion), molluscum --> pustulosis or folliculitis, weeping/oozing/yellow crust - have less AMPs due to acute/chronic lesions! Food allergies
Atopic Dermatitis (AD)
20% of children, 1% of adults "childhood eczema"; 2More common if parent has AD 3x more common now; more developed countries
Moisturizers for xerosis, antiinflammatory cortisone creams; if no relief to those, systemic immunosuppressants for severe cases (prednisone, cyclosporin); oral antibiotics for presence of secondary infections; acyclovir for secondary HSV infections (especially if periorbital)
Stasis Dermatitis (SD)
Venous insufficiency
Often require hospitalization for tx of Can be complicated by LSC venous ulcers
Lichen Simplex Chronicus (LSC)
Histology? Acanthotic
Can complicate other types of dermatitis Avoid irritant/allergen; wash immediately after exposure; calomine to soothe/dry out (AVOID sensitizers like topical benadryl/Caladryl); topical corticosteroid Anti- fungals controling Pityrosporum carriage Topical/oral antibiotics (reduce bacterial density and macrophage activation) Retinoic acid (downregulates TLR2 expression on monocytes) Do NOT give topical steroids!
Contact Dermatitis 1. Irritant 2. Allergic (ACD)
Patch testing
Seborrheic Dermatitis
Acne
N/A
Inflammation of skin related to host response to normal P. ovale flora Starts w/ occlusion of follicle and formation of microcomedone, leading to hyperkeratosis of the opening that blocks eggressive sebum. Cyst forms with sebaceous material, forming comedone. Follicular unit further expands, allowing Propionibacteria acnes growth of Propionibacterium acnes and inflammation that (nl skin flora) leads to follicular wall rupture Inflammation mediated by bacteria intxn w/ TLR2 on monocytes Colonization at birth that peaks in early adult life with increased sebaceous gland activity Malassezia furfur (P. ovale, P.orbiculare; nl Unclear factors trigger overgrowth & conversion of yeast to skin yeast) pathogenic hyphal form
Possible scarring
Tinea versicolor
N/A
hyper- or hypopigmented patches with readily inducible scale; chest & back; warm/moist environment; usually asymptomatic but may be pruritic
People living in warm/ humid climates have higher bacterial carriage
Disease
Clinical Variants
Pathogenesis
Etiologies
Hot/humid environment AB use Immunosuppressant Hi sebum prod S. aureus, occlusion of non-dermatologic areas
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Pityrosporum folliculitis Bacterial folliculitis Bacterial folliculitis
Follicular centered inflammation on chest or back
Inflammation of hair follicle due to fungal colonization/infection
People living in warm/humid climates Chronic S. aureus carrier Irritation Shaving Occlusion
Histology? Massive infiltration of neutrophils around hair follicle
Responds to anti-fungal tx
Do NOT give topical steroids!
Follicular centered pustules or erythematous papules that are slightly pruritic and/or tender
Bacterial infection of hair follicles transmitted from direct contact with infected person or autoinoculation
Clinical (pustules/papules w/ hair follicle in middle) Gram stain/Cx
Topical Abs Oral Abs (if extensive, recurrent) Self-limited Sx usually don't require tx May give Ciprofloxacin if needed Localized? Topical antibacterial cream (Mupirocin)
Abscess formation
Hot tub folliculitis
Diffuse folliculitis
Exposure to Pseudomonas in water that has not been sufficiently chlorinated
Pseudomonas aeruginosa
Clinical
Bullous impetigo (S. aureus) Impetigo Impetiginized eczema (2ndary inf)
Small vesicles/pustules, erosions w/ golden honey-colored crust
Superficial bacterial infection of epidermis caused by S. aureus, GAS; highly contagious (direct contact)
S. aureus, GAS
Increased incidence in SE, day care settings
Childhood Crowded areas Heat/humidity
Clinical (honey crust) Gram stain/Cx
Widespread? Oral Abs (Dicloxacillin, cephalexin, erythromycin, etc) Drainage (hot compresses or surgical) Oral Abs (dicloxacillin, Cephalexin, Bactrim)
Rare
Furuncle (smaller) Furuncles/ Carbuncles Carbuncle (larger!)
Inflammatory, tender nodules or abscesses around follicle (or underlying tissue if carbuncle) that is purulent or necrotic; hot/red, fluctuant (compressible)
Continuum from folliculitis --> furuncle --> carbuncle that is transmitted via autoinoculation/direct contact
S. aureus
Chronic S. aureus carrier Folliculitis Obesity Immunodeficiency
Clinical Gram stain/Cx
Abs not effective until necrotic/purulent tissue is DRAINED!! Recurrence Bacteremia (rare)
"Spider bite phenomenon" CA-MRSA Looks like spider bite, furuncle, abscesses, pyomyositis, cellulitis Bacterial infection caused by methicillin resistant S. aureus asymptomatic --> fatal Well demarcated scaly plaque w/ hyperkeratosis, may be pruritic Fungal infection of non-viable, keratinized structures like or erythematous (jock itch), moccasin scale or toe web stratum corneum, hair, nails; transmitted person-person, maceration (tinea pedis), annular w/ central clearing (tinea contact with infected fomites, autoinoculation corporis/faciei), alopetic patch w/ possible neck LN swelling (tinea capitis) Keratinases of fungal hyphae CA-MRSA
Increased prevalence as SSTI, furunculosis; can cause infections in Pts lack typical risk factors pts typically lacking RFs for MRSA (hospital/prison/ sports) Often none Humid/occluded skin Common infection even Atopy (eczema) in healthy hosts Immunodeficiency TOPICAL STEROIDS VERY common 20% of kids have at some time Common in adults Often none HIV Organ transplantation
Culture w/ sensitivity testing
NO beta-lactams, possible adjunct therapy Use Bactrim or clindamycin
Erythromycin & methicillin resisitant
Dermatophytosis
Tinea pedis (athlete's foot) T. unguium (onychomycosis) T. cruris (jock itch) T. corporis/faciei (ring worm) T. capitis (cradle cap)
Filamentous fungi (Microsporum, Trichophyton, Epidermophyton)
Histology? Fungal hyphae caused by dermatophytes in stratum corneum KOH prep Fungal Cx (takes wks) Wood's lamp (hair) Bx for histology w/ PAS stain
Topical anti-fungals (Azoles, TOPICAL STEROIDS CAN allylamines: naftifine, terbinafine) MAKE WORSE!!! Oral anti-fungals (azoles, allylamines, griseofulvin) for hair/nail infections Spontaneously resolution (SLOW) Nail disfigurement (rare) Alopecia
Verruca (warts) Verruca vulgaris Verrucus (bumpy/rough), hyperkeratotic skin colored papules; usually asymptomatic unless 2ndary infection/inflammation Infection of basal layer of skin with HPV (dsDNA virus), resulting in the slow division of cells in the spinous layer; Hyperkeratotic papules/plaques that are less exophytic, black eventually leads to hyperkeratosis and papillomatosis macules of thrombosed capillary loops ("seeds" = lay term) Transmitted from skin to skin contact, autoinoculation, Genital warts; flatter, gray/brown papules contaminated surfaces Thinlike projections common on face Pinkish warts common on hands/face HPV 2, 4
Histology? Hyperkeratosis of epidermis and granular layer, inward bending of rete ridges, papillomatosis (fingerlike projections of epithelia) Clinical Bx (rare) DNA testing to determine type of HPV present
Verruca plantaris Condylomata acuminata Filiform warts Verruca plana
HPV 1
Various OTC tx modalities that aren't all that effective (Salicylic acid, imiquimod, duct tape) Paring Cryosurgery Podophyllin (topical chem agent) Spontaneous resolution (can take up to 2y) Imiquimod Canthardin (good for kids) Liquid nitrogen Curettage Self-limited in immuno-competent host Oral antivirals for immunocompromised/ recurrent or severe episodes
possible some HPV types are cancer-forming
HPV
Molluscum Contagiosum N/A
Umbilicated (central), small, dome-shaped, pink papules
Superficial poxvirus infection of epidermis only transmitted via Molluscum skin to skin (considered STD in young adults) contagiosum virus
Children HIV Sexually active young adults
Clinical Crush prep Bx (rare) Histology? Henderson-Patterson bodies (eosinophilic inclusion bodies) Clinical Tzanck prep (cannot distinguish HSV from VZV) Direct fluorescent antibody (CAN distinguish HSV from VZV) Viral culture Bx (rare) Clinical Tzanck prep DFA (distinguish HSV from VZV) Viral Cx Bx (rare)
Herpes Simplex Virus (HSV)
HSV-1 (classically oral) HSV-2 (classically genital)
PAINFUL, TENDER grouped vesicles or erosions on erythematous base; prodrome (tingling); can occur on lips, finger (Whitlow), genitals
HSV infection of keratinized skin/mucus membranes transmitted skin-skin, skin-mucosa (possible STD) Latency phase, asymptomatic shedding VZV goes latent after active infection/vaccination in the ganglia until risk factors cause reactivation of varicella zoster virus
None - pretty ubiquitous virus
Potential risk for wide-spread dissemination Neonatal transmission POST-HERPETIC NEURALGIA
Varicella Zoster Virus (VZV) (Shingles)
N/A
PAINFUL, DERMATOMAL vesicles, crusted papules, erosions often in unilateral fashion
NOT contagious (represents reactivation state) but patients with varicella zoster can transmit chicken pox to those who have never had it
Varicella zoster virus
Lifetime risk of 10-20%
advancing age immunosuppression Stress!
ORAL ANTI-VIRALS ASAP!! (w/I first 48-72h)
dissemination transmission of varicella (chicken pox)
Topical creams (scabicides) PRURITIC, thread like linear burrows produced by the tunneling of the mite; can have erythematous papules; commonly seen on wrists, genitals, waistline, axilla, web spaces Eruption caused by tunneling of mite in stratum corneum that causes delayed type IV hypersensitivity response and Sarcoptes scabiei var. diffuse pruritic eruption after 4-8 weeks hominis Transmitted via skin-skin contact or contact with fomites Nursing home residents Children Hospitals Close contact areas Histology? Mites (ovals) in stratum corneum Mineral oil prep? Mites with oval gray eggs and fecal pellets treatment of fomites and close contacts can use oral anti-parasitic if severe (ivermectin) Antibiotics that cover staph and strep (dicloxacillin, some cephalosporins- Cefazolin, Cephalexin; vancomycin- if MRSA; Unasyn --> Augmentin if from bite) NOT Bactrim! Penicillin DOC
Scabies
N/A
Rare (psychological burden?)
Carbuncles w/ pus present? Think S. aureus Cellulitis Diffuse erythema w/ no pus? Think GAS
Rapidly spreading areas of edema, redness, heat; possible vesicles/bullae/cutaneous hemorrhage; systemic sx (fever, tachycardia, confusion, hypotension, leukocytosis)
Acute infection arising when organisms enter the deep dermis/subcutaneous layers through skin breaches
Group A Strep Other beta-hemolytic strep S. aureus (CA-MRSA)
Previous cutaneous damage (trauma, ulceration, fissured toe webs, inflammatory dermatoses) Obesity Edema (venous insufficiency, lymphatic obstruction) More common in infants/ children/ elderly
EMPIRICAL KNOWLEDGE (cx not always positive, low sensitivity of needle aspiration cx)
Eryisipelas
N/A
Raised, sharply demarcated erythematic lesions, commonly seen on face; acute onset
Acute infection caused by GAS entering the upper dermis
Group A Strep Less common than cellulitis
Diabetic foot ulcers
Acute Chronic
Infection by S. aureus or B-hemolytic Streptococci Often polymicrobial infection with enterococci, obligate anaerobes, P. aeruginosa, and/or Enterobacteriaceae Initially presents with cellulitis, blood-filled bullae, ecchymosis, systemic toxicity, elevated CPK RED FLAGS: severe pain out of proportion w/ skin findings, large bullae, skin necrosis/ecchymosis, wooden hard feel of subq tissue, numbness of skin, systemic toxicity, rapid spread w/ AB tx Rapidly progressive, toxemic infection in previously injured muscle (blunt trauma), edema, crepitus (gas bubbles), brown bullae; abrupt pain Initial break in skin from trauma or surgery causes advancing infection to fascial and/or muscle compartments Aerobic + Anaerobic bowel flora Clostridium perfringens C. novyi C. histolyticum Early? Think GAS or Clostridium GI or female GU surgery? Bowel flora Clean procedure? Skin flora (S. aureus, Strep sp) Historically seen with war injuries but now associated w. blunt trauma GAS, S. aureus, or anaerobic streptococci Less common in children NSAIDs Diabetes Venous insufficiency Completely normal hosts Abdominal Surgeries Decubitus ulcers Perianal ulcers Bartholin abscess IVDU h/o severe penetrating trauma or crush injuries XR shows edema and gas in soft tissue
clindamycin Unasyn (ampicillin + SulbactamIV) Extensive debridement, surgery Monomicrobial - clindamycin + penicillin G Polymicrobial - Ampicillin, clindamycin, and ciprofloxacin Aggressive surgical debridement PCN + clindamycin
Possible CA-MRSA infection associated with worse outcomes
Necrotizing fasciitis (NF) Monomicrobial
Usually bacteremic 30-60% mortality
Polymicrobial
Gas gangrene (myonecrosis)
N/A
Blunt trauma causes non-viable tissue to lose blood supply, creating anaerobic environment for spore-forming, gram positive rod bacteria to infect injured muscle
Spontaneous (hematogenous) gangrene from Clostridium septicum in pts with GI malignancies or neutropenia
Superficial incisional (subq space) Surgical Site Infections (SSI) Deep incisional (fascia/muscle) Organ/space Can be early onset or take 5-14 days Adverse infection associated with hospitalized patients who have undergone recent surgery
Inherent risk with clean contaminated, contaminated, or dirty-infected operative wounds
Prophylactic superficial antisepsis Perioperative ABs Incision & Drainage
Disease
Osteoporosis N/A
Clinical Variants
BMD T-score < -2.5, increased incidence of fractures
Pathogenesis
skeletal disorder characterized by compromised bone strength (bone density & bone quality- arch, turnover, mineralization, damage accum) predisposing a person to increased risk of fracture With age, lose trabecular volume, #, thickness, connectivity Decreased estrogen is related to high bone turnover that results in stressful micro-cracks and loss of bone density Estrogen deficiency = oxidative stress in bone marrow = increased ROS = activation of T cells = increasd TNF = formation of osteoclasts and bone marrow stromal cells via RANKL
Etiologies
Loss of bone trabeculae (microarchitectural deterioration) Genetic predisposition Estrogen deficiency activates immune response Increased RANKL
Epidemiology
Risk factors
Age Postmenopause FH of osteoporosis Adjustable RF? Excessive alcohol sedentary lifestyle
Lab/Imaging
Treatment
Low dose Ca/VitD Estrogen calcitonin raloxifene (estrogen Ag in bone, Antag in breast) Bisphosphonates -Alendronate, Zoledronic acid (Reclast) Anti-RANKL Ab - Denosumab Anabolic agentForteo (teriparatide) - transient PTH = bone formation Odanacatib - Cat K inh Sclerostin Ab
Complications
Long term bisphosphonate use causes increased BMD but increased fractures, increased osteonecrosis of jaw (rare) High dose calcium linked to CV events and vascular calcification
Polyostotic Paget's disease Monostotic
Genetic predisposition (chrom 18, overlap w/ familial expansile 3 stage of localized, chaotic(mosaic) bone remodeling: misshaped legs/head, gait problems, progression over 1. osteoclastic activity osteolysis, p62 time,warm to touch; moth-eaten deteriorated bone, pitting of 2. mixed osteoclastic-osteoblastic activity, where osteoblasts try mutation- nl degrades pagetic bone; usually involves spine/ skull, most painful in to compensate with deposition of disorganized, RANKL signaling; pelvis/long bones hypervascularized lamellar bone Juvenile Paget's 3. exhaustive (burnout) stage (dense pagetic bone as mutated OPG) hearing loss, platybasia (softening at skull base--> headache hypercellularity of bone diminishes) w/ valsalva), Pagetic steal syndrome (shunt blood to ext Problem with osteclasts carotid, stroke-like sx), osteoporosis circumscripta (bone loss All results in deformity, fracture, metabolic derangement (inc #, size, nuclei, fx, around skull), leontiasis ossea (rare, enlarged facial/jaw bones), sensitivity to vitD); nl DIsorganized communication btwn osteoclasts and osteoblasts osteoblasts high output heart failure (coupled chaotic activity) possible involvement of slow viral inf Dense, brittle bone that fractures, bleeding/infections, hypersplenism, hemolytic anemia Count osteoclasts - RANKL mutation (low OC #) v. TC1RG1/ ClCN7 (nl OC #)
More common in people from British Isles, Caucasians adult disease (~60y.o.) Age 200,000 cases in U.S. (~3% prev) 5-20% w/ symptoms M>F
Elevated bone-specific alkaline phosphatase (overactive osteoblasts, >2x inc) Histology? Woven mosaic bone XR? Pagetic flame lytic lesions, cotton wool skull, sclerotic + resorbed areas, inc Calvarian thickness), picture frame vertebral bodies (thick cortex frames lesion), fissure/chalk stick fractures (straight across) Bone scan? show sclerotic dz
Most people are asymptomatic sx? NSAIDs, COX2 inh, PT, surgery for fx Advanced disease? Use osteoporosis drugs (bisphosphonates, since they too kill osteoclasts) hypercalcemia tx if know pt will be immobilized
Pagetic bone is hemorrhagic so activity needs to reduced before surgery Spinal cord/nerve root compressions Fractures Osteosarcoma!! (10% of older pts) - but no inc in non-skeletal malignancy! hypercalcemia (immobilization) gout (23% of pts w/ gout have paget's) Cranial nerve compression --> blindness, deafness Death by 10y.o. if not treated
Autosomal recessive infantile malignant (ARO) Osteopetrosis Autosomal dominant (Albers-Schonberg) (ARO)
Mutation in RANKL (rare) or ion pumps (TC1RG1, ClCN7) causes defective bone resorption and apoptosis of osteoclasts Mutation in TC1RG1 causes inability of osteoclast to secrete hydrogen ions into the bone matrix, thereby decreasing bone resorption Mutation/defect in cathepsin K, so osteoclasts can no longer function properly in bone resorption Mutation in CAII renders the cell unable to generate protons from CO2 and H2O, causing loss of osteoclast resorptive function and generalized disease
Spine sclerosis with sandwich vertebrae (rugger jersey spine), variable penetrance/ severity Disproportionate (big head, small body), pectus excavatum, lumbar lordosis, nail hypoplasia (missing nails)
Bone overgrowth due to Infancy loss of osteoclast resorptive fx Late childhood/ adolescence onset Onset in infancy, early Bone overgrowth due to childhood loss of osteoclast resorptive fx Very rare! Bone overgrowth due to loss of osteoclast resorptive fx Unregulated TGF-B causes overstimulation Variable age, severity, of osteoblasts and course excessive bone formation Autosomal recessive inheritance Dutch ancestry (Afrikaners) Autosomal recessive
Osteoclast number, anemia labs
Bone marrow transplantation
XR? Rugger jersey spine
Fractures, osteomyelitis, possible nerve compression
Pycnodysostosis
N/A Facial dysmorphism? Missing jaw look, large forehead, underdeveloped nose, asymmetry renal tubular acidosis, cerebral calcifications, hypotonia, weakness, mental subnl Phenotype less severe w/ age
XR? Dense orbital ridge, sclerotic skull base, hypoplasia of facial bones, dense vertebrae w/ preservation of TVP UA - check for RTA Measured in erythrocytes
Recurrent fractures in lower limbs
Carbonic Anhydrase II deficiency
Progressive Diaphyseal disease
Camurati-Engelmann
gradual appearance of symmetric hyperostosis on periosteal and endosteal surfaces of long bones
mutation in TGF-B1, a latency protein that is a normally a chronic sequesterer and inhibitor of TGF-B in bone
Glucocorticoids for pain relief
Endosteal hyperostosis Sclerosteosis
Van Buchem
Worth type
Fibrodysplasia ossificans N/A progressive (FOP)
Osteomyelitis
Acute
Disruption of Wnt signaling system causes decreased inhibition of Wnt, resulting in the inhibition of APC/GSK3 complex. Now, B-catenin is active and able to promote transcription of genes involved in osteoblast differentiation, Heavy bones! causing osteosclerosis Progressive asymmetrical enlargement of mandible (w/o Disruption of Wnt signaling system causes decreased dental malocclusion like osteopet), pain w/ point pressure on inhibition of Wnt, resulting in the inhibition of APC/GSK3 longbones complex. Now, B-catenin is active and able to promote transcription of genes involved in osteoblast differentiation, Heavy bones! causing osteosclerosis BMD T-score >0, no fractures, nl bone remodeling, flat forehead, Disruption of Wnt signaling system causes decreased elongated mandible, toras palatinus (bony protrusion of palate), inhibition of Wnt, resulting in the inhibition of APC/GSK3 benign presentation complex. Now, B-catenin is active and able to promote transcription of genes involved in osteoblast differentiation, Heavy bones! causing osteosclerosis Inflammatory swelling of soft tissues that eventually transforms into encasement of bone during first decade of life via Soft tissue swelling that progressively turns to bone esp at sites endochondral ossification of injury (avoid trauma!!); malformed great toe, progressive heterotopic ossification pattern; spares heart/ diaphragm/ Missense mutation of ACVR/ALK2 inactivates binding site for extraocular muscles inhibitor (FKBP12), causing excessive and constitutive BMP stimulation occurs rapidly over days-wks, new bone pain at site of inf, Infection of the bone via hematogenous entry, contiguous swelling spread, or inoculation via trauma TALL, heavy, Dutch ancestry, syndactyly, pain w/ point pressure on long bones
Deactivating mutation in SOST (Wnt inhibitor)
Nl OC Possible inc alk phosphatase Possible optic atrophy, facial nerve palsy, deafness
Deactivating mutation in SOST (Wnt inhibitor)
Autosomal recessive inheritance
Nl OC Possible inc alk phosphatase
Mutation in LRP5, prevents binding of DKK1 (Wnt inhibitor)
Autosomal dominant inheritance
Excessive BMP stimulation --> increased osteoblast formation
Patients usually die of R heart failure, Pulmonary HTN NO BIOPSY!!!! Require wheelchair by 3rd decade More common in kids XR? Moth eaten appearance of bone Surgical debridement, drainage, obliteration of dead space, wound coverage Cure = resolution of signs and sx for >1y Kids - use AB that covers TB can cause Pott's disease in staph/strep (empirical) spine CT guided needle bx (adults) for Cx 4-6 wks AB tx MSSA- nafcillin, oxacillin MRSA- vanco, dapto Strep- PCN G, ceftriaxone, cefazolin Enteric GNs- Cipro, ceftriaxone Serratia, Pseudomonasceftazidime, cefepime, piperacillintazobactam Anaerobes- clinda, metronidazole Surgical debridement if necrotic
Chronic
Occurs over weeks/months/yrs; necrotic bone w/ loss of vascular supply, swelling
untreated acute osteomyelitis
Ortho surgeries
Assess response after tx with ESR, CRP
Hematogenous
bactermic seeding of bone, swelling, long bones (kids), vertebrae (adults), periosteal abscesses in kids Long bones - fever, chills, malaise, soft tissue swelling and pain Vertebrae- neck/back pain, localized tenderness, low/absent fever, neurological deficits (epidural abscess)
In presence of bacteremia, bacteria may get trapped in small end vessels. In kids, bacteria enter venous sinusoids of metaphysis in long bones via leaky capillary fenestrations. In adults, bacteria often seed in vertebral bodies (wellvascularized) or bugs can drain from Batson's venous plexus (from urinary tract) IV DRUG USERS? Sternoclavicular joint, SI joint, pubic bones
Kids- S. aureus, GBS (infants), CoAN staph Elderly- S. aureus, GramImmunocomp - fungi IVDU- S. aureus, P. aeruginosa, Serratia Sickle cell- S. aureus, Salmonella
MOST common in kids IVDU - novel organisms in unique Adults - elevated ESR/CRP sites XR? Takes a while to show signs, but periosteal elevation, areas of demineralization, loss of sharp bony margins, moth eaten appearance, possible soft tissue swelling CT? sensitive Bone scan? Early dz (lots FPs) MRI? GOLD Standard! detects early changes & abnl soft tissu; adjacent vertebrae involvement
increasing pain, skull/mandible/ small bones hand/ long bones/feet, mild fever, minimal drainage Contiguous Bacterial infection from localized ulceration/ trauma travel Diabetic osteomyelitis? Painless (due to peripheral neuropathy further to the bone in most DM pts) ulcer extending to bone, mild cellulitis, crepitance [If it probes to the bone, it's osteomyelitis]
Possible polymicrobial (see diabetic foot ulcer bacteria) Mixed gram+/-, anaerobes
Imaging hard to interpret bc surrounding soft tissue inf MOST common in adults Chronic skin ulcers (arterial sclerotic dz), trauma, diabetes, post-op ortho surgery, chronic edema Bone scan sometimes reveals contiguous spread from ulcer site Bone sample for culture
Revascularization Amputation/ surgical debridement Abs for 4-8wks (Avoid empiric ab tx)
Disease
Septic arthritis
Clinical Variants
Acute bacterial
Pathogenesis
Etiologies
Epidemiology
Risk factors
Recent trauma (animal/ human bites) Immunocompromised RA/gout/sickle cell IVDU
Lab/Imaging
Treatment
Joint drainage (serial taps, open procedure) Systemic Abs 2-4wks
Complications
swollen, hot, monoarticular arthritis w/ passive motion; less Generally hematogeous spread of bacteria or possible uncommon - fever/chills iatrogenic spread (joint injections for RA/OA) Chronic septic arthritis Other infectious diseases causing arthritis
S. aureus Streptococci GN rods Mycobacteria (Tb) Lyme disease Fungi Rubella, mumps, parvovirus
Tap joint? Elevated WBC Gram stain & cx
Disseminated gonococcial infection (DGI)
Bactermic form: Dermatitis that coincides w/ pustules/papules that are sometimes hemorrhagic; centrifugic distribution, fever, tenosynovitis, polyarthalgia/arthritis Localized form: purulent arthritis (1,2 joints) Acute onset joint pain, effusion, erythema, warmth, fever
F>M Arthritis associated with gonococcal bacteremia Neisseria gonorrhoeae declining incidence
Sexually active young adult Timing associated with menses Pts w/ terminal complement deficiencies Joint replacement
Cultures from mucosal sites
IV ceftriaxone
Prosthetic joint infection Early (<3m after surgery)
Low grade sx, implant loosening, chronic joint pain Delayed (3-24m)
Acute contiguous infection from virulent pathogens seeded after S. aureus, surgery Streptococci, Gram rods, enterococci, anaerobes, fungi (rare) Chronic contiguous infection from less virulent pathogens CoNS (form biofilms seeded after surgery; well) usually biofilm-forming pathogens Hematogenous seeding from variety of sources (skin, resp, dental, UTI)
Rising incidence w/ increased joint replacement surgeries
XR? Lucency at bone/cement interface, loose cemented prosthesis Synovial fluid aspiration? Elevated WBCs w/ increased neutrophils Synovial fluid Cx may be negative if biofilm formation
One-step procedures (remove and replace prosthesis at same time) Two step procedures (debridement, removal, then replacement later) debridement and retention (stable joint w/ early inf) long term Ab (3-6m) for all
Late (>2y) Ehlers Danlos Syndrome (EDS) Classical Skin & joint hypermobility (Beighton's score >5 for joints), atrophic scarring (not well healed), easy bruising, smooth/velvety skin, hypotonia & decreased motor development
S. aureus, Streptococci, Gram rods, enterococci, anaerobes, fungi (rare) 1/5000 individuals; classical form is most common Autosomal dominant
Sonication of removed prosthesis for cx
Clinical exam for manifestations Beighton score baseline echocardiogram for kids <10 y.o. Evaluate clotting factors Tx manifesting sx Low-resistance exercise to increase muscle tone Vit. C & D, Ca supplem Avoid high impact force
Mutation in collagen type V (COL5A1, COL5A2), disrupting structural integrity of connective tissues
Hypermobility Arthrochalasia
Hypermobile joints but do not have major/minor skin findings, soft skin w/ only minor extensibility, absence of skin/soft tissue abnl Severe generalized hypermobility, congenital bilateral hip dislocation, tissue fragility and skin hyperextensibility
Unclear but haploinsufficiency of tenascin X(TNXB) Mutation in collagen type I (COL1A1, COL1A2) causes abnormal processing of amino terminal ends
Autosomal dominant inheritance Autosomal dominant inheritance
Clinical & FH only No genetic testing Clinical genetic testing Very severe - dissection of carotid artery, arterial/digestive/ uterine fragility or rupture Clinical genetic testing Celiprolol (cardioprotective) 80% develop significant med probs by age 40 Sudden death (median age 48)
Vascular
Arterial, digestive, uterine rupture/fragility, characteristic facial appearance (acrogeria, tightened skin over face, hollow Dominant-negative mutations in pro-a1(III) chain of collagen cheeks, thin upper lip and skin), extensive bruising, spontaneous type 3 pneumo/hemothorax, hypermobility of small joints, talipes equinovarus (clubfoot)
Autosomal dominant inheritance Family history Sudden death in close relative
Dermatosparaxis Kyphoscoliosis
Severe skin fragility, sagging/redundant skin, large hernias Deficiency in type I procollagen N-peptidase Generalized joint laxity, severe hypotonia and scoliosis at birth, scleral fragility, rupture of ocular globe Extremely tall (arm span longer than height), long fingers, dilated aortic root, ectopia lentis-dislocated lens, pectus carinatum OR pectus excavatum Mutation in PLOD1 causes decreased lysyl hydroxylase in dermis and loss of connective tissue cross-linking capabilities Connective tissue disorder caused by missense mutations in FBN-1 gene on q15, disrupting TGF-B-fibrillin complex and increasing amount of active TGF-B Decreased lysyl hydroxylase Abnl Fibrillin protein 3 collagen genes: COL2A1, COL11A1, COL11A2
Autosomal recessive inheritance Autosomal recessive inheritance
Clinical findings only (no genetic test!) Clinical genetic testing Clinical exam tests? Walker Murdoch wrist sign, Steinberg thumb sign Currently testing use of angiotensin II type I receptor antagonist (Losartan)
Marfan Syndrome
N/A
Stickler Syndrome
Cleft palate, bifid uvula, midfacial hypolasia (underdeveloped cheek bones, flattening of midface), high myopia causing retinal Mutations in any of detachment, early onset arthritis, MVP, later hearing loss Type 1 - mild sx, fx w/ minor trauma, no bony deformities, bluish-grey sclerae Type II - perinatal lethal form, multiple fx in utero, dark blue Group of heritable conditions characterized by bone fragility and low bone mass; usually caused by mutations that silence sclerae one allele, resulting in decreased amount of normal type I Type III- may have in utero fx or fx @ birth, thin ribs, popcorn collagen synthesized epiphyses, short stature, hearing loss common, dentinogenesis imperfecta (gray/brown teeth that break easily Mutations in COL1A1 and COL1A2; especially, substitution of and look translucent) any amino acid for glycine disrupts collagen helical molecule Type IV- mild-mod, maybe DI, sclerae nl or grey, some hearing loss
Autosomal dominant inheritance Genetic testing Multiple family members affected
Type I Osteogenesis Imperfecta Type II (OI) Type III Type IV
Point mutations with dominant-negative Prev? 6-7/100,00 effects cause structural defects in collagen
XR? Wormian bones Most autosomal dominant inheritance Skin bx? Analyze structure/quantity of type 1 collagen molecular genetic testing
Treat fx but avoid immobilization for long periods of time! Type II - perinatal lethal Use light-weight casts PT rodding Use high-risk Obs to manage pregnancy
Disease
Clinical Variants
Short stature w/ disproportionately short arms/legs, macrocephaly, frontal bossing, mid-face hypoplasia, hypotonia in infancy, delayed developmental milestones Pain in femur/tibia/vertebrae @ night, relieved by NSAIDs
Pathogenesis
Mutations in FGFR3 genes cause excessive signaling of FGFR3, resulting in impaired chondrocyte fx w/I epiphyseal growth plates
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Compression of spinal cord/ upper airway obstruction increased risk of death in infancy
Achondroplasia
N/A
Dominant inheritance pattern
Osteoid Osteoma
Benign
BENIGN >2cm? Osteoblastoma
Males age 10-25
Histology? central nidus of woven, hemorrhagic bone surrounded by reactive sclerosis CT? sclerotic bone on outside w/ pinpoint middle nidus
Remove to prevent recurrence
Chondroma / Endochondroma Osteochondroma
Benign
(Endochondroma - inside bone; Chondroma - outside bone) Incidental finding after fx Most common bone tumor, cartilaginous entity, medullary canal is contiguous all the way thru stalk, usually stop growing w/ pt
Residual bits of cartilage that were displaced during development Occurs when bits of cartilage from the physis that get incorporated into the bone begin to grow, producing a stalk in the bone Autosomal dominant disease
XR? Popcorn calcifications Histology? Benign cartilage Histology? Cartilage cap, bone marrow inside XR? Benign polypoid projections from cortical bone Increased alkaline phosphatase XR? Lysis, blastic sclerotic bone, or even mixed; ill defined border (R/O osteomyelitis), elevated periosteum (periosteal rxn) M>F Histology? Periosteal rxn Tumor resection, prosthesis MRI? Soft tissue extension CT? metastases
None - benign If cartilage cap >1cm, start to worry about development into chondrosarcoma (RARE)
Benign
Osteosarcoma
Osteoblastic Fibroblastic Chrondroblastic Telangiectatic Parosteal Periosteal Central low-grade Secondary
Kids: occurs around knee Adults: axial skeleton Occur in the metaphysis, knee pain/swelling (loss of ROM),weight loss (disseminated), pathologic fx w/ nl activity
Neoadjuvant therapy (Chemo before surgery)
80% of metastases are to the lungs
Chondrosarcoma
Trunk/pelvis/long bones; pain, swelling, resistant to radiation/chemo (low blood supply/growth), possible dedifferentiation (abrupt transition from low--> high grade tumor) Flat or long bones of young children Translocation btwn EWS gene and FLI1 gene so ETS DNA binds at ETS DBD spot, causing loss of RNA recognitiion motif from EWS Caused by X-linked recessive mutation of dystrophin, resulting in absent (or <5%) dystrophin. W/o dystrophin, the sarcolemic membranes are leaky, there's secondary Absent dystrophin inflammation from necrosis, and cycles of degeneration & regeneration. X-linked recessive mutation resulting in decreased dystrophin Decreased dystrophin Maternal anticipation Autosomal dominant inheritance associated with trinucleotide (increases number of CTG repeats in myotonin-protein kinase gene on C19 CTG rpts) VERY VERY RARE M>F Adolescents/ young adults Most common MD, especially in children 1/3000 live births 1/30,000 live births
M=F 35-60 y.o.
XR? Popcorn calcification
Surgery only
Histology? "small round blue cell tumor" Imaging? Onion skin appearance Associated w/ dilated Histology? Increased CT, fibrofatty and macrophage infiltration, variable muscle fiber size and abnl cells, bluish cardiomyopathy Steroids at early age prolongs ability fibers are regenerating (inc DNA) to walk No cure! Limited life CK levels 10-100x>nl expectancy Similar histology to DMD Longer life expectancy (40-60y.o.)
Ewing sarcoma Muscular dystrophy Duchenne MD
Pseudohypertrophy (large calves), scoliosis, lumbar lordosis, protuberant abdomen, toe walking, Gower's sign, mental deficits Variable onset (5-15y.o.), similar symptoms as DMD but later onset and less severe Maternal anticipation, asymmetric distal weaknes w/ myotonia, pt can make a fist but can't open it back up easily; frontal balding, cataracts, cardiac conduction probs, endocrine dysfunction (hypogonadism, insulinR), GI hypomotility
Becker's MD
Myotonic dystrophy type I
5-20/100,000 live births
Clinical exam
Multisystem disorder; possible complete heart block
Congenital Myopathy
Central core disease
Autosomal dominant dz caused by point mutations of the ryanodine receptor gene on 19q, encoding the Ca-release hypotonia, poor feeding, high arched palate, delayed motor milestones, joint contractures, resp probs, pectus carinatum (bird channel of the sarcoplasmic reticulum of skeletal muscle; mutations of this gene also account for some cases of chest) inherited malignant hyperthermia exercise intolerance w/ premature fatigue in anaerobic ex, stiffness/weakness in exercising muscles relieved by rest; rhabdomyolysis w/ intense ex, second wind phenomenon Recurrent rhabdomyolysis in adults after prolonged exercise or fasting, proximal weakness later in life Maternal transmission, extra-muscular manifestations (in tissues/organs w/ high met rates) Furrowed brow, high-arched eyebrows
Autosomal dominant defect in ryanodine
Asymptomatic but affected mother --> drastic increase in trinucleotide rpts
Nl CK because not a lot of muscle degen/regen Histology? Central cores appear as central/ eccentric areas of muscle fibers w/o oxidative enzyme activity none
Known association w/ malignant hyperthermia- fever, muscle rigidity/necrosis, lactic acidosis (excessive Ca release)
Metabolic myopathy McArdle's disease
myophosphorylase deficiency, preventing the breakdown of Defect in glycogen glycogen to glucose (glycogen cannot be converted to G6P) breakdown Deficiency in enzyme required for transport of LCFA from cytosol to mitochondria
Histology? Abnormal deposits of glycogen Diagnosis needed to treat pts and avoid recurrent hospital admissions for renal failure
Carnitine palmitoyltransferase II deficiency
M>F
nl CK and EMG; dx requires direct measure of muscle CPT or genetic testing
Mitochondrial myopathy Progressive External Opthalmoplegia (PEO) - ptosis, opthalmoparesis MELAS - stroke <40, encephalopathy, RRF, lactic acidosis MERRF- myoclonus, epilepsy, ataxia, ragged red fibers Inflammatory myopathy
Abnormal amounts of mitochondria
Histology? Ragged red fibers representing abnl excess mitochondria
Histology? Perifascicular atrophy, inflammation of dermal-epidermal jx (interface dermatitis) Histology of Gottron's papules? Increased stratum cornum thickening, interface dermatitis Humoral immune process against vascular endothelium, resulting in the deposition of C5b-9 MAC from complement -> CD4+ T cell and B cell response --> ischemic muscle Complement mediated injury ischemic muscle injury 1/100,000 F>M Kids (more calcinosis) & adults Elevated muscle enzymes Myositis specific Abs (Anti Jo-1- worse prognosis, Anti Mi-2 -better prognosis) corticosteroids Methotrexate, azathioprine (LT) IV immunoglobulins
Dermatomyositis
Heliotrope rash (periocular edema + violet color) on sunexposed areas; Gottron's papules (red, thickened plaque-like rashes on extensor surfaces), nailbed hemorrhages, violaceous erythema (shawl sign), dilated capillary loops of proximal nail folds, cutaneous calcinosis (ROCK hard)
Increased risk of malignancy in +/-4 yrs before/after dx Interstitial lung disease Diaphragm/ intercostal weakness --> resp arrest Cardiac rhythm disturbance
DM = DZ of body attacking blood vessels around muscle, SYMMETRIC WEAKNESS OF PROXIMAL MUSCLES (usually causing watershed inflammation around muscle. lower extremities first, then upper extremities)
Bx evidence? Necrosis, upregulation of MAC around photoprotection blood vessels, regeneration, varied fibers, inflammation around blood vessel (not in the muscle fibers) (CD4+ T/B cells) XR? Calcinosis MRI? Muscle inflammation
Polymyositis
Proximal muscle weakness, no rash (more of just ruling out other myopathies) Most common acquired myopathy >50y.o; Distal and asymmetric weakness of finger/wrist flexors, knee extensors, ankle dorsiflexors
Cell mediated immune response within the muscle (endomysial inflammation) involving T cells & macrophages ? Myopathy from following "toxins": Alcohol, Statins, Colchicine, Glucocorticoids, AZT Myopathy associated with following systemic diseases: Hypokalemia, Hypophosphatemia, Critical illness myopathy, or endocrine disorders (thyroid dz, parathyroid dz, adrenal disorders, hypopituitarism, acromegaly)
Histology? CD8+ T cell/mo infiltration in NORMAL looking muscle! Histology? Centrally-placed nuclei, red-rimmed vacuoles (fibers w/ holes in them)
Corticosteroids
Inclusion body myopathy Toxic Myopathy
Myopathies from systemic dz
Polymyalgia Rheumatica N/A (PR)
Dx critieria: Persistent proximal pain (>1m) involving (neck, shoulders, pelvic girdle- 2), >1h morning stiffness, abrupt onset of illness (<2wks), age>50, Rapid response to low dose prednisone, elevated ESR, absence of other disorders (flu, hypothyroidism)
Polygenic (environment & genetics)
Genetic component (HLA-DR)
F>M Extremely unlikely in pts <50y.o.
Activation of innate immune system leads to elevated levels of Genetic polymorphisms NE descent: TNF in adhesion molecules & 20-53/100,000 in pts TNF >50 (less in Italians)
Can be associated w/ Giant cell arteritis
Elevated ESR/CRP Thrombocytosis (hi platelets) Nl CPK Anemia of chronic dz Negative ANA, RF Clinical dx
Corticosteroids (Should be RAPID response if right dx)
Fibromyalgia (FM)
Soft tissue pain disorder
Widespread and migratory pain/tenderness; waxes & wanes, No inflammation or tissue pathology! other nonspecifc MSK sx (IBS, headaches), fatigue, weight change, night sweats, weakness, SLEEP PROBLEMS, trouble Abnl neurochemistry affects pain perception; mood & sleep concentrating, TMJ, ENT sx, nondermatomal parasthesias disturbance along w/ changes in HPA axis causes decreased Physical/emotional blood flow to thalamus (pain perception center), resulting in triggers can precede or Chronic widespread pain involving ALL 4 quadrants and aggravate sx (virus, decreased pain thresholds axial skeleton; Presence of 11/18 tender points trauma, dep/anx)
Pain perception thresholds decreased (abnl neurochem)
Prev? 4% of population F>>M (10:1) Peak onset 30-55y.o. First degree relatives w/ FM (8x higher risk!) Mutations in serotonin gene
Clinical? Should not see weakness! Dramatic pain/tenderness at pressure points No anemia Nl CPK, aldolase Nl ESR/CRP Nl thyroid studies Negative ANA, RF
Pt education Anti-inflammatory/ analgesic meds (not better than placebo) AVOID NARCOTICS tricyclics (muscle relaxant, antidep) Serotonin reuptake inh Lyrica (decrease perception of pain) FITNESS TRAINING! (low impact aerobics and muscle strength)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Clinical exam? Prodrome malaise/fatigue, stiffness that improves w/ activity, non-reducable deformities (swanneck, boutonniere, trigger finger, MCP subluxation, ulnar dev, hammer toes) Elevated ESR/CRP Anemia Thrombocytosis +RF (80-85%, worse dz) Anti-CCP (90-95%SP) >2000 WBCs in joint fluid XR? periarticular osteopenia, uniform narrowing around joint, marginal erosions, C1-C2 subluxation, ulnar dev
Treatment
Complications
Extra-articular manifestations? Heart - pericarditis, atherosclerosis Lung - pleural effusion, interstitial lung dz Skin - nodules, vasculitis Neuro- carpal tunnel (Bilateral), cervical myelopathy, entrapment neuropathy Heme- anemic, thrombocytosis, FELTY'S TRIAD (RA, leukopenia, splenomegaly) Bone- osteopenia Eye- inflammation Kidney - rare Risk for neuro damage w/ C1-C2 subluxation
NSAIDS DMARDS: -Immunosuppressants (MTX, leflunomide, azathioprine) - secondary agents (hydroxychloroquine, glucocorticoids) -TNFa antagonists (Etanercept, Infliximab, Adalimumab, Golimumab) -IL-1R Antagonists (Anakinra) -T cell costimulatory blockers (Abatacept) -Combo tx
increased angiogenesis to joint space, Hyperplastic synovia, hypertrophic synoviocytes, painful overgrown synovia (PANNUS) Morning stiffness (>1h), 3+ joint arthritis, hand joint arthritis, symmetric, rheumatoid nodules (extensor surfaces, pressure points), +RF, XR changes [4/7 criteria for 6+ wks to R/O inf] Fusiform swelling, SPARES THE DIP JOINT! Systemic sx (fever/malaise, poor energy, weight loss, tissue damage in other organs)
Aberrant immune response in genetically predisposed person leads to synovial inflammation and destruction of the joint Genetic & environmental factors--> innate immunity->macrophages--> T cells through TNFa and osteoclasts through RANKL; when DCs get to lymphoid organs, they activate T/B cells that release inflammatory factors/antibodies into the joint. Cytokines, Proteinases, cathepsins responsible for joint destruction. RANKL increases osteoclasts causing bone erosion. Prev? 1% of pop F>M (2.5:1) Peak onset? 35-50y.o. RA in men <45 unusual! First degree relatives w/ RA HLA-DR4 (shared epitope- HLADRB1) SMOKING!!! (2 copies of SE + smoker = 21x RA risk) periodontal dz mucosal surface toxicity
Rheumatoid Arthritis
W/ age, side chains in cartilage shrink and hold less water = less resilience & more dessication = stress fx & fissures Use-related pain, loss of ROM Morning stiffness <30min Bouchards (PIP) & Heberdens (DIP) nodes Crepitus Mild effusion (but NOT warm) Mal-alignment of joints (bowlegged-varus; knock-kneed-valgus) SPARES MCP joints!! Chondrocytes try to make new collagen but there is a shift towards collagen 1, 3, 10 --> shortened proteoglycans (less H2O retention) 1. Edema of ECM w/ loss of chondrocytes & smooth cartilage causing microcracks 2. Microcracks deepen to form vertical fissures & pits 3. Fissures loosen & fragment, forming erosions & mild synovial inflammation (from MMPs). As body tries to repair, it scleroses and forms osteophytes. Focal loss of articular cartilage followed by hypertrophism of underlying bone and formation of osteophytes at joint margin Nl ESR/CRP/platelets Nl hematocrit <2000 WBC in joint fluid XR? Osteophytes (bone spurs), asymmetric joint space narrowing, NO PERIARTICULAR OSTEOPENIA!
Osteoarthritis
Degenerative joint disease
Older individuals
Trauma Infection Crystsal dz Neuropathy
Acetaminophen NSAIDs Eventual joint replacement surgery
Disease
Clinical Variants
Pathogenesis
Overproduction of uric acid? (~10%) High nucleic acid turnover in predisposed populations (Paget's, psoriasis, leukemia, etc) or problems with purine synthesis (overproduction of PRPP synthetase, deficiency of salvage enzyme HGPRT) Underexcretion of uric acid? (~90%) hereditary factors, certain meds, or other conditions cause difficulties excreting uric acid Hyperuricemia --> tophi (uric acid deposition that are engulfed by granulocytes) --> inflammation (NALP3 inflammasome)--> lactate production & pH drop --> formation of more crystals --> more inflammatory cells recruited --> renal damage if deposited on tubules
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Episodic monoarticular Gout Polyarticular Tophaceous gout
Crystals in WBCs = active gout flare Hyperuricemia (except during flare) Painful/red/swollen joints/bursa, appears like cellulitis/septic joint, fever/leukocytosis, podagra (1st MTP), tophi (distal joints, bursa; look like white dots, feel like gravel)
Prev? Males 5-28/1000; females 16/1000 Equal incidence after menopause! M>F (5:1) Age onset? M 40-50; F postmenopause
Hyperuricemia, tophi
>6.7mg/dL solubility of monosodium urate crystals Paget's, Psoriasis certain cancers excessive alcohol intake Co-infection of joint
NSAIDs- Indomethacin (acute pain relief) ALWAYS TAP JOINT & CULTURE FLUID! (yellow parallel crystals) XR? Nl mineralization, punched out erosions w/ sclerotic borders, overhanging edges Colchicine (acute pain relief, prophylactic w/ LT meds) Probenecid (chronic gout) Allopurinol (chronic gout) Initial tx for chronic gout can actually increase the severity/freq of acute attacks so take prophylactic colchicine simultaneously
Systemic Lupus Erythematosus (SLE)
Serositis (pleuritis, pericarditis) Oral ulcers (PAINLESS, often on hard palate) Arthritis (reducable deformities, polyarticular, symmetric) Photosensitivity (erythema on distal hands, sparing knuckles, retroauricular, submental regions) Blood d/o (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia) Renal d/o (proteinuria, cellular casts) +ANA Immunologic d/o (anti-DNA, anti-SM, anti-phospholipid Abs) Neurologic (seizures, psychosis) Malar rash (spares nasal labial folds!) Discoid rash (erythematous scaling;atrophy, follicular plugging, dispigmentation; isolated? cutaneous lupus) Chronic fatigue! Raynaud's periungal erythema Cutaneous vasculitis (palpable purpura) Seen w/I first few months of life
Unclear but thought to be of 2 mechanisms: 1. Autoantibody-mediated inflammation (autoantibodies form immune complexes that drive complement consumption, Chronic inflammatory causing inflammation) F>M (9:1) systemic autoimmune Peak incidence ages 15dz characterized by anti40y.o. 2. Autoantibodies to phospholipids produce nuclear autoantibodies hypercoaguble state and clots (antiphospholipid syndrome thrombosis, pregnancy morbidity, anti-cardiolipin Abs, paradoxical prolonged PTT)
Rashes? Topical steroids Joint pain? NSAIDs FH (mostly sporadic tho) Environmental factors (uv light, drugs, infections, smoking, silica) Positive ANA, anti-RNP, anti-Ro/La, positive direct Race - A.A., hispanics Coombs, low complement Prev? 1/2000 Others? Antimalarials (hydroxychloroquine) Systemic corticosteroids for serious complications Immunosuppressants for steroidresistance Accelerated atherosclerosis
Neonatal lupus
erythematous pathces that form blanchable rings on head/neck Lack skin findings, systemic arthalgias/inflammation induced/triggered by procainaminde, hydralazine, quinidine
Mom w/ lupus
Thrombocytopenia Anti-rho antibodies Positive ANA
congenital heart block
Drug-induced lupus Scleroderma (SS)
Major organ involvement! proximal scleroderma (hardening of skin) extensive fibrosis, sclerodactyly (skin tightening due to fibrotic changes --> ischemia & pitting of fingertips--> autoamputation) facial disfigurement (microstomia - pursed mouth, lip retraction, beaked nose) mat telangiectasias dilated capillary loops at proximal nail folds leukoderma (salt&pepper skin), calcinosis Positive ANA, Anti-Scl-70 (nucleolar pattern ANA), Anticentromere Lung impairment (dyspnea on exertion, cough, pulmonary fibrosis)
(General)
Unclear but key features? Endothelial cell damage (vascular injury), inflammation precedes fibrosis, excess deposition of collagen by fibroblasts --> all lead to impaired fx of skin, lungs, affected organs Autoimmune mediated diffuse fibrosis of skin & internal organs
F>M Cell mediated and humoral immunity Onset age? 30-50y.o. (somewhat older than lupus)
XR? Bone resoprtion of digits, subcutaneous calcinosis
Widemouth diverticuli Watermelon stomach (telangiectases in stomach) pericarditis, arrythmias
Widespread skin involvement & rapid progression Crackles w/ inhalation Onset of skin changes w/I 1 year of Raynauds Truncal & acral skin involvement
PFTs detect poor gas exchange XR? Interstitial fibrosis CT? ground glass opacities in lung SRC histology? Sheared RBCs, narrowing of lumen, wall fibrosis SRC - anti-RNA pol III Anti-Scl-70 Ab Tendon friction rubs SRC? ACE inh GERD? PPIs MSK? NSAIDs, PT, low dose steroids (but watch renal!) Raynauds? Smoking cessation Lungs? Heavy immunosuppression
Pulmonary fibrosis (caused by fibrosing alveolitis, pulmonary vasculopathy)- early onset Dysphagia, GERD (from fibrotic esophagus) Scleroderma renal crisis (SRC) malignant hypertension, renal insufficiency, microangiopathic hemolytic anemia - tx ACE inh
Diffuse
Localized skin involvement (distal/upper extremities), nail fold involvement, slower pace of progression Limited (CREST) Calcinosis, Raynaud's (long duration), Esophageal dysmotility, Sclerodactyly, Telangiectases Localized cutaneous SS morphea (erythematous plaques that are proximal, skin discoloration/firmness/induration) Scleroderma + one or more features of other connective tissue disease Overlap syndromes Mixed connective tissue disease (MCTD) - SLE, SS, polymyositis, & positive anti-RNP Anti-RNP Abs Histology? Nl epidermis but extensive collagen deposition & loss of epidermal appendage structures Anti-centromere Abs
GERD? PPIs MSK? NSAIDs, PT, low dose steroids (but watch renal!) Raynaud's? Smoking cessation PAH? Oxygen, calcium channel blockers, prostacyclin derivatives
Pulmonary hypertension (no fibrosis) - later onset Dysphagia, GERD (from fibrotic esophagus)
NSAIDs & glucocortocoids for pain & inflammation Chronic inflammation causes bone formation and erosion --> fusion of joints (ossification of annulus fibrosus in vertebrae) Axial arthritis (bilateral sacroilitis, spondylitis), arthritis of girdle joints, acute anterior uveitis (inflamed iris), extraskeltal manifestations (aortic insufficiency, conduction abnl, decreased chest wall expansion, spinal cord compression, cauda equina syndrome) Loss of nl spine curvature & ability to flex Symptoms progress upwards (start in SI joint --> cervical spine) Molecular mimicry impt- genetically susceptible person w/ HLAB27 is exposed to unkwn antigen that causes an immune response that exhibits cross-reactivity w/ self tissues, causing clinical expression of spondyloarthropathy (joint dz of vertebral column) High levels of TNFa in SI joints, peripheral joints, & serum of affected pts. Enthesitis = primary hallmark of Spondyloarthropathies; causes dz bc 1.Inflammation, 2. Deregulated osteoclast activity --> bone erosion, 3. dysregulated endochondral bone formation at sites of enthesopathy, causing syndesmophyte formation Immunosuppressants only help peripheral arthritis TNF inhibitors relieve axial arthritis XR? Fuzzy, hard to trace bone margins of SI joint, bamboo spine (syndesmophytes- new bone formed in inappropriate location cause fusion through T-spine)
Ankylosing Spondylitis
M>F Age onset? 20s
HLA-B27
Pneumonia, loss of flexion at back
Classic - DIP joints of hands & feet Arthritis mutilans w/ sacroilitis Peripheral polyarthritis (symmetrical), asymmetrical sacroilitis & spondylitis, dactylitis (sausage digits- PIP swelling & inflammation), arthritis mutilans (teloscoping digitsjust skin bc bone has been eroded away), conjunctivitis, iritis, Asymmetric, pauciarticular (<4), small joint enthesitis, psoriatic nails involvement w/ sausage digits Symmetric polyarthritis (indistinguishable from RA except RF-) Ankylosing spondylitis w/ or w/o peripheral arthritis but +psoriasis Inflammatory arthritis associated w/ psoriasis HLA-B27 (see AS path) XR? Pencil and cup formation (peripheral phalynx whittled down to pencil joint and distally has extra bone formation to where it looks like a cup), erosion of entire bone in digit (telescoping), excess bone formation near where tendon would insert (enthesitis evidence)
Psoriatic Arthritis
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
"Can't see, can't pee, can't climb a tree" Arthritis, enthesopathy, tendonitis, tenosynovitis, osteitis, myalgia, skin (kertoderma blenorrhagicum- palms & soles, whitish pustule that develops scales; Circinate balanitis- painless, shallow erythematous ulcer on gland skin) & mucus membrane lesions, uveitis, conjunctivitis, Sterile joint inflammation that develops after infection (throat, GU, GI infections - Chlamydia, Salmonella, Shigella, Campylobacter, Yersinia, C.dificile) (See AS path)
Reiter's / Reactive arthritis
M=F young adults
HLA-B27
Spontaneous recovery, but can have recurrences
Inflammatory bowel associated arthritis
peripheral joint arthritis (pauciarticular, mostly asymmetrical, joint activity parallels bowel dz, enthesopathies), axial involvement (identical to AS, joint activity does not parallel bowel dz); extra-articular features (erythema nodosumPAINFUL, pyoderma - deep ulcer w/ lots of pus, uveitis)
NSAIDs & glucocortocoids for pain & inflammation Arthritis associated with Crohn's Dz & ulcerative colitis HLA-B27 (See AS path) Immunosuppressants only help peripheral arthritis TNF inhibitors relieve axial arthritis
Screening / Education
Protective clothing, daily use of sunscreen, no sunbathing/ tanning bed, vit D supplementation for immunocomp; screening for field disease changes - CAPABLE OF DEVELOPING INTO SCC
Protective clothing, daily use of sunscreen, no sunbathing/ tanning bed, vit D supplementation for immunocomp; screening for recurrent BCC
Protective clothing, daily use of sunscreen, no sunbathing/ tanning bed, vit D supplementation for immunocomp;
Importance for early detection and treatment (cure rates >90%) Staging - 0 (tumor in epidermis), 1&2 (thicker but limited to skin), 3 (LN), 4 (metastatic, systemicmedian survival of 7.5m) Emphasize prevention (sunscreen, protective clothing, avoid mid-day sun, self-skin exams, TBSE, vit D supplemenation)
Need to talk to parents about how size of congenital nevi can affect risk for development of MM; surgical options (staged removals, grafting); monitor CHANGES in lesion
Oral form of Mucus Membrane Pemphigoid has better prognosis (very little scarring)
Pretty good prognosis with treatment
Worrisome in diabetics or pts with autoimmune dz
Prevention to avoid recurrenceAntibmicrobial washes, bleach bathes
Avoid gross hot tubs!
Prevention (bleach baths, treating chronic carrier state w/ nasal Ab creams)
Prevention (bleach baths, treating chronic carrier state w/ nasal Ab creams)
Examine (& possibly treat) home/school for infected contacts!
Screen for STDs in young adults
Avoid skin-skin contact during active outbreaks
Prevention with immunization w/ zoster in people > 50y.o.
GAS/GBS screening for women undergoing C/S
Adjustment of risk factors (excessive alcohol, sedentary lifestyle)
Prophylactic bisphosphonate treatment prior to surgery!!!
Stay active!!
Diagnosis is impt in case patient needs surgery ever- need to be aware of risk for malignant hyperthermia w/ anesthesia
age/gender appropriate cancer screening
Avoid sun exposure, use sunscreen!
Counsel on posture, stretching, spinal extension exercises high risk for traumatic fractures
Disease
Pulmonary Edema
Clinical Variants
tachypnea, hypoxia hydrostatic pulm edema: fluid accumulates in low P, hi comp areas (perihilar interstitium, alv interstitium, alveolus); bronchospasm seen more commonly, sx of congestive heart failure, cardiac dysfxn, fluid overload, NO PREEXISTING ACUTE TRAUMA
Pathogenesis
abnl accumulation of fluid in the lung outside of the vasculature
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Resolution? Hydrostatic: intact alv epithelium pumps fluid out w/ Na/K ATPase; tx underlying cause;
Complications
increased hospital stay (leading to other comorbidities) and high mortality for permeability edema
Thickened membranes = diffusion; LV heart failure (MI, chronic CHF), renal failure, Hydrostatic edema (most common): Increased hydrostatic IV fluids pressure (due to LV heart failure) injury to capillaries = Pulm edema --> backup of (free radicals, fluid into pulm vasculature --> chemicals) blood vessel distention by Jreceptors --> tachypnea Starlings law reasons for edema: Permeability edema (more gradient btwn severe): direct injury to capillary & capillaries (ALI, ARDS) capillary leakage into interstitial interstitial hydrost permeability pulm pressure; edema: diffuse leakage of space overflows the alveolus gradient btwn with proteinaceous fluid (can fluid (patchy, bilateral interstitial fluid & be caused by pneumonia, accumulation), aspiration, inhalation, sepsis, oncotic press, gravitational gradient (more edema at base); trauma, pancreatitis, transfusion) leakiness of capillaries; protein leakage; acute lymphatic flow inf, no CHF Emphysema, chronic bronchitis, asthma severe dynamic compression --> hyperinflation as a compensatory mechanism to get more air out allows increased lung recoil so lung can expel more air; destroyed alveoli--> decreased functional space & DLCO ability to move air out of lungs is impaired so takes longer
Hydrostatic: risk CXR: Hydrostatic: factors for heart bilat interstitial dz markings @ basal lung/ perihilar area; Kerly's B lines (horizontal lines towards edge of XR), enlarged heart; Permeability - patchy, asymm infiltrates, nl heart histology: Hydrostatic - alv spaces filled w/ pink edema, nl anatomy; permeability: dense liver appearance, abnl anatomy, heterogenous patchiness,RBCs/ WBCs, separation of interstitium w/ protein coat (pink hyaline membrane) PFTs: FEV1/FVC<70, FVC, FEV, concavity on exp limb of flow-vol, volumes (due to air trapping), spirogram shows slow initial upstroke & late vol changes; DLCO
Permeability: alv epithelium injured so takes longer to resolve; tx primary injury cause, manage fluid balance, supportive care
Obstructive lung disease
Restrictive lung disease
Parenchymal lung reduced lung volumes disease (interstitial lung dz); nonparenchymal (chest wall disorder; muscular weakness; less shifted towards RV)
less total volume but no problems with air flow
PFTs: nl or >70 FEV1/FVC; FVC, FEV, spirogram shows no late vol changes/ rapid upstroke, flow-volume has VC, volumes shift towards RV neuromuscular dz: somewhat higher RV, low IC PFTs: FVC nl/, FEV1 nl, FEV1/FVC nl, TLC nl/, RV nl, DLCO
pulmonary vascular disorder
Central Airway Obstruction
Extra-thoracic obstruction Plateau on inspiration; disease/ obstruction outside of the lung
Equal pressure point has variable migration depending on transmural pressure; reduced airflow during inspiration (-)P inside the airway sucks trachea walls in while Patm around trachea pulls airways closed)
Patm > Paw during inspiration reduces airflow and causes aw collapse; nl expiration
Tracheomalacia, PFT: Plateau in insp laryngeal limb paralysis, laryngeal edema, tracheal strictures from ET tube, tracheal stenosis, OBESITY
Disease
Clinical Variants
Intra-thoracic obstruction
Plateau on expiration
Pathogenesis
Equal pressure point has variable migration depending on transmural pressure; reduced airflow during expiration
Etiologies
Ppl > Paw during expiration reduces airflow and causes aw collapse; nl inspiration asthma
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Tracheal lesions, PFT: plateau in exp tracheal tumors, limb tracheomalacia, tracheal inflammation, mediastinal lymph nodes
Disease
Clinical Variants
Fixed lesion
Plateau on inspiration & expiration
Pathogenesis
Etiologies
large tumor
Epidemiology
Risk factors
Lab/Imaging
PFT: plateau in exp & insp limbs PFT: see obstructive dz; lung vol (TLC & RV, inspiratory capacity), DLCO all persons >45 y.o. w/ chronic cough/ sputum production & exposure/ risk factor hx should be tested for airflow limitation (even if no dyspnea) spirometry = gold std CXR: retrosternal air space ( lucency), flat diaphragm, bullous changes, hyperinflation CT R/Os alt dx
Treatment
Complications
COPD
Emphysema (blow a balloon up and release it? No air flows out bc loss of elastic recoil)
Equal pressure point migrates independently of location/ pressure relationships Airflow limitation that is exposure to smoke = activation of alveolar macrophages = not fully reversible, release of chemotactic factors = progressive, and recruitment of D13 = release of associated w/ abnl inflammatory response proteases (presence of protease inhibitors less effective due to to noxious tobacco) = destruction of particles/gases alveolar wall hyperinflation of lungs (low diaphragm position, Alveoli destruction = VQ hyper-resonance, distant mismatch, alveolar ventilation, breath/heart sounds, tetherings that support airway = barrel chest), dypsnea or dynamic airway acute chest illness compression = abnl (initially DOE but then enlargement of small airways starts to affect DALYs), (bullae = sac-like wheezing, prolonged abnormalities) expiratory time, Severe (pursed-lip breathing, problems with driving pressure accessory muscle use, (decreased elastic recoil) retraction of intercostal and/or airflow resistance spaces), tripod position
Subglottic stenosis, goiter, tracheal stricture hyper capillary surface #4 mortality in responsiveness, area = diffusion; world & USA lung growth, cell mediators? F>M exposure to Epithelial cells, tobacco smoke/ macrophages, middle aged occupational CD8+ (TH1), (~50y.o.) dusts & chems/ neutrophils infections/ SES SMOKING (USA) develops in about nutrition 15% of smokers Air pollution (global) decreased elastic recoil
management? Prevent dz progression, relieve sx, improve ex tolerance, improve health status, prevent/ treat exacerbations, reduce mortality drugs generally less effective Short acting bronchodilators (Bagonists - albuterol, levalbuterol, metaproterenol, pirbuterol; anticholinergics like ipatropium)
hoarseness = common side effect of steroids Could require oxygen, pulmonary rehabilitation, lung volume reduction surgery, and/or lung transplantation cor pulmonale
A1AT deficiency panacinar emphysema
DOE, cough, wheezing, early presentation
A1AT def (protease inhibitor that most common prevents destruction of alveolar phenotype? PiZZ wall)--> loss of a1 globulin (Z allele is a single point mutation that causes severe dz)
alpha1antitrypsin deficiency, FH of A1AT def, smoke, dust, kerosine, PiSZ smokers
long acting bronchodilators (Bagonists - salmeterol, CXR: radiolucency in formoterol) base of lung (vs. diffuse sometimes emphysema in other phosphodiesterase variants) inhibitors (theophyline, roflumilast) PFT: see obstructive dz responds poorly to meds anti-inflammatory inhaled steroids (fluticasone, budesonide, mometasone) home O2 if hypoxemic (prevents cor pulmonale)
Chronic bronchitis
typically presented as overweight, cyanotic, edematous, productive cough, dyspnea at rest
exposure to smoke = activation SMOKING of alveolar macrophages = release of chemotactic factors = loss of elastic recruitment of neutrophils = recoil release of proteases (presence of protease inhibitors less chronic productive cough for 3 consecutive effective due to tobacco/infection) = mucus months for 2 hypersecretion consecutive years
Disease
Asthma
Clinical Variants
Pathogenesis
hygiene hypothesis: early exposure to infectious agents= TH1 response= suppression of TH2 activation= allergy /asthma frequency; people less likely to be exposed to these infections today= TH2 cells mediate onset of asthma Airway remodeling occurs in pts w/ uncontrolled chronic asthma (older pts) morphological changes in asthma (hyperplastic mucus gland/goblet cells, infiltration of inflammatory cells, thick BM, edema, fibrosis, epithelial damage) = Smooth muscle hypertrophy = reversible bronchoconstriction, hyperresponsive airflow limitation
Etiologies
inflammatory cell mediators? Epith cells, mast cells, CD4+ (TH2), eosin, IL4, IgE, Factors contributing to severity? Environmental (animal/insect/ mold/outdoor allergens), occupational exp, indoor/ outdoor pollutants, foods/ preservatives, certain meds, infections, immunotherapy cold= vagal reflex = ACh = bronchoconstriction
Epidemiology
Risk factors
Lab/Imaging
PFT: exp arm has concavity; FEV1/FVC <70 but other values highly variable; significant bronchodilator response (loss of FVC, FEV1, FEV1/FVC; nl DLCO)
Treatment
Complications
exercise-induced asthma Airflow obstruction (15-30min post exercise- (wheezing, prolong forced short sprints; vagal reflex) expiratory time), lung hyperinflation (low allergic asthma diaphragm position, hyperresonance, distant nocturnal asthma (vagal heart/breath sounds) reflex) severe disease? Accessory resp muscles, immediate Type I IgE retraction of intercostal mediated spaces bronchoconstriction chronic, inflammatory airway dz w/ recurrent sz (esp @ night, early AM; widespread/ varying obstruction;
peak flow meters for varying levels of home monitoring severity (intermittent, mild persistent, maintenance meds moderate persistent, severe persistent) (inhaled corticosteroids + avoid chronic LABA steroid use leukotrieneR blockers - Singulair, theophylline, Xolair) methacholine + rescue meds challenge (high NPV (SABA - albuterol) so R/O asthma in pt w/ Short term oral atypical sx) steroids (prednisone) for CXR: nl flareups subQ allergen immunotherapy if allergic asthma
Disease
Hypoxia Primary cilia dyskinesia (PCD), immotile ciliary syndrome, Kartagener syndrome (KS)
Clinical Variants
Acute Chronic
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
PIO2:FIO2 2,3-DPG
Treatment
Complications
defective ciliary action lining the TRIAD: L-R pattern defects (situs inversus), respiratory tract, fallopian tubes, and sperm flagella chronic sinusitis/ bronchiectasis, male/female infertility; hydrocephaly (CSF doesn't move in brain ventricles)
Autosomal recessive mutation in gene hydin failed dynein motors or central pair assembly = cilia paralysis
Pneumothorax (atelectasis - partial collapse of lung, collapse of alveoli)
Collapsed lung (air btwn visceral & parietal pleura); sudden onset of dypsnea (less efficient muscle fx); focal area of absent breath sounds, Tension (causes heart to hyperresonant push to opposite side) percussion, decreased lung vol, hypoxemia (VQ Traumatic (Penetrating mismatch), Pleuritic trauma, iatrogenic) chest pain!! Spontaneous (Primary absence of lung disease; Secondary - complication of underlying lung dz like COPD) Tension? Hi RR, HR; low BP (due to low venous return), trachea shifts to opposite side
(Subplural alveoli rupture into trauma, active pleural space) Hole in the lung-- inspiration > Ppl = 0 (since now in connection w/ atm, & no flow); when the pt inspires, pressure -> more (-) but lung does not inflate; w/o (-)Ppl, the lung collapses
CXR: increased lucency, tension pnemothorax can push heart over to opposite side; acquires soft tissue (gray-white) density, thin white line (Spont)
Histology: 2nd spont PTX has rupture of subpleural emphysematous blebs in lung apices Repeated PTXs? Pleurodesis MRI: ruptured bullae (installment of from emphysema (2 sclerosing agent -talcso visceral & parietal spont) surfaces adhere)
Small PTX in healthy Tension PTX is person? Observe, medical emergency!! supplemental O2 Causes shift of mediastinum = Large PTX or increased symptomatic person? interthoracic pressure = disrupts systemic Chest tube circulation placement, emergent decompression w/ needle (esp for Tension PTX!)
Flail chest Upon inspiration, ribs go in & try to deflate the lung; upon expiration, ribs go out & try to inflate the lung Balls of air in lung
Multiple rib fractures, some ribs trauma free-flowing; causes air to move back & forth rather than pulling air from outside into the chest Destruction of alveoli in emphysema/ lung dz cause damaged areas to fill with air & bulge Non-subpleural alveolar rupture with air pouring into the mediastinum; rupture of trachea/ main bronchi; dissection of air from neck/abdomen Emphysema CXR: bilateral balls of air
Bind and fixate the ribsPoor prognosis due to ineffective ventilation
Lung bullae
Pneumomediastinum
gas in the interstices of mediastinum
Tracheo-bronchial tree/ esophagus rupture from trauma/ prolonged vomiting Fistula btwn 2 structures; Ventilators
CXR: air along L heart border, continuous diaphragm sign
Pneumopericardium
Air in the pericardial space (around heart); muffled heart sounds
Requires immediate identification and treatment, or else death! CXR: Air collection btwn right diaphragm & liver or peritoneal cavity CXR: Abnormal lucencies w/I lung parenchyma
Pneumoperitoneum
Lung cavities
Pulmonary nodules (<3cm); pulmonary masses (>3cm); consolidation (think pneumonia)
Infection; vasculitis; tumors
Disease
Atelectasis
Clinical Variants
Mediastinum pulled towards affected side on CXR
Pathogenesis
Collapse of alveoli or partial lung --> VQ mismatch hypoxemia (perfusion, low ventilation) OR R->L shunt hypoxemia infiltration of lymphocytes & monocytes expands the interstitium either spontaneously resolves or persists (if persists, leads to interstitial fibrosis)
Etiologies
Obstructive Atx of whole lung? Cancer, mucus plug, foreign body Viral, mycoplasma pneumoniae, hypersensitivity rxns
Epidemiology
Risk factors
Lab/Imaging
CXR: Complete Opacification Hemithorax; consolidation Histology: thickened septa due to infiltration of inflammatory cells; empty alveolus space CXR: Complete Opacification Hemithorax; blunted costophrenic angle, meniscus sign (upside down U), loss of nl structures at lung base thoracentesis!! (dx & tx effects) Light's criteria >1 exudative Cell types: Neutrophils? inf/symp causes; Lymphocytes? cancer, TB; RBCs: hemorrhagic (malignancy, TB, PE, trauma), hemothorax
Treatment
Complications
Alveolitis
Pleural effusion
pathological accumulation of Mediastinum pushed away from affected side fluid in pleural space, which becomes a vulnerable place due to large size & surface area, Common sx? Dyspnea (increased inefficiency of negative pressure pulls fluid in, and relatively leaky borders from resp muscles, NOT gap jx btwn mesothelial cells hypoxemia), cough, Exudative (occur when pleuritic chest pain Starling's forces: Pcap (CHF, local dz stimulates pleural fluid formation; inc cap Decreased breath sounds vol overload), cap oncotic over area of pleural perm -pneumonia; pressure (cirrhosis, nephrotic effusion (Base of lung), obstruct of lymph synd), Lymphatic clearance dullness to percussion drainage - cancer); (lung cancer, lymphoma) capillary barrier disrupted so high protein content Increased permeability pleural dz, malignancy, infxn Transudative (occur when systemic imbalance of Starling's forces - inc hydrostatic press, dec serum onc press) - low protein content decreased pleural pressure (atelectasis, trapped lung) - fluid moves into lung
Kidney, heart, liver 1.5 million pleural failure effusions yrly malignancy, PNA/ Infxn, PE, post surgical TB (global cause)
Hepatic hydrothorax
transudative pleural effusion ascites
liver related pleural effusion due cirrhosis, liver to high portal pressure (from failure cirrhosis usually) RUQ
diuretics Beta blocker to decrease portal pressure transplant
do not attempt pleurodesis!!
Parapneumonic Effusions (PPE)
Exudative pleural effusion no bacteria or pus in pleural fluid
Pleural effusion ipsilaterally Pneumonias associated with underlying pneumonia; due to inflammed visceral fluid (inc fluid prod, less resorption) 3 stages: 1. exudative: inflammatory/ capillary leakage, tx w/ Abx 2. fibrinopurulent: loculations, requires chest tube drainage 3. organized: scarring, pleural peel formation, requires surgical decortication
40% of bacterial pneumonia develop PPE
Thickened visceral membrane (makes lung expansion difficult)
Antiobiotics for exudative stage; chest tube drainage for fibrinopurulent stage; decortication for organized stage
complicated bloody surgical procedure
Disease
Empyema
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Exudative pleural effusion Infection (collection of pus) in pleural space
CXR: distinguish from Drainage neoplasm (which always appears spherical) - empyema will look different based on viewing position Thoracentesis: gross pus or positive gram stain, pleural fluid culturesfluid cytology pleural (always low positive in 60-80% possible pleural bx
Malignant Pleural effusion
Exudative pleural effusion
hematogenous metastases to parietal pleura cancer cells erode through visceral pleura cancer cells occlude lymphatics
2nd most common cause for exudative effusion
pleurodesis
high recurrence rate, usually represent an advanced malignancy
Chylothorax
Exudative pleural effusion turbid, milky white pleural effusion; does not smell (empyema), no pus
disruption of thoracic duct or LN dissection; represents high lipid content in pleural space
trauma or CANCER!
Pulmonary Arterial PAH Hypertension (PAH) (WHO Group 1)
mPAP >= 25 PWP <= 15 No significant obstructive/ restrictive lung dz, left heart dz, or thromboembolic dz
Proliferation, vasoconstriction, thrombosis, remodeling
idiopathic (see below), heritable (BMPR2, Alk1, d/os like CTD (Scleroderma), endoglin), drug/ HIV(s vascular mediators to toxin induced favor vasoconstriction), (amphetamines, cocaine, St. John's portopulmonary dz ( portal vein press, backflows to heart), wort), other disorders, congenital heart dz (atrialpersistent septal defect shunts systemic pulmonary HTN of blood into pulm circ), newborns schistosomiasis (eggs from (foramen ovale organism occlude pulm artery, remodeling), chronic hemolytic doesn't close) anemia ( NO = vasoconstriction) Endothelin pathway: in PAH= vasoconstriction & smooth muscle hypertrophy Nitric oxide pathway: in PAH, nl causes vasodilation, broken down by phosphodiesterase
CXR: right heart enlargement EKG: signs of right heart strain (high R wave in V1 suggests increased ventricular mass) Doppler Echo: bulging of RV septum, regurgitant tricuspid valve, enlarged RV Right heart catheterization: evaluation of mPAP & PCW Blood tests for underlying causes
oral anticoagulants, Pts with HIV or diuretics, scleroderma need supplemental O2, aggressive tx digoxin for CHF, inotropes for Class IV prostacyclins, endothelin antagonists, PDE-5 inhibitors monitor tx effects via exercise capacity, hemodynamic improvement, functional class, Echo, QoL
Disease
Clinical Variants
Idiopathic Pulmonary Arterial Hypertension
slowly progressive DOE, syncope w/ exertion, chest pain, palpitations loud pulmonic valve closure (P2), tricuspid regurgitation murmur on LSB, right sided fourth heart sound (increased press through tricuspid valve), right ventricular heave, peripheral edema, ascites, JVD
Pathogenesis
Etiologies
Epidemiology
20-30 y.o. F>M (2:1)
Risk factors
Lab/Imaging
histology? Intimal/ smooth muscle/ adventitia hypertrophy & formation of plexiform lesions
Treatment
see PAH
Complications
High mortality without treatment (median survival 2.8 yrs) - cor pulmonale
Significant overgrowth in Unknown? endothelial layer of pulmonary arterioles (vascular remodeling) = obstruction of blood flow (plexiform lesions) = pulmonary vascular resistance (PVR is too high!!), problems w/ perfusion natural hx? Pre-symptomatic (RV hypertrophy to compensate for increased PVR, allows CO to keep up), symptomatic (vascular remodeling causes decreased CO, while PAP & PVR continue to increase), declining (loss of PAP = declining CO & cor pulmonale)
Pulmonary venoocclusive disease (PVOD) (WHO Group 1')
shared similarities with PAH
venular proliferation on postleft-sided capillary side (left heart) leads to predominant dz narrowed lumen of small pulmonary veins --> development of pulmonary infiltrates, edema, severe hypoxemia increased mPAP and PVR due to vasomotor constriction or pulmonary vascular remodeling
see PAH
Pulmonary arterial hypertension from Left heart disease (WHO Group 2)
Valvular diseases, systemic dysfunction, diastolic dysfunction
mPAP >= 25 PWP > 15
no meds approved for this population
Pulmonary arterial hypertension from lung disease/ hypoxia (WHO Group 3)
severely decreased DLCO
chronic hypoxemia leads to shunting of blood away from non-ventilated areas and increased backflow to RV (L-R shunt); increases vasoconstriction of pulmonary arteries
COPD, ILD, mixed restrictive/ obstructive lung dzs, sleep apnea, alveolar hypoventilation disorders, chronic exposure to hi loss of pulmonary vasculature altitudes, (COPD) increases workload for developmental abnl remaining vessels
see PAH
Chronic Thromboembolic Pulmonary HTN (CTEPH) (WHO Group 4)
DOE after asymptomatic period of months - years
uncommon, subacute manifestation of pulmonary embolic disease that evolves via proximal pulmonary artery obstruction from failed clot resolution --> remodeling to increase pressure backflow to RV
incidence of CTEPH happens w/I 2y of acute VTE
younger age, larger PE, idiopathic VTE, hx of previous PE
10% of pts have antiphospholipid antibody syndrome
only PAH that is curable!! (pulmonary thromboDx requires VQ scan endarterectomy) (shows areas of mechanically dissect mismatched flow) clot off the artery
Disease
Pulmonary arterial hypertension w/ unclear or multifactoral causes (WHO Group 5)
Clinical Variants
Pathogenesis
miscellaneous diseases that all cause PAH
Etiologies
Chronic myeloproliferative dz, splenectomy, sarcoidosis, LAM, pulmonary langerhans cell histiocytosis, glycogen storage diseases, hyper/ hypothyroidism, end stage renal dz
Epidemiology
Risk factors
Lab/Imaging
Treatment
see PAH
Complications
Hepatopulmonary syndrome
Secondary to liver disease
Diffusion-perfusion impairment = overdistention of capillary = RBCs escape w.o oxygen traveling to other side (bc capillary is too wide) = R-L shunt hypoxemia (PVR is too low!!)
Liver disease (causes vasodilation & capillary overdistention)
supplemental oxygen can cause R-->L shunting w/ severe pulmonary vascular dilation
Hyperventilation / Hypocapnia
increased effective minute Brain: hypocapnia --> ventilation = PaCO2 < 35 vasoconstriction --> (hypocapnia) hyperexcitability of neurons and poor perfusion to brain --> seizures neuro signs (seizures, syncope, visual changes, <3: hypocapnia --> demand, dizziness), CV signs (arrythmia, chest pain), O2 delivery = electrical increased work of abnormality --> arrythmia breathing, dypsnea, muscle weakness, Lung: hypocapnia --> smooth parasthesias, carpopedal muscle contraction and mucus spasm, tetany, NO edema (stiffer, more resistant) -> HEADACHES hyperventilation, dypsnea & work of breathing nl/ hi pO2, nl pCO2 w/ sleep-psych hypervent
Physiologic causes? Hypoxia, acidosis, irritants (P.E., inhalants), CHF (J-receptors) Non-physiologic causes? Pain, anxiety, psychogenic sepsis, PE, pregnancy
NOT related to RR
treat underlying disease, brown Diagnostics? paper bag Pregnancy test, ABG (increases blood (pH, pO2, HCO3-, CO2 because closed pCO2), kussmaul system), breathing (slow deep reassurance, breathing classic in sedation? acidosis)
Hypoventilation / Hypercapnia
decreased effective minute ventilation = PaCO2 > 45 (hypercapnia)
Brain: congenital central hypoventilation (hirchsprung's dz), chronic hypercapnia? pH w/ hypothyroid, time, kidney compensates w/ central alveolar HCO3; RBCs (polycythemia), sedatives/narcotics hypoventilation? No baroreceptor sensitivity (high / benzos, anesthesia, dypsnea, hypoxemia PCO2 causes less minute secondary to hypercapnia ventilation than expected); rely Ondine's curse; on secondary drive to breath muscle & PNS: ALS, MG, MD, neuromuscular (hypoxia) kyphoscoliosis, hypoventilation? obesity Orthopnea (loss of 2 consequences? -HCO3, hypoventilation diaphragm fx), cor cerebral vasodilation syndrome; lung: pulmonale (terminal (headaches), sleep arousal COPD, Asthma, event) (sleep disturbance, bronchiectasis, somnolence), Hb desaturation/ pulm fibrosis erythropoiesis (cyanosis, polycythemia), pulm common cause for vasoconstriction (pulm HTN, cor resp acidosis? pulmonale) DRUGS, stroke
hypoventilation = acute CO2 = pH = O2
Central cause? Nl PFT, nl muscle fx, impaired hypoxic drive (problems with unconscious breathing only) Neuromuscular cause? FEV1, FVC, TLC, RV (restrictive pattern), weak muscle fx (low pressure, forces, MVV), rapid shallow Lung dz cause? obst/rest pattern on PFT, nl muscle strength but low MVV/endurance; hypoxic drive alone w/ chronic hypercapnia
Respiratory acidosis? Correct w/ drug antagonist, intubate Central alveolar hypoventilation? Respiratory stimulants, diaphragmatic pacing, nocturnal ventilation neuromuscular? NO stimulants, tx underlying condition, nocturnal ventilation pulm? Treat underlying dz, careful O2 supplementation, nocturnal ventilation
do not give supplemental oxygen to patients with chronic hypercapnia (only drive to breathe is hypoxia!!)
Disease
Hypoxemia
Clinical Variants
General
Pathogenesis
Etiologies
FIO2; hypoventilation; diffusion impairment; VQ mismatch; shunt (RL), altitude induced hypoxemia
Epidemiology
Risk factors
Lab/Imaging
Check A-A gradient
Treatment
Complications
hypoventilation induced hypoxemia
PaCO2 > 45 mmHg; nl A- elevated PaCO2 means there is extra-pulmonary less amount of O2 in the causes a gradient, responds to alveolus = less O2 that will move increased FiO2 from alveoli to pulmonary capillary = hypoxemia; no abnormalities in gas exchange disease process causes amplification of VQ mismatch, where composition of alveolar gas varies in different lung regions, causing hypoxemia hi ventilation, low perfusion (PE) low ventilation, hi perfusion (pneumonia, PECHF, ALI/ARDS, atelectasis, pulmonary fibrosis, COPD) anatomic shunt (intracardiac shunts, pulmonary AV malformations, hepatopulmonary syndrome) physiologic shunt (atelectasis, pneumonia, ALI/ARDS)
usually corrects with small doses of O2 (FiO2); correct with drug antagonist (opoid antidote)
VQ mismatch hypoxemia increased A-a gradient, nl PaCO2 (unless severe hypoxemia), respond to increased FiO2
patients respond to increased FiO2
Right to Left Shunt hypoxemia
severe hypoxemia that is not readily fixed with increased FiO2, increased A-a gradient, nl PaCO2
blood moves from right side of heart to left side of heart without being oxygenated (extreme form of VQ mismatch)
Diffusion limitation hypoxemia
increased A-a gradient, exercise-induced hypoxemia, usually responds to FiO2 increases
difficulty moving the oxygen out of the alveoli and into the pulmonary capillary exercise-induced hypoxemia? Blood moves faster during exercise, so not enough time for O2 to diffuse from alveoli to capillaries; nl there are compensation mechanisms (dilate cap surface area, increase alveolar O2 content) but in these patients, compensatory mechanisms are impaired
interstitial lung disease, pulmonary fibrosis
Disease
Acute respiratory failure (ARF)
Clinical Variants
Pathogenesis
Etiologies
nl CXR? Possible causes = CNS event (stroke, drug OD, head injury), neuromusc dz, airway obst (asthma, COPD), PE abnl CXR? Possible causes = ALI/ARDS, aspiration, pneumonia, hydrostatic pulm edema, obst lung dz (nl/abnl CXR), PE (nl/abnl CXR), pneumothorax
Epidemiology
Risk factors
at-risk dx? Direct lung injury (aspiration of GI contents, pulmonary contusion, pneumonia/ sepsis); indirect lung injury (nonpulm sepsis, abdominal trauma, multiple fx, hypertransfusion)
Lab/Imaging
300<PaO2/FiO2<200 CXR: bilateral infiltrates ABG: worsening CO2 and O2 levels despite increased oxygenation
Treatment
manage underlying cause provide supportive care restore oxygenation to better levels (PaO2 of 55-60, O2 sat 88-90%) intubation & low tidal volume mech ventilation if necessary
Complications
mortality ~30-40%, long recovery time
Acute lung injury (ALI) defining criteria? Acute respiratory distress syndrome (ARDS) Acute onset post "at risk" dx Bilat infiltrates on CXR PaO2/FiO2<300 (ALI) PaO2/FiO2<200 (ARDS)
Acute lung injury --> flooding of alveoli w/ edematous fluid = VQ mismatch, shunting, & capillary leakage; decreased surfactant production/function; all leads to stiff lungs from diffuse alveolar damage & pulm edema --> respiratory load = No LA HTN (no evidence worse alv ventilation = lung of CHF) compliance (low compliance means more pressure required to make a change in vol)
Pulmonary hypertension
loss of capillary volume
ILD
Pulmonary embolism
chest pain, dyspnea, apprehension, syncope, cough, hemoptysis, sweats
Large clots increase the pressure of RV, which cannot compensate to acute changes in pressures --> enlargement of RV --> decreased preload & contraction of LV (can't fill anymore) --> decreased CO virchow's triad
600,000 PE, 1 same as those million silent PE; for DVT 3rd most common CV disease in US
DLCO gross: thickened pulmonary arteries (white macaroni) DLCO
anti-coagulation!! (short term - LMWH Well's criteria: >6pts = heparin, unfract high risk (78%), 2-6 heparin; long-term pts= mod risk (28%), coumadin) <2pts = low risk (3.4%); modified (>4 Thrombolytics if pts = PE likely!!) low BP (shock state) Christopher study: low modified Wells = D-dimer (nl - done; abnl - CT scan), CT scan (nl - done, positive -tx); hi modified Wells = CT scan (nl - done; positive- tx) Alternatives? VQ scan, abnl pulm angiography
increased mortality if PE+shock 65% of people die w/I 1st hr of dx Thrombolytics contraind in pts >80, major surg w/I 7d, major trauma w/I 10d, TIA/ neurosurgery in last 6m, GI bleed in last 3m, uncontrolled HTN, known bleeding disorder Thrombolytics have increased risk of intercranial hemorrhage
Disease
Deep Vein Thrombosis
Clinical Variants
swollen leg, tenderness in leg near deep veins, unilateral swelling >3cm, unilateral pitting edema
Pathogenesis
Etiologies
Epidemiology
2 million cases, 1/1000 per yr; M>F, blacks more affected
Risk factors
Trauma, spinal cord injury, ortho surgery, Gyn surgery, critical care
Lab/Imaging
Well's criteria: >3 pts = high risk (75% chance of DVT), 1-2 pts (moderate risk), <1 pt (low risk)
Treatment
Prox/ pelvic DVT? Catheter-directed thrombolysis
Complications
AVOID giving anticoagulation prophylaxis to spinal surgery patients
direct injury to deep veins or occurs in deep endothelial cell activation --> veins of pelvis and activation of tissue factor (TF) -- proximal thigh > activation of extrinsic coagulation cascade --> activates VIIa --> activates thrombin --> cross-linked fibrin clot Virchow's triad: vessel wall damage, venous stasis (stagnant blood coagulates), increased blood coagulability (cancer, Factor V Leiden)
Obj confirmed DVT? Fast-acting antiImmobilization, Suspect DVT? coagulation bone fxs, age, D-dimer (R/Os (LMWH) for 5 days, prior DVT, thrombosis) - abnl? also start vitK antag cancer, varicose Ultrasound of whole (coumadin), veins, leg - abnl? Rpt 1 compression anesthesia, week later stockings severe COPD, high estrogen 3m follow up duration of antistates, HIT, regardless coagulation depends thrombophilias on rev/irrev cause
Pulmonary fibrosis
increased membrane thickness, increased VQ mismatch hypoxemia, increased diffusion limitations (fibrosis prevents O2 movement out of alveoli and into capillary) chronic inflammation = increased cytokines = induced fibroblast secretion of collagen = fibrous scarring
DLCO histology: blue-pink color as collagen deposits develop fibrosis; thick, stiff looking alveolar spaces; temporal heterogeneity (normal septum next to disease septum) gross: honeycombing (bumpy cobblestone pleura; tethering of fibrin); traction bronchiectasis (dilated bronchi)
Obesity hypoventilation syndrome
"Pickwinian's syndrome"
morbid obesity, sleepiness & hypoventilation during day, hypercapnia, cyanosis, hypersomnolence
increased capillary blood volume
DLCO
weight loss
cor pulmonale difficult to reverse
Acute Laryngotracheitis
"Croup"
sound horrible but ventilating ok starts w/ rhinorrhea/ sore throat/ mild fever --> barking cough w/ inspiratory stridor --> resp stridor, tachypnea/cardia, nasal flaring, retractions --> inc distress--> fatigue, cyanosis, biphasic stridor --> silent airway tota obst)
inflammation of larynx, trachea Parainfluenza viruses 1-3 are most common agent (>75%) less common? RSV, influenza, adenovirus, herpesvirus (more severe illness) preceded by coryza-like illnesses/URIs before croup onset
viral extrathoracic obstruction
uncommon in kids < 6m (maternal Abs) peaks btwn 1824m most common cause of upper airway obstruction in kids
Clinical dx, can make child worse by trying to get CXR CXR: steeple sign (narrowing of subglottic region)
Spontaneous resolution w/ hydration, antipyretics, humidified air severe cases? Oral corticosteroids, nebulized epinephrine for immediate symptomatic relief (does nothing for tx though!!)
inflammation can extend into lower airways/bronchi = laryngeal tracheal bronchitis
Disease
Epiglottitis
Clinical Variants
Pathogenesis
Etiologies
reduced vaccination rates
Epidemiology
can occur at any age, but most common in kids < 5 y.o.
Risk factors
Lab/Imaging
"Beefy red" & swollen epiglottis w/ bronchoscopy
Treatment
secure airway!!
Complications
dyspnea, stridor, tripod bacterial cellulitis of superior glottis structures position abrupt onset w/ early toxicity preceding URI (sometimes), very sore throat w/ choking sensation, difficulty swallowing, drooling, respiratory distress, anxiety, high fever, muffled voice (dysphagia), toxic appearance Haemophilus influenzae type B (Hib) - but more rare now that there's vaccination B-hemolytic streps (A, B, C) Staph aureus other organisms cause more gradual onset but slower recovery
MEDICAL EMERGENCY!! High Do NOT inspect risk of death (if edema progresses airway or place IV thumb sign on lateral enough to position XR (but really would intubation by most epiglottis over the never get bc could experienced person airway) worsen obstruction) Hib manifestations swollen, enlarged IV fluids, labs, elsewhere (meningitis, epiglottis antibiotics (3rd gen otitis, pnuemonia, cephalosporin), cellulitis) airway/blood cultures, rifampin prophylaxis for close contacts, NO nebulized epinephrine peanuts, popcorn, hotwheels, any small toy CXR: hyperinflation of affected airway (air trapping) OR completely nl CXR!! Atelectasis w/ aspiration remove foreign object
Foreign Body Aspiration
sudden cough/ wheeze after eating or playing (although sometimes onset may be insidious) persistent cough or wheeze, current/persistent pneumonia, decreased breath sounds, delayed air entry
typically objects are aspirated down the right main bronchus because shorter and straighter than left bronchus intrathoracic obstruction
foreign objects
Bronchiolitis
tachypnea (RR>50,60), chest retractions, cough, wheezing, prolonged expiratory phase, crackles, signficant resp distress, apnea in young infants, irritable, dehydration
inflammation of bronchioles, intrathoracic obstruction caused by RSV --> necrosis of airway epithelium --> influx of inflammatory cells --> release of inflammatory mediators = edema = narrowing of airways
RSV, followed by parainfluenza
usually limited to URI in respiratory droplet transmission healthy infants; in <40% it progresses to bronchiolitis
most commonly in daycare, hospital, ICU, children <2 y.o. regional differences, Most common cause of hospital premature admission for <1 infants, winter or late fall birth y.o. month, M>F, anatomic abnl, malnutrition, metabolic/ genetic diseases, SES
CXR: hyperinflation (air trapping), flat diaphragm, peribronchial thickening, collapsed lung (RUL), dense infiltrates behind heart (frank consolidation, pneumonia)
hospitalize young child if it looks like RSV bc high incidence of sleep apnea --> SIDS possible O2 supplementation fluids (hypertonic saline), hold feeds, humidified O2, infection control no routine bronchodilators, antivirals, corticosteroids, or antibiotics
Many develop recurrent wheezing that may be associated with persistent abnormalities in lung function
Childhood wheezing Transient early wheeze
early wheezing but sx resolve btwn ages 3-5
NOT FH of asthma reduced lung fx before respiratory event (prematurity, day care, prenatal maternal smoking, post natal smoking exposure) preschool age kids
Non-atopic wheeze
lower lung fx earlier in life associated w/ viral respiratory RSV, rhinovirus that improves w/ age; tract infections generally resolves by age 6
Disease
Clinical Variants
Ig-associated wheeze (asthma)
Wheezing before age 6
Pathogenesis
atopy, increased airway hyperresponsiveness, & elevated IgE; more persistent disease w/ early exposure to allergens decreased risk w/ exposure to other children (daycare) and animal exposure
Etiologies
Epidemiology
Risk factors
FH of asthma, allergy, elevated IgE @ age1, early sensitization to mold, obese females, maternal prenatal smoking
Lab/Imaging
Treatment
inhaled corticosteroids
Complications
Cystic fibrosis
Multisystem disorder reproductive (congenital bilateral absence of vas deferens, decreased female fertility), sweat glands (increased salt sweat content), GI (pancreatic insuff, meconium ileus, intest obstruction, biliary obstruct, DM) sinusitis, nasal polyps, chronic bronchitis (leads to atelectasis, bronchiectasis, pneumothorax, hemoptysis, resp failure)
autosomal recessive mutation in long arm of chrom 7 creates gene product CFTR, which is an ATP dependent chloride channel and also regulates ENaC (CFTR: regulates movement of salt & H2O across membrane) Abnl CFTR = decreased Cl secretion = increased Na reabsorption = decreased airway surface liquid = dysfunctional cilia, chronic mucus infection, & airway inflammation (due to hyperresponse inflammatory response) --> bronchiectasis
>1500 CFTR muts but 50% of pts are homozygous for delta508 mutation in CFTR (deletion in phenylalanine); Class I (nonsense mutation); Class II (protein degradation by proteosome; milder); Class III &IV (defective regulation but CFTR makes it to cell surface; mildest); Class V (linsuff production of functioning protein); Class VI (accelerated protein turnover)
Most common life- 1/3200 births in shortening genetic whites dz in Caucasians 30,000 Americans, 60,000 cases globally;
Sweat test (pilocarpine iontophoresis) - nl ~40; CF ~90-100
Spirometry CFTR modulators (Ivacaftor, VX-809, PTC124) aw clearance Gentoyping (specific, (dornase alfa, not sensitive) hypertonic saline, bronchodilators, PT) Newborn screening Aerosilized abs for (measures IRT exacerbations combined w/ Anti-inflammatories genotyping; confirmed (prednisone, by sweat test) macrolidesPsuedomonas) Late stage PE findings Nutrition: caloric (respiratory failure, foods, appetite FTT, malnutrition, stimul, tx constipat, steathorrhea) pancreatic enzymes & PPIs to minimize CT: air trapping, malabsorp bronchiectasis yearly CT scans @ age 1 lung transplant CT: cysts Gross pathology: irreversible damage PFTs: restrictive pattern (low TLC0, decreased DLCO (thickened alv membrane) CXR: bilateral reticular infitrates, basilar distn, small lung vol CT: diffuse ground glass infiltrate, mixed pattern (consolidation + GG), reticular peripheral infiltrates; honeycombing (advanced fibrosis), traction bronchiectasis ABG: hypoxemia
Life expectancy ~40y.o. but improving w. earlier dx and better tx Increased tendency for infections (never really eradicated, just controlled) - Staph, H.flu, Pseudomonas Pulmonary exacerbations usually require hospitalization (better adherence w/ aw clearance therapies) prednisone leads to decreased loss of lung fx but toxic w/ chronic use
Bronchiectasis
irreversible lung damage
Interstitial Lung Disease (ILD) general overview
Dry cough, DOE, insidious onset, end inspiratory crackles @ lung bases, possible digital clubbing, no wheezing
Injury results in inflammation & tissue remodeling in lung - if uncontrolled, tissue progresses to fibrosis & scarring of lung
connective tissue diseases, exposures contributing to hypersensitivity pneumonitis, drug/smoking induced, radiation, toxic inhalation unk causes? IPF, other idiopathic interstitial pneumonias (COP, NSIP, LIP, AIP), sarcoidosis, eosinophilic pneumonia, rare (LAM, PLCH, PAP)
Disease
Clinical Variants
Chronic, progressive, fibrosing, interstitial limited to lungs! Dyspnea (insidious but progressively worsening); non productive cough (difficult to control), clubbing, decreased breath sounds, bilateral crackles DDx? Other ILD, connective tissue dz (RA, scleroderma), occupational exposure, meds (MTX, bleomycin, nitrofurantoin)
Pathogenesis
"repeated cycles" of epithelial activation or injury by some unknown agent
Etiologies
Unknown?
Epidemiology
high mortality!!
Risk factors
Lab/Imaging
DX = exclusion of other causes, +UIP pattern on HRCT/bx CXR: restrictive findings (smaller lung volumes), fibrotic changes CT: honeycombing, reticulation, traction bronchiectasis, subpleural & basilar changes histology: dense fibrosis + honeycombing, subpleural involv, temporal heterogeneity, fibroblastic foci
Treatment
No FDA approved med tx steroids HARMFUL!! treat GERD Enroll in clinical trials Evaluate for lung transplant O2 supplementation, pulm rehab, vaccination for flu/pneumonia, tx comorbidities, maintain BMI
Complications
About 50% survival after 2 years dx; 1520% 5 yr survival
Idiopathic Interstitial Idiopathic Pulmonary Pneumonias fibrosis
Age (>50) familial pulm Older adults, M>F fibrosis 128,000 pts (US) smoking 40,000 new GERD cases/yr exp to metal 25-30/100,000 dust, wood dust, solvents
Desquamative interstitial pneumonia (DIP)
Chronic onset of dyspnea & cough; sometimes clubbing
M>F, mean age 45 y.o.
>90% of cases involve smokers!
CXR: nl in 1/5 pts smoking cessation mortality rate 20-30%; CT: diffuse/patchy mean survival 12 ground glass steroids sometimes years opacifications effective PFTs: restriction + low DLCO histology: increased alveolar macrophages, pigmented
Acute interstitial pneumonia (AIP) Respiratory bronchiolitis interstitial lung disease Cryptogenic organizing pneumonia (COP) "Bronchiolitis obliterans organizing pneumonia" BOOP
localized or diffuse fibrous plugs filling airway into alveoli sometimes present w/ fever (after which Abs don't help)
consequence of infection or inhalational injury
a/w CTD, drugs, idiopathic
CTDs
CT: multiple patchy consolidations; sometimes GG Histology? Fibrous plugging of airway
responsive to steroids!! (~6m)
Lymphocytic interstitial pneumonia (LIP) Non-specific interstitial pneumonia (NSIP)
chronic onset of dyspnea varying degrees of inflammation & cough; sometimes fever & fibrosis w/I alveolar walls, temporally uniform
Females > Males; Connective younger mean age tissue diseases of onset (46-55) (more females!), HSP, other exposures
CT: UIP pattern HRCT: reticular infiltrates, peripheral & basilar distn, ++ ground glass, NO HONEYCOMBING, TEMPORALLY UNIFORM Histology? Inflammatory cells, fibrosis, uniform thickening of lung interstitium
better prognosis than UIP!! Good results with steroids
Disease
Clinical Variants
Drug-induced ILD
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
remove responsible drug!
Complications
Lung toxicity in response to Talc in illicit drugs antibiotics (nitrofurantoin), antiinflammatory agents (methotrexate, cyclophosphamide), cardiac drugs (amiodarone), chemotherapeutic agents (bleomycin, busulfan), recreational drugs non-necrotozing granulomatous dz immunologic-mediated, inflammatory reaction around small airways in response to inhaled antigen (organic dust) Microbial agents (bacteria, fungi, amoeba, atypical mycobacteria), Animal proteins (bird antigens), low & high MW chemicals Non-smokers Histology: bronchiocentric lymphoplastic infiltration, poorly formed nonnecrotizing granulomas, mutlinucleated giant cells around bronchioles, CXR: may be normal CT: sometimes nl HRCT: mid to UL s (chronic HP), fibrosis/ honeycomb (chronic HP), any pattern (GG, retic, nodul, consolidn) IgG- not spec/ sens BAL: CD8 predominance (diff from sarcoid)
Hypersensitivity Pneumonitis (extrinsic allergic alveolitis)
Farmer's lung Pigeon breeder's lung Humidifier lung
NO WHEEZING! NOT multisystemic (like early stage: type III mediated sarcoidosis) Acute HP (sx w/i 48h, selflate stage: type IV delayedresolving, recurring type hypersensitivity reaction episodes more severe, against antigen nonspecific sx; tachypnea, tachycardia, fine crackles), does not involve IgE subacute/ intermittent HP (gradual sx, low dose rptd exp, sx resolve w/i 24h of removal from agent, tachypnea, crackles) chronic HP (chronic exp, prod cough, DOE, weight loss, tachypnea, crackles, irreversible after removal of agent) multi-organ (hilar/ mediastinal LNs, lungs, liver, spleen) granulomatous dz of unknown etiology abnl immune response to unk antigens --> increased proliferation of CD4+ T helper cells in involved tissues = recruitment of macrophages = formation of granuloma CD4+ alveolitis
must stop exposure!! Only then will steroids be effective
may progress to chronic HP w/ end stage fibrosis & honeycombing
Sarcoidosis
asymptomatic Non-infectious, nonnecrotizing granuloma Systemic disease, nonspecific & variable presentation (lungs, skin) Heerfordt's syndrome: parotid swelling, uveitis, Bell's Palsy, fever Lofgren's triad: arthritis, erythema nodosum, hilar adenopathy - good prognosis The sicker a person appears on presentation, the better the prognosis!
Unknown?
3x higher incidence/ severity in African Americans
histology: nodular aggregate of mo w/o necrotizing center; periphery of lymphocytes (wreath Scandavian arrangement of countries decreased risk nuclei), in HIV pts! multinucleated giant young person's cells disease (age<50) Worse CXR: prognosis? Pts lymphadenopathy in F>M >40y.o, A.A., young person; hypercalcemia, interstitial fibrosis; nephrosclerosis, determines staging (0extrapulm dz no pulm inv, 4irreversible fibrosis), nodular sarcoids PFT: any pattern but classic (nl ratio, low DLCO, restriction or mixed pattern) BAL: increased lymphocytes, >3:1 ratio of CD4:CD8
Some genetic component (HLA II on chromosome 6 short arm)
spontaneous resolution but management differs based on location of involvement glucocorticoids if worsening pulm sx, worse lung fx, changes in CXR; 612m lung transplant if stage 4
should always stain tissue bx with acid fast for bacilli to avoid missing TB (early TB looks very similar to sarcoidosis)
Disease
Pneumoconsioses (occupational lung dz)
Clinical Variants
Asbestosis
diffuse fibrosis
Pathogenesis
Etiologies
Epidemiology
Risk factors
industries that mine, fabricate, or install asbestos (roofing, insulation, brakes, shipyards)
Lab/Imaging
Histology: alveolitis & development of giant cells, interstitial fibrosis
Treatment
Complications
amphibole body a/w mesothelioma asbestos exposure also increases risk for bronchogenic carcinoma, benign pleural plaques (marker of asbestos exp), and mesothelioma
inhalation of asbestos body Asbestos body (amphibole more pathogenic DOE, productive cough than serpentine) causes the recruitment of macrophages --> failed attempt to phagocytose --> formation of fibrogenic cytokines -> gradual development fibrosis
Coal workers pneumoconiosis Silicosis
CT: diffuse nodules nodular fibrosis that gradually 10-15 years of develops following the inhalation silica exposure increased susceptibility of cystalline silica in occupational settings --> intxt to TB!!! w/ epithelial cells & macrophages --> phagocytosis of silica particles --> activation / release of mediators by macrophages --> eventual death of macrophages --> fibrosis acute & chronic exposure to NON-NECROTIZING GRANULOMAS (similar beryllium in fluorescent light bulbs, mining & industry --> to sarcoidosis) hypersensitivity reaction nodular fibrosis mining and processing of ores; stone cutting/ polishing, sandblasting, working w/ abrasives (pottery) histology: nodular type pattern of fibrosis, silica particles (needle like structures) visible under polarized lens high incidence of TB (silicosis = macrophage wasting dz so can't fight off TB) slight risk for carcinoma cor pulmonale mining & industry Histology? Appears just like sarcoidosis, would require special testing to distinguish
Berylliosis
Anthracosis
Community acquired pneumonia (CAP) Typical pneumonia (Pneumococcal pneumonia)
usually harmless except in coal miners w/ massive exposure detectable on gram stain; abrupt onset of fever/chills, dyspnea, cough (productive, purulent, sometimes blood-tinged, rusty sputum - classic for S. pneumo), localized lobar infiltrate, elevated systemic WBC, fever, pleuritic
massive amounts of carbon pigment in the lung Strep pneumo enters human host via airborne droplet spread --> person can become asymptomatic carrier (children) or become locally infected (ear, sinuses) Aspiration of nasopharyngeal carriage --> pneumonia settling in the alveoli Strep pneumo can invade the blood stream and enter joints (septic joint) or meninges (menigitis) Strep pneumo, H. Blacks > Whites Elderly & influenzae, others risk increases with infants age HIV, diabetes, splenic dysfunction (SSD), cirrhosis, defective antibodies; African/ Native Americans (due more to SES) CXR: lobar consolidation, pleural effusions sometimes Macrolides (arithromycin), doxycycline, 3rd gen Sputum gram stain: cephalosporins, many neutrophils, sometimes gram+ cocci in pairs fluoroquinolone & chains blood cx positive in 20% of patients Strep pneumo is #1 cause of meningitis in all age groups can also cause other clinical syndromes (bacteremia, otitis media, sinusitis, bronchitis, bacterial peritonitis, bone/joint infs, endocarditis) Increased rate of blactam resistance (altered PBPs)
CAP - Atypical pneumonia
general
can't be seen on gram stain, require special media to grow in cx, dry cough, dyspnea, patchy infiltrates, milder (EXCEPT Legionella), insidious onset w/ URI sx
Mycoplasma pneumoniae, Legionella, Chlamydia pneumoniae, viral
Disease
Clinical Variants
Legionella
Pontiac fever - acute, self-limiting flu-like illness; high attack rate among exposed Legionnaires' dz - mild respiratory dz to severe, life-threatening pneumonia; HI fever, malaise, myalgias, anorexia, headache, diarrhea, dry cough, hyponatremia, pleural effusion
Pathogenesis
Enters alveolar macrophages thru coiling phagocytosis, multiplies in the phagosomes, reaches critical mass, then lyses the macrophage transmitted to humans via aerosolization of contaminated water Cell mediated immunity = host defense
Etiologies
Epidemiology
Risk factors
Smokers or people with damaged mucociliary defenses (COPD)
Lab/Imaging
Gram stain: Gram rod that does not stain well; requires fuchsin, silver stains for visualization
Treatment
Fluoroquinolones (Levofloxacin, moxifloxacin, ciprofloxacin)
Complications
L. pneumophilia = rare in healthy children, young Gram negative, aerobic, non-spore adults forming, unencapsulated bacilli
Macrolide (Azithromycin) Legionella urinary immuno-deficient antigen - + in 80-90% Alternatives? of dz age> 50 Doxycycline culture on selective NO B-LACTAMS!! media - slow but GS serology- slow...
Mycoplasma pneumoniae 2-3 week incubation transmitted via person-to-person period, insidious onset, droplet spread fever, malaise, headache, "walking pneumonia" persistent cough, focal pneumonia myalgias, disparity btwn CXR and physical findings (few)
YOUNG PEOPLE! older adults with bronchitis or (5-20 years old) pneumonia; closed populations (military recruits, boarding schools, dorms)
Empiric dx due to difficult cx
No tx for localized URIs (without pneumonia)
cold agglutinins: antibodies to RBC I Ag B-LACTAMS do not work (no cell wall!!) = agglutination of RBCs at 4 degs C Pneumonia Antigen & NA present? Use detection kits (future) macrolides (erthromycin, azithromycin), doxycycline (adults), fluoroquinolones (adults) CXR: patchy infiltrates Empirical tx CBC: nl WBC cell cx not really tried PCR/NA techniques (Future) doxycycline, macrolides, fluoroquinolones NO B-lactams!!
immune mediated systemic manifestations (Derm- SJS, CNSencephalitis, Heme hemolytic anemia, MSK- myalgias, arthalgias, etc)
Chlamydia pneumoniae
re-infection possible, asymptomatic carriage, 21 day incubation period; mild URI sx followed by prolonged cough, malaise, no fever really, nl WBC count
Infectious spores (EB) attach and enter host cell, endocytosed and transformed into metabolically active RBs; RB multiply via binary fission; RBs transformed into EB to make cytoplasmic inclusion, after which the EB's are released to infect next host cell person to person droplet spread
>1/4 of no seasonal pneumonias in variation school-aged kids
Coxiella burnetti (Q fever) often asymptomatic
focal pneumonia caused by inhalation of aerosols of birth products from sheep, cattle, goats, cats, rabbits lymphocytic response due to intracellular nature of organism
histology? interstitial & alveolar infiltrates of macrophages
Disease
Clinical Variants
Viral pneumonias
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
difficult to detect but may diffuse alveolar damage & precede bacterial necrosis caused by CMV, HSV, pneumonia adenovirus, or measles virus
CMV? Adenovirus? Immunocompro Exudates w/ necrosis mised individuals & hemorr; intranuclr inclusions w/ blurred nuclr membrane smudge cell; CMV? Intra-alveolar hemorr, edema, cytomegalic cells (large cells with intranuclr & cytoplasm inclusions) HSV? Eosins w/ halo Measles? multinucl giant cells w/ intranuclr inclusions w/ indistinct halo & cytoplasm inclusions
Pneumocystis jirovecii pneumonia (PCP)
focal infiltrates
fungal pneumonia that invades immunocompromised hosts with CD4 T cell count <200 (presence of PCP = AIDS dx)
immunocompro mised pts (AIDS, transplant, cancer, steroids)
Histology? Looks bubbly with widened alveolar septa due to inflammatory cells; characteristic cysts seen w/ silver staining antimicrobial Gross: cavitation (gangrene of lung) w/ surrounding fibrosis, pus filled CXR: abscess formation Histology: alveolar space filled w/ PMNs scarring --> fibrosis R/O carcinoma extension into brain, hemorrhage
Necrotizing Pneumonia (Lung Abscess)
inflammation & pus that has been walled off; characterized by cough, fever, foul-smelling purulent sputum, digital clubbing
can be caused by aspiration of infective material (especially when cough reflex is depressed); antecedent bacterial pneumonia; septic embolism; neoplasm (postobstructive pneumonia)
S. aureus, S. pyogenes, Pseudomonas, POLY-MICROBIAL
Immunocompro mise; transplant
Aspiration pneumonia
(severe necrotizing bronchopneumonia)
Aspiration of gastric contents Polymicrobial or oral flora resulting in a necrotizing pneumonia that has chemical (irritant) and polymicrobial components
debilitated pts unconscious pts repeated vomiting
Histology: hemoptysis & necrosis
High mortality lung abscess in those who do survive
Disease
Tuberculosis
Clinical Variants
Active TB
Pathogenesis
Etiologies
Epidemiology
1.5 million deaths/yr; 2nd leading cause of death after HIV; #1 cause of death in HIV pts most cases in Asia & Africa HIV epidemic is driving TB coinfection
Risk factors
HIV poor, crowded, poorly ventilated settings malnutrition immunosuppress ed (TNF-a inhibitors, prednisone) recent inf w/ latent TB (<2y) substance abuse DM, renal failure, cancer, chemo, silicosis, fibrotic changes on CXR
Lab/Imaging
Acid Fast Bacillus Broth cx w/ Ab susceptibility - GS DNA probes on smear + specimens (NAAT - hi sen/spc) to ID species (TB rough colonies) CXR: typical UL infiltrates;variable patterns (hilar adenopathy, bilat infiltrates, cavitary UL) in HIV coinfected; miliary nodules histology: necrotizing granulomas in center, AFB stain= "red snappers", Ghon focus, Ghon complex, cavitations (caseous)
Treatment
RIPE = Rifampin, isoniazid, pyrazinamide, ethambutol for 6-9mdrug susc TB start on 4 drugs if suspicious of TB, once have susceptibilities, can cut back to 2 drugs (4 drugs - 2m, 2 drugs 2m)
Complications
Lots of undetected TB cases globally so need single point of care test (GeneXpert RT-PCR $$) MDR-TB (resistance to at least INH + RIF) XDR-TB (resistance to INH, RIF, + fluoroquinolones/ injectable Abs)
Pulmonary TB: insidious onset of prolonged Latent TB (not all cough, pleuritic chest organisms are eradicated pain, hemoptysis, fever, but immune system night sweats, weight/ controls inf; not infectious appetite loss, fatigue but at risk for reactivation in future) TB + HIV: extrapulmonary dz, atypical CXR findings primary progressive dz (LL & interstitial infiltrates, (inf followed by active dz adenopathy) usually in HIV pts) Miliary TB = disseminated (looks like millet seeds in the lung) NECROTIZING GRANULOMAS
person to person transmission Mycobacterium of airborne droplets, especially tuberculosis with prolonged exposure; 3 outcomes with exp? 1. active TB inf, 2. latent inf, 3. no inf most infectious pts? Cough + AFB smear+ MTB enters alv macrophages and replicate in phagosome (leads to asymptomatic bacteremia & multiple seeding sites); ~3wks later, TH1 response is mounted (due to inc IL-12); TH1 cells make IFN-y which stimulates macrophages to contain the MTB inf --> formation of necrotizing granulomas, hypersensitivity, & tissue destruction
cavitations on CXR: resistance = higher 4 drugs -2m, 2drugs- morbidity, mortality, 7m cost DOT!!! immune reconstitution inflammatory LTBI - tx with INH for syndrome (IRIS) 9 months (or INH/RIF response in TB-HIV pts started on ARVs for 1x q 12wks)
Atypical Mycobacteria
M. avium intracelluaire complex (MAC)
Hot tub lung, pre-existing lung conditions susceptible; especially aggressive in AIDS pts (feverish, night sweats, weight loss) non-AIDS pts rarely become infected (but if so, productive cough +/weight loss/fever)
HIV, COPD/other lung dz
Multi-drug therapy
DIFFICULT TO ERADICATE
Granulomatous fungal diseases (very similar to TB clinically, pathologically) dimorphic: mold in the cold, yeast in the heat! GEOGRAPHIC localization
Cryptococcus
granulomatous inflammatory response
caused by Cryptococcus neoformans, which is an encapsulated yeast and transmited to humans via inhalation of soil & bird droppings
opportunistic infection!
Gross: caseous necrosis of lung just like TB Histology: yeast (spheres) surrounded by clear space (capsule), which can be stained with mucicarmin capsules turn pink
Histoplasmosis
narrow based budding
Inhalation of histoplasma capsulatum causes isolation of spores into the lung, after which only the fungi intracellularly reside immunocompromised individuals progress w/ in macrophages production of Histoplasmoma - localized lung granulomas lesion that becomes walled off and calcified NOT really capsulated! chronic fibrosing histoplasmosis - aw centered fibrosing lung dz Histoplasma pneumonia granulomatous pneumonia Disseminated histoplasmosisresembles miliary TB
nl & immunoHistology: calcified Ohio & Mississippi River compromised pts necrosis, unencapsulated valleys organisms seen w/ silver stain inside alveolar macrophages, narrow based budding if replicating
Disease
Clinical Variants
Coccoidoidomycosis
multiple budding various dz presentation, mostly asymptomatic (80% of people in endemic areas infected) but some people can have lung lesions, fever, cough, pleuritic pains, erythema multiforme
Pathogenesis
inhalation of spores from Coccidiodes immitis causes delayed type hypersensitivity to the fungus
Etiologies
Epidemiology
Southwest & Western US
Risk factors
Lab/Imaging
Histology? Large organism containg secondary component (spherule w/ endospores) multiple budding
Treatment
Complications
Blastomycosis
Inhalation of spores from Blastomyces dermatitidis, Pulmonary, skin, & bone producing various dz presentations lesions broad based budding pulm sx (productive cough, chest pain, abdominal pain, night sweats, chills, anorexia, weight loss)
Southeastern & south central US
Histology? Broad based budding CXR: UL involvement
Spontaneous resolution, or can persist as a chronic lesion
Wegener's Granulomatosis
unknown but probably represents resembles TB but must be distinguished bc diff T cell mediated hypersensitivity reaction to tx inhaled infectious or environmental agents (due to Necrotizing systemic response to immunosuppressive vasculitis agents) ELK Triad: Ear/nose/throat, Lung, Kidney involvement saddle nose deformity ANCA associated vasculitis const sx (fever, migratory arthalgias, malaise, anorexia, weight loss); ENT sx (sinusitis, otitis), pulm sx (cough, wheezing, stridor, dyspnea, hemoptysis)
M=F, mean age of 40 y.o, more common in Caucasians
Histology (surg bx): cavitation, necrotizing granulomas, alveolar hemorrhage w/ capillaritis, mediumsmall vessel vasculitis Blood test ANCA (cytoplasmic, perinuclear): IgG autoantibody w/ specificity against antineutrophil granules & lysosomes in monocytes; useful marker for dz activity & evaluation of systemic vasculitis; + in other dz!!
if untreated, mortality corticosteroids + cyclo-phosphamide w/I 1 year poor prognosis related to # sites involved, renal involvement, age, delay in dx, Can give azathioprine & MTX medication to maintain remission intolerance CXR/CT to monitor response to tx
Foreign Body Granulomas
Diffuse pulmonary emboli
entrapped foreign material (not blood clot!) in pulmonary vasculature
talc from IVDU Iatrogenic (indwelling catheter, IV line, silicone from breast implants)
IVDU
Histology? Multinucleated giant cells, birefringent (polarized light will show talc)
Localized parenchymal mass
tissue reaction to foreign material, commonly seen with aspiration pneumonia or lipoid pneumonia (lipid in the lung)
Histology? Lipids in alveoli cause formation of granulomas
Disease
Influenza virus (Orthomyxoviridae)
Clinical Variants
Incubation period (2d_, abrupt onset, shedding of virus 1d before & 5d after sx begin HI fever, severe myalgias, headache, chills, cough, DOE, GI sx
Pathogenesis
person-to-person, airborne transmission of influenza virus from symptomatic or asymptomatic hosts
Etiologies
Epidemiology
5-20% of US population gets flu each yr; 36,000 deaths/yr (>90% in people >65 yo)
Risk factors
Elderly (seasonal flu) Middle aged adults (H1N1)
Lab/Imaging
Rapid Antigen Detection - poor sensitivity Viral cx - takes a few days PCR (future)
Treatment
Oseltamivir/Tamiflu (tx, prophylaxis) Tamiflu allergy? Zanamivir/Relenza Tamiflu resistant flu subtype? Amantadine, Rimantadine
Complications
More complications & mortality in elderly EXCEPTION: deaths from H1N1 were middle aged adults primary viral pneumonia, secondary bacterial pneumonia, otitis media, Reye's Syndrome (aspirin +flu), myopericarditis, ?encephalitis
Disease
Parainfluenzae virus (Paramyxoviridae)
Clinical Variants
Laryngotracheobronchitis (Croup) Bronchiolitis (RSV first, then parainfluenza) Less common cause of pneumonia
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
No specific antiviral no vaccine supportive care
Complications
20% of resp infs in young children kids, very few in adults
Respiratory Syncytial Virus (RSV) (Paramyxoviridae)
severe lower respiratory tract disease in infants bronchiolitis, bronchopneumonia, bronchitis in older children/adults incubation period of 2-8 days; viral shedding for 1-2 weeks or longer
droplet transmission and direct contact
community outbreaks in late fall to early spring
severe inf risk diagnosed via Cx, increased w/ kids antigen detection, who have cong PCR heart failure, underlying pulm dz, premature birth significant resp pathogen in transplant pop
Ribavirin hi secondary (aerosolized form for infection rates infants, oral form for transplant pop) inhaled form of ribavirin can cause supportive care bronchospasms in transplant pts
Human metapneumovirus (paramyxoviridae)
clinically indistinguishable illnesses similar to RSV; from RSV coinfection w/ RSV = severe illness upper & lower respiratory tract infections 50% of inf are asymptomatic
seasonal (winter/spring) pattern where it is transmitted by close contact
elderly, immunocomp, young children
Molecular detection w/ PCR
severe lung dz in lung transplant pts
Adenovirus
spread by droplet nuclei, fecaloral route, and can persist for some time in the environment
Infants: pharyngitis, otitis infected epithelial cells undergo media, pneumonia, necrosis --> intense diarrhea inflammatory responses --> possible viremia Children: URI, pneumonia, diarrhea, Latent infection that can hemorrhagic cystitis reactivate & cause severe inf in Adults: URI, pneumonia, transplant pts conjunctivitis (pink eye) Immunocomp: pneumonia, gastroenteritis, hemorrhagic cystitis, hepatitis, interstitial nephritis
Cx less valuable Infection control because virus may not be shed for years after Antiviral therapy inf cidofovir for disseminated sx direct antigen assay for conjunctivitis PCR
Common cold
Rhinovirus (Picornaviridae) Coronavirus
30-50% of common colds
circulate in spring, summer, early fall circulate in fall, winter
PCR
10-30% of common colds SARS = virus endemic in bats that crossed into humans via intermediary (cats); risk of SARS (severe acute respiratory syndrome) transmission greatest around day 10 of illness; HCWs were high risk group for acquisition
PCR
Disease
Sleep apnea
Clinical Variants
Central Sleep Apnea
cessation of airflow during sleep due to cessation of respiratory effort as result of decreased ventilatory motor output nl or slightly lower PaCO2 levels during the day, chronic hypercapnia @ night Cheyne-Stokes respiration
Pathogenesis
nl - reset of CO2 setpoint during sleep (transient period PaCO2 is below apnea threshold = min vent = PaCO2 to apnea threshold = minute ventilation
Etiologies
hi altitude (longer periods of sleep apnea) hypercapnia, chronic hypoventilation
Epidemiology
Risk factors
Lab/Imaging
Treatment
maintain resp drive (respiratory stimulants theophylline, progesteron; increase metabolic acidosis by alkalinizing urine best for altitude induced) treat underlying conditions (CHF CPAP mask)
Complications
Chronic hypoventilation = impaired CO2 drive since have hi PaCO2 levels = cyclical sleep CHF (CheyneStokes,inc onset central apnea ( apnea feedback delay) time, arousal) in normocapneic CSA, PaCO2 becomes higher than setpoint= hyperventilate = PaCO2 becomes too low = hypoventilation (Cheyne-Stokes respirations) = Increased feedback delay (brain responding to old news and tends to overcompensate) or LOOP GAIN (small stimulus = gigantor response!!) Increased hypersensitivity/ loop gain (from oversensitive medulla, exaggerated output to resp muscles, or overefficiency of lungs in gas exchange)
Obstructive Sleep Apnea
Aw becomes more compliant, complete blockage of airway despite efforts to pharynx narrows, and resistance to breathing increases with breathe sleep; in OSA, muscle tone SNORING that wakes up can't compensate to keep the aw open so increased snoring bed partner and OSA clinical features: left heart failure, unexplained as pts start to snore and try harder to breathe out, increased nocturnal death, pulmonary hypertension, resistance outside of thorax and right heart failure, chronic negative pressure inside pharynx pulls airway closed = less airflow hypoventilation, = transient hypoxia, excessive daytime hypercapnia, acidosis = sleepiness, restless arousal from sleep sleep sleep onset -> apnea -> hypoxia, hypercapnia, acidosis -> arousal from sleep -> resumption of airflow -> return to sleep -> cycle starts over
Obesity (narrow airways), large neck, thick tongue, URIs, nasal trauma negative oropharyngeal press (small pharyngeal cavity, hi pharyngeal compliance, decreased upper aw muscle activity)
20 million Americans, many undiagnosed; 95% of all sleep apnea
MRI: narrowed CPAP (changes 30% noncomplicance pharynx behind tongue negative airway to CPAP pressure to positive, STOP BANG so distends the questionnaire pharynx during (Snoring, Tired, inspiration) Observed apneas, Pressure - HTN, pharyngeoplasty BMI>35, Age>50, (effective in 50% of neck circumference, pts but very painful, gender -male) last resort option) increased risk for OSA if 3/8 factors mandibular advancement devices (makes snoring difficult by holding tongue down) weight loss
Pursed lip breathing (creates increased pressure near mouth that changes press gradient;Ppl>Paw occurs higher in the trachea where it's noncompressible) SMOKING CESSATION!!! Reduction of risk factors, Flu vaccine Lifestyle modifications most impt tx (other treamtnes not too effective)
Flu & pneumococcal vaccines; possible augmentation therapy of missing protein PiZZ ($$)
SMOKING CESSATION!!! Reduction of risk factors, flu vaccine
asthma control parameters? No daytime sx (<2x/wk), no limitation of DALYs/exercise, no nocturnal sx, no need for reliever tx (<2x/wk), nl/near nl lung fx, no exacerbations mandatory patient education and environmental control; comorbidity treatment high level therapy then step down
Prognosis? Class I (no limitation w/ exertion), Class II (mild limitation but no probs at rest), Class III (marked limitation of activity), Class IV (no physical activity possible)
DVT prophylaxis (intermittent sequential compression device adherence issues; anticoagulation - LDUH, LMWH heparin, factor Xa inhibitors)
infection control practices at home mandatory!! (must clean everything)
Prophylactic treatment for close contacts
RSV prophylaxis (Synagis) - monthly IM injections during RSV season, $$, given to children who meet certain criteria (infants born <28 wks gestation, those born 29-32 wks gestation during RSV season, those born 3236 wks gestation & risk factors - daycare, school age siblings; full term kids < 2y.o. w/ CLD, CF, CHD)
importance of nutrition & exercise breathing techniques to augment airway clearance lung transplantation patients feel better but still have persistent diseases (complicated by chronic lung rej & bronchiolitis obliterans)
23 valent Polysaccharide vaccine - T cell independent (no memory produced, not fully functional in infants) used in older children/ adults with risk factors; all adults > 65 Protein conjugate vaccine - T cell dependent (effective memory cell response; better at protecting against localized dz; reduces carriage in kids); 13 valent conjugate for routine infant use and adults > 50 years old
HIV testing to ALL pts with TB Start ARVs ASAP (w/I 2 weeks) for HIV+ pts SCREEN ALL CLOSE CONTACTS w/ TST (requires 2 tests, cross reacts with BCG vaccine) or IGRA (does not crossreact with BCG vaccine; single step so better for homeless) TST cutoff: 5mm= HIV, immunodef, contacts w/ TB inf indi; 10mm = immigrants, HCWs, IDU; 15mm = nl IGRA = IFN-y release assay (T cells, if exposed to TB Ags, will release IFNy if inf)
Inactivated split vaccine (trivalent) - one A H3N2, one A H1N1, one B strain - contraind w/ allergy to chicken eggs or Guillian Barre Live attent Nasal spray mist (better mucosal immunity) - contraind in people w/ reactive aw dz or pregnancy vaccination for everyone >6m Fluzone Hi dose - new vaccine for pts > 65 y.o. (4x dose & greater efficacy) Vaccinate HCWs!!
RSV prophylaxis (Synagis, mAB) - high risk infants/premies
vaccination w/ oral live attentuatd virus for military recruits
Disease
Clinical Variants Defining Characteristics
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Left to right Atrial septal shunts defect (oxygenated blood flows thru a defect)acyanotic!
parasternal impulse (severe); fixed splitting of S2 (inspiration & expiration); diastolic murmur at tricuspid (severe)
Hole in wall btwn 2 atria --> volume Down syndrome overload on RV; 85% of ASDs occur in the (primum defect) fossa ovalis - secundum (loss of tissue = hole between atria); primum defects are missing the upper cushion between atria; O2 step up in RA oxygenation; RVVO -> RV dilation increased preload on right heart
diastolic murmur across tricuspid; systolic murmur across pulmonic = more severe
septal occluder
right heart failure; Afib; pulmonary hypertension (increased amt of blood in RH and PA)
Ventricular septal high pitched holosystolic defect murmur (LLSE); displaced apex (if severe); diastolic rumble
membranous defect (high in septum) = hole betwn RV & LV --> blood moves directly into PA --> LVVO --> LV dilation (increased preload in left heart); O2 step up in RV muscular defect (lower part of septum; holes in septum) --> blood moves directly into RV --> RVVO (parasternal lift, systolic murmur over tricuspid area)
Down syndrome; maternal alcohol intake; trauma/MI (muscular defect)
usually closes spontaneously by age 10-12; if not, clamshell occluder
if small, asymptomatic; if large, pt will have dyspnea, slow growth, shunt reversal (cyanotic; Eisenmengers); HF, IE
Patent ductus arteriosus
nl at birth but closes w/I 48 normally functions to move blood from hours descending aorta to placenta and closes w/I 2 weeks of birth; after birth, it's a continuous murmur ULSE remaining fistula between aorta (hi press) diastolic rumble (MV) and pulmonary artery (low press) --> displaced apex PAVO & LVVO (if severe); O2 step up in PA
rubella, premature birth, high altitude
CXR: inc cardiac silhouette (displaced apex from LVVO) Angiogram: blood moves from PA into aorta
HF, Eisenmengers (deoxy blood in left heart from PA --> aorta movement causes PA hypertrophy = inc PA press = unoxy blood in left heart = cyanosis) septal occluder DVTs, MI, & cryptogenic stroke!!
Patent foramen ovale
normally functions to move 90% of blood from RA to LA (shunts away from lungs); congenital abnl when it never seals off; PFO stays open so blood (AND clots) can pass through to LA
increased right heart pressure (valsalva, exercise) pushes more blood across PFO & into LA!
Right to left shunts (de-oxy blood flows into systemic circ)cyanotic!
Tetralogy of Fallot cyanotic skin during crying/feeding 4 parts: 1. LARGE VSD 2. PS (RVOT obst) 3. RVH 4. AO override Eisenmenger
congenital abnl from the incomplete closure of intrauterine cnxtn btwn pulm artery & aorta --> decreased pulmnary blood flow more severe PS = more RVOT obstruction
CXR: hyperlucent lungs (lack of blood getting to the lungs)
central cyanosis, clubbing, hypoxemia, growth retardation, polycythemia (thrombosis, CVA), PH, paradoxical embolus
L-->R shunt that eventually reverses to R->L (acyanotic --> cyanotic shunt w/ increased pressure)
Vascular/ Valvular congenital disease
Bicuspid aortic valve pulmonic stenosis late peaking systolic murmur parasternal lift big "a" wave
narrowing of pulmonic valve blocks blood usually part of from leaving RV --> increased afterload on tetralogy of RV --> RVPO --> RVH fallot Noonan's syndrome
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Tachycardia
Sinus, atrial, ventricular
HR > 100bpm
Atrial Fibrillation Paroxysmal, chronic
no atrial activity so immediate loss of 20-25% of cardiac output, grossly irregular, rapid rate (110180)
increased heart rate shortens diastole, reduces LV filling, and reduces coronary artery filling loss of atrial contraction = blood stagnation or stasis in left atrium/ left atrium appendage = increased risk for thrombi/emboli
RA/LA dilation; 3-4% of pts > 70 SA node years old inhibition; hyperthyroidism
Systemic Arterial Primary / Hypertension Essential (idiopathic)
asymptomatic systolic BP
Age (vessels stiffen, need more pressure PE: normal position apex, for blood flow) different contour to apex Idiopathic (95%) pre-hypertension (120Coarct (5-7%), 139/80-89) white coat high pressure in aorta = obstruction after Stage 1 (140-159/ 90-99) effect, Stage 2 (>160/>100) aortic valve = LVPO = LVH = increased medications, incidence of MI & atherosclerosis alcohol, salt, PE: BP in BOTH arms, decreased K or decreased aorta complicance (stiffer aorta) Ca intake, check weight/ waist circumference, fundoscopy, [inc systolic BP = inc pulse wave velocity insulin from loss of elasticity; dec diastolic BP = bruits, heart/lung/neuro resistance, loss of elasticity = stiffened LV = less exams; sedentary S4 (LVH causes decreased ventricular relaxation] lifestyle LV cavity size so atrial kick needs to push more blood in), sustained apical impulse
BP level that increases risk for CVD and target organ damage (pressure overload makes heart work harder to maintain CO; increased peripheral resistance causes vascular inelasticity/stiffness; kidneys & retina affected; aortic dissection; LVH/ CAD/ HF/ Afib; stroke/ TIA)
60 million Americans
EKG: fast, irreg fibrillatory waves in middle, NOT Pwaves PE: pulse deficit, S1 intensity variation male gender EKG (but women R/O secondary catch up after causes (UA, FBS, menopauses), Hct, K/creatinine/ African calcium, lipid Americans, profile) increased age, obesity, environmental (stroke belt), hereditary kidney or smooth muscle defects, FH
Thrombi/ emboli formation
pre-hypertension? Lifestyle mods (less salt, exercise, diet); modify risk factors (smoking, obesity, lipidemia, diabetes) hard to treat bc systolic BP is less likely to decrease, while diastolic BP quickly goes down w/ meds (causes syncope)
damage to target organs MI, atherosclerosis, aortic dissection, stroke, retina/kidney changes
Secondary (about 5% of HTN)
renal (abnl BUN, creatinine, UA), renovascular, coarct, endocrine (pheochromocyt oma, Cushing's, PTH disease), drugs, obstruct sleep apnea
Malignant Hypertension
DBP > 120 mm Hg presents w/ acute pulmonary edema, renal failure, cerebral probs (blurry vision, stroke) patients present w/ acute CVA (SAH, cerebral infarction), cardiac probs (ACS, HF, acute pulm edema), aortic dissection, retinopathy, pregnancy
arteriolar effects on brain causes hemorrhage, thrombosis, or ischemia
Renal disease, accelerated mild HTN
Hypertensive Emergency
Cocaine!
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Aortic dissection proximal dissection (proximal to left subclavian a; ascending aorta)
large difference between blood pressures of each arm (but same BP in each arm does NOT R/O AD!) cold leg, tearing chest pain through the back & is maximal at onset can also present w/ stroke, MI, tamponade
in patients w/ HTN, the intima is damaged and friable (cystic medial necrosis= degenerative changes in media); high pressure/ shear force from LV tears the intima and separates it from the media, creating a false lumen
uncontrolled HTN (95%), bicuspid aortic valve, Marfan's, AMA pregnancy, Turner syndrome, coarct
cocaine, pregnancy
EKG CT w/ contrast TEE (intimal flap) CXR (wide mediastinum bc now have 2 aortic lumens --> aortic dilation)
nitroprusside (lowers BP) & beta blockers (lowers shear stress) until EMERGENCY surgery
50% of patients w/ proximal AD will die w/I 48h AR, pericardial effusion w/ tamponade bleeding into pericardium, infarct, shock
distal dissection
can only treat medically by lowering BP and dropping shear force (betablockers) heart is sheared at the ligamentum arteriosum necrosis of all layers of aorta from MMP severe back pain, other activation --> profound inflammatory vascular sx (erectile dysfunction, intermittent response (T cell & monocyte activation) claudication, lower most commonly located below renal peripheral disease) arteries (infrarenal) most patients are -aorta is exposed to deformation/ strain; ASYMPTOMATIC! increased BP = increased strain; shear stress of blood flow (viscous drag of blood PE: pulsating abdominal flow across aorta surface): low and/or mass oscillatory shear stress= disturbed blood flow = increased atherosclerosis = matrix dysregulation = accumulation/ adherence of macrophages = propagation of inflammation into media & adventitia; -increased expression of AngII receptors and VCAM-1 on abdominal aorta w/ increased disturbed flow (low or oscillatory shear stress) trauma Marfan's, syphilis, idiopathic, atherosclerosis (cholesterol + angiotensin II) 6% of individuals tobacco use, > age 70 FH, M>>>F, white middle aged men, age amputees (asymmetric reversal of blood flow) Endovascular repair (catheter based, stent material), open surgical (graft material) progressive aneurysm expansion despite tx
Aortic transection Abdominal Aortic Aneurysms (AAA)
aneurysm >5cm = increased risk of future treatments: mortality external polymer + (PERFORM doxycycline to SURGERY!!) provide mechanical risk of surgical support and inhibit repair? Damage to MMPs spinal arteries --> spinal ischemia/ paralysis
Peripheral Vascular Disease
large difference between blood pressures of each arm claudication (stress ischemia in legs; predictable pain/ tightness/ weak/ tiredness) Ankle-brachial index (abnl < 0.9 represents obstruction)
disorders of circulatory system to extremities, viscera, & head
Atherosclerosis 10 million Americans; 5% of people > 55 claudication - blood supply is limited due to have ischemia so pts have calf pain w/ exercise claudication -> rest pain --> ulceration --> gangrene --> limb loss
tobacco use, hi chol, HTN, DM, obesity, sedentary, male gender, age
Duplex US: increased stenosis & velocity; used to check intervention success CT angiography: anatomic vessel narrowing
risk factor modification, aspirin, control of DM/BP/ chol, exercise ACEI, antiplatelet (aspirin, clopidogrel) surgery: endarterectomy, bypass, thrombectomy, ligation; catheterdirected
life expectancy reduced 10 years in patients w/ PVD increased risk for death from stroke, MI decreased ABI = increased risk of mortality HEMORRHAGE w/ procedures
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Carotid Artery Disease
symptomatic? Stroke, TIA (amaurosis fugax transient monocular blindness, transient weakness)
atherosclerosis of internal carotid artery: pieces of plaque embolize and enter internal carotid artery --> brain
recent MI unstable angina uncompensate d CHF severe valvular dz (aortic stenosis)
duplex US:carotid artery bifurcation CT angiograph stenosis of carotid
symptomatic: treat/ surgery if stroke involves <1/2 or 1/3 of hemisphere; asymptomatic: operate once stroke risk > surgery risk Meds: statins, plavix, BBs
50-75% stroke --> carotid stenosis!! BP control impt for pre& postoperative status (o/w inc risk of stroke & hyperperfusion syndrome poor BBB)
shunt use if incomplete circle of surgery: carotid Willis? only if revascularization + seizure or loss of patching neuro capabilities perioperative Endarterectomy higher MI rate Stenting - higher stroke rate Coarctation radial- femoral asynchrony; distal to subclavian; pressure overload --> leg fatigue LVH apex in nl location but diff contour very little hx: decreased exercise tolerance, maybe some fatigue, some DOE sx: chronic vasodilation (warm, diaphoresis), high output state (head bobbing, neck pulsations) acute AR: shock, acute pulm edema PE: hyperkinetic carotid w/ bifid pulse; displaced apical impulse (dilated LV), early decrescendo murmur that masks S2 (longer murmur, Austin- Flint diastolic rumble, wide pulse pressure = more severe) *acute AR - nl carotid, nl apex location, diastolic murmur @ URSE, Austin Flint @ apex Turner syndrome rib notching (large intercostal artery erodes rib) HTN
Aortic regurgitation (AR)
Acute AR: sudden large regurgitant volume on nl LV = no compensation time for noncompliant LV = hi LVEDP (LV dilation) = early closure of MV = low SV = hi HR
problem w/ aortic root that Abnl regurgitation of blood from aorta to LV pulls leaflets apart (acuteoccurring during diastole (retrograde AD, aortic diastolic flow =loss of isovolumic transection; relaxation = LVVO >> LVPO) --> higher preload, somewhat higher afterload (hence chronic Marfan's, Aortic the mildly hypertrophied LV too per aneurysm, LaPlace's Law) = higher LV contractility syphilis) (SV), compliance, & wall stress DIASTOLIC PROBLEM eccentric hypertrophy (dilation/ LVEDV + some hypertrophy) - pressure in LV is much higher if dilation only, so compensates w/ mild hypertrophy Austin-Flint diastolic rumble -mid-diastole; nl MV is wide open w/ diastole but hi LVP causes MV to close sooner; distinguish from MS diastolic rumble bc NO OS or presystolic accentuation problem w/ AV leaflets (acuteendocarditis, trauma; chronic bicuspid valve, rheumatic HD, AV prolapse)
CXR: enlarged LV silhouette, enlarged aortic bump (chronic AR only); no cardiac silhouette & pulm edema (acute AR) EKG: enlarged LV (LVVO) ECHO: degree of AR (backwards diastolic flow) + cause usually Cath: rapid decrease in aortic pressure
ACUTE AR = surgical emergency!! Use vasodilators (nitroprusside; decrease afterload) while waiting CHRONIC AR = reduce afterload; surgery if symptomatic
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Aortic stenosis (AS)
subvalvular (HCM, membranous AS, narrow LVOT); supravalvular; VALVULAR
narrowing of aortic valve area < 3cm CO maintained @ rest, NOT @ exercise LVOT obst sx: angina, effort syncope (fixed orifice + vasodilation), DOE (LV failure) PE: hypokinetic carotid, hypotension (low PP), nl neck veins, nl location apex, sustained PMI, palpable S4, systolic ejection murmur,decreased aortic sound @ URSE, S4 @ apex, +/- paradoxical split
SYSTOLIC PROBLEM but DIASTOLIC DYSFXN endothelial disruption (leaflet injury from atherosclerosis calcification or wear & tear) --> entry of inflamm cells & lipids --> sclerosis --> stenosis blood flow across AV impeded during systole (inc afterload)--> LVPO--> concentric LVH --> dec compliance of LV (inc LVEDP) --> LA hypertrophy & diastolic dysfxn
increased age, bicuspid valve, rheumatic heart dz
mild AS: >1.5cm mod AS: 1.0-1.5cm severe AS: <1.0cm, mid to late systolic murmur a/w coarct in Turner's syndrome, mitral annular calcification, heart block (conduction probs), aortic diss (w/ bicuspid AV)
NO exercise stress aortic valve test! replacement (percutaneous, CXR: nl cardiac surgical) silhouette EKG: LVH NO exercise!! ECHO: thickened ventricle; abnl AV Very limited meds (tri-leaflet & calcified; bicuspid & +/- calcifcation) cath: lower AV pressure (100/80); hi LV press (200/2040)
inc LAP -> inc afterload = inc LV dysfxn = LVVO + LVPO that backtracks into pulm system = systolic HF! Mortality >90% after sx develop aortic regurgitation, Afib, endocarditis, sudden death
Mitral regurgitation (MR)
asymptomatic for years until LV dysfxn Sx: fatigue + weakness (low CO); acute MR - pulm edema PE: nl carotid (less blood but coming out faster so feels nl), nl venous system, enlarged & laterally displaced apex (LVVO = LV dilation), S3, mid-diastolic rumble, holosystolic murmur @ apex that intensifies w/ handgrip Acute MR: pulm edema, decrescendo systolic murmur, nl apical impulse, S3+S4, parasternal lift (RV dilation)
SYSTOLIC PROBLEM Retrograde systolic flow from LV to LA = hi LAP + hi LA volume = hi LV volume when blood pumped backwards returns to LV during diastole = pure LVVO (hi LVEDV, NO afterload) = loss of isovolumic contraction CHRONIC MR: Compensatory mechanisms = eccentric hypertrophy (LV dilation + some LVH) = higher compliance (LVEDV w/o LVEDP) = early effect of higher SV and EF; eventually LA dilates = prevention of hi PAP but decreases CO --> Afib +/- thrombi ACUTE MR: non-compensated LV so regurgitated blood goes all the way back towards lungs --> pulm edema
MV apparatus parts: 1. annulus (aging, HTN) 2. LV dilation (large distance from pap muscles) 3. leaflets (MVP, RHD, endocarditis, SAM in HCM) 4. chordae tendonae (trauma, endocarditis) 5. papillary muscles (MI, rupture, dilated CM)
CXR: acute MR (pulm edema), chronic MR (LV + LA enlargement) EKG: LA enlargement + LVH ECHO: MR cause + severity grade Cath: acute MR: large v wave = increased PCWP = increased LA pressure
decrease afterload, surgical repair/replacement for chronic MR acute MR: nitroprusside, EMERGENCY surgery
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Mitral stenosis (MS)
mild MS area >1.5cm; severe MS area <1.0cm
dyspnea (hi LAP = pulm venous HTN); orthopnea/ PND, acute pulmonary edema, fatigue (low CO), palpitations (Afib) PE: hypotensive, low PP (low CO), hypokinetic carotid, giant "a" wave (PAH) or big "cv" wave (TR), parasternal heave (hi RV pressure), loud S1 at aortic area (prominent MV closure sound), loud P2 +/- PR murmur (Graham-Steele - PAH), TR murmur +/- S3 (if severe), OS (after S2, tensing of chordae & stenotic leaflets w/ MV opening)/ diastolic rumble w/ presystolic accentulation @ apex
Rheumatic Heart Disease obstruction to flow from LA to LV, impeding (remember LA emptying (hi LAP) and causing impaired CANCER mneumonic; LV filling (hi LVEDP) Carditis, Arthritis, symptoms from LA distensibility (small Nodules, thick-walled LA = inceased pressure = Chorea, dilation of LA = increased volume Erythema migranatum, Rheumatic fever) DIASTOLIC PROBLEM
Pathology: fused commissures CXR: LA enlargement, interstitial edema, Kerly's B lines (pulm edema), prominent pulm arteries EKG: LA enlargement w/ possible Afib, RV hypertrophy if PAH developed Echo: thickened mitral leaflets + abnl fusion of commisures, possible intra-atrial thrombus
diuretics for HF, BB for afib, anticoagulation for afib;
afib (chronic hi LAP = LA dilation), right heart failure, thromboemboli, hoarseness if LA percutaneous gets so large it balloon valvoplasty impedes recurrent or valve laryngeal n. replacement more severe if earlier opening snap or longer diastolic rumble
Mitral Valve Prolapse (MVP)
Hx: usually asymptomatic, SYSTOLIC PROLAPSE atypical chest pain (sticks, billowing of mitral leaflets into the LA stabs), palpitations during ventricular systole due to PE: "click + murmur" (may protrusion of enlarged/thickened valve be absent)= mid-systolic leaflets (esp the posterior leaflet) OR click (leaflets popping back) thin/elongated chordae tendonae that DYNAMIC auscultations: fail to keep leaflets in apposition when pregnancy, handgrip, cavity is reduced during ejection squatting increase LV cavity = later/shorter LV needs to be large for chordae to match murmur; Valsalva, (since elongated in MVP); therefore, increased LV cavity (maneuvers like standing = decrease LV squatting, handgrip) has less mitral cavity = earlier/longer regurgitation murmur; pectus excavatum
familial type due 2-4% of women to Marfan's syndrome or CTD (Ehler'sDanlos)
ECHO: posterior displacement of one or both mitral leaflets during systole
95% are benign so endocarditis, progressive MR, reassurance!! fibrin emboli to eye/brain (abnl If symptomatic, use beta-blockers leaflets can collect microthrombi), arrythmias, if severe MR (uncommon), valve spontaneous chordae tear repair preferred over replacement Men over age 45 have increased risk for thickened leaflets & MR
Tricuspid Regurgitation
PE: "cv" regurgitant wave, parasternal heave (RV dilation), holosystolic murmur that increases w/ inspiration @ tricuspid area; S3 or mid-diastolic rumble if severe
acute - infective endocarditis; chronic - RHD, carcinoid syndrome pulmonary hypertension from MS or RHF
Tricuspid Stenosis
PE: giant "a" wave, diastolic rumble that increases w/ inspiration at tricuspid area, OS at tricuspid area
RHD, carcinoid syndrome, RA myxoma
extremely rare!
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Pulmonic Stenosis
PE: giant "a" wave, parasternal lift, soft P2/ES that increases with inspiration, systolic murmur @ pulmonic listening area PE: hi pitched diastolic blowing murmur sustained apical impulse normal placed PMI palpable S2 (presystolic component)
congenital (Tetralogy of Fallot), carcinoid syndrome
Pulmonary Regurgitation Left ventricular hypertrophy
severe PAH, congenital increased pressure overload on LV causes HTN increased wall thickness and decreased LV AS cavity HOCM coarctation Pregnancy, exercise (nl)
Diastolic dysfunction (thick ventricle walls = decreased compliance = small cavity = decreased filling during diastole!) myocardial ischemia (decreased coronary blood flow) systolic dysfunction (late! Due to narrowed pulse pressure)
Peripartum cardio-myopathy (PPCM)
No pre-existing heart disease; presentation during last month or postpartum cough, dyspnea, fatigue PE: JVD, tachycardia, S3/S4, +/- edema
postpartum thyroiditis
1/3000-4000 pregnancies
AMA, ECHO multiparity, CXR multiple thyroid panel gestations, obesity, HTN/ pre-eclampsia, tocolysis w/ bagonists
standard heart highest mortality in failure mgmt; anti- 1st 3 months coagulation until pregnancy ends LV thrombi (1/8 risk) --> stroke
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Acute Pericarditis
Serous (scant cells; early acute inflammatory pericarditis) Fibrinous (plasma proteins + thickened/ fused visceral & parietal pericardium;TB/ chronic inflamm) Purulent (uncommon, bacterial inf) Hemorrhagic (bloody pericardial inflamm due to TB, aortic dissection, tumor, trauma, uremia)
Pain is worsened w/ position (lying down)/ expiration/ swallowing pericardial rub + soft heart sounds pain relieved by leaning forward
inflammation has 3 outcomes: 1. local vasodilation & transudation of serous fluid 2. increased vascular permeability (protein spills into pericardial fluid) 3. Leukocyte exudation (neutrophils, mononuclear cells) post-MI pericarditis: 1. early onset (<1wk post-MI) - inflamm from infarction spreads/extends into pericardium 2. Dressler syndrome (>2wks post-MI) antigens from dying myocytes = activated autoimmune reseponse = inflammation of pericardium
ATRIUM (A = AIDS/ Autoimmune dz, T = tumor/ trauma/ TB; R = Radiation/ rheumatic fever; I = idiopathic/ inf/ infarct; U = uremia from renal failure; M = meds)
EKG: diffuse ST elevation that disappear as patient recovers; diffuse T abnl that persist for some time ECHO: +/pericardial effusion
post-MI pericarditis (tx w/ hi dose aspirin) NSAIDS, colchicine if chronic pericarditis
Pericardial effusion
Symptomatic - accumulate lots of fluid quickly under hi press (chest trauma); asymptomatic - accumulate fluid slowly so that pericardium stretches w/o marked increase in pressure
Silent or symptomatic? 1. volume of fluid 2. rate of fluid accumulation 3. compliance of pericardium
idiopathic, malignancies, radiation, viral causes, TB
Fluid analysis to R/O malignancy TTE: pericardial collections (quantifies volume of fluid, determines if ventricular filling is impaired, & guides pericardiocentesis)
treat underlying disorder (dialysis for uremia) Observe asymptomatic effusions pericardiocentesis for therapeutic drainage & analysis
Increased capillary permeability (hypothyroidism), increased capillary hydrostatic pressure (HF; lymphatics are unable to handle extra fluid), or decreased muffled heart sounds, plasma oncotic pressure (nephrotic reduced intensity friction syndrome - low blood proteins) = abnormal rub, Ewart sign (dullness to fluid in the pericardium = increased percussion over posterior pressure in a non-distensible sac --> left lung by scapula) enormous compression force on the heart (cardiac tamponade)
EKG: electrical alternans (QRS pericardial window complex height procedure varies from beat to beat)
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Cardiac tamponade
CC: breathlessness (decreased CO & max increased EDPs = increased press in alveoli); low output state (shocklike), hypotension, tachycardia BECK'S TRIAD: Hypotension, increased JVP (elevated venous pressure; deep "x", flat "y" - decreased filling of ventricles), muffled heart sounds pulsus paradoxus (decreased systolic BP of >10 w/ inspiration)
pericardial fluid under acute increased pressure compresses the heart continously through cardiac cycle, limiting ventricular filling --> increased venous pressure to compensate for decreased filling --> equalization of diastolic pressures to intrapericardial pressure (IPP=LVEDP= LAP = PCWP=PAP=RVEDP=RAP)
any cause of acute pericarditis can progress to tamponade (ATRIUM); acute hemorrhage (acute ascending aortic dissection, blunt trauma, LV rupture)
TTE: smaller, compressed, & collapsed RV during diastole catheterization = gold standard
Pericardiocentesis; pericardial window procedure (removal of pericardium allowing fluid to drain freely into mediastinum * absorbed by lymphatics; simultaneous bx)
life-threatening emergency!! (if worsens, there is no filling during diastole = zero CO = pulseless arrest)
Constrictive pericarditis
deep Y descent; pressures are equalized & elevated (LVEDP = PCWP = PAP= RVEDP = RAP) cirrhotic appearance (ankle/leg edema, ascites, hepatomegaly); tachycardia, hypotension, decreased pulse pressure, inc CVP, Kussmaul (inc JVP w/ inspiration), difficult to find PMI, early to mid diastole knock
physiologic abnormalities during diastole; rigid/ scarred pericardium prevents normal mid-late filling of cardiac chambers (early filling only!) --> filling is arrested --> increased systemic venous perssure & signs of RHF; impaired filling of LV = reduced SV & CO = hypotension
chronic changes from inflammation; idiopathic pericarditis (postviral); radiation, TB, RA, bacterial inf
Pathology: pericardial pericardium stripping surgery becomes immovable shell w/ fused/ thick layers from chronic inflamm CXR: calcified pericardium Catheterization: elevation & equalization of pressures, dip & plateau in early diastole, y descent in RA, discordance in RV & LV pressures w. inspiration
can have effusiveconstrictive pericarditis (tamponade physiology --> effusion drainage -> constriction physiology)
Arteriosclerosis
Medial calcific sclerosis
affects arteries of lower extremities and genitalia; does NOT produce ischemia Arteriolo-sclerosis disorders of small arterioles, particularly in the kidney
calcification of the tunica media, the muscular coat of the artery
intermittent episodes of HTN? marker of HTN; common in diabetes
age > 40-50
thickening of the arteriole wall that results in some degree of ischemia
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Atherosclerosis
vulnerable, hi risk plaques? Large extracellular lipid content, thin fibrous cap, high content of inflammatory cells (lymph/monocytes)
accumulation of lipid, inflammatory cells, & ECM (collagen) in the arterial intima (large & muscular arteries at bends, branches)
localized flow abnl --> turbulent flow in arterial system --> endothelial dysfxn--> increased ROS production, decreased NO production --> increased permeability of Stable plaque? Smaller lipid lipids & inflamm cells,expression of VCAM core, larger fibrous cellular Monocytes --> macrophages in the tissue by M-CSF; macrophages have scavenger matrix, less inflammation receptors that internalize LDL --> foam renal arteries often spared! cells, LDL is oxidized to cholesterol & cholesteryl esters; foam cells die, releasing cytokines and leaving cholesterol crystals, which stimulate collagen & plaque formation; cytokines are fibrogenic so increases ECM secretion (collagen) --> plaque formation
fatty streaks seen in 50% of teens and >85% of people over age 20
localized flow abnl, increased LDL, HTN, smoking, diabetes (all increase ROS and decrease NO) age male gender
pathology: gross large arteries (yellow spots = foam cells; fatty streaks; friable cracks/ fissures) histology: clear cells in intima (fatty streaks - early lesions), bubbly foam cells; histiocyte giant cells surround cholesterol crystals; new matrix being deposited; muscular arteries fibrous cap & lipid pool (stable v. unstable plaques) stress test: ST depression (ischemia) & area of ischemia (suggests anatomic stenosis) Resting EKG CT angiography Cardiac cath if + stress test histology: increased proliferative SMCs and fibrous tissue; does not look vulnerable bc lipid core is far from lumen & thick fibrous cap Lifestyle modification, PCI, CABG, medical therapy PCI if intolerable angina despite maximal med tx & anatomy that doesn't require CABG; older ptshi risk for CABG
myocardial ischemia, claudication; sites for thrombus development (mural thrombus in aorta common in HTN, smoking men); abdominal aortic aneurysm if top of plaque ruptures, lipids are released into circulation and activate thrombosis --> ischemia, MI other complications if embolization of plaque material MI @ sites of unremarkable lesions single occlusion = diffuse disease CABG decreases risk for rpt interventions
Chronic Stable Stable Angina Coronary Artery pectoris Disease
chest/ jaw discomfort provoked by exercise that lasts 4-5mins; stable sx & predictable onset; no sx at rest PE: during angina, you might hear a new S4, S3, or paradoxically split S2; MR; abnl PMI (if LV dysfxn); elevated JVP (if RV dysfxn) asymptomatic often in women & diabetics; infarct risk does NOT correlate w/ amt of occlusion!; reduced blood flow does not cause cells to die like in MI! --> instead, dysfunctional myocytes
reduced perfusion from chronic stenosis; ischemia results from increased oxygen demand (exertion) but disappears w/ rest in a predictable fashion >75% stenosis usually but no plaque disruption or thrombus formation Unlikely to rupture: thick fibrous cap, less inflammatory cells, lots SMCs, intact endothelium
AS
high LDL, low HDL, FH, waist circumference (W>35; M>40), smoking, HTN, prior known CAD
Prinzmetal angina uncommon, episodic, occurs at rest
coronary artery vasospasm, not much atherosclerosis & no thrombus/plaque formation
no diff btwn PCI & med w/ # MIs; CABG if left main no diff btwn PCI & coronary narrowing CABG for pt (>50%) or 3 vessel survival CAD MI, CHF, Meds: increase life arrythmias, valve (BBs, statins, dysfxn, LV aspirin); reduce sx thrombus, by dec O2 demand myocardial rupture (BBs, CCBs, nitrates)
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Unstable angina pectoris
variable progressively worse sx & frequent plaque rupture with thrombus formation; partially occlusive thrombus stenosis pain more frequent/intense w/ less starts as lumen compression w/ little lipid exertion core but grows with lipid deposit increasing persistent, unrelenting pain -->thin fibrous cap-->subject to rupture--> thrombus formation--> vulnerable plaque for several hours (due to contributing to MI, sudden death rupture plaque) Rupture? thin fibrous cap, increased inflammatory cells, fewer SMCs, large lipid deposits, eroded endothelium
Ischemic Heart (General) disease (also includes angina but see above)
Transmural MI
atherosclerotic CAD (90%), coronary artery heart perfused by coronary arteries vasospasm from outside --> inside (cocaine), coronary artery emboli; exacerbations myocardial hypertrophy, shock, anemia, tachycardia entire thickness of disruption of variabe stenosis but unstable plaque ventricular wall affected by with disruption & consequent occlusive endothelium the MI thrombus forming on the plaque --> atheromyocardial wall damage chest pain, weak rapid sclerosis pulse, dyspnea, 1. disruption of plaque diaphoresis 2. fissure/cracking of plaque exposes non-atheroscl thrombogenic areas (collagen, vWF, FN) causes: 3. platelets adhere, becoming activated arrythmia, and aggregated coronary art 4. coagulation cascade is activated vasospasm, (fibronogen --> fibrin via thrombin) coronary art 5. occlusive thrombus forms emboli, anemia, 6. downstream ischemia --> depletion of hypotension, ATP --> loss of contractility --> irreversible CABG, coronary cell injury (20-40min; not all cells affected stent thrombosis equally - epicenter cells > peripheral cells) -> microvascular injury (>1h) imbalance of O2 supply and demand NSTEMI: partial occlusion STEMI: complete occlusion
500,000 deaths/yr in U.S; 250,000 die before reaching hospital
DM, HTN, smoking, lipidemia, age (although 10% of MI in age<40)
most common MI
6am-11am (catecholamine s are highest and platelets stickiest!)
EKG: deep Q waves; ST abnl (STEMI, NSTEMI)
prognosis depends on infarct size, site, extent; quality of LV fxn, extent of labs: elevated CK- vascular disease, mb & troponin I/ T ability to perfuse viable myocardium 0-12h no changes; 24h (dark mottling; first medical coag necrosis contact time to loss of nuclei) balloon! 1-3d (mottling w/ yellow center; neutrophils) 3-10d (red border, yellow center/ neutrophils & macrophages) 14d (red-gray/ granulation tissue) >3m (scar)
30% overall mortality- 1st year RV infarction infarct extension new necrosis next to the infarct region; infarct expansion dilation of infarct region; contractile dysfxn, arrythmias, pericarditis, myocardial rupture (highest risk 4-7 days post-MI; most often at vent free wall, also vent septum - L-R shunt& papillary muscle acute MR), vent aneurysm, mural thrombus, pap muscle dysfxn, late CHF
Subendocardial MI
most susceptible to ischemia bc farthest away
ischemic cardiomyopathy
variable stenosis, variable plaque disruption causes partially occlusive thrombus that damages the subendocardium but not the areas closest to blood supply progressive heart failure ischemic myocardial damage from due to ischemic myocardial coronary artery disease (atherosclerosis) damage or previous MI --> enlarged LV (hypertrophic, dilated) --> lack of perfusion -> heart remodeling
EKG: do not always elicit changes; non-Qwave MI elderly patients
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Sudden death
unexpected death from severe stenosis with frequent plaque cardiac cause early after or disruption and large occlusive thrombus --> w/o onset of sx fibrotic scarred myocardium that cannot conduct electricity efficiently
lethal arrhythmia; nonatheroscl causes (congenital abnl, AS, MVP, myocarditis, dilated CM, hypertrophic CM, PH, conduction abnl, isolated hypertrophy) secondary causes? Diabetes, hypothyroidism, liver dz, kidney dz, progestins/ steroid drugs DIET, genetic errors of metabolism, metabolic causes (insulin resistance pre diabetes; hypothyroidism hormones), drug side effects, smoking low triglyceride diet nutrition referral increased LDL:HDL predicts higher risk for CV event
Dyslipidemia
(General)
Familial Hyperhigh fasting triglyceride chylomicronemia levels and low LDL levels pediatric presentation w/ chronic abdominal pain (pancreatitis), hepatomegaly, xanthomas Familial Hypercholesterolemia abnl high LDL (heterozygote LDL > 200; homozygotes LDL > 500) cutaneous manifestations (xanthelasma, corneal arcus, thickened Achille's) premature vascular dz
defect in LPL or its cofactor apoC-II so autosomal 1 in 1 million kids cannot break down chylomicrons (>90% of recessive TGs) mutation in LPL gene or ApoC-II gene
defects in LDLR so LDL is not taken up by the liver; instead, LDL remains exceedingly high in the bloodstream; more LDL in circulation = more LDL that is able to pass through endothelium into the intimal layer of arterial wall --> atherosclerosis
autosomal dominant mutation in LDLR
1 in 500
homozygous FH patients have more severe risk & dz (little or no LDLR)
no specific mutation testing but cascade genetic testing for family risk assessment impt
aggressive + early increased risk for tx (combo therapy CV event even at young age of statin + cholesterol absorption inhibitor); niacin; LDL apheresis
Vasculitis
(General)
can affect the skin (purpuric, non-blanching papules/macules), lung (hemoptysis), GI (bloody stools, melena), renal (hematuria)
inflammatory damage to the blood vessels, secondary resulting in hemorrhage (extravasation of causes (meds, RBCs) & possibly ischemia if damage to infections) larger vessels skin is the most commonly affected site
autoimmune dz (SLE, RA, dermatomyositis), meds/toxins, infections
Histology: fibrinoid necrosis & leukocytoclastic vasculitis (neutrophils!)
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Cutaneous vasculitis
purpuric lesions, nonblanching, ulceration/ necrosis seen sometimes (vascular damage & ischemia) lower legs = primary site
lower extremity vasculitis from blood & extravasated erythrocytes that infiltrated the tissue
Giant cell (temporal) arteritis
Large vessel vasculitis scalp pain/tenderness distributed along temporal artery, visual disturbances/blindness (if opthalmic a involved), polymyalgia rheumatica in upper neck/shoulders "hunched over elderly person w/ lateral headache"
not well understood
elderly patients (>60 y.o.), females 3:1
histology (hi false positive rate): NO NEUTROPHILS, mostly histiocytes & lymphocytes granulomas, destruction of internal elastic lamina & narrowing of vascular lumen, eosinophilic line
high dose corticosteroids for months (reduce inflammation and prevent subsequent sequelae)
Elevated ESR/CRP
Takayasu arteritis Large vessel vasculitis (aorta & subclavian a) Pulseless disease, low blood pressure, ocular disturbances, carotid tenderness
aorta & major branches become inflamed w/ granulomatous infiltrates so arteries do not distend or carry pulse wave
more common in Asia, patients < 40 y.o., Females 7:1
histology: NO NEUTROPHILS, mostly histiocytes & lymphocytes granulomas (cannot be distinguished from temporal arteritis histologically) Elevated ESR
unpredictable course: rapid progression + quiescent stages
polyarteritis nodosa (PAN)
medium vessel vasculitis systemic sx (fever, weight loss, HTN, abdominal pain/ melena, neuropathy, myalgias, purpuric skin lesions), NO lung involvement
not well understood
HepB
elevated BUN or creatinine, HepB antigen, ANCA negative histology: necrotizing vasculitis of medium sized vessels
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Kawasaki disease medium vessel vasculitis multisystemic sx (polymorphous skin eruption, erythema of conjunctiva/oral mucosa/tongue "strawberry tongue", cervical lymphadenopathy, edema in hands/feet, desquamation of fingertips/toes) CV INVOLVEMENT! (myocarditis --> CHF, coronary vasculitis --> ischemic dz/infarct, aneurysms) Wegener's granulomatosis small vessel vasculitis ELK: Ear/nose/throat (URI, saddle nose deformity), Lung (cough, hemoptysis, cavitary necrotizing lesions), Kidney involvement (hematuria, proteinuria) other multisystemic manifestations? Cutaneous, middle ear, peripheral nerves, CNS, ocular, oral cavity (midline destructive lesions)
not well understood
may be a/w strep/ staph infection
pediatric presentation
anti-endothelial antibodies ANCA negative
IV IgG and aspirin to reduce inflammation and avoid sequelae
approximately 50% of cases will have CV involvement lifelong risk for coronary artery aneurysm MI in kids!!
not well understood
middle aged; males 3:2
pathology: cavitary lesion in lung UA: hematuria, red cell cast in urine c-ANCA positive (proteinase-3) histology: vasculitis w/ necrotizing granulomatous inflammation
Allergic granulomatosis (Churg-Strauss)
small vessel vasculitis Multisystemic disorder (fever, cardiac involvement - arrythmia, ventricular insufficiency, coronary arteritis, peri/myocarditis), pulmonary infiltrates (noncavitating), renal glomerulonephritis)
not well understood
Young adults; M>F
history of asthma or allergic rhinitis
peripheral eosinophilia, elevated ESR p-ANCA positive histology: vasculitis w/ necrotizing granulomatous inflammation & abundant eosinophils, involves dermis & subcutis (cutaneous only involves superficial layers)
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
HenochSchonlein purpura
small vessel vasculitis Multisystemic disorder (cutaneous purpura w/ leukocytoclastic vasculitis, abdominal pain - bloody stools, melena; arthalgias, renal glomerulonephritis)
not well understood
possibly children <10 infection or drug y.o., M>F related
Immunoflourescenc e: IgA deposition in vessel walls ANCA negative UA: hematuria, proteinuria histology: leukocytoclastic vasculitis of superficial skin (not specific)
Microscopic polyangitis
small vessel vasculitis diagnosis of exclusion (overlaps w/ PAN) Multisystemic vasculitis (cutaneous purpura, abdominal pain, pulmonary involvement!!! - hemoptysis, intrapulmonary hemorrhage, renal glomerulonephritis, myalgias) pulmonary involvement distinguishes from PAN
not well understood
possibly Adults infection related (strep), drug related?
Elevated ESR, anemia, renal failure UA: hematuria, proteinuria p-ANCA or cANCA positive
Cocaineassociated vasculitis
ear vasculitis
COCAINE contaminant (levamisole)
elevated serologies common in cocaine abuse (antihistones, c-ANCA & p-ANCA, dsDNA) - human neutrophil elastase cross reacts w/ ANCA impt to do urine drug screen!! Histology: leukocytoclastic vasculitis, focal thrombosis
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Heart failure
(General) 3 characteristic sx: 1. impaired CO (weak pump) 2. venous congestion 3. overall fluid retention def: inability of heart to pump blood forward to meet metabolic oxygenation demand of tissues while maintaining nl filling pressures backwards!
dyspnea, orthopnea, PND, PM dry cough; stomach/ liver congestion (early satiety, anorexia, n/v), edema (ascites, pulm edema, periph edema); cold extremities (inc catecholamines= vasoconstriction = low CO); tachycardia/pneic PE: JVD (inc cardiac filling pressures & volume); rales (basilar; acute CHF); pleural effusions (chronic CHF); distended abdomen/ hepatomegaly; peripheral edema; S3, displaced PMI, MR (if severe dilation)
acute HF: no compensatory changes from body yet so cardiac output =/= peripheral tissue metabolic demand; elevated SVR (vasoconstriction; "cold") & LVEDP (inc afterload; decreased filling of LV; PCWP > 18); expanded plasma volume ("wet"); "noisy" - no lymphatic compensation=fluid leaks into alveoli (PE, rales, increased RR, dyspnea) chronic HF: "silent" - compensatory mech (inc colloid pressure = enhanced lymphatics so no rales! retain more salt = renal failure) = maintained CO, SV but inc LVEDP; <3remodeling! Right sided HF: inc RA pressure (>10 mm Hg); a/w sleep apnea, COPD, cor pulmonale, PE, severe pulmonary hypertension, left HF Left sided HF: inc LVEDP due to intrinsic LH dz; sx of lung congestion (not so much peripheral) & low CO (cold, clammy extemities, low urine output) impaired contractility, volume overload (increased sodium = inc total body water), & pulm congestion
Ischemic cardiomyopathy (atherosclerosis! !) hi CO conditions ("warm, wet"): hyperthyroidism, anemia, AV fistula, Paget's, Beri-Beri low CO conditions ("cold, wet"): valvular dz, dilated CMP, HTN, CAD
5 million Americans have CHF, 1 million hospitalizations/ yr
CXR: cardiomegaly if chronic HF (cardiac remodeling) Elevated BNP (nl <100)
development of kidney failure (nl creatinine = 1) most impt negative prognostic factor! Afib (atria become inflamed/scarred/ dilated) - use cardioversion!
Systolic heart failure
reduced EF (LVEF < 4050%) = impaired contractility w/ progressive dilation & eccentric remodeling Almost all pts w/ systolic dysfxn have comcomitant diastolic dysfxn (impaired relaxation)
CAD, HTN, dilated CMP, valvular dysfxn thin walled, dilated ventricle
triad of meds (carvedilol - BB; lisinopril, spironolactone) decrease afterload = improved SV = less ischemia; = reduced preload = reduced remodeling increased prevalence w/ age requires clinical evidence of impaired RV relaxation or LV passive stiffness: no treatment, just symptom relief presence of symptoms = worse prognosis high comorbidity burden (usually elderly patients w/ dHF) majority of dHF patients die from non-cardiac causes
Diastolic heart failure
impaired relaxation = elevated LVEDP; nl LV volume, concentric remodeling, EF > 50%
diastolic dysfxn (abnl distensibility, relaxation, or filling of LV) + signs/symptoms of HF
hypertensive CMP, HOCM, amyloidosis hypertrophied, enlarged, thickened cardiac myocytes
Abnormalites in LV diastolic dysfxn? can be just as symptomatic slowed/delayed/incomplete relaxation; decreased early diastolic suction/recoil; as sHF if patients have mod-severe diastolic dysfxn increased LA pressure during early filling; shift of filling from early to late diastole; impaired rate/extent of LV filling; inability to augment relaxation w/ exercise; increased LVEDP, LAEDP, PVEDP at rest/exercise w/ diastolic dysfxn, filling is impaired bc ventricle doesn't relax; therefore, early rapid filling phase is delayed and need compensation by atrial contraction (atrial kick)
be careful w/ diuretics (pts have small/ stiff LVs so elevated BNP diuretics can CXR: pulm edema cause LV ECHO: R/O other underfilling --> causes for hypotension, impaired LV filling; syncope, falls!) shows LA enlargement, nl EF control BP, ventricular rate & heart cath = gold rhythm std but invasive; use ECHO instead
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Heart failure w/ normal EF (HFnEF)
60% of HF patients have nl EF
Cardiomyopathies
(General)
any disease of the heart muscle, leading to decreased fxn
asymptomatic diastolic dysfunction increased age (ventricular filling) associated w/ restrictive (age has a CM, HCM, infiltrative CM greater impact on ventricular filling than on diastolic dysfxn = abnl diastolic distensibility, relaxation, or filling of LV EF or systolic fxn) Acquired (CAD, HTN, valvular, viral, alcohol, chemo, peripartum, infiltrative); genetic (hypertrophic, dilated, arrythymogenic, restrictive, noncompaction)
elderly women w/ HTN, DM, or both, CAD, Afib
Hypertensive cardiomyopathy
dilated, thick heart on ECHO increased diastolic pressure (>85 or 90) dilated LV (nl 4-5cm) causes poor systolic fxn (can barely contract) PE: displaced PMI, S3
african americans
Familial dilated cardiomyopathy
autosomal dominant mutation in myosin heavy chain or troponin T
younger age (20- multiple family genetic testing 30s) members affected
CHF tx (BB, ACEI, CHF, arrhythmias diuretics) (ventricular tachycardia) ICD (internal cardiac defibrillator to prevent SCD) LVAD or transplant if unresponsive to meds
Arrhythmogenic Right Ventricle Cardiomyopathy (ARVC)
autosomal dominant mutation in desmoplakin, plakophilin-2, desmoglein-2 dilated and poorly fxning RV; fibro-fatty replacement of myocardium
1 per 1000-2500 clustering of cases in Veneto region of Italy
genetic testing ECHO: dilated RV EKG: epsilon waves in ST segment (delayed depolarization) aneurysms of RV wall on cardiac MRI, angiogram pathology: buildup of scar tissue; white and yellow fibrosis (RV muscle replaced w/ fibrotic tissue)
SCD Ventricular tachycardia
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Restrictive cardiomyopathy
sx of CHF (dyspnea, volume overload, edema) very difficult to distinguish from pericardial constriction
non-dilated, non-hypertrophied LV w/ advanced diastolic dysfxn (thin walled, stiff ventricle that can't relax during diastole) stiffness in ventricle causes chronically elevated atrial pressures (dilated atria)
idiopathic infiltrative dz (amyloid, sarcoid) prior radiation
ECHO: huge, thin dilated atria w/ normal appearing ventricles and normal systolic function
Left Ventricle Noncompaction
decreased LV function, increased LV dilation
Embryological problem where the LV wall variable genetics, is not compacted properly so has appearance of crypts, recesses, craters sporadic (similar to RV) rather than being smooth (like normal LV) sarcomeric mutations but also other nonsarcomeric mutations implicated
increased risk for LV dilation, CHF, thromboembolic events
Hypertrophic Cardiomyopathy
most common of all genetic cardiac dz LV thickening (appears later in life) heterogenous hypertrophy (interventricular septum; septal base, ventricle, apex) Sx: dyspnea, angina, syncope (drop in BP, VT, SAM) PE: holosystolic murmur (MR;from obst of MV) that worsens w/ squatting--> standing, valsava, handgrip; S4 (atrial kick against stiff ventricle); bisferiens pulse
autosomal dominant sarcomeric mutation (B-myosin heavy chain, myosin binding protein C, troponin T) that causes LV hypertrophy in absence of another identifiable cause
LVOT obstruction SAM associatd MR (systolic anterior motion of MV)
1 in 500 adults
family history of HCM/SCD
Increased LV pressure (higher than aortic pressure) during systole sucks MV in Diastolic obstructing the LVOT dysfunction squatting--> standing makes murmur worse (decreased preload = less venous return = LV cavity shrinks = smaller distance btwn MV and septum = worsened obstruction); valsalva increases intrathoracic pressure = decreased preload = smaller LV cavity = worse obstruction bisfeirens pulse (early rapid ejection of blood from ventricle followed by MV obstruction; LV overcomes obst so late ejection of blood)
histology:collagen, myocyte disarray EKG: Brockenbrough's sign (PVC --> press gradient --> aortic press drop), tall QRS, invert T ECHO: thick LV wall w/ nl systolic fxn; SAM of MV; aortic midsystolic notching (late ejection from obst) Doppler: turbulent flow (MV obstruction in LVOT), possible MR (MV pulled open in systole) Pathology: calloused IVS from MV hitting
HR,(-) inotropy (BB, CCBs,disopyramide)
most common cause of SCD in athletes! (especially if surgical myectomy- intramural scarring -> Vtach) remove part of septum= widen MVseptum gap; Increased collagen alcohol septal = increased ablation- induce MI arrhythmia risk in basal septum= fibrosis/shrinking) ICD: indicated if aborted SCD or sustained VT; 2+ risk factors (FH, unexplained syncope, wall thickness >30mm, abnl BP drop, nonsustained VT
Non-neoplastic Thrombi Cardiac masses
most common masses in nonbacterial thrombotic endocarditis - fibrin- MI, DVT composed thrombi on valves that do NOT heart! destroy the normal anatomic structure of valve post-MI thrombus, paradoxical embolus (thrombus from a DVT enters systemic circulation via PFO)
hypercoagulable states; Afib (or other rhythm disorders)
Tuberculoma
normally TB will affect the pericardium but there is potential for it to appear as a myocardial lesion
Infective endocarditis
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Primary cardiac tumors
(General)
diagnosis often dependent anatomic site? Mostly atria (due to on anatomic location myxomas - most common cardiac tumor) (pericardium, myocardium, endocardium) majority are benign (due to myxomas) clinical manifestations: most common pediatric cardiac tumor? impaired cardiac fxn, fever, Rhabdomyoma inc ESR, emboli most common malignant cardiac tumor? Angiosarcoma
very rare
delayed dx bc mimic many dz that impair cardiac fxn
Cardiac myxomas most common primary tumor found most commonly in LA possible MV dysfunction; usually solitary (if multiple, could be syndromic association); systemic manifestations (fever, malaise, ESR)
cytokine associated (IL6)
10% are inherited (multiple myxomas think Carney complex/ NAME/ LAMB see below)
macroscopic: pedunculated (move w/ position, pressure) or sessile (no movement), can be bilateral/ multiple (more likely to be syndromic), +/calcifications microscopic: myxoid (gelatinous) matrix, variable cellularity, mucinsecreting cells
embolus (stroke, GI infarct, distal toe/finger infarct)
Carney/LAMB/NAME genetic syndromes w/ myxomas
autosomal dominant mutation that results in cardiac myxomas(multiples), cutaneous myxomas (multiple papules around eyes), lentigenes (freckle like lesions - different from sun induced bc occur also in axilla, etc), melanotic schwannomas (neural tumors), blue nevi, endocrine d/o (Cushings, etc), breast & testicular disorders
genetic
FH
differentiate from other lentigenescausing syndromes: LEOPARD - no cardiac myxomas w/ this syndrome: lentigenes, EKG abnormalities, ocular hypertelorism, pulmonary stenosis, gonadal hypoplasia, retarded growth,deafness
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
cardiac rhabdomyomas
most common pediatric tumors involves the ventricles; usually multiple; clinical features depend on size of tumor; spontaneous remission often; a/w tuberous sclerosis (autosomal dom neurocutaneous syndrome w/ CNS tumors/seizures, rhabdomyomas of heart, mental impairment, cutaneous lesoins, renal tmors)
can occur spontaneously but often caused tuberous by tuberous sclerosis sclerosis
macroscopic: circumscribed ventricular mass (not encapsulated), white-yellow & waxy appearing
Primary cardiac sarcomas 1. angiosarcoma 2. pleomorphic undifferentiated sarcoma 3. rhabdomyosarcoma
malignant! vague sx (dyspnea, chest pain, tamponade, palpitations), usually in atria Angiosarcoma = most common cardiac sarcoma; infiltrative mass in RA , early mets (usually lungs); 3m survival pleomorphic undiff sarcoma: = cell origin is unknown, occurs in atrium (commonly posterior wall), low survival Rhabdomyosarcoma = atrial & ventricular lesions, mimics atrial myxoma, mean ages affected 2030s; survival 1.5-6m
mean age around 40 y.o., M=F; rare to see childhood sarcomas
Macroscopic: angiosarcoma (violaceous/ reddish purple color - blood forming tumor) microscopic: rhabdomyosarcoma has rhabdomyoblast (eccentric nuclei + eosinophilic cytoplasm)
resection is not curative
most of the time, the sarcoma is confined to the heart bc low survival (pts dont survive long enough for metastasis) angiosarcomas have early metstasis (lungs, vertebrae, liver brain) mean survival 7m2y
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Metastatic tumors clinically uncommon, Lymphatic spread: epithelial tumors, to heart usually incidental finding melanoma on autopsy hematogenous spread: sarcomas, melanoma, renal cell carcinoma usually involve pericardium direct extension: mediastinal tumors sx: dyspnea, pleural/ intracavitary extension to IVC or RA pericardial effusions (direct extension): hepatocellular (breast/ lung ca), arrhythmias, outflow obst, carcinoma, renal cell carcinoma, adrenal tumors, uterine tumors ischemic disease (tumor emboli), pericarditis melanomas --> myocardium multiple melanoma mets lung, breast --> pericardium (hence + new heart finding - think pericardial effusions), sometimes myocardium cardiac metastasis sarcomas --> myocardium, sometimes hx of lung/breast cancer pericardium + pericardial effusion or leukemia/lymphoma --> anywhere pericarditis - think cardiac squamous cell carcinoma --> endocardium metastasis Pulmonary stenosis Deep vein thrombosis LEOPARD syndrome Virchow's Triad: Venous stasis + venous stasis- 2 million/yr immobilization, Intimal (endothelial) injury + other (age>40, Hypercoagulable state varicose veins, Wells' Clinical Prediction Rule for DVT: severe COPD, anesthesia, MI, active cancer (rx<6m) = 1 obesity) leg paralysis/ immob = 1 endothel injbedridden >3d from surgery = 1 surgery, gen local tenderness along deep veins = 1 inflamm, prior unilateral swelling (>3cm), pitting = 1 DVT, central collateral superficial veins = 1 line, trauma, alternative dx more likely = -2 **High risk (>3pts), mod risk (1-2pts), low major venous surgery, risk (<1pt) smoking; hypercoag cancer, hi estrogen, IBD, sepsis, blood transfus, HIT, primary thrombophilias
highly metastatic cancers? Melanoma intermediate metastatic cancers? Breast & lung cancers, RCC, leukemia/ lymphoma, sarcomas low metastatic cancers? Prostate, GI, hepatocellular, pancreatic, ovarian
often asymptomatic unilateral calf swelling (large clots overwhelm lymphatics); calf tenderness, positive Homan's sign (inflamed venous wall), venous cords
pregnancy, male gender, African Americans
High Wells' score? D-dimer (if nl, no further testing but 3m f/u; if abnl US); US (if nl - 3m f/u; if abnl - treat + 3m f/u)
immediated LMWH or heparin, overlap with oral anticoagulation (coumadin), IVC filter (if cannot take anticoag)
chronic swelling, pain, skin ulceration, recurrent episodes of DVT, pulmonary emboli!
Disease
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Pulmonary embolism
dyspnea, pleuritic chest pain, cough, apprehension, syncope, rales/crackles, tachycardia, diaphoresis/ hemoptysis (if severe!)
acute RV afterload increased (dilation, ischemia, RV dysfxn) --> increased RV volume --> decreased LV distensibility --> decreased LV preload --> dec CO hemodynamic response determined by: 1. amt of vasculature occluded 2. underlying cardiopulm status 3. neurohormonal adaptations (make PE worse!!) Wells' clinical pred for PE: Sx of DVT (3), other dx less likely than PE (3), HR> 100bpm (1.5), immob/ surgery past 4wks (1.5), previous DVT/PE (1.5), hemoptysis (1), malignancy (1) - score 4+ intermediate to hi risk; score <4 intermediate to low risk
pulmonary artery obstruction;Chro nic pulmonary hypertension w/ recurrent emboli; paradoxical emboli (PFO, ASD); chronic thromboembolic dz
3rd most common CV illness in US; 25% mortality if untreated
Virchow's triad
ECHO: RVPO (large PE) spiral CT: best!
anticoagulants
thrombolytics (patient in shock; If low to int wells - contraindicated in get D-dimer (if nl - age>80, major pulm hemorrhage, done; if abnl - get surgery in pats 7 acute cor pulmonale CT) days, major trauma in 10 days, TIA/ If int to high Wells- CVA, GI bleed in 3 get CT scan (if nl, months, uncont PE excluded; if HTN, known abnl - treat for PE) bleeding disorder)
decreased CO and BP --> Vtach, Vfib pulseless activity to heart
Pulmonary arterial hypertension
1. PAH (primary) dyspnea on exertion, fatigue, angina, syncope 2. Pulm venous (fixed CO so BP drops w/ HTN (Left heart vasodilation; arrythmias), dysfxn) edema (RV failure) 3. PH w/ lung dz clubbing, small carotid pulse, giant "a" or "cv" 4. PH w/ chronic wave, absent PMI, RV lift thromboemboli @ LSE, palpable PA impulse @ ULSE, loud 5. PH from direct S2P, ejection sound, effect on pulm Graham Steele diastolic vasculature but murmur (ULSE), right unclear cause sided S3 (RVH), TR murmur
Fixed obstruction in lungs prevent flow from right to left heart = reduced CO = reduced oxygen transport = hypoxia in lungs = increased work of breathing & ischemia (angina) pulmonary arterial hypertension (primary) PAP > 25 mmHg, normal PCWP (<15; general pulm hypertension has ANY wedge press), always elevated transpulmonary gradient mediators: increased activity of vasoconstrictors (endothelin 1), reduced activity of vasodilators (prostacyclin, NO)
stiffened LV causes inc LA pressure = inc PAP (#2) sarcoidosis, hyper/ hypothyroidism, renal dz (#5) idiopathic (#1)
younger CXR: enlarged RV, people, female prominent right gender (#1) heart border (RA) ECHO: dilated large RV and flattened septum compressing LV Cath: increased RVEDP, PAP Pathology (#1): SMC proliferation (endothelin) & vascular remodeling
#4 is surgically treatable (pulm thromboendartectomy) #2 needs BB, ACEI, diuretics nitrates #1 requires heart & lung transplant; CCBs if vasoresponsive diuretics to prevent RHF; anticoagulants to prevent clots; digoxin if arrhythmias, exercise, supplemental O2 if hypoxic
poor survival, cor pulmonale, atrial arrhythmias, paradoxical emboli, chronic severe hypoxia from shunting, cerebral abcess, sudden death
5 mm Hg increase in DBP or SBP = 2030% increase in CVD increased SBP = decreased survival BP monitoring at home (night BP nl dips 10-20%; non-dippers have increased risk of CVD)
DHHS: screen men aged 65-75 who have ever smoked w/ 1x abdominal US; if positive, yearly screening recommended Society of vascular surgery: screen all men btwn age 60-85, all women age 6085 w/ CV risk factors, and all men/women over age 50 w/ +FH for AAA with abdominal US if you see PVD, make sure the patient isn't going to have a stroke/ MI - their legs can wait!
50% maternal mortality w/ subsequent pregnancies if CM persists avoid combined oral contraceptives increased risk of recurrence!
functional class: Class I - angina w/ strenuous ex Class II - angina w/ walking or stairs; or > 2 blocks on level ground; Class III: angina w/ one flight of stairs or <2blocks Class IV: angina w/ walking around house or at rest BP control; SMOKING CESSATION, weigh reduction, daily exercise, lipid mgmt (diet)
Screening / Education Stages: A = at risk (DM, HTN, etc); B = asymptomatic ventricular dysfxn; C = symptomatic dysfxn; D = end stage HF Can't move between stages; but can move between functional classes
competitive sports restriction
common cause of SCD in athletes
competitive sports restriction
ALL first degree relatives need to be screened Screening of adolescents & competitive athletes q 1218m Screening of adults q 5y
DVT prophylaxis mechanical, medical (anticoagulation!unfractionated heparin, LMWH)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Periodontal disease
immunodeficient can loss of tooth supporting tissues have rapidly (gingiva, periodontal ligament, progressive forms bone, cementum) --> mobile teeth Odontogenic infection Mandibular infection --> submandibular sace involvement --> Ludwig's angina (airway compromise due to displacement of tongue) Maxillary infection --> midface (facial veins) --> cavernous sinus thrombosis Primary oral herpetic lesions (12% of infected)
dental plaque/host interaction
systemic diseases (ChediakHigashi, chronic granulomatous dz, neutropenia, DM, HIV)
65% of US adult population
mixed microflora infection within and around the teeth, usually secondary to dental caries
mid-face infection, swelling [maxillary anterior infxn] or airway compromise [mandibular infxn] bacterial endocarditis (GAS; HACEK); CNS abscess or septic embolus
HSV
(General)
HSV-1, HSV-2; dormant virus resides in trigeminal nerve sensory ganglion
Antibodies in 90% of U.S. population
Clinically & histologically indistinguishable for Varicella Zoster 3Ms: multinucleated cells, nuclear molding, chromatin margination; lots of eosinophils
Primary Herpetic Gingivostomatitis
Secondary oral herpetic lesions
1-2% of population that comes in contact multiple, painful, ulcerated vesicles on lips, gingiva, palate, with HSV will develop this entity tongue; high fever; cervical lymphadenopathy; distinguish from impetigo or eczema by PAIN vermillion border of lips; if in mouth, exclusively on attached gingiva (never on movable mucosa!), hard palate, or tongue sometimes prodrome present (tingling prior to lesion)
HSV
Young children
Self-resolving +/- acyclovir
Hospitalization for dehydration
HSV
40% of U.S. population
prophylaxis w/ acyclovir
immunocompromised have more widespread lesions
Aphthous stomatitis
occurs on movable mucosa (labial/buccal mucosa, soft palate, floor of mouth) appear round or oval with yellow center and erythematous border
stress induced; associated with Crohn's disease
?? Not known
20-60% of population
High SES, immunocomp (more severe)
self-resolving +/corticosteroids
can become a functional problem if large
Behcet syndrome
multiple oral, genital ulcerations +/- relatpsing iridocyclitis (eye) can have recurrent arthritis & thrombotic CVD most common URT malignancy occurs most commonly on lateral and ventral borders of tongue (NEVER the dorsal tongue), floor of mouth, soft palate and less commonly on gingiva and buccal mucosa white patch anatomic site can increase lesion risk: lateral tongue, central tongue, floor of mouth, soft palate red patch (large, red persistent lesion) hard palate, maxillary gingiva; maxillary sinus arises from enamel forming tissues; benign but locally destructive; posterior mandible parotid gland (usually benign), submandibular gland (50% benign), sublingual (malignant mostly), and minor glands (malignant mostly)
HLA types B5, B27, B12
Oral Squamous Cell Carcinoma
Ulcerative, exophytic, plaque like
tobacco!! Can also have a synergistic effect w/ alcohol; Plummer-Vinson syndrome, betel leaf (India), HPV
M>>>F; 5th-6th decade; age, tobacco use 2-4% of all U.S. malignancies
surgical + adjunct radiation/chemo
prognosis related to stage (overall 5y survival 20-60%) increased risk for 2nd primary tumor surgery often causes functional impairment 1-17% of the dysplastic lesions can transform to malignancies
Premalignant oral lesions
Leukoplakia
oral hyperkeratosis or callous but some degree of dysplasia
VERY common
Erythroplakia Oral/ sinonasal melanoma Ameloblastoma
VERY uncommon VERY rare compared to cutaneous melanoma most common odontogenic neoplasm
almost always a/w in situ or invasive SCC 20% 5y survival
en bloc resection (treated as if can be fatal if affect maxilla malignancy because so destructive)
Salivary gland neoplasm
(general)
Salivary gland neoplasm
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Pleomorphic adenoma
most common type of benign salivary gland neoplasm 85% occur in parotid Most common bilateral tumor commonly in parotid most common malignant salivary neoplasm (60-90% occur in parotid despite parotid glands nl having benign lesions) extremely aggressive; minor glands; invasive growth pattern Maxillary sinus most frequently affected
F>M
varied histopathology
Warthin tumor
contain salivary and lymphoid tissue
M>F
smoking!!!
Mucoepidermoid carcinoma
histology: large deposits of mucin
40% 5y survival but gradedependent prognosis
Adenoid cystic carcinoma Paranasal sinus neoplasms Squamous cell carcinoma Adenocarcinoma
histology: perineural invasion
high recurrence rate
Gastroesophageal reflux (GERD)
smoking, nickel, chromium, wood working industry (soft wood) Nasal cavity & maxillary sinus smoking, nickel, chromium, wood working industry (hard wood) symptoms or tissue damage due external factors (diet, fatty foods, smoking, diet, obesity, smoking, to reflux of gastric contents into meds - b-agonists); diminished esophagus impaired esophageal mucosa esophageal clearance (defective resistance peristalsis, saliva); gastric factors sx: heartburn, regurg, chest (overproduction of acid - meds, H.pylori; pain; dysphagia, water brash bile acid; gastric emptying - DM; gastric (increased salivation); atypical distention - causes LES to relax more); sx (laryngitis, hoarseness, defective anti-reflux barrier chronic cough, asthma, dental (PROLONGED transient LES erosions, laryngeal cancer) relaxations, low resting pressures of LES scleroderma, CT d/o) --> overall causes impaired esophageal mucosa resistance complication of untreated GERD (>5 years GERD Barrett's mucosa (normal of moderate to severe symptoms; 3x/week squamous epithelium of esophagus replaced by intestinal to daily) columnar epithelium)
uncommon
10% of population globally; 15-44% of Americans affected monthly
diet, obesity, CT disorders, CVD/asthma (bagonists), DM
PPI trial (hi dose x 30d) - if lifestyle mods (avoid trigger response, taper to tolerable foods, small frequent meals, dose; if no response, use quit smoking) endopscopy to r/o mucosal d/o H2 blockers, PPIs, antacids Endoscopy - negative in 50% for breakthrough sx of patients w/ GERD surgery (Nissen gold std - ambulatory pH test fundoplication) (done in pts w. refract/ atyp sx complications in 5-10% (ileus, pneumothorax, gas bloat or typ sx if neg endoscope) syndrome, diarrhea) histology: intestinal metaplasia (columnar epithelium + Goblet cells + villus pattern development) endoscope: salmon colored mucosa above Zline Barium swallow: narrowing of esophageal lumen, nodular appearance (could not R/O adenocarcinoma v. Barrett's... need endoscopy & bx) endoscope: food + concentric esophageal rings + linear furrows pathology: >15 eosinophiles per field (distinguishes from reflux esophagitis, which can also have eosinophils) endoscopy: coated white plaques w/ raw erythema below barium swallow: shaggy appearance; pan esophageal deep, penetrating ulcers histology: pseudohyphae
erosive esophagitis/ reflux esophagitis (inflamm of esophagus from stomach contents) esophageal strictures (narrowing due to inflammation) esophageal adenocarcinoma Barrett's esophagus (see below)
Barrett's esophagus
more common in middle to older aged Caucasian men
Barretts --> dysplasia -> esophageal adenocarcinoma
Eosinophilic Esophagitis
acute dysphagia and food impaction
infiltrative disorder -possible that certain foods trigger eosinophilic infiltration of esophageal body
hx of atopy (asthma, allergic rhinitis, eczema); younger men
PPIs, steroids (oral flonase), mast cell inhibitors, allergy referral
Candida esophagitis
odynophagia (painful swallowing) + dysphagia
candida
immunocomp (HIV, chemo, chronic steroid use - asthmatics)
anti-fungals (Fluconazole)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Viral esophagitis
odynophagia (painful swallowing) + dysphagia
Herpes, CMV
immunocomp (HIV, chemo, chronic steroid use - asthmatics)
Endoscopy: herpes - multiple clustered ulcers; CMV - large ulcers Barium swallow: herpes: small shallow ulcers w/ nl esophagus between the ulcers; CMV: deep large penetrating ulcers >1cm in size histology: herpes multinucleated giant cells w/ chromatin pushed to periphery; CMV - viral inclusion bodies w/ surrounding halos - owl's eye appearance
esophageal neoplasm
(General)
Squamous cell carcinoma
progressive dysphagia, weight loss, +/- chest pain/cough/ hematemesis weight loss, aspiration (if TEE fistula), hemorrhage
Barium swallow: apple core lesions Surface epithelium dysplasia from exposure to mutating agents --> in situ SCC --> invasive SCC smoking, alcohol [synergistic effect] --> mutations in p53 HPV, chronic esophagitis; dietary carcinogens (aflatoxin) most common type worldwide 6/100,000 in U.S. gross: irregular, ulcerative lesion in middle 1/3 of esop; polypoid SCC occur in upper 1/3 histology: no glands; keratinized/ squamous pearl;equipotent replicative ability; mitotic figures, loss of nl maturation and polarity; chronic inflamm cells present gross: white mucosa replaced by red mucosa from stomach; firm; oval/long appearance; ulcerative histology: glandular structures eroding through esophageal wall gross: umbilicated ulceration at surgical resection organ surface large tumors & metastases treated by Imantinib (Gleevec) metastasis (middle esophagus --> mediastinal, paratracheal LN; lower 1/3 esop --> perigastric, celiac LNs; upper 1/3 --> cervical LNs) hemorrhage & sepsis tracheo-esophageal fistulas
Esophageal adenocarcinoma
GERD, Barrett's
more common now due to Barrett's
Caucasians
GI stromal tumors (GIST)
begin in the muscularis propria (interstitial cells of Cajal myenteric plexusi) of esophagus, stomach, or intestine; then protrude through submucosa & mucosa into lumen bleeding
mutation in c-kit
Small cell carcinoma Melanoma Achalasia
Primary esophageal motility disorders
dysphagia to liquids and solids aperistalsis of the esophagus, resulting in but worse w/ solids; regurgitation; non-progressive contractions and failed chest pain; cough/ heartburn opening of LES inflammatory infiltration of myenteric plexus --> defective NO --> chronic excitation --> chronically closed LES
Manometry: failed relaxation of LES (no drop in LES pressure) and absent peristalsis
Endoscopic pneumatic dilation; botox injection in LES during endoscopy (short term)
Medical tx: CCBs, nitrates [overall less effective] Barium swallow: bird's beak, dilated/distended esophagus full of debris endoscopy: pinhole opening of LES gross: enlarged venous channels @ GE junction; ruptured submucosal veins chronic alcoholics; acute illness w/ increased vomiting
Esophageal varices
life threatening bleeding
variceal rupture produces massive hemorrhage into esoph lumen longitudinal tears at the GE junction from severe retching or vomiting
cirrhosis, portal hypertension
endoscopic sclerosing or banding most patients have coexisting hiatal hernia (stomach slips into esophageal hiatus)
Esophageal lacerations (MalloryWeiss tears)
bleeding (hematemesis)
alcoholic binge
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Peptic ulcer disease
gastric, duodenal
NSAIDs cause mostly gastric ulcers (worse with food)
imbalance btwn aggressive (acid, pepsin) & defensive (protective mucus layer) factors in gastroduodenal mucosa
H. pylori causes mostly duodenal ulcers (relieved by food) prostaglandins - inhibit gastric acid production AND maintain protective vague abd discomfort surface layer (meds - NSAIDs that complaints; usually decrease prostaglandins weaken asymptomatic but most common protective layer...); NSAIDs also directly sx = dyspepsia (upper damage epithelium abdomen- fullness, bloating, H. pylori adheres to gastric mucosa and distention, nausea; 1-3h produces urease and consequently postprandial, middle of the ammonium to protect from acidic environ; night, improves w/ antacids) inflammation --> ulcer formation; affects duodenal mucosa by instigating metaplasia [destroys D cells] of duodenal mucosa to gastric mucosa
increased gastric acid secretion (nl in gastric ulcers, 30% increase in duodenal ulcers); H. pylori & NSAIDs!!
5-10% lifetime prevalence
H. pylori, NSAIDs, short trial of PPIs/H2 blockers smoking, ZollingerEllison test for H. pylori (urea breath test, IgG serology if patient NSAID-induced NEVER treated before, stool ulceration: incr antigen test; invasive - biopsy) risk w/ age>60, concurrent steroid stop NSAIDs use, incr duration & dosage, immediate endoscopy ONLY if anticoagulation weight loss, bleeding, n/v, age use, prior hx of > 45 w/ dyspepsia PUD barium swallow: smooth/ uniform collection of barium representing ulcerations in stomach wall
If due to H. pylori - need to eradicate H. pylori so use PPI (omeprazol) + 2 antibiotics (amoxicillin, clarithromycin) as first line
Bleeding (most common; 1520% of PUD pts; hematochezia- red or coffee grounds, hematemesis, melena; a/w NSAID intake; usually self-resolving; 2nd line (rescue therapy): endoscopy for dx/tx but no omeprazol + bismuth + effect on mort) tetracycline + metronizadole Perforation (sudden severe epigastric pain, peritonitis If due to NSAIDs, stop rebound tenderness, NSAIDs!! rigidity, gurarding; dx: XR/CT shows free air under Surgery?? (vagotomy + diaphragm; requires drainage proceduressurgery!!) decrease vagal stimulation to Obstruction (due to inflam, parietal cells, followed by edema, scarring; n/v 30-60m antrectomy/pyloroplasty/ postprandial, bloating, early gastrojejunostomy to help satiety; succession splash; empty stomach) requires surgery!!) Penetrating ulcer (severe persistent pain, pancreatitis)
Gastritis
Acute gastritis
sudden inflammation of stomach transient mucosal inflammatory process lining due to numerous etiologies asymptomatic or variable epigastric pain, n/v disruption of mucus layer protective mechanisms (reduced mucin synthesis, reduced bicarbonate secretion, direct injury by chem/alcohol ingestion chronic presence of etiologic agent --> mucosal atrophy --> intestinal metaplasia
Alcohol, NSAIDs, ischemia
Chronic gastritis
less severe symptoms than acute gastritis but persistent
H. pylori, autoimmune gastritis, chronic alcohol abuse, radiation, post surgical
histology: overwhelming amt of inflammatory cells; intestinal metaplasia (Goblet cells); can sometimes see H. pylori w.i gastric gland
increased risk of dysplasia and adenocarcinoma w/ intestinal metaplasia
Gastric polyps
Autoimmune gastritis antibodies against gastric autoimmune gastritis - lymphocytes parietal cells; pernicious anemia; damage cells in the stomach (most vit B12 deficiency commonly the parietal cells), causing atrophic gastritis Hamartomatous majority of gastric polyps (80glandular hyperplasia 90%) non-neoplastic but may be regenerative
10% of chronic gastritis
F>M
associated with Peutz-Jegher syndrome (intestinal/gastric polyps + peri-oral pigmentation), FAP (fundic gland polyps; adenomatous polyps in large intestine that become adenocarcinomas)
found most commonly in people 50-60y.o.
histology: regenerative, dilated gland but not neoplastic
Adenomatous
Gastric adenocarcinoma
(General)
10% of gastric polyps neoplastic; unrestricted growth with malignant potential most common malignant gastric tumor (90-95%) usually in antrum/pylorus, lesser curvature although cardia tumors are arising due to Barrett's esophagus exophytic, flat, or ulcerative
usually progress from atrophy and intestinal metaplasia (commonly in the background of chronic gastritis) environmental factors (H.pylori, hi nitrate/nitrite diet, hi smoked/salty diet, smoking, lack of fruits/veggies, low SES) host factors (chronic gastritis, intestinal metaplasia, adenomatous gastric polyps, Barrett's esophagus, partial gastrectomy, Menetrier disease) Genetic factors (+FH, HNPCCDNA mismatch repair gene mut; familial gastric cancer syndrome- E cadherin mut; autoimmune gastritis) leading cause of cancer death globally, more common in Japan, Chile, China, Russia M>F; usually >50 y.o..
larger size lesion = increased risk adenocarcinoma Staging: depth of invasion (Tis = in situ; T1 = lamina propria/submucosa; T2 = muscularis propria; T3 = serosa; T4 = adjacent structures)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Intestinal type
most common type slightly better prognosis than diffuse type
a/w: intestinal metaplasia from environmental factors; chronic gastritis; and adenomatous polyps
older patients w/ known risk factors
gross: solitary lesions, exophytic but nl stomach ruggal folds histology: arise from intestinal metaplasia, some signet/donut signs, large hyperchromatic cells, irregular nuclear contour; formation of glands
Diffuse type
usually diagnosed at a high stage so worse prognosis (plus easily invades due to lack of adherence molecules)
E-cadherin mutations (CDH1 gene) --> loss of cell adherence
younger patients with no known risk factors besides perhaps genetics M=F
gross: thick stomach wall, enhanced ruggae (linitis plastica morph), flatter lesions histology: lots of signet ring/ donut signs (eccentric nucleijammed to side by mucin); cells appear to be falling apart due to loss of cadherin antibiotic therapy (get rid of H. good prognosis; however, Histology: normal cells pylori then MALT lymphoma tumors with translocation (uniform, typical) but dense resolves) t11:18 have worse lymphocyte infiltration prognosis histology: dense sheets of surgery, chemo, radiation poor prognosis lymphocytes; hyperchomatic cells w/ irregular nuclear contours
Gastric lymphomas
MALT lymphoma
Low grade
Diffuse large B-cell lymphoma
high grade
chronic inflammation --> lymphoid stimulus H. pylori --> clonal proliferation of small B lymphocytes --> development of lymphoma arise de novo or in MALT lymphoma
Gastric carcinoids
symptoms depend on hormones being produced often secrete gastrin rare in stomach (more common in SI & lungs) patients can present w/ duodenal ulcers, diarrhea if ZE
neuroendocrine tumors a/w endocrine cell MEN-1, ZE syndrome hyperplasia, chronic atrophic gastritis, or (excessive gastrin --> Zollinger-Ellison syndrome increased gastric acid levels; extensive PUD)
Menetrier Disease
weight loss, diarrhea, peripheral edema hypochlorhydria (low gastric acid in stomach) most common congenital GI malformation majority are asymp Newborns: bilious emesis, late stage signs (hematemesis, hematochezia, tenderness/pain, peritonitis, shock = intestinal necrosis) = very poor prog Older kids/adults: intermittent vomiting, abd pain, volvulus, pancreatitis, enteropathy, peritonitis
excessive secretion of TGF-a (transforming growth factor), causing diffuse hyperplasia of foveolar epithelium of body/fundus of stomach
?? Unknown
VERY rare M>F; 30-50 y.o.
gross: hypertrophy of gastric folds histology: foveolar hyperplasia Upper GI series: No duodenal Ladd procedure (required for ALL malrotations regardless C- loop (ligament of Treitz of symptoms) doesn't cross the midline)
increased risk of adenocarcinoma
Malrotation
1% of congenital population (incidence ranges from 1/6000 1/200) M slightly more than F majority diagnosed w/ 1 year of life but some go undetected until incidental find on GI imaging/surgery
Intestinal atresia
bilious emesis IMMEDIATELY following birth = hi grade obstruction Abd distention = mod grade obstruction
maldevelopment (muscular, neurological, or both) of GI tract likely due to chromosomal abnormality although not truly elucidated
associated with 30% of Down Syndrome cases
XR: double bubble = duodenal atresia
surgical emergency!!
Congenital hypertrophic pyloric stenosis
intermitt abd pain + failure to thrive = partial obstruction/ atresia babies born nl but display non- diffuse hypertrophy and hyperplasia of first part of pylorus --> narrowed channel bilious emesis @ ~1m between antrum and duodenum often misdiagnosed as GERD
more common in males
benign course post-surgical splitting of pyloric muscle
none, usually resolves postsurgery
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Hirchsprung's disease (aganglionic bowel)
arrest of neural crest cell migration --> autosomal recessive and aganglionic zone of bowel (no ganglions in dominant mutations myenteric plexus despite normal muscle layers) RET (receptor tyrosine kinase) - associated w/ MEN 15% have total colonic HD (high lacks inhibitory parasympathetic type Iia grade obstruction) innervation; absent NOS in myenteric 5-10% have total colonic + small plexus therefore reduced nitric oxide bowel HD (hi mortality at birth) [anal sphincter cannot relax so unable to defecate] Presentation: delayed passing of meconium, abd distention, constipation, vomiting, +/diarrhea Rectosigmoid area is most affected (constipation, stool overflow) starts @ birth (unlike funct constip) and rarely has fecal soiling (unlike funct constip again)
1/5000 M>F in short segment; M=F in long segment dz
positive FH sometimes
rectal biopsy - ganglion cells? HD pts have no ganglion cells and nerve hypertrophy Barium enema: determines transition area where no contraction/distention anorectal manometry: differentiates normal v. abnl functioning bowel by recto-anal inhibitory reflex
resection of aganglionic segments
lifelong implications 15% of HD babies have other associated congenital anomalies :( high complication risk postsurgery: strictures, impactions, soiling, constipation
Gilbert syndrome
Crigler Najjar Syndrome
Type 1
Elevated indirect (unconjugated) bilirubin; benign - asymptomatic jaundice elevated indirect (unconjugated) bilirubin
reduced UDP glucoronyl transferase activity causes impaired conjugation of bilirubin completely absent UDP glucoronyl transferase activity
precipiated by fasting, stress, EtOH
Prevalence ~ 5%; M>F
family history
increased indirect bilirubin
none
Type 2
severe/fatal elevated indirect (unconjugated) reduced UDP glucoronyl transferase bilirubin; activity less severe (Arias syndrome) neonatal jaundice (unconjugated hyperbilirubinemia) --> kernicterus (toxic encephalopathy)
Neonatal hyperbilirubinemia
blood group incompatability between mom & baby PLUS newborn's inadequate UDPglucoronyl transferase activity
blue fluorescent light exposure (increases conversion of bili in skin to more polar/water soluble isomers) IM injection of tinmesoporphyrin (inhibits heme oxygenase to prevent formation of bilirubin)
Viral hepatitis
Hepatitis A
viral prodrome (fatigue, n/v, arth/myalgias, headache) followed by jaundice 1-2 weeks later
non-enveloped RNA virus that is transmitted via fecal-oral route and then replicates in the liver; most infectious during incubation period (minimal infectivity once jaundice occurs)
contaminated food products (fecal-oral)
poor hygiene, overcrowding, institutions, endemic countries (Latin America, Africa, Asia), food outbreaks cases in U.S. are usually immigrants or vertical transmission to infants born in U.S. by immigrant moms
increased ALT (liver damage) IgM - suggests new/acute infection IgG persists to provide total immunity
NO risk for chronic infection or cirrhosis!!!
Hepatitis B
small DNA virus that is transmitted primarily through blood and sexual exposure, then replicating (using active viral reverse transcriptase w/ high mutation rate) in liver or extrahepatic reservoirs
U.S. - horizontal transmission of body fluids (IVDU, needle stick- HCW, unprotected sex; MSM)
Globally - horizontal transmission + vertical 400 million carriers in world (75% in Asia) surface proteins: HBeAg, HBsAg, HBcAg, transmission DNA polymerase test immigrants from endemic region, MSM, LONG incubation period; may be multiple sex partners, IVDU, contagious up to 15 weeks postinmates, dialysis pts, HIV pts, symptoms pregnant women, close contacts of known cases, pts w/ abnl liver enzymes
endemic countries IgM = acute infection (Africa, Asia) HBeAg = active infection middle aged (infectious state) adults (not vaccinated) will anti-HBs + no anti-HBc = have higher vaccination chance for acute infection anti-HBc + HBsAg = chronic infection
boost immune response via risk of chronic infection, pegylated interfeon or cirrhosis, liver failure, & nucleoside/tide analogs ($$) HCC some drugs have activity against HBV and HIV
risk of chronicity determined by age of infection acquisition pregnant? Tenofovir in 3rd (younger individuals w/ Hep trimester; give infant HBIG + B = hi risk for chronic hep B) HepB vaccine w/I 12h of birth #1 cause for cirrhosis & HCC globally anti-HBc = represents natural infection (either acutely or chronically)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Hepatitis C
ssRNA virus from flavivirus family (same as dengue, WNV) that is transmitted primarily through blood and infects hepatocytes + B lymphocytes; replicates in liver using RNA dependent RNA pol (hi mutation rate)
blood transfusions before 1992, IVDU, unk risk factors (sharing razors/toothbrush, piercings, tattoos, etc) other: needlesticks in HCW, vertical transmission, nonsexual household contact, sexual transmission IVDU, blood transfusion
leading cause of liver if exposed, 80% histology: progression of fibrosis --> cirrhosis if chronic transplant for cirrhosis of people will in U.S. develop chronic (stellate cells, collagen bridges) hepatitis, after 4 million U.S. people which 15% of have been exposed; 3.2 these will million U.S. people have develop cirrhosis chronic HepC and 1% will develop HCC
pegylated interferon + ribavirin
HIGH likelihood of chronic infection w/ subsequent risk of cirrhosis, liver new therapy: peg interferon + failure, & HCC ribavirin + protease inhibitor decompensated cirrhosis (telaprevir/ bocepravir) (ascites, encephalopathy, varices)
Hepatitis D
enveloped ssRNA virus known as a delta agent because only propagates in the presence of Hepatitis B!! Transmitted via blood or sex (usually exposed to HepB & HepD at same time)
treat hepatitis B to get rid of hepD
Hepatitis E
non-eveloped ssRNA virus that is transmitted via fecal-oral route and can be detected in stool/bile/liver; does NOT cause chronic infection
contaminated food products (fecal-oral)
CAN BE FATAL IN PREGNANT WOMEN!!!
(Alcohol) hepatic steatosis
occurs w. moderate-marked EtOH intake asymp in most cases clinical presentation: hepatomegaly, elevated liver enzymes REVERSIBLE!
alcohol shunts toward lipid biosynthesis (due to increased NADH and decreased FA oxidation), but lipid assembly and secretion are impaired (decreased MT transport; altered membrane permeability) also increased peripheral catabolism of fat, which causes fatty acids to be delivered to the liver where they accumulated (steatosis) excessive alcohol increases formation of toxic metabolites, overwhelming liver's metabolic ability; mitochondria & MT dysfunction
hepatic steatosis: alcohol, protein deficiency, drugs, pregnancy (3rd trimester), infection (hepC, HIV), Reye's syndrome, parenteral nutrition, DM, NASH
gross: hepatomegaly, yellow, greasy surface histology: intra & extrahepatic lipid accumulation; no necrosis, +/- fibrosis
benign course usually
Alcohol hepatitis
acute onset following binge drinking
minimal --> severe symptoms (malaise, fever, abd pain, tender liver, elevated hepatic enzymes - liver is more susceptible to injury in the AST/ALT >2; peripheral setting of reduced glutathione levels neutrophilia) increased endotoxin release from gut bacteria reaches liver via portal circulation
gross: steatosis typically present (represents hx of alcohol abuse), +/hepatomegaly (unless cirrhotic) histology: hepatocyte swelling/necrosis, Mallory bodies (bright pink inclusions representing aggregates of cytokeratin; also seen in Wilson's dz & cholestasis), neutrophilic infiltrate; possible steatosis & fibrosis ?? Liver enzyme elevation (loss/death of hepatocytes so not really too many left to be injured) decreased liver synthetic function tests gross: decreased size, diffuse nodularity, brown/ green pigmentation (bile stasis) histology: marked fibrosis, regenerative nodules, variable inflamm infiltrate, bile stasis; trichrome stain identifies collagen
10-20% risk of death
Alcohol-related hepatic cirrhosis
may be synergistic w/ other 10-15% of alcoholics diseases (hepB, hepC, (no current marker for alcohol injury/inflammation --> pro-fibrotic autoimmune hep, susceptibility) clinical presentation: weight loss, cytokines --> release of growth factors and hemochromatosis, drugs- MTX, amiodarone) increased collagen production --> anorexia, malaise, ascites, fibrosis jaundice, peripheral edema, portal HTN, esophageal varices, liver will be hard to palpate bc synergistic pathogenesis shrunken size represents years of EtOH abuse IRREVERSIBLE!!
not really understood
increased HCC risk
Drug-induced liver injury (DILI)
dose-dependent (acetaminophen --> accumulation of NAPQI)
Hy's law: >10% of patients w/ DILI + jaundice progress to death or transplantation, even after cessation of drug unpredictable timeline of DILI presentation; can mimic autoimmune hepatitis
>900 drugs implicated; many drugs have cholestatic or hepatocellular signature toxicity (after which they cause elevated liver enzymes) metabolic: accumulation of toxic metabolites in hepatocytes; steatosis; autoimmune (methyldopa); mitochondrial toxicity (HIV meds, amiodarone)
antibiotics, anti-seizure meds relatively low incidence (phenytoin), HIV meds (ARVs), hyperthyroidism drugs (propylthiouracil), amiodarone, MTX, NSAIDs, antifungals, INH (increased age), statins (very few causes of DILI but do elevate LFTs in 1-3% of patients) dependent on drug, environ (diet, toxins, exposures), and host (age, gender, weight, genetics, immune diseases) factors patients w/ comorbidities like
Adults obesity malnutrition pregnancy other drugs alcohol hx of DILI genetics PMH of liver dz
[iver injury] elevated LFT, acute hypersensitivity: a/w rash, fever, liver failure, hepatic necrosis eosinophilia, extra hepatic manifestations [sulfonamides, amoxicillin-clavulanate, [cholestatic injury] - elevated phenytoin, HIV meds] bili, ALP, pruritis, jaundice minocycline - acute hepatitis & SJS, chronic hepatitis, acute Acetaminophen toxicity results because depletion of glutathione, so liver is no
histology: massive/zonal necrosis, inflammation (if + eosinophils, think hypersensitivity), granulomas, steatosis (microvesicular has worse prognosis), phospholipidosis (deposition of phospholipids in hepatocytes), SOS (sinusoidal obstructive syndrome; fibrosis around highest risk central vein); more damage in profile? Obese F zone 3 > 50y.o. who drinks EtOH dx of exclusion monitor LFTs in patients taking INH
withdraw offending agent liver transplant (acute liver failure) N-acetylcysteine (Mucomyst) if acetaminophen toxicity steroids if autoimmune hepatitis carnitine if valproic acid toxicity
Acute liver failure, transplantation, death
Drug-induced liver Disease injury (DILI)
Clinical Variants DILI + jaundice progress to Defining Characteristics cholestatic orPathogenesis hepatocellular signature
death or transplantation, even after cessation of drug Idiosyncratic (individualized; immune-mediated) unpredictable timeline of DILI presentation; can mimic autoimmune hepatitis
Hy's law: >10% of patients w/
>900 drugs implicated; many drugs have toxicity (after which they cause elevated liver enzymes) metabolic: accumulation of toxic metabolites in hepatocytes; steatosis; autoimmune (methyldopa); mitochondrial toxicity (HIV meds, amiodarone)
antibiotics, anti-seizure meds relatively low incidence Etiologies Epidemiology (phenytoin), HIV meds (ARVs), hyperthyroidism drugs (propylthiouracil), amiodarone, MTX, NSAIDs, antifungals, INH (increased age), statins (very few causes of DILI but do elevate LFTs in 1-3% of patients) dependent on drug, environ (diet, toxins, exposures), and host (age, gender, weight, genetics, immune diseases) factors patients w/ comorbidities like HepB, hepC are at greater risk!
Adults Risk obesity factors malnutrition pregnancy other drugs alcohol hx of DILI genetics PMH of liver dz
[iver injury] elevated LFT, acute hypersensitivity: a/w rash, fever, liver failure, hepatic necrosis eosinophilia, extra hepatic manifestations [sulfonamides, amoxicillin-clavulanate, [cholestatic injury] - elevated phenytoin, HIV meds] bili, ALP, pruritis, jaundice minocycline - acute hepatitis & Acetaminophen toxicity results because depletion of glutathione, so liver is no SJS, chronic hepatitis, acute liver failure, cholestatic hepatitis longer able to clear NAPQI (toxic met) cocaine - liver necrosis & acyte hepatitis Non-alcoholic Fatty Liver Disease (NAFLD) steatosis --> steatohepatitis --> cirrhosis
histology: massive/zonal Lab/Imaging necrosis, inflammation (if + eosinophils, think hypersensitivity), granulomas, steatosis (microvesicular has worse prognosis), phospholipidosis (deposition of phospholipids in hepatocytes), SOS (sinusoidal obstructive syndrome; fibrosis around highest risk central vein); more damage in profile? Obese F zone 3 > 50y.o. who drinks EtOH dx of exclusion monitor LFTs in patients taking INH
withdraw offending agent
Treatment
Acute liver failure, Complications transplantation, death
liver transplant (acute liver failure) N-acetylcysteine (Mucomyst) if acetaminophen toxicity steroids if autoimmune hepatitis carnitine if valproic acid toxicity
"two hit hypothesis" - insuline resistance metabolic syndrome increases fatty acid delivery to liver; (obesity, DM, dyslipidemia) oxidative stress increases free radical usually asymptomatic, fatigue, formation --> lipid peroxidation --> cellular damage RUQ pain; central obesity, hepatomegaly
20% prevalence in U.S. metabolic syndrome
elevated ALT (AST/ALT <1) U/S: increased echogenicity from fatty infiltrate biopsy: steatosis, inflammation, fibrosis
weight loss & metabolic control (treat DM w/ metformin, treat dyslipidemia w/ statins)
Wilson's disease
pediatric or young adult presentation w/ liver disease
Autoimmune hepatitis
hepatic (variable - abnl liver enzymes --> cirrhosis & portal HTN), neurological (rigidity, spasticity, tremors, ataxia), hematologic(hemolytic anemia), psych (depression, psychosis), opthalmologic (KayserFleischer rings, sunflower cataracts) aberrant immune response directed fatigue, hepatomegaly, towards own hepatocytes --> jaundice hepatocellular disorder, inflammation, & fibrosis a/w other autoimmune disorders (thyroid disease)
gene defect responsible for copper autosomal recessive transport --> decreased biliary excretion of inheritance copper --> increased copper deposition throughout body --> increased oxidative stress & damage
1/30,000 people age of onset typically 1525
low serum ceruloplasmin (nl diet: eliminate copper rich foods (organ meats, shellfish, carries copper but is broken down if copper is not attached) chocolate, mushrooms, nuts) KF rings on slit-lamp eye exam increased 24h copper excretion in urine lifelong chelation liver transplant is curative
genetic predisposition, 200,000 U.S. patients; exposure to unk environmental F>M; average age 20-40 factor
Elevated transaminases, elevated IgG, +ANA/SMA/ liver-kidney microsomal-1 antibodies (1 of the 3 usually) histology: interface hepatitis, hepatic rosettes (small gland like clusters of surviving hepatocytes within inflammatory infiltrate), variable fibrosis depending on dz stage MUST exclude other dx elevated ALP, nl or mildly elevated transminases, IgM, hypercholesterolemia, fat soluble vitamin deficiency (ADEK), anti-mitochondrial antibody (AMA) histology: bile duct destruction w/ mononuclear cell inflammatory infiltrate
increase immunosuppression 87% remission within 3y of (prednisone, combo therapy) treatment
Primary Biliary Cirrhosis (PBC)
autoimmune disorder characterized by progressive destruction of intrahepatic bile ducts (microscopic injury)
aberrant immune response directed at own biliary epithelial cells (small bile ducts)
5/100,000 F>M median age of dx 50-55
ursodeoxycholic acid slowly progressive disease (synthetic bile acid - 32% risk leading to cirrhosis in 10reduction in death/ liver 20 years transplantation)
Primary Sclerosing Cholangitis (PSC)
fatigue, pruritis, jaundice (10%), hepatomegaly, xanthelasma/ xanthomas, associated autoimmune disorders (thyroid, Sjogren's, scleroderma, inflamm arthritis), maldigestive fatty diarrhea sx: fatigue, pruritis, jaundice, autoimmune disorder characterized by weight loss, fever, fibrosing inflammation of both intrahepatic hepatomegaly, splenomegaly, AND extrahepatic bile ducts hyperpigmentation, xanthomas majority of patients have IBD (UC)
8.5/100,000 M>F avg age of dx 40
elevated ALP, mild elevations in transaminases cholangiogram: multiple bile duct strictures w/ proximal dilations (beaded appearance) - "beating of the bile ducts"
liver transplant!
irreversible damage to bile ducts --> cholestasis --> cirrhosis increased risk of cholangiocarcinoma median survival 12-16 years post dx
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Glycogen storage disease
GSD-1
hypoglycemia very quickly after last meal, hepatomegaly (glycogen stores build up bc cannot be broken down), seizures at age 3-4m, failure to thrive, increased uric acid, lactic acidosis, and increased triglyceride levels severe liver dz in young infants (bleeding problems - unable to produce clotting factors; FTT) neurological problems, renal involvement
mutation in either GLUT2 or glucose-6phosphatase --> hypoglycemia (glucose-6phosphate cannot be converted to glucose OR glucose cannot be transported out of liver for usage)
uric acidosis, lactic acidosis, elevated triglycericides liver biopsy (measure amt of glucose-6-phosphatase)
nutritional management (continuous night feeding via ng tube; uncooked corn starch before bed; frequent feedings) liver transplant when dietary treatment fails or when adenomas develop
Tyrosinemia
type 1
defective enzyme (FAH) causes buildup of toxic metabolite FAA; FAA is converted to another toxin SAA
newborn screening (elevated tyrosine --> repeat and check for urine SAA)
NTBC (inhibits buildup of toxic substances) dietary (reduce protein intake)
Lysosomal storage disease
Gaucher's disease, progressive hepatomegaly, Fabry's disease, Tay- splenomegaly, loss of Sach's disease developmental skills, abnormal facial features
Alpha1- antitrypsin deficiency (A1AT)
most common inborn dz affecting the liver neonatal hepatitis (usually spontaneously resolves but can cause chronic response fibrosis) also a/w early onset COPD in non-smokers iron overload syndrome --> liver injury, fibrosis, cirrhosis, HCC
alpha 1 antitrypsin binds and promotes degradation of serum proteases; produced mainly in liver but functions in lung to inhibit elastase; mutation in this enzyme causes A1AT clumping --> inflammatory response lack of protein in lung --> COPD mutant protein in liver --> toxicity homozygous missense mutation in C282 tyrosine OR heterozygous missense mutation in C282Y/H63D 1/250 people have mutation but not everyone asymptomatic
family history
enzyme replacement therapy (unless child has a deletion mutation, then they would develop an immune response and require induced immune tolerance) minimize enviromental factors (smoking, occupational lung hazards) IV augmentation therapy (antienzyme therapy) - helps lung fxn but not liver disease (malformed protein is still being produced) monitor serum ferritin or transferrin saturation frequent phlebotomy to remove RBCs (and hence drop iron levels) cirrhosis, HCC, diabetes (toxicity to pancreas),
Hereditary hemochromatosis
fatigue, hyperpigmentation, RUQ pain, arthritis/joint swelling, gene involved normally encodes HFE, impotence which regulates iron by modulating activity of ferroportin on enterocytes (absorb Fe) and hepatocytes/macrophages (store Fe); hi Fe = increased HFE = decreased ferroportin = less absorption of Fe in patients w/ missense mutation, low HFE levels cause increased ferroportin and consequently absorption of Fe
Cirrhosis
compensated
scarred liver --> distorted sinusoidal architecture --> increased resistance and disturbed blood flow --> shunting of coronary vein blood flow AWAY from liver (hi resistance) --> engorgement of chronic liver disease manifestations (muscle wasting/ gastroesophageal plexus --> variceal bleeding cachexia, spider angiomas portal-systemic collaterals; blood in portal vein is also shunted away palmar erythema, from liver --> increased back pressure on gynecomastia) mesenteric venous drainage of gut --> splanchnic hemodynamic derangement palpable left liver lobe, small liver span (percussion), splenomegaly, thrombocytopenia radiographic signs characteristic of cirrhosis but no symptoms
chronic abnl LFTs, histology: regenerative hx of chronic liver nodules surrounded by disease extensive scarring or fibrotic tissue liver insufficiency (hypoalbuminemia, increased INR, hyperbilirubinemia) Doppler U/S (ICU pts only) splenomegaly, cirrhotic liver contour, reversed blood flow MRI - nodular liver, splenomegaly, varices
(hi resistance) --> engorgement of gastroesophageal plexus --> variceal bleeding blood in portal vein is also shunted away from liver --> increased back pressure on mesenteric venous drainage of gut --> splanchnic hemodynamic derangement
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
decompensated
Cirrhotic changes + SYMPTOMS compensated signs + jaundice, ascites, asterixis (hepatic encephalopathy)
no biopsy needed (imaging + symptoms sufficient) ascites fluid - serum albumin to ascites gradient (SAAG) > 1.1 (hydrostatic process suggesting transudative ascites; if less than 1.1. think neoplasm or infectious cause of ascites)
chronic ascites? Minimize sodium diet; diuretics, paracentesis (especially if ACS), TIPS (if refractory ascites) early antibiotics if SBP
cerebral vasodilation (hepatic encephalopathy), peripheral vasodilation (shock), pulmonary vasodilation (portopulmonary hypetension, hepatopulmonary syndrome, hepatic hydrothorax), metabolic/ hemodynamic derangements abdominal compartment syndrome (restrictive lung physiology) spontaneous bacterial peritonitis: > 250 neutrophil count in pericentesis hypoglycemia (BAD sign)
Portal hypertension
variceal hemorrhage, ascites, splenomegaly
splanchnic vasodilation (increased flow) + scarred/fibrotic liver (increased resistance + stellate cell mediated sinusoidal vasoconstriction) = increased portal pressure as back pressure to gut increases, gut bacteria are translocated and enter mesenteric lymph nodes, where they increase NO production; more NO = splanchnic arterial vasodilation
cirrhosis (increased resistance in sinusoidal space) Other causes? Portal/ splenic vein thrombosis, schistosomiasis, venoocclusive disease, Budd-Chiari
hepatic encephalopathy
neurologic & psychiatric dysfunction in presence of decompensated cirrhosis hyperammonemic state different dz manifestations depending on setting of acute or chronic liver dz; acute liver dz (development of intracranial HTN & cerebral edema --> herniation); chronic liver dz (less injury bc upregulation of ammonia backup systems)
conversion of ammonia (which is not eliminated by dysfunctional liver) to glutamine --> astrocyte swelling & altered neurotransmission
Infection, GI bleed, dehydration
systemic manifestations; splanchnic vasodilation --> pathologic shunting of blood away from liver --> increased Hepatic pressure venous cardiac output into gradient (HVPG) = WHVP splanchnics --> decreased (wedge pressure) - FHVP (free effective arterial blood hepatic pressure); nl 3-5 mmHg volume --> compensatory upregulation of neurohormonal systems (RAAS, SNS, ADH) --> inc intravascular volume (renal vasoconstriction or Na/H2O retention) --> hepatorenal syndrome OR ascites/ hyponatremia serum ammonia level not eliminate ammonia production reversible with treatment! sensitive but can use serial sources using lactulose, levels to measure treatment rifaximin, or metronidazole response low platelet count (thrombocytopenia)
Cirrhotic cardiomyopathy
resembles septic hypotension (low BP = low SVR) compensatory mechanisms will be seen: tachycardia, wide pulse pressure, bounding pulses, hypotensive abnormal dilation of pulmonary vasculature causing hypoxemia (in absence of radiographic shunt lesion) Platypnea (SOB when upright; opposite of CHF patients)
hemodynamic circulation due to peripheral vasodilation and sympathetic activation causes decreased arterial blood volume, systolic & diastolic dysfunction, conductance abnormalities, and impaired B-adrenergic receptor function dilation of basal pulmonary vasculature impedes diffusion mediated transfer of oxygen bubble study - detection of microbubbles in left heart after 3-6 cardiac cycles (in contrast to 1 cycle if intracardiac shunt lesion) supplemental O2 with curative liver transplantation
Hepatopulmonary syndrome (HPS)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Portopulmonary Hypertension (PPHTN)
pulmonary hypertension in the setting of decompensated cirrhosis --> right heart failure RHF, ascites, pulm edema, peripheral edema
unk?? Vascular injury/ inflammation mediated by serum factors abnormally persist in hepatic outflow
ECHO (screens) + RH catheterization (confirms)
Diuresis, prostaglandin therapy if acute RV failure Liver transplantation does not immediately reverse PPHTN (so patients must continue prostaglandins) - difference btwn HPS & PPHTN
Hepatic hydrothorax
transudative pleural effusion resulting from ascites tracking across diaphragm into negative intrathoracic space dyspnea, hypoxemia
accumulation of ascitic fluid in pleural space, particularly right hemithorax --> right sided pleural effusion
CXR
Thoracentesis diuretics TIPS = transjugular intrahepatic portosystemic shunt splanchnic vasoconstrictors (ocreotide), BB to decrease HR, empiric antibiotics Band ligation via endoscopy if esophageal varices TIPS if failed variceal banding or gastric varices
respiratory faulure spontaneous bacterial empyema
Variceal hemorrhage
hematemesis, hematochezia
significant portal hypertension causes back flow of blood to gastroesophageal plexus --> varice formation --> rupture --> potentially fatal hemorrhage
endoscopy
Hepatorenal Syndrome (HRS)
functional renal failure in presence of decompensated cirrhosis
splanchnic vasodilation--> decreased effective arterial blood volume (per the kidneys) --> compensatory mechanisms by kidneys --> functional renal failure structurally normal kidneys
terlipressin (splanchnic vasoconstrictor)
Annular pancreas
incomplete rotation of ventral pancreatic bud infants: n/v, FTT, feeding problems
normally in embryologic development, ventral portion of pancreas fuses with dorsal part of pancreas
1/20,000
surgical bypass of the area wrapped around the duodenum
Here, incomplete rotation so despite the ventral and dorsal pancreas attaching, adults: PUD, duodenal stenosis, the ventral part remains in the initial pancreatitis position and wraps around second part of duodenum Pancreas Divisum most common congenital anomaly of pancreas failed fusion of dorsal and ventral pancreatic ducts 5-7% of population endoscopic or surgical sphincterectomy, stent placement
associated with other congenital anomalies (Down syndrome, duodenal atresia, congenital heart defects, tracheoesophageal fistula) can have strictures/ obstruction in duodenum
Ectopic pancreas
most pts are asymptomatic; normally, main pancreas duct drains into major papilla but in divisum, the ducts do recurrent pancreatitis or chronic idiopathic pancreatitis not fuse properly so majority of pancreas drains into minor papilla --> pressure buildup and pancreatitis accesory pancreas most people are asymptomatic can cause nodules or tiny polypoid lesions in other parts of GI tract most are asymptomatic but if anomalous development of pancreatic symptomatic, it will occur before ductal system age 2 (abdominal distention, n/v, jaundice, pancreatitis) Cholesterol (80%) intense RUQ/epigastric pain that radiates to back about 1h black pigment postprandial (cirrhosis, hemolysis, pancreatitis) sometimes n/v brown pigment (biliary infections) 1. secretion of free cholesterol into bile; 2. hypersecretion (increased chol synthesis and/or decreased bile acid secretion) of cholesterol from liver into the bile, forming cholesterol vesicles and eventually crystallizations cholesterol supersaturation (chol>> bile acids), accelerated nucleation, gallbladder hypomotility (biliary sludge) gallbladder hypomotility (at risk? Pregnant, long term parenteral nutrition, rapid weight loss, hormonal treatments like ocreotide acromegaly)
1-2% of population
Congenital pancreatic cysts
very rare!
surgical resection if symptomatic
Cholelithiasis (gallstones)
10-15% of men > 60y.o.; age, obesity, child U/S - 98% sensitivity 20-40% of women > 60 bearing, estrogen MRI - better or equivalent to y.o. use, OCPs, DM, U/S hyperF>M triglyceridemia, IBD, terminal ileum disease, other comorbidities FFFF (fat, female, 40s, fertile)
no intervention if asymptomatic cholecystectomy + R/O complications ursodeoxycholic acid (secondary bile acid that reduces chol secretion into bile)
acute cholecystitis gallstone ileus biliary pancreatitis (distal impaction) Acute cholangitis Choledocholithiasis Mirizzi syndrome
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Biliary colic
ACUTE cholelithiasis RUQ/epigastric pain that radiates to right shoulder/scapula; worse with meals, steady pain (15-60min) that slowly resolves; NL physical exam (+/- RUQ tenderness); nl labs; most common complication of gallstones
intermittent obstruction of cystic duct; may or may not have gallbladder inflammation
U/S gold standard diagnosis
recurrent? Elective cholecystectomy +/intraoperative cholangiogram to clear out any stones in bile duct if needed
Acute Cholecystitis
positive Murphy's sign (inspiratory halt upon palpation of gallbladder); palpable acalculus cholecystitis - inflammation + gallbladder in some due to hypomotility of gallbladder but no stone inflammation; right subcostal (usually ICU or intubated patients) tenderness RUQ pain - dull, persistent ache that radiates to right scapula; lasts longer than 6hours; n/v fever, elevated WBC
chronic obstruction of gallbladder outlet by gallstone --> bile stasis --> severe inflammation --> damage to gallbladder mucosa
1/3 of patients with gallstones
cholelithiasis
mostly clinical diagnosis but cholecystectomy + antibiotics U/S is accurate in up to 88%: (Gram negatives), IV fluids gallstones + gallbladder wall thickening/edema + distended lumen Elevated WBC, mild jaundice (slightly elevated bili), slightly elevated AST/ALT/ALP If U/S is questionable, proceed with HIDA scan (would not see any radioactivity in gallbladder diagnostic of acute cholecystitis)
majority of people have no complications diabetics can have gangrenous cholecystitis gallbladder empyema perforation (distention, ischemia, pericholecystic fluid collection --> abscess)
Choledocholithiasis
often asymptomatic but wil have intermittent obstruction of common bile abnl labs/imaging duct (usually due to gallstones but small minority arise de novo) jaundice, pruritis, cholangitis (if bacterial infection too)
mild hyperbilirubinemia, elevated ALP, transient AST/ALT spike would suggest passage of stone into duodenum U/S - identifies common bile duct stones in 50% of patients ERCP - diagnostic & therapeutic elevated WBC, bilirubin, ALP positive blood cultures
ERCP + cholecystectomy (unless high risk patients these will have ERCP + URSA to dissolve the stones)
Cholangitis
Charcot's triad (fever, RUQ pain, jaundice) Reynold's pentad (charcot's + altered mental status + hypotension)
impacted stone in common bile duct leads to permanent obstruction (unlike choledocholithiasis - mobile stones); increased pressure above the stone --> bacterial proliferation --> septicemia (gram negative bugs like E.coli, Klebsiella, Pseudomonas, Enterococcus, Clostridium)
Gallstone ileus
Mirizzi Syndrome
Irritable Bowel Syndrome (IBS)
abdominal distention, usually in stone forms fistula between gallbladder elderly so delayed diagnosis due and small bowel, escapes the gallbladder, and then migrates to become obstructed in to other comorbidities terminal ileum common hepatic duct obstruction by stone in the cystic duct (stone from the outside obstructs the hepatic duct) caused by increased intestinal motility --> heightened sensitivity due to abdominal pain for at least 3 altered visceral sensation through enteric stressors months, with onset at least 6 months ago, that improves w/ and extrinsic nervous system --> dysregulation of brain-gut communication defecation and is associated w/ change in frequency or form more of a psychiatric problem of stool!! NO STRUCTURAL ABNORMALITIES involves small and large intestine NOT a/w fever or dehydration!!
1. IV antibiotics 2. Elective ERCP to remove stone EUS/MRCP (regular U/S would 3. PCT if ERCP unsuccessful miss bile duct stones) 4. cholecystectomy (after infection cleared and stone is CT if worried about out) complications remove stone + hi mortality/morbidity cholecystectomy
Cholecystectomy + ERCP or cholangiogram to open the bile duct 1. reassurance + lifestyle/dietary mods 2. increased severity? Agents that treat motility (antidiarrheals, anti-constipation) 3. no response to above? Psych referral for pain management
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Acute pancreatitis
epigastric pain (severe, persistent) that radiates to back or left scapula n/v, possible jaundice (if stones in common bile duct), tachycardia self-limiting!!
nl have protective mechanisms against pancreatitis (inactive enzyme produce as proenzymes - can only be activated by enterokinase in small intestine; trypsin inhibitors to prevent auto-digestion) insult (gallstones, alcohol) --> loss of protective mechanisms --> proenzyme activation --> digestion of pancreas --> acute changes --> ischemia --> release of inflammatory mediators --> systemic response (sometimes if severe)
gallbladder stones that have migrated to become obstructed in the Ampulla of Vater (pancreatic duct + common bile duct) alcohol idiopathic other (drug induced dideoxyinosine/DDI, 6mercaptopurine/ azathrioprine), iatrogenic ERCP, sphincter of Oddi, high lipids, infection, pancreas divisum, autoimmune, CF, trauma, neoplasm)
abdominal pain + elevated lipase/ amylase Gallstone pancreatitis? Elevated bilirubin, liver enzymes, lipase/amylase, WBC, + gallstones on imaging
supportive care, IV fluids, pain meds
no damage to pancreas; majority of patients do NOT have any complications
Chronic pancreatitis
weight loss, n/v, anorexia, abdominal pain (although some patients are relatively painless), maldigestive diarrhea (steatorrhea, azotorrhea), pancreatic diabetes
hereditary pancreatitis? Gene mutations in alcohol PRSS1, SPINK1 (PST1) idiopathic others (hereditary, CF, CF? gene mutation in CFTR causes pancreas divisum, impaired chloride conductance --> thick autoimmune) secretions/ mucus --> blocks pancreatic duct autoimmune pancreatitis? Lymphocyte infiltration causes fibrosis of pancreas --> pancreatic dysfunction
Autoimmune pancreatitis? Swollen pancreas on CT, +ANA, +IgG4 Structural: dilated pancreatic duct or dilated side branch of pancreatic duct on imaging; calcium deposits throughout pancreas head (ERCP, CT, U/S) Functional: parenchymal changes denoted by secretin/CCK test
ERCP if gallstone in common systemic response: ARDS, bile duct pleural effusion, acute renal antibiotics if infected/necrosis failure, myocardial depression, metabolic complications cholecystectomy if infected (after antibiotics) mortality in <20% cessation of alcohol if etiology early complications (DIC, shock, multiple organ failure); later complications after 1 wk (pseudocyst, increased pancreatic infections, sepsis, hemorrhage) control pain (NSAIDs, permanent damage to narcotics, intestinal uncoated pancreas pancreatic enzyme therapy) pseudocysts, pancreatic ascites, pancreatic fistula, control diarrhea (intestinal splenic vein thrombosis coated pancreatic enzyme therapy)
Acute diverticulitis
visceral dull pain that localizes and becomes severe somatoparietal pain in LLQ constipation, diarrhea, fever more common in sigmoid and descending colon loss of vascular supply by superior/ inferior sudden onset, crampy epigastric & periumbilical pain, mesenteric arteries diarrhea, vomiting, bloating, melena BUT minimal abdominal findings diarrhea, vomiting, melena pain out of proportion to findings acute sudden onset severe midabdominal "tearing" pain pulsatile, tender abdominal mass lightheaded, diaphoresis, nausea
antibiotics, surgical resection of affected colon
Acute mesenteric ischemia
superior mesenteric artery embolus nonocclusive mesenteric ischemia
endoscopy: huge ulcers due to loss of blood supply
Abdominal Aortic Aneurysm (AAA)
Celiac disease
affects duodenum > ileum
immune response to gliaden fraction of gluten --> tissue transglutaminase (tTG) alters gluten peptides when encountering malabsorptive fatty diarrhea, DQ2 or DQ8 --> formation of complexes iron deficiency anemia, osteopenia, bloating, dermatitis that activate T cells --> inflammation & herpetaformis (IgA deposits on villi destruction skin)
gluten allergy a/w autoimmune disorders (SLE, DM type I, RA, thyroid disease)
1/100
Irish / European descent family history
iron, folate, fat-soluble vitamin deficiencies
gluten- free diet
steroids in refractory cases serum tissue transglutaminase replace deficient vitamins (tTG) or anti-endomysial antibody Endoscopy: scalloped pattern histology: flattened/ atrophied mucosal villi; lymphocytic & plasma cell infiltration; hyperplasia of crypts
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Benign liver neoplasms
Cavernous hemangioma
most common benign liver neoplasm
vascular tumor defined by the proliferation of blood vessels
gross: enlarged blood vessels in the cavernous; appear as exophytic red/blue spongy masses that rise and push up against capsule; no evidence of cirrhosis histology: multiple large vascular channels (full of blood or thrombosed) histology: no inflammatory infiltrates; glycogen, no bile ducts visible gross: very bloody mass
NO needle biopsy (could cause bleeding!) surgical excision after > 910cm
possible that they could spontaneously rupture but very rare
Hepatic adenoma
most patients who have these benign neoplasm of hepatocytes present with hemorrhaged hepatic adenoma - sudden RUQ pain
women of childbearing age who have used OCPs
age, OCPs
Bleeding risk!! (especially subcapsular adenomas) Common cause for sudden peritoneal hemorrhage in young women increased risk for HCC
Non-neoplastic hepatocellular nodules
often mistaken for neoplasms
result from vascular malformation after local vascular injury or AVM
women of reproductive age
histology: focal nodular hyperplasia, LOTS of bile ducts gross: central scar (stellate shaped) gross: large nodule arising through a cirrhotic-appearing liver capsule; multifocal carcinoma areas only in HCC from chronic hep/ cirrhosis; o/w HCC is solitary lesion histology: liver lobule cords become 4-5 cells thick, mitotic figures; markedly enlarged and fatty appearing cells; vascular invasion (worse prognosis) elevated alpha-fetoprotein
Hepatocellular carcinoma
[FYI: most common malignant neoplasm of liver? Metastatic carcinomas from GI/colon, breast, lung]
most common primary malignant neoplasm silent hepatomegaly (if noncirrhotics), rapid increase in liver size, worsened ascites, increased pain
cirrhosis hemochromatosis chronic HBV or HCV chronic alcoholism aflatoxin exposure hemochromatosis
prognosis best if single tumor is <2cm in size and good liver function
Cholangiocarcinoma
markedly distended abdomen type of adenocarcinoma involving intrahepatic and extrahepatic bile ducts from ascites (obstruction of lymphatic drainage --> large fluid majority arise from extrahepatic biliary accumulation) tract, especially at hilum (Klatskin tumors jaundice - common hepatic duct) more common than cholangiocarcinoma arises in patients with recurrent trauma and inflammation due to chronic cholecystitis and/or cholelithiasis
PSC, cysts of biliary tree, chronic infection w/ liver fluke CIRRHOSIS PATIENTS DO NOT HAVE INCREASED RISK! usually occurs in presence of gallstones
histology: formation of haphazard glandular structures gross: dilated duct lumen from obstruction Hispanics, Native histology: malginant lesions Americans have loss of cell polarity, eccentric nuclei, & hypochromatic areas; resembles glandular structures Female Female
Adenocarcinoma of gallbladder
Cystic pancreatic neoplasms
serous cystic neoplasms mucinous cystic neoplasms
females; generally benign Females
Pancreatoblastoma
less predictable biologic behavior solid pesudopapillary young females tumors mostly indolent but some have aggressive growth malignant tumor of infancy/childhood
YOUNG FEMALES
epithelial and mesenchymal elements
KIDS!!! (rare cases in adults, who would have worse prognosis)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Pancreatic ductal adenocarcinoma
etiologic agent causes genetic mutations environmental: cigarete in k-ras oncogene, p15 tumor suppressor, smoking, petroleum product p53 tumor suppressor, DPC4, BRCA2 exp, lack of fruits/veggies, asymptomatic until late stage alcohol (due to chronic progression from PanIN to then present with epigastric pancreatitis) pain, unexplained weight loss, adenocarcinoma - PanIN- 1: mild dysplasia (Her-2neu, host: chronic pancreatitis, painless jaundice, + Kras) diabetes, pancreatic Trousseau's sign (migratory - PanIN-2: moderate dysplasia (p16) intraepithelial neoplasia thrombophlebitis) - PanIN-3: severe dysplasia (p53, BRCA3, (PanIN) DPC4) most common malignancy of pancreas (80-90%) distributed most commonly in pancreas head, but time of diagnosis, they have metastasized to liver, LNs, peritoneum
4th leading cause of cancer death
age (older patients elevated CA 19-9 surgery for symptom relief but <5% 5y prognosis 60-80 y.o.) majority are surgically gross: area of scarring/fibrosis unresectable Staging (T1- limited to around growing tumor pancreas, small; T2 - limited genetics: 1st to pancreas, larger; T3degree relatives (yellowish/whitish and firm to beyond pancreas but not yet touch) - same fibrosis as w/ hx, HNPCC, celiac axis or SMA; T4 hereditary breast/ chronic pancreatitis! beyond pancreas, involving ovarian cancer celiac axis and/or SMA) (BRCA2), familial Histology: fibrous tissue + abnl epithelial cells (resembles atypical mole syndrome, Peutz- chronic pancreatitis) Jegher's syndrome, hereditary pancreatitis
Pancreatic Acinar Cell carcinoma
rare malignant tumor tumors secrete lipase/ trypsin/ amylase
arise from acinar cells - secrete digestive enzymes
poor prognosis but slightly better than ductal adenocarcinoma
Pancreatic Islet Cell Neoplasms
Clostridium dificile
subcutaneous fat necrosis in the skin (painful) majority are functional (secrete Insulinoma - body & tail, usually benign; enzymes that determine hard to control hypoglycemia; abnl HI symptoms) insulin secretion 15-35% are silent (subclinical gastrinoma - 2/3 malignant, excess acid hormone levels) production --> PUD; Zollinger-Ellison syndrome associated w/ MEN-1 VIPoma- watery diarrhea + hypokalemia syndrome + achlorhydria Glucagonoma - body & tail, malignant, difficult to predict biologic refractory hyperglycemia/ diabetes, behavior necrolytic migratory erythema Somatostinoma - inhibitory so shuts everything down; DM, steatorrhea, hypochlorhydria, cholithiasis toxigenic, gram positive spore forming Antibiotic induced diarrhea! inflammatory diarrhea anaerobic bacillus characterized by tender LLQ, increased frequency in bowel colonization --> disruption of normal flora movements by antibiotics --> toxin elaboration (particularly toxin B) --> diarrhea & colitis pseudomembranous colitis a/w fever, dehydration, tachycardia majority of cases are asymptomatic 1-2 week incubation period
2% of all pancreatic tumors
gross: abundant blood supply (unlike adenocarcinomas which are more white/ yellowish) histology: monotonous appearing
malignancy determined by hormone secreted, size of tumor, & aggressiveness
Antibiotic use, hospital setting, elderly, chemotherapy, surgery, Ulcerative colitis
CT: pericolonic stranding & colonic wall thickening indicating infectious process
Metronidazole (Flagyl) if mild- shock, toxic megacolon, moderate perforation, sepsis, & death
oral vancomycin for severe positive C. dif toxins (A/B) on cases PCR probiotics decrease recurrence metronidazole or tinidazole [toxicity/ side effect = disulfuram effect = nausea and severe symptoms]
Giardia lamblia
(Flagellate)
Entamoeba histolytica
symptoms: malabsorptive diarrhea, steatorrhea, cramps, bloating, nausea, weight loss, vomiting, fever ingestion of cysts from environment leds bloody stools (inflammatory), to development of trophozoites in large dysentery colon --> invasion into epithelia (unlike Giardia, which is local and stays in duodenum/jejunum) Cryptosporidium parvum self-limiting watery diarrhea (can sexual & asexual stage be very mild) immunosuppresed have chronic refractory illness w/ high recurrence rate
cysts in environment/water are ingested -> once in GI tract, they develop trophozoites that attach to duodenal/ jejunal mucosa --> local inflammation & villi blunting --> hypersecretion & malabsorption
contaminated water supplies; found worldwide streams, ponds (near reservoirs - beavers, muskrats) daycare centers
daycare, camping stool microscopy for O&P
immigrants & travelers to developing world
stool microscopy & immunoantigens liver abscess aspirate = "anchovy paste" - rust colored
metronidazole for trophozoites; paranomycin for cysts
extra-intestinal manifestations (amoebic liver/lung/ brain abscess)
Apicomplexa parasites
contaminated surface water or global water supplies
Isospora belli Cyclospora cayetanesis
mostly tropical regions contaminated fruits & veggies mostly tropical regions
Microsporidia
Enterocytozoan bienusi
fungal organisms that produce pathology when spores are inhaled or ingested
global
histology: small round oocysts seen with AFB stain; within epithelial cells but do not invade farther than this barrier histology: shaped like an "I" but has 2 nuclei histology: small round oocysts seen with AFB stain; within epithelial cells but do not invade farther than this barrier histology: polar tubules
Nitazoxanide (NTZ)
TMP-SMX (trimethoprimsulfamethoxazole; Bactrim)
ALB (albendazole), FMG (fumagillin)
self-limiting watery diarrhea (can be very mild) immunosuppresed have chronic refractory illness w/ high recurrence rate
Disease
Microsporidia
Clinical Variants
Pathogenesis
fungal organisms that produce pathology when spores are inhaled or ingested
Etiologies
Epidemiology
global
Risk factors
Lab/Imaging
histology: polar tubules
Treatment
ALB (albendazole), FMG (fumagillin)
Complications
Strongyloides stercoralis
Encephalitozoon intestinalis (Nematodes)
symptoms: itchy rash/ ground itch (initial penetration), larva currens (serpentigous mobile rash), urticaria; Loeffler's syndrome (wheezing, transitory pulm infiltrates, eosinophilia), GI symptoms (if high worm burden: abdominal pain, diarrhea, malabsorption) hyperinfection - fever, abd pain, wheezing, dyspnea, hemoptysis, sepsis most common infection worldwide
infection from skin penertration by larvae soil in soil --> larvae migrate to blood, gaining access to alveoli & lungs--> move towards trachea where they are swallowed --> reach GI tract (small bowel) --> larvae mature and burrow in duodenum & jejunum --> lay eggs that hatch in the intestine --> autoinfection --> hyperinfection syndrome
tropical, subtropical areas; southern US
poor sanitation places barefeet immunocomp at risk for hyperinfection syndrome
serology biopsy would show adult worm burrowing in small bowel
IVERMECTIN (binds to glutamate-gated chloride channels causing parasite paralysis & death)
Other nematodes
Ascariasis
ingestion of eggs
poor sanitation places
stool exam +/- eosinophils
Enterobiasis
migrates from skin & lung as adult worm to asymptomatic unless high worm jejenum burden --> obstruction ingestion of eggs --> infection of colon & pinworm anus most common helminth in U.S. female nematodes migrate out of rectum to the anus, where they lay eggs ANAL ITCHING whipworm colitis (bloody stools), rectal prolapse major contributor to global malnourishment high worm burden --> significant blood loss, low albumin, and low nutrients cysticercosis --> epilepsy hyatid cysts vitamin B12 deficiency, macrocytic anemia swimmer's itchy, Katayama fever, chronic dz increased risk of Cholangiocarcinoma RUQ pain, fever, jaundice occur usually after travel to resource poor country; shortlived secretory diarrhea invades & destroys colon mucosa, causing colitis & rectal prolapse infects cecum & colon acquired through skin, after which the worm uses teeth to attach to lungs & small bowel mucosa tropical areas
ALB (albendazole- inhibits polymerization of tubulin & tubulin dependent glucose uptake), MBZ (mebendazole) ALB, MBZ
daycare!!!
scotch tape - characteristic eggs
Trichuriasis
stool exam +/- eosinophils
Hookworm
700 million people affected; primarily developing countries
Cestodes/ flatworms
Blood flukes Liver flukes
Taenia solium Taenia saginata Echinococcus Diphyllobothrium latum Schistosomiasis Clonorchis sinensis Fasciola hepatica ETEC (Traveler's diarrhea)
PORK BEEF DOG, SHEEP FRESHWATER FISH FRESHWATER RAW FRESHWATER FISH WATERCRESS contaminated food & water
E. coli
EHEC (SHEC; E.coli hemorrhagic colitis (bloody O157:H7) diarrhea)
heat labile enterotoxin causes increased cAMP secretion --> secretion of chloride into lumen --> water follows chloride (hence watery diarrhea) Shiga cytotoxin damages cells/brush border/ mucosa --> bloody colitis
hydration; antimotility meds; fluoroquinolones (CIPRO) appears colorless on sorbitol SUPPORTIVE CARE ONLY agar plate; Shiga toxin assay (antibiotics are contraindicated) Hemolytic uremic syndrome (HUS) = anemia,thrombocytopenia, renal failure [1wk post diarrhea; more common in children, but 12% affected require dialysis or die from ESRD]
food, water, & person-toperson transmission
Salmonella
Salmonella typhi Salmonella typhimurium Salmonella enteritidis
typhoid fever self-limited acute enterocolitis; 6-48h post-food ingestion & lasts 3-7days watery stools, abdominal cramping, n/v
contaminated human sewage contaminated food with animal waste
seen often during environmental crises elderly, immunocomp, invasive disease, Sickle cell ANTIBIOTIC TX NOT decreased gastric acidity RECOMMENDED in lowers infectious dose uncomplicated gastroenteritis increased susceptibility (could increase organism carriage)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
Food Poisoning
immediate disease about 1-16h preformed toxins (S. aureus - potato salad, cream pastries, mayo; Bacillus post ingestion cereus - fried rice, spores) n/v, watery or inflammatory quickly produced toxins (C. perfringens, diarrhea, abdominal cramps B. cereus) microbial contamination of food products (V.cholera - shellfish; ETEC, EHEC- ground beef, raw veggies, unpast juice; Salmonella - poultry, eggs, beef, dairy, peanuts; Campylobacter - poultry, raw milk; Shigella; Vibrio parahemolyticus mollusks, crustaceans; norovirus)
Rotavirus
primary cause of acute gastroenteritis in young children in U.S. Vomiting, fever, watery diarrhea --> dehydration & electrolyte abnl
nonenveloped dsRNA virus
fecal-oral; possible airborne spread winter season
600-850K deaths/ year globall
antigen assays, RT-PCR, culture
rehydration
Norovirus
most common cause of foodborne outbreaks investigated sudden onset N/V; short lasting watery diarrhea acute onset, intermittent abdominal pain; vomiting (bilious, fecal), obstipation, abdominal distention
relatively low infectious dose so easy to spread from person to person
fecal-oral; aerosol-vomitus; fomites; contaminated food
cruise ships
supportive treatment only
Small bowel obstruction
post-operative intra-abdominal adhesions; hernias (bowel leaves peritoneal cavity and becomes obstructed); neoplasms;congenital atresia/stenosis, inflammatory causes PE: periods of increased bowel (IBD, ischemia, diverticulitis, radiation, drugs), intussusception (bowel telescopes sounds followed by intervals of quiet; hi pitched or musical BS; into another part of the bowel); gallstones, abdominal tenderness; guarding volvulus, metastasis, endometriosis, abscess (strangulation/ bowel ischemia); systemic manifestions of dehydration (tachycardia, tachypnea, AMS, oliguria, hypotension) sigmiod colon & cecum are malignancy, volvulus, stricture most common sites for colonic secondary to diverticulitis; Crohn's, endometriosis, intussusception, extrinsic volvulus tumors, fecal impaction periumbilical/ hypogastric abd pain, abd distention, diarrhea or obstipation benign colonic strictures? Thinner stool malignant colonic strictures? Hematochezia, iron def anemia, weakness, weight loss, vomiting, insiduous onset
Elevated WBC count; abnl IV fluids, correct serum serum electrolytes; renal failure electrolytes; NG tube (decompress stomach, XR: dilated SB loops minimize further distention) CT: dilated SB loops + complete SBO +/- evidence of transition point where peritonitis - systemic Abs + obstruction occurs laparotomy air fluid levels partial SBO - above recommendations unless no improvement, then proceed to surgery
Large Bowel Obstruction (colonic)
CT, barium studies, XR
IV fluids, correct serum electrolytes; NG tube colonic obstruction secondary (decompress stomach, to malignancy? Dilated colon minimize further distention) until tumor, after which colon Benign strictures - surgery narrows off (should use colonoscopy to biopsy tumor) malignant strictures - surgery sigmoid volvulus? Bent inner or colonic stents tube appearance + dilated sigmoid volvulus colon protoscopic/colonoscopic decompression; rectal tube; sigmoid resection & coloproctostomy cecal volvulus - NO COLONOSCOPY; cecostomy, resection NPO until symptoms resolve; NG tube; correct electrolytes; limit narcotics; get patient moving out of bed!
Bowel ileus
failure of nl intestinal motility postoperative; inflammatory (diverticulitis, in absence of obtructing lesion pancreatitis), metabolic (abnl electrolytes); neurogenic, meds (narcotics) poorly localized abdominal pain, abdominal distention, n/v, obstipation hypoactive bowel sounds
XR/CT: presence of gas in stomach, SI, colon + dilated small bowel no mechanical obstruction!!
Disease
Clinical Variants
Pathogenesis
Etiologies
Epidemiology
Risk factors
Lab/Imaging
Treatment
Complications
acute colonic pseudo obstruction
severe abdominal distention with absence of stool/gas passage
critically ill patients dilation of ALL segments of colon
Inflammatory bowel disease
Crohn's disease
RLQ pain, weight loss, arthritis/arthalgias, watery diarrhea inflammatory; obstructing; fistulizing/microperforating subtypes extraintestinal manifestations? FTT, erythema nodosum (extensor surfaces), pyoderma gangrenosum, monoart/ asymm/ large joint peripheral arthritis, uveitis, episcleritis, PSC (more in UC; runs independent course from IBD), sacroileitis, ankylosing spondylitis bloody diarrhea, tenesmus, LLQ pain, rectal bleeding, arthritis/ arthalgias extraintestinal manifestations? FTT, erythema nodosum (extensor surfaces), pyoderma gangrenosum, monoart/ asymm/ large joint peripheral arthritis, uveitis, episcleritis, PSC (more in UC; runs independent course from IBD), sacroileitis, ankylosing spondylitis
persistent infection (H. pylori, highest prevalence in invasive E. coli, Listeria), Europe & North America defective mucosal integrity (altered mucus, increased M=F disruption of intestinal epithelial barrier + perm, impaired resolution), dysregulated immune dysregulated immune response --> response, dysbiosis secretion of IL-23 by macrophages --> induction of TH17 cells to activate IL-17 -- (decreased protective bacteria, increased pathogenic bacteria) > abnormal processing of antigens (deficient autophagy) affects any portion of GI tract; skip lesions, spares rectum, transmural inflammation; granulomas CARD15/NOD2 mutation - a/w ileocolonic dz; early onset; early surgery; early recurrence post-surgery; familial CD
Caucasians Ashkenazi Jews; SMOKING in Crohn's disease NSAIDs genetic predisposition
correct reversible causes; mortality 0-32% neostigmine (AChE inhibitor), endoscopic decompression, percutaneous cecostomy, surgical decompression CBC, elevated ESR/CRP, low induction of remission? mostly affects ileocolic albumin if weight loss area/terminal ileum, small Steroids, antibiotics bowel, & colon but can affect ANY part of GI tract colonoscopy: severe maintenance of remission? (stomach, esophagus) inflammation leading to Antibiotics + 6MP/AZA ulcerations/ obstruction (inhibit purine biosyn in B & T cells) + biologics (antibodies histology: transmural inflamm against cytokines & adhesion process w/ lymphocyte molecules) infiltrates; non-necrotizing granulomas
Ulcerative colitis
only involves colon, rectum ALWAYS involves, continuous distribution in involved area (no skip lesions), inflammation in mucosa only disruption of intestinal epithelial barrier + dysregulated immune response --> secretion of IL-23 by macrophages --> induction of TH17 cells to activate IL-17 -> defective epithelial barrier function
CBC: microcytic anemia; low albumin (if weight loss), elevated ESR/CRP, stool culture to R/O infection; endoscopy w/ bx endoscopy: mild (erythema, preserved circular muscles); moderate (edema, inflammatory cell infiltrate, bleeding/ ulcerations); severe (denuded mucosa, blunted haustrations, thickend w/ inflamm material)
induction of remission? Steroids, 5-ASA (reduce prostaglandins) Maintenance of remission? 5-ASA, 6MP/AZA, biologics
40% proctitis alone; 30% left sided disease; 30% pancolitis
intractable disease; hemorrhage; perforation; toxic megacolon; colon extremely severe? Colectomy cancer (correlates w/ duration, extent, severity of UC)
Acute appendicitis
obstruction of appendix lumen by fecolith early: non-specific, dull --> appendix distention, inflammation & periumbilical pain later: well-localized RUQ pain @ infection McBurney's point, n/v, fever
250,000 cases per year in US ages 10-30 M>F
histology: erosion of mucosa, crypt abscesses (due to neutrophilic infiltration) elevated WBC count pre-op antibiotics + perforation --> peritonitis, immediate appendectomy if abscess formation, sepsis CT: donut sign = thickened sx present for 24-72h appendix wall if sx longer than 5d, delayed surgery in lieu of long course antibiotics
Diverticulosis
Diverticulitis
complicated diverticulitis perforation, abscess, fistulization uncomplicated - inflammation w/o complications; MAJORITY of cases LLQ pain & tenderness; low grade fever
herniations of mucosa and submucosa through defects in muscularis; usually in sigmoid colon microscopic or macroscopic perforation of diverticulum (usually via erosion of wall by fecoliths or by increased intraluminal pressure)
western world
low fiber diet age!!
10-25% of patients w/ diverticulosis
CT - complicated will show 20-40% of patients will have uncomplicated? Cipro + peritonitis, perforation, abscess metronidazole, colonoscopy a second attack, after which formation complications are more likely after recovery complicated? Peritonitis (IV antibiotics + surgical exploration); abscess requires drainage surgery (laparoscopic resection) after complicated episode or 2-3 episodes of uncomplicated; immunosuppressed
certain foods or trauma can precipitate the lesion
cancers a/w HPV have better prognosis though!
Prognosis determined by depth of invasion
Prognosis determined by depth of invasion
aggressive behavior determined by size and number of mitoses
indications for surgery (PUD bleeding): massive hemorrhage leading to shock; prolonged blood loss w/ more than 6 units transfusion; recurrent bleeding despite endoscopic tx; recurrent bleeding during hospitalization
IgG antibody vaccination to protect against HepA
vaccination [IM injection @ 0, 1, 6 months] provides HBaAg required for all HCWs Hepatitis B immunoglobulin (HBIG) - offered to high risk patients, exposed infants, or liver transplant patients (before new liver in, 1 week post-transplant)
screen all baby boomers!!
1. R/O other causes of liver disease 2. consider every drug/ med/ herbal 3. stop all non-essential meds 4. known common patterns (INH, statins, etc) 5. Know potential specific treatments 6. DO NOT RECHALLENGE (exception: tylenol)
1. R/O other causes of Screening / liver disease Education 2. consider every drug/ med/ herbal 3. stop all non-essential meds 4. known common patterns (INH, statins, etc) 5. Know potential specific treatments 6. DO NOT RECHALLENGE (exception: tylenol)
Ranson criteria for severity upon admission: initial admission- assess patients age > 55, WBC, AST, LDH enzymes, & glucose; within 48h, assess Ht, Ca++, BUN, pO2, fluid deficit, base deficit; if initial and/or 48h labs meet criteria, can figure out morbidity & mortality
bottled beverages; avoid ice & uncooked food
cook ground beef; avoid food cross contamination; hand wash after all animal contact; diaper hygiene at pools
live, oral vaccines for infants (Rotarix)
Disease Fanconi's Syndrome
Clinical Variants
Pathogenesis
Etiologies Cystinosis (auto recessive; most common cause in childhood)
Epi
Risk factors
Lab/Imaging
Treatment
Complications
metabolic acidosis (bicarb proximal tubule dysfunction from global wasting), hypophosphatemia defect in all PT transporters (Ricket's - bow legged, prominent forehead, wrist widening, FTT; osteomalacia), glucosuria, low serum uric acid, amino aciduria Adrenal adenoma metabolic alkalosis, hypokalemia, adrenal gland autonomously produces refractory HTN aldosterone, without signals from ATII; thus, aldosterone is constitutively active despite volume repletion. Aldosterone then acts on CCD to increase Na+ reabsorption and K+ secretion [excess aldosterone effect] A- obstructive sleep Apnea, Adrenal glands (cortex aldosterone, cortisol; medulla pheochromocytoma) B - bruits (renal artery stenosis), bad kidneys C- catecholamines, coarct of aorta, Cushing's syndrome D - drugs, diet E - erythropoietin excess, endocrine (thyroid, growth hormone) severe HTN from Na retention, 1/2 of collecting duct sodium channels have low aldosterone & renin levels, mutation that renders them constitutively hypokalemia, metabolic alkalosis active despite normal volume levels and no aldosterone present; hence, constant CD sodium reabsorption and K, H secretion volume depletion --> renin secretion --> ATII production; however, the adrenal gland has genetic defect in which it cannot respond to ATII to make aldosterone [aldosterone deficiency/ absence] elevated aldosterone levels, absence of functional sodium channels in hyponatremia, profound cortical collecting duct, thus CCD cells do not metabolic acidosis, hyperkalemia reabsorb Na or secrete K despite very high levels of aldosterone [aldosterone deficiency/ absence] similar symptoms to side effects genetic defect in Na/Cl cotransporter in DCT of thiazide diuretics (same transporter that is blocked w/ thiazides) volume depletion, hypokalemia, metabolic alkalosis, hypomagnesemia, salt cravings, hypocalciuria, hyponatremia early age presentation similar sx to side effects of loop diuretics hyponatremia, hypokalemia, hypochloridemia, metabolic alkalosis, hypercalciuria
Secondary causes of hypertension
(listing)
Liddle syndrome
autosomal dominant disorder
Congenital adrenal hyperplasia
21-hydroxylase life-threatening hyperkalemia, deficiency profound metabolic acidosis, hyponatremia, severe volume depletion
autosomal recessive disorder
usually diagnosed @ birth w/ NBS
synthetic aldosterone infusion
Pseudohypoaldosteronism Type I
Gitelman syndrome
check magnesium because hypomagnesemia can cause refractory hypokalemia
replace K, Mg losses; restore intravascular volume w/ salt
Bartter syndrome
genetic defect in NKCC co-transporter in TAL autosomal recessive of loop of Henle, causing volume depletion disorder and aldosterone production
Disease Hyponatremia
Clinical Variants
Defining Characteristics seizures (neuro emergency) or can be gradual onset (intact neuro exam)
Pathogenesis decreased effective circulating volume from true volume loss (GI loss) or perceived volume loss (edematous states - CHF, cirrhosis, nephrotic syndrome), thiazides, SIAD, cortisol deficiency, hypothyroidism, primary (psychogenic) polydipsia, decreased solute intake (beer potomania), or reset osmostat
Etiologies
Epi
Risk factors
Lab/Imaging electrolyte panel, calculate serum osmolality thyroid function tests, med hx, urine osmolality
Treatment
Complications
acute - water restriction seizures (<150 mL/day), hypertonic saline, loop overcorrection can diuretic (creates cause CPM isoosmotic medulla, preventing water reabsorpton), Vaptan (V2 receptor antagonist- $$) chronic (tumor)- water restriction (though horrible QoL), hi salt/ hi protein diet, loop diuretic, demeclocycline (contraind in liver dz), urea, lithium (manic depressive d/o), vaptan
Syndrome of Inappropriate Anti-Diuresis (SIAD)
1. normovolemic, mildly hypervolemic (NEVER hypovolemic) 2. nl renal, adrenal, and thyroid functions 3. serum hypotonicity WITHOUT maximally dilute urine (patients have inappropriately concentrated urine)
normally, ADH is released with hypovolemia (hi serum osmolality), resulting in the retention of water; however, patients with SIAD have hyponatremia with very concentrated urine - suggesting that ADH is active despite normal or hypertonic volume levels (would expect very dilute urine in low serum osmolality situations)
CNS disorders, pulmonary disorders, ectopic ADH production, meds (chlorpropamide, cyclo-phosphamide IV, carbamezepine)
Imaging of head/lungs, normal urine osmolality, low serum osmolality, hyponatremia
Treat sodium deficit (Na+ hyponatremia can needed = 0.6x body cause seizures, weight (kg) x (120cerebral edema plasma Na) overcorrection of normal saline is sodium levels can contraindicated!! cause central pontine neurolysis 3% hypertonic saline + (CPM) loop diuretic
Hypernatremia
water loss (insensible loss from skin, lungs; renal loss from DI, osmotic diuresis; GI loss, loss into cells from seizures, severe exercise, rhabdomyolysis) hypertonic saline IV problem with the production (damage to idiopathic, hypothalamus) or secretion of ADH (damage hypothalamus to posterior pituitary) trauma, hypoxic encephalopathy, posthypophysectomy, neoplastic infiltration, sarcoidosis, Sheehan's syndrome
Central diabetes insipidus
complete, partial
polyuria, dilute urine, hypernatremia
water deprivation study (water deprivation = increased plasma osmolality but NO concurrent increase in urine osmolality)
exogenous ADH helpful for complete and partial central DI [dDAVP desmopressin nasal spray; vasopressin tannate in oil, aqueous vasopressin] partial central DI - can also use chlorpropamide, carbamezipine, or clofibrate
Nephrogenic diabetes insipidus
Congenital
high urine output (20L/day), bladder enlargement & obstruction (from attempts to retain urine), hypernatremia polyuria, dilute urine, hypernatremia
Acquired complete, partial
X- linked mutation in V2 vasopressin receptor OR autosomal recessive mutation in aquaporin P2 water channels causes failure to respond to ADH, thus water is not reabsorbed (water wasting) destruction of renal medulla (papillary necrosis) from sickle cell anemia, analgesic nephropathy, or renal failure osmotic diuretics like glucose, mannitol, urea electrolyte abnl (hypercalcemia, hypokalemia)
children
hydration + low sodium diet
water deprivation study (water deprivation = increased plasma osmolality but NO concurrent increase in urine osmolality)
not responsive to exogenous ADH (because problem with end-organ!) thiazide diuretics + low sodium diet (decreases overall urine output by keeping mild volume depletion state and increasing PCT reabsorption)
Disease Edematous states
Clinical Variants CHF
Defining Characteristics edema
Pathogenesis Na retention: Chronic CHF = decreased baroreceptor sensitivity & increased SNS/RAAS activity = increased PTC reabsorption of Na, H2O = decreased delivery of Na, H2O to distal tubule = activation of aldosterone (failure to escape ald) = even more Na, H2O retention = increased cardiac filling pressure water retention: chronic CHF = non- osmotic ADH release = activation of V1 receptor (heart remodeling, coronary constriction, vasoconstriction, myocardial ischemia, and increased cardiac afterload) and V2 receptor (water retention in CCD, increased preload) = worsening wall stress
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Cirrhosis
ascites
early cirrhosis results in hepatocyte damage and NO release = splanchnic arterial vasodilation and mechanical obstruction to portal flow = portal hypertension (portal press > 12mmHg) = activation of SNS (NE), RAAS, & ADH = Na & H2O retention = ascites = increased plasma volume and cardiac output
Nephrotic syndrome
(general)
severe proteinuria (>3.5g / 24h urine), low serum albumin, generalized edema (due to loss of oncotic pressure from loss of large blood proteins), hyperlipidemia (triggered by hypoalbuminemia), hyperlipiduria
Derangement in the glomerular capillary walls increased permeability to plasma proteins massive proteinuria and loss of albumin (so much that the liver cant catch up) loss of albumin (oncotic pressure) causes leakiness of the vasculature edema
95% of cases in children related to systemic disease w/ primary glom renal manifestations dz (only 60% (DM, SLE, of adult Amyloidosis, drugs - cases) gold, penicillamine, Liver realizes that so much protein is being heroin; infection 40% of adult lost and ramps up production of lipoproteins; malaria, syphilis, cases from increased production accompanied by hep, HIV; systemic dz abnormal transport and decreased malignancy w/ renal catabolism leads to hyperlipidemia carcinoma, manifestation lymphoma, s melanoma; misc bee sting allergy) genetics most common in Finland
Primary glomerular disease
UA 24h urine protein albumin blood test, lipid panel renal biopsy w/ immunofluorescence
hepatorenal syndrome (cirrhosis = portal HTN = splanchnic vasodilation = stimulation of vasoconstriction in kidney = hepatorenal syndrome) renal failure infection (Staph, pneumococci; loss of proteins like Ig, complement) thrombosis, thromboembolism (loss of anticoagulant factors)
Congenital Nephrotic Syndrome
onset of nephrotic syndrome (massive proteinuria, hypoalbuminemia) within the first 3 months of life, but usually within a few days a/w premature birth, large placenta, skeletal deformities, poor motor development, progressive renal failure elevated creatinine subepithelial dense deposits and thickened GBM 60% of pts will have persistent proteinuria (10-30% may have partial --> complete remission); 40% develop progressive renal insufficiency or ESRD
resistant to most treatments; severe cases require bilateral nephrectomies and subsequent lifelong dialysis
death secondary to sepsis other complications hyper-coagulopathy, infection, stroke
Membranous nephropathy
vast majority are primary/ idiopathic
onset ages 30-50 y.o.
15% of cases are One of most result of systemic dz common (autoimmune - SLE, primary infxn - hepB/C, glomerular syphilis, malaria, causes of schistomiasis; drugs - nephrotic penicillamine, syndrome in captopril, gold, Hg, adults NSAIDs; malignancies - colon, lung, melanoma)
Renal bx: PAS - increased mesangial matrix, thickened capillary loops; Silver stain - thickend GBM, glomerular spikes EM: subepithelial immune complex deposits; thickened GBM IF: granular subepithelial deposits for IgG along capillary loops
ACEI + steroids (or immunosuppresants like cyclophosphamide if not response)
Disease
Clinical Variants Minimal change disease
Defining Characteristics normal biopsy findings EXCEPT diffuse foot process effacement insidious onset in o/w healthy kids; proteinuria w/ preserved kidney function
Pathogenesis epithelial cell (podocyte) injury
Etiologies
Epi most common nephrotic syndrome in kids
Risk factors
Lab/Imaging Creatinine: nl (nl GFR) LM: nl glomerulus IF: none EM: diffuse foot process effacement (fusion)
Treatment
Complications
steroids (90% resolution) <5% develop chronic renal failure
Focal Segmental Glomerulosclerosis (FSGS)
important to distinguish from minimal change dz!!! Sclerosis involving segments of some, but not all, glomeruli (hence focal/segmental) Abnl creatinine (abnl renal function), can have RBCs/ hematuria on UA (in addition to typical nephrotic syndrome sx), HTN little tendency for spontaneous remission
primary /idiopathic secondary (HIVcollapsing variant of FSGS; heroin use, HTN, reflux nephropathy, unilateral renal agenesis/ dysplasia; primary glomerulopathies, SCC, renal transplant, diabetic nephropathy, obesity)
renal bx: scarred interstitium poor response to steroids (thyroidization), pink dense obsolete & scarred glomeruli; focal/ segmental scarring of glomerulus (proteinaceous collection of hyaline in the sclerotic segment @ higher power) IF: none EM: diffuse foot process effacement + focal/segmental sclerosis of glomerulus
50% have renal failure in 10y 20% rapidly progress to ESRD in 2y recurrence in 2550% of transplants
Nephritic presentation
(general)
hematuria (gross, microscopic, +/- RBC casts in UA), acute renal failure (azotemia increased BUN; oliguria), HTN, +/- proteinuria, +/- edema, usually secondary to acute GN very similar to expt acute serum sickness! strains of group A B- decreasing hemolytic freq in U.S. one-shot antigenemia results in deposition streptococci Abrupt onset of malaise, fever, Children 6of circulating immune complexes in nausea, oliguria, & hematuria 1-4 glomeruli and activation of classical pathway 10 y.o. but weeks after streptococcal also adults of complement infection of pharynx or skin (impetigo) also has in-situ formation of immune complexes from cross-rxn of anti-strep coca-cola colored urine antibodies w/ glomerular antigens RBC casts in urine, mild proteinuria, periorbital edema, mild-mod HTN similar to EASS serology: elevated anti-streptolysin >95% of kids recover w/ conservative tx (selfO (ASO) titers, hypocomplementemia, +/- cryoglobulins limiting dz) histology: diffuse (>50%) proliferation of glomeruli, hypercellularity (PMNs), RBC casts in tubules; endocapillary proliferation EM: sparsely distributed subepithelial humps, mesangial immune deposits IF: starry sky for IgG, C3 <1% of kids do not improve, become severely oliguric, and develop rapidly progressive GN
Acute poststreptococcal GN (postinfectious GN)
Membranoproliferative GN Type I (MPGN1)
variable presentation (hematuria, mild proteinuria, mixed nephroticnephritic) MPGN is predominantly hematuric but an be nephrotic/nephritic; poor prognosis in contrast to APSGN; characterized by diffuse proliferative GN but looks like APSGN under LM; predominantly C3 deposition; subendothelial immune deposits under EM; mesangial interpositioning and tram-tracking by silver stain
kids > adults
histology: diffuse proliferative GN w/ lobular appearance; mesangial proliferation, thickened capillary loops, variable endocapillary prolif IF: granular pattern of C3 deposition EM: subENDOthelial immune deposits, mesangial interpositioning w/ formation of new GBM silver stain: tram-tracking
none very effective
few spont remissions slowly progressive but unremitting (50% develop chron renal failure in 10 y)
Disease
Clinical Variants Membranoproliferative GN Type II (MPGN2)
Defining Characteristics looks similar to Type I under LM dense deposit disease linearized bands of C3 deposits a/w partial lipodystrophy hypocomplementemia for C3 only!!
Pathogenesis abnormalities suggest activation of alternative complement pathway: decreased serum C3 but normal C1, C4; diminished levels of factor B and properdin (components of alternative complement pathway) C3 convertase cleaves C3 to C3bBb; C3 convertase normally stabilized by properdin & C3NeF = C3 nephritic factor (70% of patients w/ MPGN2) to keep alternative pathway active C3NeF = autoantibody that binds to C3 convertase, stabilizing the convertase and protecting it from enzymatic degradation; thus, persistent C3 degradation and hypocomplementemia
Etiologies
Epi
Risk factors
Lab/Imaging LM: diffuse proliferative GN w/ lobular appearance (just like type I) linearized bands within the GBM IF: linearized C3 dense deposits along peripheral capillary loops, some mesangial deposits
Treatment
Complications
Crescentic GN (Anti-GBM, Goodpasture's dz)
Anti- GBM dz: limited to kidneys, in-situ antibody formation to fixed antigen in rapidly progressive GN (RPGN) non-collagenous domain of Collagen type IV in GBM w/ nephritic presentation and ARF ruptured GBM from antibodies attacking antiNC1 domain causes destruction of collagen Goodpasture's: involves type IV and release of fibrin, stimulating the kidneys & lungs (pulmonaryproliferation of parietal epithelial cells and renal syndrome - ARDs + formation of cellular crescents RPGN) similar to expt anti-GBM dz Goodpasture's dz: anti-NC1 domain Abs cross react w/ pulmonary BMs, causing rupture and pulmonary hemorrhage
IF: linear IgG appearance along glomerular capillary loops histology: cellular crescents (parietal epithelial cell proliferation)
Systemic diseases w/ renal manifestations
Diabetes mellitus diabetic nephropathy
Type I (10%) - deficiency of insulin secretion Type II (80-90%) - peripheral insulin resistance, inadeq pancreas compensatory response Early events: microalbuminuria, hyperfiltration (inc GFR), kidney enlargement, inc mesangial matrix & GBM thickening
Diabetic nephropathy: affects glomeruli, vessels, & tubointerstitium 1. High level of glucose causes nonenzymatic glycosylation of proteins, creating advanced glycosylation end-products that can result in tissue damage 2. Hyperglycemia activates PKC, inducing activation of pro-angiogenic molecules like VEGF 3. Hyperglycemia disturbs the polyol pathway, causing the metabolism of sorbitol diffuse/nodular GS, glom and decreased intracellular antioxidant hyalinosis lesions, glom capillary reserves, increasing susceptibility to free microaneurysms, interstitial radical damage fibrosis, tubular atrophy, hyaline ateriolo-sclerosis, accelerated atherosclerosis
25.8 million children and adults in the U.S.
renal bx: inc mesangial matrix, hypercellularity, glomerular hyalinosis, slit-like lumen, glomerular microaneurysms, hyaline arteriolo-sclerosis of afferent & efferent glomerular arterioles, thickened tubular BM (tubulointerstitial scarring) IF: none EM: greatly expanded mesangium, thick GBM, foot process effacement time course: thick GBM --> diffuse mesang sclerosis --> nodular glomerulo-sclerosis (KimmelstielWilson nodules)
atherosclerosis (AAA, MI, PVD); amputation; HTN; CVA, stroke; retinopathy, peripheral neuropathy, infection, nephropathy leading cause of kidney failure papillary necrosis (acute pyelonephritis seen more in DM but also PN w/ obst and NSAID abuse)
year 2: kidney enlarges, increased GFR year 5: GFR drops and plateaus year 15-25: steady decline in GFR (leading to massive proteinuria)
Systemic lupus erythematous lupus nephritis
general: unpredictable lupus flares (hematologic sx, arthritis, skin rash, fever, fatigue, weight loss, renal involvement, etc.) anti-dsDNA - suggests kidney involvement Class II (mesangio-proliferativebenign presentation), IV (diffuse LN- sx + active sed UA + proteinuria, dec GFR, elev creat & serologies, hypocomp), V (membranous LN)
breakdown of central and peripheral selftolerance --> autoimmunity resulting in a wide range of autoantibodies
renal involvement 30-90% of SLE patients
serologies: ANA, anti-dsDNA; antiSm;hypo-complementemia histology: endocap proliferation; cellular crescents, karyorrhexis, fibrinoid necrosis (pink fibrin material), wire loops, pseudothrombi (pink globs) Class II: LM (meangial expansion; IF & EM (mesang deposits - IgG) Class IV: >50% of glomeruli have histologic activity, subend dep Class V: granular IF of glom cap loops, subepit dep w/ spike form, uniform thickened cap loops
Disease
Clinical Variants Microscopic polyangitis
Defining Characteristics P-ANCA vasculitis palpable purpura - skin, mucus membranes, lungs, brain, heart, GI, kidneys, nerves, muscle clinical features depend on involved organ system: hemoptysis, arthalgia, abd pain, hematuria/ proteinuria, hemorrhage, muscle pain/ weakness kidneys: leukocytoclastic vasculitis and acute necrotizing (and often crescentic) GN
Pathogenesis systemic necrotizing vasculitis of small vessels (arterioles, venules, capillaries) autoantibodies against myeloperoxidase Pauci-immune mechanism: presumed immune mech but no IF or EM evidence of immune complex deposition in organs
Etiologies precipitating immune reaction (PCN, microbes- Strep, heterologous proteins, tumor antigens)
Epi
Risk factors
Lab/Imaging histology: leukocytoclastic vasculitis (fibrinoid necrosis, transmural arteritis, fibrinoid arteriolitis); acute necrotizing GN (segmental fibrinoid necrosis of glomerulus w/ +/formation of cellular crescents)
Treatment
Complications
Wegener's Classic triad (acute necrotizing granulomatosis granulomas of ENT, lungs hemoptysis; necrotizing vasculitis of small & med vessels; acute necrotizing/crescentic GN) C-ANCA mimics TB -necrotizing granulomas, cavitary lesions
autoantibodies directed against proteinase-3 affecting both small and medium sized vessels
M>F avg age 40; peak incid in 50y.o.'s
histology: transmural arteritis + granulomatous vasculitis
Henochdeposition of polymeric IgA1 within arterioles unknown palpable cutaneous purpura Schonlein (usually on lower half of body); causes leukocytoclastic vasculitis and activation of alternative complement pathway Purpura (HSP) - arthritis, acute abd pain (+/HSP nephritis bloody diarrhea), HSP nephritis (IgA nephropathy; hematuria + proteinuria)
children & young adults
cutaneous bx: fibrinoid necrosis of blood vessel (fibrinoid arteriolitis) + perivascular cuffing of inflamm cells IF: IgA within dermal capillaries kidney bx: mesangial prolif, mesangial dense deposits; IF: deposition of IgA in mesangium
Plasma cell myeloma (multiple myeloma) light chain cast nephropathy
multifocal destructive bone tumors composed of plasma cells --> osteoplastic breakdown manifested most often in vertebral column (lower back), ribs, skull, pelvis, femur, clavicle, scapula unbound light chains become filtered in the urine as BenceJones proteinuria bone pain/ fractures due to osteoclastic lesions, hypercalcemia, anemia/ thrombocytopenia, inc infection susceptibility
proliferation of a single B-cell clone that synthesizes and secretes a single homogenous immunoglobulin or its fragments (plasma cell dyscrasia) proliferation and survival of myeloma cells dependent on IL-6 (hi IL-6 levels a/w poor prognosis & chromosomal abberations) neoplastic plasma cells make excess fragments of light or heavy chains along with the complete Ig excess light chains cross glomerular filtration barrier, eventually occluding and damaging the renal tubules
50-60 y.o.
bx: atypical plasma cells in bone marrow (lots of neoplastic Ig and light chains in cytoplasm; forms cytoplasmic inclusions - Russell bodies) XR: buckshot lesions of the calvarium M-protein (neoplastic Ig) + BenceJones protein (kappa chain) in serum/urine (respectively) protein electrophoresis histo: light chain cast nephropathy w/ eosiniphilic casts (light pink blobs) & ATN
generally poor prognosis
Disease
Clinical Variants
Defining Characteristics single injection of Ag (acute antigenemia) stereotypical course self-limited, short duration
Pathogenesis After injection of antigen, the concentration drops precipitously as Ag becomes bound to circulating Ab, forming immune complexes; more immune complexes = more GN; as free Ag is cleared, GN frequency drops
Etiologies
Epi
Risk factors
Lab/Imaging biopsy: diffuse proliferative GN (>50% of glomeruli have lesions), heavy mononuclear infiltrate, endothelial cell swelling, subepithelial humps IF: IgG mesangial deposits + starry sky pattern
Treatment
Complications
Glomeruloneph Experimental ritis acute serum sickness (similar to human poststreptococcal GN)
deposition of circulating plasma soluble immune complexes in the C3 complement also activated by immune glomeruli; dense deposits in complexes; specifically, the classical pathway mesangium, endothelial wall is activated, allowing formation of MACs and subsequent direct injury (lytic pores), activation/ recruitment of neutrophils & used as model for postmonocytes --> inflammation streptococcal GN in humans
Heymann nephritis (idiopathic membranous nephropathy in humans)
In situ formation of immune complexes
expt model for idiopathic membranous nephropathy in humans, target antigen = PLA2 antibodies then shed and aggregate on the receptor EBM, condensing into subepithelial deposits and causing foot process effacement
circulating Abs bind in situ target antigen = megalin (rats)= scavenger receptor on podocytes & PT brush border that mediates endocytosis of protein, lipoproteins, calcium, and certain drugs
bx: foot process effacement, subepithelial deposits w/ regular periodicity and spike formation (chronic antigenemia) IF: granular IgG and C3 deposits along capillary loops with relative periodicity
Masugi in situ formation of immune Nephritis (Anti- complexes GBM disease) Anti-GBM dz does occur in humans, but target Ag = NC1 of collagen type IV
Animal model: Anti-GBM antibodies are preformed in animals, extracted, and injected into other animals; target heparan sulfate, stripping the GBM of its anionic charge --> formation of immune complexes within GBM, activating complement and causing GN
EM: NO dense deposits (Immune complexes planted in each ind anionic site; unable to aggregate) IF: linear IF for IgG along capillary loops
IgA asymptomatic & persistent Nephropathy hematuria (gross or micro), +/(IgAN, Berger's proteinuria; mesangiopathic dz disease) usually manifests as slow insidious progression towards ESRD Hyperkalemia EKG abnormalities (can be life threatening - SCD), weakness (diminished reflexes, strength), respiratory failure from diaphragm paralysis
alteration in IgA type I, resulting loss of glycosylation pattern --> underglycosylation --> aggregation into polymeric IgA1 --> uptake by MPS and activation of mesangial cell proliferation/expansion
most common GN in developing world (Western Pacific rim)
bx: proliferation of mesangial cells (>3 cells in mesangial matrix) IF: IgA deposition in mesangium EM: mesangial immune deposits, attenuated GBM
no effective tx
50% ultimately die from ESRD (although dz is decades in length)
redistribution - K+ moves from inside --> outside of cells; due to rhabdomyolysis, necrosis, cell death, tumor lysis, DKA, hyperosmolar hyperglycemic state (HHS), insulin deficiency, resp acidosis, non-org metab acidosis, solvent drag (impt for hyperkal in DKA, HHS) reduced excretion - decreased effective volume (less urine output so less excretion of K+), primary/ secondary hypoaldosteronism, tubular mineralicorticoid resistance, acute kidney injury, oliguria (low urine output), meds (ACE, NSAIDs, K+ sparing diuretics, bactrim); increased intake (usually only if abnl kidneys)
crush injuries
EKG - peaked T waves, flattened P waves, prolonged QRS duration; R/O pseudohyperkalemia (hyperkalemia but no EKG changes; due to hi WBCs, platelets, or hemolysis) transtubular K+ gradient (nl 6-12; if hyperkalemic and TTKG is hi suggests extra-renal etiology)
1. stabilize cardiac membrane (esp if serious EKG changes) - give calcium (Ca gluconate by periph IV) 2. redistribute K+ by giving insulin (causes K+ to go back into cells) or B2 agonists 3. remove K+ by giving kayexalate/sorbitol (bind K+, causing diarrhea) or hemodialysis
Ca IV is avoid potassium contraindicated if pt in diet for 6 on digoxin!! months (artichokes, Do not mix Ca IV w/ avocados, tomato NaHCO3 solutions paste, OJ, (causes precipitation potatoes, milk, of CaCO3) bananas, steak, hamburger, etc)
Disease Hypokalemia
Clinical Variants
Pathogenesis
Etiologies If HTN, think about conditions w/ inc aldosterone secretion (renal artery stenosis, hyper-aldosteronism, Liddle's syndrome) if normal BP, think about diuretics, Gitelmans, Bartter syndrome, vomiting
Epi
Risk factors
Lab/Imaging EKG shows U waves after T waves TTKG > 4 suggests renal loss
Treatment
Complications
weakness, muscle cramps, decreased intake - starvation palpitations, fatigue, constipation, redistribution - insulin, B2 agonists, resp impairment (if severe) pseudohypokalemia (large # abnl leukocytes) non-renal K+ loss - diarrhea, severe burns, profuse sweating renal K+ loss - diuretics, vomiting, mineralicorticoid excess, renal dysfxn
for mild cases, oral management preferred over IV - KCl if from diuretics, vol depletion Check acid-base status (acidosis renal tubular acidosis, DKA, meds) (if - KP if phosphorus alkalosis, then measure BP; hi BP - depletion - KHCO3 if acidosis mineralicorticoid excess, Liddle syndrome; low/nl BP - loop/ thiazide - K Citrate if renal stone prevention diuretics, Bartter syndrome, Gitelman's syndrome, vomiting) If must give IV, you need to have less than 60 mmol K in 1L IV fluid given at a rate of 10 mmol/h Diabetes, HTN CVD = leading cause of death decreased life expectancy Staging: 1. kidney damage w/ nl or inc GFR (>90) 2. mild dec GFR (60-89) + kidney damage 3. moderate dec GFR (30-59) 4. severe dec GFR (15-29) 5. Kidney failure (GFR<15)
Chronic Kidney Disease (CKD)
Renal agenesis unilateral
normal function but late complications of glomerulosclerosis
failure to form ureteric bud or induce differentiation of metanephrogenic blastema minority of cases due to involution of dysplastic kidneys
sporadic inheritance 1/1000 births; 3:1 M:F
bilateral
in utero demise or death shortly after birth due to renal or pulmonary insufficiency (Potter syndrome) associated 2ndary anomalies of Potter syndrome: absent fetal urine --> reduced amniotic fluid production (oligohydramnios), characteristic facial features (beak nose, skin folds under eyes, flat/low set ears), limb deformities, pulmonary hypoplasia, amnion nodosum
sporadic inheritance 1/4000 births; 2:1 M:F
Renal hypoplasia
unilateral - no problems bilateral - variable degree of renal insufficiency, hypertension <6 pyramids (nl 10); kidney weight < 50% of expected weight for age
very rare
Renal atrophy
diminutive kidney
less likely to be hypoplasia more likely to be caused by renal artery atherosclerosis, especially in adults
Disease Renal ectopia
Clinical Variants
Defining Characteristics kidney in abnl anatomic location (NOT T11-L1) simple - pelvic, subdiaphragmatic, thoracic crossed - with or without fusion a/w other GU malformations
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications increased risk of UTI from stasis increased risk of injury
sporadic (very rarely 1/900 familial)
Horseshoe kidney
incidental finding most of time; generally normal fxn (even used for transplantation)
fused lower (95%) or upper (5%) poles; fusion during development prevents rotation so renal pelvis faces anteriorly unable to migrate out of pelvic cavity because inferior mesenteric artery blocks them
sporadic
1/400-600
incidental finding during imaging, surgery, autopsy
slight risk of infections, kidney stones, and renal pelvis tumors increased risk of Wilms tumor (isthmus)
Renal tubular acidosis
Type I (DT)
normal anion gap acidosis; moderate renal failure (GFR 2050), impaired NH4+ and phosphate excretion urine is not maximally acidic (pH > 5.3), severe serum acidosis (HCO3- <10), hypokalemia
distal tubule nl secretes H+ for the formation of carbonic acid, which is broken down into CO2 & H2O by CA; problems with distal tubule prevents H+ secretion so unable to maximally acidify (because does not have ammonia for the H+ to attach and be excreted in urine) the urine for excretion of acid --> acidosis
Hereditary (auto recessive mutation in Cl/HCO3exchanger), interstitial nephritis (lead/lithium/ analgesic abuse; autoimmune Sjogren's, RA, SLE, PBC, thyroiditis; nephrocalcinosis; drugs - amphotericin B, toluene)
UAG > 0 (not much NH4+)
easy to correct w/ low doses of HCO3-
Type 2 (PT)
normal anion gap acidosis; moderate renal failure (GFR 2050), impaired NH4+ and phosphate excretion
Type 4
Childhood hereditary dz (cystinosis, tyrosinemia, GSD, Wilson's, Lowe's, variable urine pH (diet dep), galactosemia), serum bicarb 14-20, normal/low carbonic anhydrase K+ inhibitors (acetozolamide, topiramate), interstitial nephritis (rare), renal transplant rejection (very rare), amyloidosis, multiple myeloma normal anion gap acidosis; low renin, hypoaldosteronism, or aldosterone drugs (ACEI, AngII moderate renal failure (GFR 20- resistance prevents the secretion of K+ inhibitors, 50), impaired NH4+ and (hyperkalemia), indirectly causing charge aldosterone phosphate excretion exchange during which causes H+ to enter antagonists) the cells [low aldosterone prevents K+ maximally acidic urine (pH < secretion; hi K+ blocks ammonium 5.3), mild acidosis (HCO3production, so H+ in urine is not bound to >15), hyperkalemia ammonia --> maximally acidic urine]
Problems in proximal tubule prevent reabsorption of HCO3- and the formation of ammonia from glutamine --> acidosis
requires high doses of HCO3- to correct!!
fix hyperkalemia - usually fixes the acidosis (if not, minimal HCO3- needed)
Disease
Clinical Variants
Defining Characteristics high anion gap acidosis
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Lactic acidosis Type A LA
increased L-lactate production from no Krebs altered redox states, cycle --> leads to decreased tissue increased metabolic oxygenation rate (sepsis, seizures, exercise, shivering, cancer, hypoglycemia, thiamine def), decreased O2 delivery (shock, sepsis, CO toxicity), hereditary metabolic defects (mitochondrial myopathies) decreased L-lactate destruction liver disease, ETOH, renal failure, metformin, salycilate OD urine nitroprusside test detects acetone and acetoacetate serum ketone test detects Bhydroxybutyrate (DKA - 75%; AKA >90%)
Type B LA
high anion gap acidosis
Ketoacidosis
Diabetic KA
Alcoholic KA
pancreatic beta cell destruction causes decreased insulin, increased glucagon --> leading to the formation of acetoacetate and B-hydroxybutyrate Decreased carb intake causes decreased insulin; decreased gluconeogenesis causes increased glucagon; ethanol results in increased lipolysis and free fatty acids Generation (bicarb addition or acid loss; anion drag) or maintenance (prevention of bicarb excretion) chloride sensitive metabolic alkalosis from bicarb load/drag (calcium alkali syndrome) or Generation: vomiting, NG suction, decreased EABV increased distal Na+ delivery in volume (vomiting, increased depleted states (loop/ thiazide diuretics, nonreabsorb anions), respiratory comp (post Na+ deliverychronic hypercapnia), alkali consumption/ diuretics, postadmin; mineralocorticoid excess, MC excess hypercapnic state, hypercalcemia) syndromes (Bartters, pseudo-hyperald) Maintenance: low EABV (chloride deficiency activates RAAS preventing base secretion & increasing HCO3 reabs secondary to Na+; insuff Cl- to exchange w/ HCO3 in distal nephron), pathologic mineralocorticoid excess, severe hypokalemia chloride resistant metabolic alkalosis (hi renin: renal artery stenosis, malignant HTN; low renin: primary aldosteronism, Cushing's syndrome, Liddle syndrome) common; incidence increased w/ age
Metabolic alkalosis
spot urine to determine if chloride sensitive or chloride resistant [Ucl > 20 mEq/L implies chloride resistant met alk] hi FP rate for Ucl > 20 so check Uk (if < 30, replete K+ and rpt Ucl) and HTN (if no HTN, recheck Ucl)
chloride supplementation reverses the alkalosis (if chloride sensitive)
Benign renal neoplasms
Papillary (cortical) adenoma
a/w long term hemodialysis and papillary RCC
pathology: small (<5 mm diameter), well circumscribed lesions histology: finger like projections (fibrovascular projections) histology: angioma + myoma + lipoma < 4cm size: follow w/ CT scan or surgery if growing rapidly > 4cm size: surgical removal to prevent complications majority are asymptomatic but if large, might need surgical removal if compressing adjacent structures spont retroperitoneal hemorrhage (pts present w/ severe back pain)
Angiomyolipoma
usually one large mass; if multiple mass - suggests tuberous sclerosis!! Can present w/ pain or hematuria
benign neoplasm composed of thick walled blood vessels, smooth muscle, and fat
<1% of renal tumors usually in adults
Oncocytoma
usually unilateral, but if multifocal or bilateral - think syndromes uniform population of pink cells loose fibrous stroma mixed w/I tumor cells
4-7% of adult renal epithelial tumors age > 50 y.o usually M:F 2:1
pathology: well described lesion w/ brown central stellate scar histology: numerous cells w/ abundant cytoplasm (low NC ratio) and no nuclear pleomorphism
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment hereditary? CT imaging to monitor dz progression; nephron sparing surgery, radical nephrectomy, cryotherapy (if not surgery candidate); screen family members
Complications
Malignant renal (general) neoplasms
"classic triad" (<10% of patients) - sporadic - single lesion, unilateral lesions, onset 60-70 y.o., males abdominal mass, hematuria, flank pain hereditary - multiple lesions, bilateral lesions, earlier onset in life, M=F 85% are renal cell carcinomas (clear cell, papillary) 1% are bilateral (majority are unilateral!) paraneoplastic syndromes hypercalcemia, elevated LFTs (Stauffer's syndrome), anemia, erythro/ thrombocytosis
30K new US smoking, often found incidentally w/ imaging! cases / yr HTN, obesity, Path: necrosis + hemorrhage 12K US meds deaths/ yr (diuretics), acquired usually > 50 renal cystic y.o. dz (dialysis), occupat exp M>F (asbestos, petroleum, cadmium, lead), genetics (VHL) 65,000 cases, 13500 deaths in U.S. Rising incidence usually > 50 y.o. M>F smoking, obesity in women, HTN, VHL disease (develop RCC in 50% of cases), hereditary RCC w/o VHL, tuberous sclerosis pathology: very fatty (yellow) appearing lesion histology: clear tumor (intracytoplasmic lipids & glycogen), very round nuclei, pale cytoplasm, highly vascularized (chicken wire vasculature) high grade tumors will actually appear darker from increased nuclei, atypical mitotic figures, and spindle cell differentiation path: hemorrhagic (sometimes necrotic) appearance
poor prognosis if not staging (based detected early! on tumor size!!): T1 = good Can cause tumor prognosis; T4 = thrombus if enters bad prognosis renal vein, IVC, RA
Conventional (clear cell) RCC
most common type of renal cancer (70%) majority are unilateral
genetic mutation or deletion in 3p25 locus of von Hippel Lindau gene (VHL gene) --> tumors that arise from proximal convoluted tubules
partial nephrectomy (nephron sparing surgery) radical nephrectomy cryoablation (small tumor, poor surgical candidates)
metastases (LUNGS, lymph nodes, liver, bone, adrenals, contralateral kidney, brain, heart, spleen, intestine, skin)
Fuhrman nuclear grading system (Grade IV - bad!!) - prognostic combined w/ staging (see above)
Papillary renal cell carcinoma
associated with trisomy 7, trisomy 17, or loss of Y chromosome!! Tumors arise from proximal OR distal convoluted tubules
hereditary papillary carcinoma (VERY rare)
10-20% of adults RCCs males 3:1
Urothelilal arises from renal pelvis (collecting system hematuria carcinoma urothelium) (transitional 40-50% of cases have cocell carcinoma) existing bladder urothelial tumors most common tumor of renal collecting system and ureter
adults (7% of smoking primary renal cancers) phenacetin nephropathy 70% males thorotrast mean age 70 radiologic dye cyclophosph amide horseshoe kidney
histology: large tumor w/ papillary structures (finger like vasculature; fibrovascular cords); calcium deposits, infiltration of macrophages / histiocytes histology: papillary tumor arising from nephroureterectomy urothelial lining (NOT renal tubules), presence of fibrovascular cords
Inherited disorders of RCC
von Hippel Lindau (VHL) syndrome
increased risk of clear cell RCC retinal angiomas, CNS hemangioblastomas, endolymphatic sac tumors, epididymal tumors, pheochromocytomas, pancreatic cysts, renal cysts, clear cell RCC
autosomal dominant mutation in VHL gene (3p25); variable expression & reduced penetrance mutations promote transcription of vascular growth factors --> unusual vascular tumors 20% de novo mutations (neg FH does not R/O VHL!!)
Hereditary papillary renal cell cancer Hereditary leiomyomatosis RCC
increased risk of papillary type 1 RCC increased risk for papillary type 2 FH gene codes for fumerase hydratase RCC enzyme; benign skin leiomyomata, benign autosomal dominant w/ close to 100% uterine fibroids, aggressive type penetrance for SOME manifestation of 2 papillary RCC syndrome 10-16% risk RCC
Disease
Clinical Variants
Pathogenesis autosomal dominant mutation in BHD gene (17p11.2), disrupting BHD protein which makes folliculin penetrance of cancer is lower than some of the other syndrome manifestations not a/w certain pathological type of RCC
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Birt-Hogg-Dube variable risk for oncocytoma fibrofolliculomas, pulmonary cysts, renal cysts, RCC, colon cancer, spontaneous pneumothorax
Familial Renal Oncocytoma Lynch Syndrome Wilms' tumor (nephroblastom a)
increased risk for oncocytoma increased risk for CRC & endometrial/ovarian cancer; transitional cell pathology pediatric - 90% < age 6 presents as large abdominal mass a/w syndromes: WAGR syndrome (Wilms' tumor, Aniridia, GU anomalies, mental Retardation); Denys-Drash syndrome (gonadal dysgenesis male pseudohermaphroditism; glomerulosclerosis, Wilms tumor); Beckwith-Wiedemann syndrome (exophthalmos, macroglossia, gigantism, hemihypertrophy) most common kidney tumor of childhood 1/8K-10K no gender preference histology: triphasic (blastema, epithelium, stroma); very multinucleated, + mitotic figures nephrectomy and/or chemotherapy very aggressive, a/w poor prognosis lung metastases (cough) or traumatic rupture
Tuberous sclerosis
autosomal dominant neurocutanous disorder a/w harmatomas, mental retardation, infantile/ childhood from mutations in TSC1 and TSC2 genes seizures, cutaneous angiofibromas, heart (rhabdomyomas), lung (LAM) if see angiomyoplipomas on kidneys - think tuberous sclerosis!
increased risk for RCC (clear cell or others) a/w ADPKD
Bladder exstrophy
exposed bladder --> increased risk of infections & ulceration
developmental defect in lower abdominal wall and anterior wall of bladder from the failure of the cloacal membrane to properly glandular or squamous differentiate --> exposure of bladder to metaplasia --> adenocarcinoma body surface (opened sac) or squamous cell carcinoma bladder is on outside of patient (no skin covering bladder mesenchymal defect)
infection ulceration adeno-carcinoma squamous cell carcinoma death - esp if no access to HC (developing world) pyelonephritis!!!
Acute cystitis
triad: urinary frequency + lower younger women (pregnant) - head of fetus Infectious: E.coli, compresses distal aspect of bladder, leading candida or abd pain + dysuria (pain/ to obstruction and urinary retention cryptococcus in burning during urination) immunocomp, older men - benign prostatic hyperplasia adenovirus, inflammation of urothelium leads to compression of urethra, causing chlamydia, urinary retention and infection mycoplasma non-infectious: chemo, radiation, trauma
older men younger women of reproductive age immunosupp
histology: thickened urothelium, infiltration of histiocytes/PMNs
broad spectrum Abs, removal/treatment of obstruction
Disease Schistosomiasi s
Clinical Variants
Defining Characteristics world's leading cause of hematuria and bladder cancer
Pathogenesis ova are deposited in veins of muscularis propria, leading to degeneration and inflammation early changes - necrosis, eosinophils w/ mucosal ulceration later changes - fibrosis w/ lymphocytes, histiocytes, foreign body granulomas, dystrophic calcification; squamous metaplasia leads to squamous cell carcinoma
Etiologies Schistosoma hematobium common in Egypt (water borne parasite; lodges in pelvic veins around bladder)
Epi Africa & Middle East
Risk factors
Lab/Imaging histology: pink cytoplasm & granules represent eosinophils; squamous metaplasia w/ Schisto oval cystoscopy
Treatment
Complications hydroureter, hydronephrosis, bladder ulcers, bacterial infections, renal failure squamous cell carcinoma
Hemorrhagic cystitis
irritative voiding symptoms, gross destruction of overlying vessels in bladder --> cyclohematuria (Med emergency!!) excessive bleeding phosphamide, radiation HSV, CMV, adenovirus benign course once injury source chronically inflamed bladder w/ grossly noted bladder removed polypoid lesions w/ edema or papillary catheterization, lesions fistulous tracts benign lesions occuring most defects in phagocytic or degradative E. coli commonly in bladder but also functions of histiocytes in response to GN Proteus ureters, urethra, renal pelvis, etc. bacteria common incidental finding; mostly benign reactive phenomenon that implies infection of chronic cystitis the bladder & presence of glandular bladder exstrophy structures ureteral reimplantation neurogenic bladder bladder trigone in females becomes glycogenated, or lined by squamous epithelium instead of urothelium schistosoma infection (globally)
histology: hemorrhage of bladder
may require cystectomy if death secondary to bleeding will not stop! severe hemorrhage
Polypoid cystitis Malakoplakia
immunocomp, women
Cystitis cystica et glandularis
histology: can see polyps + edematous area from subepithelial fluid accumulation (polypoid) histology: large histiocytes & small extracytoplasmic calculospherules (Michaelis-Gutmann bodies - look like eyeballs!) histology: glandular (intestinal) metaplasia
remove source of injury
remote risk of adenocarcinoma
Squamous metaplasia of bladder
Nonoccurs commonly in females, keratinizing particularly at bladder trigone (glycogenated) benign - not a/w SCC Keratinizing long-standing cases may be associated with squamous cell carcinoma
histology: hyperkeratosis
Bladder cancer (general)
long standing in dwelling catheters (US) Normal urothelium --> dysplasia painless hematuria smoking, chronic (preneoplastic atypia - transformation to abnl cystitis (SCC), appearing nucleus) --> carcinoma (CIS flat chemical exposure, urothelial carcinomas are the most common bladder cancers lesions OR noninvasive papillary lesions) --> cyclophosphamide, invasion radiation (>90%)
most common urinary tract cancer
smoking histology: dysplasia - enlarged arylamines urothelium (dyes) Schistosoma hematobium 4th most (70% cases common are SCC) cause of Phenacetin cancer death use in males long term cyclophosph M>F amide use histology: cells at least 5x size of stromal lymphocytes, enlarged/ hyperchromatic nuclei, discohesion (shedding), prominence of vessels, high N/C ratio (CIS cells have very little cytoplasm), pagetoid cells (malignant cells interspersed w/ benign cells) urine cytology - can sometimes show CIS if discohesive visible on cytoscopy (but need histo to tell if malignant or benign lesion) histology: finger like projections w/ presence of umbrella cells and abundant cytoplasm (low N/C ratio)
bleeding, obstruction, metastasis
staging: pTa & pTis = noninvasive (>95% 5y survival); T1T4 based on depth of tumor invasion
Urothelial carcinoma in situ (CIS)
malignant noninvasive flat cancer hematuria
presence of cytotologically malignant cells regardless of quantity as grade increases, the cells become more discohesive and can end up in urine
Urothelial papilloma
benign uncommon lesion seen discrete papillary growth w/ central fibrovascular core lined by urothelium of in younger patients normal thickness and cytology small size (3.0 mm)
Disease
Clinical Variants Low grade papillary urothelial carcinoma
Defining Characteristics malignant non-invasive usually orderly arrangement w/ minimal variation in polarity; minimal atypia (scattered enlarged hyperchromatic nuclei), few mitotic figures malignant usually invasive overall disorderly arrangement w/ irregular clusters of cells & fused papillae; marked atypia (similar to CIS), numerous mitotic figures; discohesive single cells
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging histology: finger like projections w/ cohesive epithelial cell lining; fibrovascular core w/ blood vessels, few mitotic figures
Treatment
Complications
High grade papillary urothelial carcinoma
histology: scattered single cells (discohesion), apoptotic bodies, increased # mitotic figures, nuclear polymorphism, hyperchromatic (Dark appearing), increased vasculature look for invasion for grading purposes (lamina propria - T1,better prognosis; muscularis propria infiltration of thick muscle bundles, numerus thick walled blood vessels poor prognosis) dedifferentiation background of keratinizing squamous metaplasia long term catheterization Schistosoma hematobium bladder exstrophy smoking 5% of bladder tumors in US; 75% of bladder tumors in Egypt, Sudan smoking, Schisto infection, chronic catheter placement
does tumor invade muscularis propria? NO local chemotherapeutic agents; YES - cystectomy or cystoprostectomy
Squamous cell malignant carcinoma
Adenocarcinoma
malignant
can sometimes arise from urachus (dome of the bladder, connected from ligament of gland forming - produces mucin umbilicus) or other parts of bladder wall malignant
glands + mucin
Small cell carcinoma Renal obstruction Unilateral
histology: high N/C ratio but small cells; necrosis (pink), rapid proliferation obstruction affects distal tubules, impairing urine concentrating ability and response to ADH; decreased secretion of H+, excretion of phosphate and K+ impaired urine concentrating ability followed by marked diuresis & natriuresis after release chronic obstruction that occasionally causes acute symptoms abnormal muscle developmenet, crossing vessel that kinks ureter crystals form in the urine when certain substances reach supersaturation at a particular pH and temperature if crystals are retained, they can aggregate to form stones genetic predisposition, dehydration urinary stasis, dehydration, infection, metabolic states (hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria) immobilized, RTA, sarcoidosis, hyper-PTH, short bowel syndrome removal of stone, increased fluid intake ureteral stones usually at UPJ, crossing of iliacs, uretero-vesical junction (most common), ureteral orifice acute obstruction = pain, infection, chronic obstruction = loss of kidney function may spontaneously resolve in infants urinary stasis, decreased renal function (reversibility related inversely to amount of time obstructed), HTN, postobst diuresis, electrolyte abnl
acute - painful renal colic + CVA tenderness chronic - silent fluid overload, weight gain, less pain than unilateral obstruction occasionally, acute symptoms hydronephrosis renal distention increases susceptibility to trauma
bilateral
UPJ
Nephrolithiasis
calcium oxalate - most common, can occur @ any pH Struvite (MAP) stones - rare, seen in people w/ recurrent infxns; require alkaline pH Calcium phosphate stones - RTA patients; require alkaline pH Uric acid stones - require acidic pH (only stones to be treated by pH adjustment) Cysteine stones - genetic abnl
IBS + calcium oxalate stones - disrupted bowel mucosa so unable to absorb bile salts = excess bile salts in bowel lumen = bile salts bind calcium = loss of calcium increases oxalate absorption, favoring formation of IBS patients at risk for calcium calcium oxalate stones oxalate AND uric acid stones IBS + uric acid stones - diarrhea = dehydration = low urine volume + decreased pH, favoring formation of uric acid stones
Disease Kidney infections
Clinical Variants Pyelonephritis
Defining Characteristics Acute - fever, chills, n/v, abd pain, diarrhea, anorexia, hypotension, flank pain, CVA tenderness, WBCs on UA; inpt mgmt if dizziness when standing, dehydration, n/v, & confusion + signs of PN Chronic - loss of renal parenchyma
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
women w/ Microscopy: WBC casts FH or PMH of recurrent CT Imaging if persistent sx despite tx UTIs; men (R/O complications) w/ GU abnl; diabetics; elderly
IV antibiotic therapy obstruction (stones) Fluoroquinoles preferred over TMP-SMX [Cipro] uncomplicated? Same as cystitis but for 10-14days (depends on local resistance to TMP-SMX)
Pyonephrosis
infection + obstruction (secondary to stagnant pus building up in the collecting system) Emphysematou EMERGENCY - requires acute air filled pockets within kidney parenchyma s drainage due to infiltration of gas-forming bacteria pyelonephritis severe necrotizing infection due to anaerobic, gas forming uropathogens Abscess Perinephric - occurs secondary to obstruction of inf kidney; E.coli or Proteus Intrarenal - comp of ascending PN or hematogenous seeding of kidneys; S. aureus TB infection, fungal infection of kidney unable to void urine
diabetes
CT shows gas formation within the kidney
urgent nephrectomy
70% mortality even w/ app Abs
perinephric renal calculi, DM, prior GU sx
Others Urinary retention
problem w/ bladder not being able to squeeze (detrusor muscle) or obstruction of bladder outflow pathway
neurologic issues; certain drugs; prostate enlargement; urethral stricture; trauma (urethral disruption)
Urinary incontinence
(general)
involuntary loss of urine through urethral meatus treatment dependent on type of incontinence & cause
leakage of urine despite higher brain function
Stress Urge
Overflow
Stress incontinence - increased abd pressure stressing the ureter Urge incontience - accompanied by sudden urge to void; bladder irritation (infection) causes strong bladder spasms overflow incontinence - bladder has reached capacity (autonomic neuropathy in diabetics)
coughing, laughing, sneezing, valsalva bladder infection
diabetes
Total
Total incontinence - complete inability to hold complicated urine; fistula or ectopic ureter childbirth
developing countries FEMALES
Vesicoureteral reflux
bidirectional urine flow stasis --> infection, scarring, chronic pyelonephritis
congenital bladder anomaly
genetics
Urethral stricture
(when the bladder squeezes, urine moves back up to kidneys; when pt voids, increased vesicular pressure pushes urine back up to the kidney) pathologic narrowing of the urethra inflammatory, trauma males (long interrupting flow of urine (stasis) and possible (catheters, straddle urethra) obstruction injury, pelvic fx), STDs (gonorrhea urethritis), prior instrumentation only urologic cancer more common in females; very rare!
obstruction
Urethral cancer
Squamous cell carcinoma is most common type obstructive symptoms
Disease Benign prostatic hypertrophy/ hyperplasia (BPH)
Clinical Variants
Defining Characteristics occurs most commonly in transition zone obstructive sx (prostatism)hesistancy, weak stream, dribbling, straining to pass urine, prolonged micturition (urination), feeling of incomplete bladder emptying (interruption of primary stream), urinary retention irritative sx - (less specific for BPH) urgency, frequency, nocturia, urge incontinence (make sure you R/O cancer!!)
Pathogenesis enlargement of prostate gland from upregulation of androgen-R (inc prod of DHT) = overgrowth of stromal tissue, inhibition of glandular cell apoptosis = hyperplasia glands & stroma enlarge = compression of prostatic urethra = need for higher pressure in order to open the bladder neck & pass urine = bladder muscle hypertrophy (weakened) & thickening (trabeculation) + diverticula = functional degeneration (can't store urine or empty easily) 2 main pathophys mechanisms: blockage of outflow tract (= obstruction) & bladder hypertrophy/ diverticula irritative sx due to hypersensitivity of bladder
Etiologies presence of androgens (DHT testosterone converted to DHT by stromal cells via 5a reductase)
Epi
Risk factors age
Lab/Imaging prostate exam cystoscopy for bladder diverticulum gross: nodular hyperplasia, medial lobe hypertrophy, hypertrophied detrusor muscle
Treatment
Complications
reduce symptoms & limit stasis of urine = progression infxn, stone, renal dysfxn, urinary watching waiting retention, bleeding
uncontrolled BPH meds (a-adrenergic can cause infection, blockers- open the ext urethral sphincter & cancer, stones histology: hyperplasia of stroma (fibro- relaxes smooth muscle, muscular) & glands 5a-reductase inhibitors - catheterization if decrease DHT to shrink urinary retention prostate; anticholinergics - relax the bladder to prevent uregency; combo tx) surgery (TURP transurethral resection of prostate)
Prostate cancer
occurs most commonly in require androgens in order to progress peripheral zone (posterior part) patterns of spread: direct local extension adenocarcinoma into seminal vesicles (T3) or base of bladder (T4); lymphatic spread occurs most are very slow growing first to pelvic / obturator LNs; (although some can be hematogenous spread (vertebrae, pelvis, biologically aggressive) proximal femur) if metastasize to bone, usually osteoblastic so a/w elevated serum alkaline phosphatase
BPH
highest incidence of all US male cancers (outside of skin Ca) 2nd leading cause of cancer deaths in men
age, FH, race (African Americans), diet (lycopene maybe protective)
PSA screening (measurable levels increase in pathologic states)
bone scan for metastatic metastasis to earlier screening lesions regional LNs in for African pelvic area, bones, Americans if elevated - needle biopsy for radical prostatectomy w/ then solid organs grading (Gleason score - <6 is better removal of LNs + [except liver - rare!!] prognosis but rarely see that) radiation surgery can cut histo: large prominent nucleoli, poorly anti-androgen tx (scrotal cavernous nerves differentiated glands that start to orchiectomy, estrogen, (ED) leading to grow together GnRH analogues) impotence; incontinence estrogen increases hypercoag (coronary art thrombosis)
Scrotal swellings
hydrocele
serous fluid surrounding the testes from the acute testicular/scrotal pain, perineum space; fluid came down with the nausea, vomiting (think testicular torsion! Occurs most testis in the tunica vaginalis in adolescents or perinatal) internal spermatic fascia and tunica vaginalis wrapped around the testis, filling it full of fluid hydrocele occurs inside the testis so feels like a huge mass
if torsioned, untwist the spermatic cord
testicular torsion (dead testis from lack of bloodflow)
spermatocele / spermatocele occurs outside epididymal cyst the testis so almost feels like extra testicle varicocele blood filled, enlarged veins
blocked cysts or ducts from the epididymis
dilation of veins of spermatic cord (pampiniform plexus)
more common on left side, most occurs more commonly on left side because common cause of male the right gonadal vein actually drains into the infertility vena cava; left gonadal vein is more at a right angle so more prone to static flow from valve dysfunction benign solid mass malignant solid mass (testicular cancer) outside the testis within the testis parenchyma usually discovered by abnl self exam involves most commonly the germ cells (seminiferous tubules)
10-15% of men; 10% of these are bilateral
unilateral right varicocele concerning bc probably due to pressure on the vena cava directly from kidney tumor or retroperitoneal mass
peak incidence in males aged 15-34
undescended testes genetics HIV atrophy FH? Trauma?
U/S - abnl heterogeneity, hypo & hyperechoicity (should nl look like snow on TV) path - central necrosis area w/ surrounding tumor
removal of retroperitoneal LNs (both sides since L to R spread) - interaorto-caval LNs, retrocaval LNs, right paracaval LNs chemo removal of testis
surgery can result in cutting of sympathetics --> retrograde ejaculation
Disease Male infertility Epididymitis
Clinical Variants
Pathogenesis
Etiologies varicoceles most common factor
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Erectile dysfunction
male infertility occurs in 50% of infertile couples sudden scrotal pain & swelling acute inflammation of the epididymis that is often caused by reflux of urine through the ejaculatory duct problem w/ vascular, neurologic, inability to achieve and/or maintain an erection sufficient psychogenic, or endocrine factors for sexual function
any age
Flouroquinolones (Cipro)
sometimes send for cardio referral tx patient, partner, & couple PDE5 inhibitors (sildenafil, vardenafil, tadalafil, avanafil) contraind if pt is on nitrates
exercise in earlier ages prevents ED
Peyronie's disease
curvature of penis - usually on dorsal side
acquired abnl curvature of the penis during genetic erection that interferes w/ sexual intercourse, predisposition but thought to be a/w causing psychological stress to the patient trauma interferes w/ intercourse, pain can happen early, often a/w ED right hook, left hook, upward bend, downward bend, hourglass in later stages (veins that maintain erection can become repetitive trauma through intercourse in compressed) predisposed individual causes micro tear in corpus cavernosum or tunica ablicans, leading to formation of scar/ fibrosis almost always occur in uncircumcised males usually squamous cell carcinoma (bc skin cancers) spread by local extension rather than lymphatics
10% of men by age of 5060 mostly Caucasians but other races too
Penile cancer
Urinary tract infections
(general)
urinary frequency, urgency, and burning on urination E. coli is the most frequent cause of UTIs!! Elderly - often have asympt bacteriuria,so need to find signs/sx of UTI - elevated WBC count, fever, AMS
mechanism: ascending route (bacteria in perineum travel up urinary tract; 90% of UTIs; bowel flora - E. coli, GN rods, enterococci, Candida); hematogenous route (secondary seeding of urinary tract from primary bacteremia; S. aureus, Candida, TB) E. coli > Proteus > Klebsiella S. saprophyticus (5-15% of cystitis in young sexually active F) Ureaplasma urealyticum, Mycoplasma hominis - produce sx but hard to culture (culture neg) healthcare/Ab associated - Enterobacter, Pseudomonas, Enterococci, Candida, S. epidermidis, Corynebacteria Adenovirus causes hemorrhagic cystitis in kids & BMT pts
loss of nl bacterial flora (Abs), environment of bladder, disruptions in urine flow (obstruction, vesicoureteral reflux), foreign bodies
rare (however, 1% of cancers in Africa are penile) women @ higer risk (shorter urethra, sexual activity, pregnancy); males most common as infants (suggests GU abnl) elderly (inc bactereriuria, Estrogen, prostatic secretions; comorbid conditions)
genetics (P group Ag on RBCs & uroepith cells)
Urine microscopy - clean catch, midstream; pyuria (>5-10 WBC/mm^3), WBC casts UA - LE+ (any inflam etiology), nitrite+ (nitrate reducing bacteria) [if both LE & nitrite are neg, >97% predictive value that UTI is NOT present]
treat all sx patients! 1. Trimetoprim/ Sulfamethoxazole (Bactrim) OR fluoroquinolones (Cipro) 2. Amoxicillin, Cephalosporins, nitrofurantoin
Gram stain - hi sens & spec but rarely correct underlying risk done unless requested factors urine cx - atyp present, early sx of recurrence after tx, clinical susp for pyelonephritis, recurrent infxn prev treated w/ Abs pregnancy? 7d w/ amoxicillin/ oral cephalosporin, nitrofurantoin, or TMPSMX; avoid flouroquinolones!! lower threshold for hospitalization D/C indwelling devices ASAP
void after intercourse; cranberry juice/ supp to reduce sx; intravag estradiol in postmenop women; correct underlying structural abnl; Ab prophylaxis (LAST RESORT)
Symptomatic bacteriuria/ uncomplicated UTI
kids: non-spec sx; fever, incontinence, FTT, vomiting adults: urgency, frequency, dysuria elderly: worsening incontinence, abd pain, AMS, FTT
Disease
Clinical Variants Complicated UTIs (e.g. catheterassociated UTIs)
Defining Characteristics patients who need longer course of therapy, interventional procedures, have pathogens w/ Ab resistance, or secondary complications
Pathogenesis urinary stasis and obstruction are primary mechanisms for complicated UTIs biofilm formation by uropathogens can cause chronic bacterial presence on devices (catheters) --> resistance
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment remove underlying mechanism (catheter, obstruction) minimize unneccessary tx (asymp bacteriuria) Limit Ab use unless underlying process is resolved! Avoid routinely changing catheter bags, antibmicrobial prophylaxis, bladder irrigation, antiseptic solutions in drainage bags, routine screening for asympt bacteriuria
Complications indwelling devices can become havens for biofilms; encrusted
Screening / Education 1. insert catheters only for appropriate indications 2. remove ASAP 3. properly train those who insert/maintain 4. aseptic technique 5. maintain closed drainage system 6. maintain unobst urine flow 7. hand hygiene
GU tuberculosis
elevated WBC without microbial growth (sterile pyuria)
secondary seeding from hematogenous spread of TB (only 20-30% have concomitant pulm TB) to involve the lower GU tract (epididymis, testis, bladder, ureter, and prostate)
15% of homeless extrapulm TB disease
imaging: renal/ GU mass, calcifications, or stricture Urine AFB culture or biopsy
may respond to TB therapy but usually requires surgery bc very extensive dz by time dx
Asymptomatic bacteriuria
positive urine cultures in absence significance? Presence during preg of clinical signs or symptoms increases risk of PN, a/w bacteremia during procedural manipulation of GU tract; a/w GU treatment requires symptoms!!! abnl in kids; higher mortality rates in hospitalized patients
changes in GU tract prevalence (occur w/ age) inc w/ age catheters --> asympt Candiduria
catheters
Only time you treat asymp bacteriuria: Kids: workup for congenital/ obstruct abnl Pregnancy: treat bc hi risk fo PN & complications Pre-op pts: treat to avoid bacteremia
otherwise, remove catheters if source (and no longer needed)
Cystitis
lower tract infection frequency, urgency, suprapubic pain, dysuria, gross hematuria
if local TMP-SMX resistance <20%: TMPSMX DS BID x3d If local resistance >20%: Cipro 250 PO BID; Levofloxacin 250 daily x3d; Nitrofurantoin x7d sexual mandatory pelvic exam for vag d/c or lesions (Chlamydia/ gonorrhea, history of HSV, trichomonas, BV) new partners or hi risk sexual practice unclear mechanism - possibly due to urethral GN enteric reflux or post-GU instrumentation organisms (E.coli) very small proportion of prostate cases urine cx: increased WBCs and positive culture would NOT want prostate specimen (tenderness of prostate; inc risk for bacteremia) PSA - mod to marked elevation treat based on culture results initial therapy: IV Ab (fluoroquinolones) later therapy: oral Ab Prostate abscess
Vaginitis, urethritis
gradual onset of milder dysuria, +/- freq and/or urgency; dysuria w/o pyuria
Prostatitis
Acute bacterial very severe clinical onset prostatitis fevers, chills, perineal pain, (Type I) back pain, UTI sx, possible obstruction PE: VERY tender prostate
Chronic bacterial prostatitis (Type II)
indolent course - may present as recurrent UTI
Ureaplasma, Chlamydia
R/O complications if unresponsive prostate massage: less inflammation treat based on culture but positive culture results semen culture if prostate massage uncomfortable fluoroquinolones, sometimes doxycycline or macrolides
Disease
Clinical Variants Chronic pelvic pain, no detectable inflamm (Type III)
Defining Characteristics most frequently seen conditions (>90%) sometimes evidence of WBCs & inflamm cells in expressed prostatic secretions; no active bacterial process incidental finding related to elevated PSA large, fluid filled cysts and enlarged kidneys BUT nl renal fxn (differentiates from acquired PKD) a/w tuberous sclerosis U/S criteria for dx: +FH and 3 cysts distributed bilaterally in pt <40y.o., 4 cysts in pt 40-60y.o.; 8 cysts >60y.o.; no FH and 5 cysts bilaterally w/ consistent phenotype extral-renal: liver cystic dz (massive polycystic liver dz females, mild renal involvement, more hospitalizations), intracranial aneurysms, HTN, proteinuria
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging usually negative culture but some inflamm cells present after prostate massage
Treatment
Complications
Asymptomatic inflamm (Type IV) Autosomal dominant polycystic kidney disease (ADPKD)
culture negative, less likely to see inflamm cells autosomal dominant mutation in PKD1 gene (which lies very close to TSC2 gene so patients can have tuberous sclerosis too!) + second acquired mutation =phenotype 10-15% spont PKD1 mutations phenotype: renal cysts, liver cysts, asymp intracranial aneurysms, HTN, proteinuria ARPKD (PKD2) appears same loss of primary cilia fxn: altered mechanosensation of Ca+2 currents altered mitotic orient & cell polarity cystic epith cells: dedifferentiated, no polarization, abnl cell matrix proteins, hi rate of div & apop, form cysts instead of tubules, secrete fluid Hx: n/v/d/bleeding - true vol depletion; CHF, liver/ renal dz - dec EABV; new edema, HTN, rash, urine color - acute GN; meds - ATN, AIN; IV contrast - ATN; stones/ prostate dz - postrenal; diff urine vol - anuria CT for complications comp of polycystic liver dz (ascites, portal hypertension, varices, hepatic venous obst, liver cyst infection) HTN, gross hematuria, pain, nephrolithiasis, UTI long before dec GFR! PKD2 patients have 12.5 million better prognosis than peeps PKD1 worldwide M=F more severe CT/MRI: fluid filled sacs w/ nl renal massive enlargement & disease in parenchyma on either side; enlarged variable cyst burden men kidneys before loss of renal fxn so hard to decide when to treat hemorrhage of cysts - acute onset of pain localized to kidney ESRD
Acute renal failure/ acute kidney injury
(general)
clinical definitions vary based on rapid inability of kidney to maintain excretion creatinine, urine output, or need of nitrogenous wastes, fluid balance by for renal replacement therapy excretion of free water, and acid/base balance RIFLE - risk, injury, failure, loss, causes of anuria - prerenal (bilateral renal a ESRD occlusion), intrinsic (acute GN, renal cortical necrosis, ATN - rare); postrenal (bilateral Stage 1 - inc serum Cr >0.3 ureteral obstruction, bladder neck obst, obstr mg/dL above baseline in kidney) Stage 2 - serum Cr >200-300% above baseline Stage 3 - serum Cr >300% or 4.0mg/dL nonoliguric: urine vol >400 mL/d oliguric: urine vol 100-400 anuric: urine vol <100
inc mortality risk? Pts who need renal perfusion (give vol, dialysis, increased treat primary prob if dec age, multiple organ EABV); change drug system failure, dosing; dietary malignancies restrictions, early PE: volume status (orthostatics, skin nephrology consult, poor renal recovery? turgor, JVD/S3/rub; crackles; corticosteroids (acute Oliguric/ anuric distended bladder; enlarged prostate; GN); plasmapheresis ARF, renal cortical ext edema/ cyanosis (anti-GBM) necrosis, atheroembolic renal UA & microscopy (muddy casts dialysis if acidotic, abnl infarct ATN; uric acid cryst- tumor lysis; electrolytes, ARF from calcium oxalate - ethylene glycol intoxications, overload in ingest anuric patients, uremia [AEIOU]
Prerenal azotemia
ARF caused by hypoperfusion of glomerulus; true volume decreased glomerular capillary hydrostatic depletion pressure decreased EABV severe renal true vol depletion - GI loss (v/d, upper/low vasoconst bleed); renal loss (diuretics, DI), skin/resp occlusion of renal loss (insensible, burns), sequestration into arteries 3rd space (crush injuries, acute pancreatitis, internal hemorrhage) dec EABV - CHF/MI (low CO), AV fistula (hi CO), advanced liver disease (nl-hi CO), early sepsis (hi CO)
increased BUN/Cr ratio, Uosm >500, Una <20, FENA <1%; FEurea <35%
Disease
Clinical Variants Intrinsic Renal Failure
Pathogenesis
Etiologies ATN - ischemic causes, nephrotoxins (Abs, contrast dyes, heavy metals, chemo agents; myoglobin, Hg, calcium phosphate stones, uric acid) AIN - drugs (NSAIDs, Abs, diuretics, others); Infxn (PN), immuno (SLE, rejection), infilt (sarcoid, leuk, lymphoma) UUT nephrolithiasis, blood clot, retroperitoneal fibrosis, malignancy LUT - stricture, BPH, prostate Ca Neurogenic - DM, anticholinergics, neurologic d/o
Epi
Risk factors
Lab/Imaging path: muddy brown casts - ATN; eosin infiltrate + edema between tubules - AIN BUN/Cr ratio 10-15:1; Uosm <350; Una >40; FENA >2; FEurea >50
Treatment
Complications
ATN, AIN, acute GN or vasculitis, ATN - prolonged ischemia or toxins leading to tubular damage (PT or TAL); decreased acute renovascular dz Kf, decreased hydrostatic glomerular pressure, increased hydrostatic pressure in BC; hemodynamic - vasoconst of blood supply, tubular obst, backleak of urine; cell fate - injured tubular cells = loss of polarity = apop/nec; interactive cell bio - injured tubular cells interact, releasing inflamm mediators & cytotoxins AIN - immune mediated injury in the interstitium; non-oliguric
Postrenal failure
mechanical or functional obstruction to flow; increased hydrostatic pressure in BC
U/S for obstruction
Disease Diabetes mellitus
Clinical Variants (general)
Defining Characteristics 3Ps (polyuria - osmotic diuresis, polydypsiarehydration, polyphagiareplenish carbs), weight loss (urine carb loss), fatigue (unable to utilize glucose), blurred vision, dry mouth, dry skin, poor wound healing, impotence, tachypnea (metab acidosis compensation), fruity odor (increased breakdown of fats to form ketones)
Pathogenesis hyperglycemia & glycosuria due to inability to oxidize/utilize carbs + disturbance in insulin function + imperfect fat combustion (hi ketones)
Etiologies
Epi
Risk factors
Lab/Imaging Inc urine volume + hi SG (polyuria); inc BUN:Cr ratio (catabolic state, dehydration), + urine glucose (weight loss), + ketones (fruity odor, lipolysis), ABG: low pH, low HCO3-, low pCO2 (metabolic acidosis w/ resp compensation)
Treatment
Complications Diabetic ketoacidosis, hypoglycemia, see chronic complications below
pancreas: inc glucagon, dec insulin secretion fat: dec glucose nutrients pass into the urine uptake, inc (weight loss, polyphagia); FFA output dehydration bc body H2O is muscle: dec used to eliminate extracell glucose uptake glucose in the urine liver: inc hepatic dec intracell glucose = dec glucose output energy; body attempts to inc gut: slowed chronic hyperglycemia: 3Ps intracell glucose and dec gastric motility, + severe cachexia (unable extracell glucose (osmotic inc glucose diuresis); as unable to use to drive glucose intracell) uptake glucose, body attempts to brain: dec increase energy by using fats = satiety, ANS ketones = acid = DKA reg excessive urination, excessive thirst, fatigue, weight loss progressive autoimmune destruction of B-cells --> insulin deficiency (causing the opposite of insulin - rather than storing energy, the body tries to make glucose & breaks down glycogen, fats, & protein) CD4, CD8, & MOs infiltrate & accumulate in islet cells --> insulitis; unk triggering event occurs promoting autoimmune destruction of islet cells clinical manifestations when 8090% B-cells destroyed
Type 1 DM
0.3% general DR 3/4 genotype Serum glucose (>200 mg/dL Caucasian (HLA) - 8-10x w/ sx; >125 mg/dL fasting) population higher risk Large urine ketones; 20/100,000 FH: 15% w/ positive antibodies (anti+FH; ident twins GAD65 Ab- these pts have bimodal age (25-50%), highest risk for T1DM; islet distn (4-6y, 10- siblings (5% cell Ab, insulin auto-Ab) 14y) risk), father (6%), mom (3%) Whites colder climate
subcutaneous insulin DKA therapy that mimics physiologic insulin (continuous insulin - pump or basal injection w/ bolus injection at meals)
Type 2 DM
metabolic syndrome: waist circum > 32"F or 38"M + any 2 factors (HTN, low HDL <40M or <50F, hyperlipidemia >150, impaired FBS >100) - a/w underlying insulin resistance inc risk of CVD & DM insulin action impaired but does not get much worse btwn pre-diabetes to DM; insulin secretion dec significantly w/ impaired glucose tolerance, suggesting dual defects in T2DM DKA, inc FBS, inc postprand gluc
MODY: mutations w/ B-cell fxn = T2DM in nl weight kids w/ -FH typical T2DM: inability of B-cells to overcome insulin resistance (dec insulin action - same amt of insulin = less response) & dec insulin secretion insulin resist (aging, weight, sedentary activity) compensated early by inc in beta cell fxn; beta cell fxn falls = inc glucose levels (1. postprandial, 2. pre-prandial) insulin resist: post-receptor defects (dec phosph after insulin binds); hi triglyc deposit = inc DAG accum = dec insulin signaling; sequest of GLUT4 inside the cell insulin secretion defects: no 1st phase, blunted 2nd phase; hyperinsulinemia islet cell dysfxn: inc glucagon, dec insulin obese adipose tissue = inc oxid stress from inc NADPH oxidase
polygenic muts in TCF7-L2 (dec insulin secretion) + dec insulin action (resist via inactivity + obesity)
strong FH, minority groups, overweight, no physical activity, prevalence is pregnancy highest in older people Diet: more trans (60+) but fat, more sat fat, highest higher glycemic inc IHL a/w dec incidence in load (less fruits, insulin action; middle aged veggies, more fat) inc oxid stress (40-59) a/w inc B-cell Native apop, dec Americans> insulin syn & blacks> secret hispanics >> dec insulin, inc Asians> glucagon post whites prandial (opp of nl)
24 million diabetics in U.S. in 2012
FBS > 126 OR 2h 75g OGTT dec insulin resistance: > 200 OR random BG > 200 lifestyle mods (diet- dec caloric intake, ex, w/ sx metformin, TZDs) A1C > 6.5% Repair dual defect: inc insulin action (metformin, TZDs); inc insulin secretion (B-cell enhancers, insulin - basal & bolus, incretins - assist B-cells) B-cell rest for pre-DM (dec insulin resistance, glucose levels, inflamm/ox stress/ ER stress) = dec need for endogenous insulin and less B-cell apoptosis = dec progression of DM
Disease
Clinical Variants Gestational diabetes
Pathogenesis
Etiologies
Epi 7% of all pregnancies complicated by GD 1/3 of GDM patients will have DM postpartum 50% of GDM patients will develop DM within 10y of affected pregnancy
Risk factors FH of DM h/o macrosomia obesity AMA (>35y.o.) h/o poor obstetric outcome h/o GD ethnicity (AA, hispanic, NA, PI)
Lab/Imaging universal screening 24-28 weeks: 1h 50g glucose challenge test (>140 - 80% of GDM, 14% FP; >130 - 90% of GDM, 25%FP; >200 diagnosed w/ GDM & do not need 3h GTT) if failed 1h glucola, then give 3h GTT (diagnosis requires 2 abnl blood draws: fasting > 95, 1h > 180, 2h > 155, 3h > 140) UA: check for ketonuria postpartum screening: if DM - refer to endocrinology; if nl - assess q 3y, counsel for weight loss; if impaired weight loss, activity, nutrition, metformin, assess q 1y elevated anion gap metabolic acidosis hyperglycemia (usually > 300) ketosis pseudo-hyponatremia (dilutional), hyperkalemia pre-renal azotemia
Treatment A1: 30kcal/kg/day diet BMI>30: 30% caloric restriction nutritional counseling. Ex during pregnancy, maintain FBS < 95 & 2h postprandial <120 A2s: lifestyle mods + glyburide (low doses 2.5 mg --> 10 mg); if still not controlled, add insulin (does not cross placenta) OCP postpartum, preconceptual glycemic control imperative (diet, ex, behavioral mods to avoid GDM recurrence)
Complications frequently resolves after delivery Maternal comps - HTN d/o (pre-eclampsia, eclampsia); C/S; stillbirth; trauma fetal comps macrosomia, hyperbilirubinemia, operative delivery, shoulder dystocia, birth trauma, neonatal hypoglycemia, resp distress syndrome, childhood obesity
carbohydrate intolerance - maternal hyperglycemia --> fetal hyperinsulinemia --> inc -> hyperglycemia with onset during pregnancy production of fetal fat cells --> obesity --> insulin resistance --> A1: controlled w/ diet & ex impaired glucose tolerance in A2: require meds for control childhood --> DM macrosomia (excessive fat deposition on fetal shoulders & trunk due to stimulation by IGF-I & 2) insulin resistance increases as pregnancy progresses (higher the maternal glucose levels = worse fetal outcomes)
Diabetic Ketoacidosis (DKA)
severe insulin deficiency nth degree of diabetes sx: massive polyuria, massive dehydration, life threatening electrolyte shifts and metabolic acidosis
increased gluconeogenesis causes hyperglycemia increased lipolysis = release of FFA, inc B-oxidation of FFA = inc acetyl CoA which is converted to ketone bodies in the liver
medical illness, stress, or omission of insulin
T1DM
Chronic complications of DM
Retinopathy microvascular
Nephromicrovascular pathy Neuropathy microvascular CAD, macrovascular ischemic heart dz
insulin is not needed for glucose utilization in the microvasculature; inc glucose = inc metabolism to sorbitol & fructose = inc osmolarity = inc water = osmotic cell injury inc glycation products (HbA1C) react w/ arterial wall components, cross link collagen, & inc arterial stiffness inc LDL promotes atherogenesis
Hypoglycemia
(general)
most common complication clinical syndrome w/ diverse causes related to decreased ANS sx: sweating, anxiety, plasma glucose levels nausea, trembling, feelings of warmth eventually leads to neuroglycopenia (low sugar in neuroglycopenia: dizziness, the brain) fatigue, HA, confusion, difficulty speaking, unable to concentrate, seizures, coma
low blood glucose (sx usually when <60 mg/dL; brain fxn impaired < 50 mg/dL) + presence of cortisol, GH, epinephrine urine or serum ketones ketotic or non-ketotic hypoglycemia
oral glucose (tablets, sugary sodas), glucagon (if seizures or coma), IV glucose (if compromised airway)
neurological compromise or mental retardation
Disease
Clinical Defining Characteristics Pathogenesis Variants Ketotic hypo- Ketones in urine or serum substrate limited: unavailable glycemia carbs/ poor storage = unable to fast for a long time w/o becoming ketotic (MSUD) Hormone deficiency: panhyopopituitarism (GH, ACTH def), glucagon def, epi def, cortisol def (Addison's, congenital adrenal hyperplasia) Others: drug-induced, systemic d/o (can't meet body's energy demands), liver disorders (can't make or use glucose - hepatitis, cirrhosis) Alcohol? metab by alcohol dehydrogenase in liver, requires NAD+; results in NADPH accumulation, inhibiting gluconeogenesis by inh malate -> OAA Non-ketotic hypoglycemia
Etiologies Substratelimited Hormone deficiencies GSDs D/Os of gluconeogenesis Drugs alcohol, salicylates, quinine, valproic acid, insulin
Epi
Risk factors
Lab/Imaging
Treatment
Complications
hyperinsulinism shuts down the hyperinsulinism production of ketones Fatty acid ox D/O d/o in fatty acid oxidation carnitine or prevents the generation of CPT I or II ketones (Acyl dehydrogenase deficiency deficiencies like MCADD) carnitine (akee fruit - Jamaican vomiting sickness) or CPT deficiencies prevent the shuttling of fatty acids into mitochondria autosomal recessive mutations in ACADM gene that results in abnormality in B-oxidation --> non-ketotic hypoglycemia
Medium Chain Acyl Dehydrogenas e Deficiency (MCADD) HyperCongenital insulinism
presents at 3-24 months (peak at 15 months), during periods of fasting or sickness PHHI = persistent hyperinsulinemic hypoglycemia of infancy
1/15,000
avoid periods of reduced carb intake (problematic when sleeping)
mutations in ABCC8 gene (SUR1) causes abnl of the outer subunit (50-60% of cases) or the KCNJ11 gene (kir6.2) causes abnl in the inner subunit; dx w/i 1st weeks of life; transient to severe; inability these mutations cause K-ATP to maintain glucose levels channel to be permanently closed, so insulin is despite oral or IV supplementation constitutively released
K-ATP channel 1/40,000 mutation (SUR1/Kir6.2) K-ATP >> GDH > glutamate glucokinase dehydrogenas e mutation (AD)
GOF GDH mutation: hyperinsulinism + hyperammonemia (which does not inc w/ protein feeds) intra-arterial calcium gluconate infusion: determine insulin levels across pancreas (splenic a, SMA, gastroduodenal a, celiac axis); areas of highest insulin levels are prob location of faulty enzymes and must be removed surgically (focal or diffuse lesions) PET scan to eval high uptake at high insulin concentrations (only avail at CHOP)
pancreatectomy if AR KATP mutation of clonal loss of heterozygosity diazoxide TID if mild AD K-ATP, GDH, or glucokinase mutations carb load before protein (Leucine) intake if GDH mutation
autosomal recessive KATP mutations are most severe (diffuse islet cell hyperplasia) while autosomal dominant K-ATP muts are more mild severe developmental disorders and mental retardation from lack of blood sugar to brain
glucokinase also called nesidioblastosis, GOF muts (activated by leucine) mutation (AD) B-cell hyperplasia, B-cell of glutamate dehydrogenase = dysmaturation syndrome inc oxid of glutamate = inc aketoglutarate, ATP, & insulin glucokinase mut decreased glucose GOF muts of glucokinase threshold for insulin to (glucose sensor, 1st step in glycogen synthesis & glycolysis) shut down = activation of insulin until BG is GDH mut - inc NH3 levels around 40
acute tx: oral glucose (best if possible) of sugary most patients with diffuse areas of liquids or IV glucose hyperinsulinism will develop DM chronic tx: diazoxide, ocreotide (somatostatin), hi calorie feeds, surgery; HRT
Disease
Clinical Variants Acquired
Defining Characteristics Whipples triad suggests insulinoma (hypoglycemia + symptoms - weakness, tremors, sweating, hunger, palpitations, weight gain, exercise induced, CNS sx, psychiatric probs, relief w/ glucose)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment glucose tablets, IV glucose, or glucagon (if seizing or unconscious)
Complications reactive hypoglycemia can be a precursor to T2DM
exogenous delivery to someone Exogenous who doesnt need insulin = delivery hypoglycemia insulinoma insulinoma = tumor that secretes insulin retroperitoneal tumors retroperitoneal tumors = tumors that mediate IGF-2, which binds reactive insulin receptors hypoglycemia reactive hypoglycemia = ingestion of simple sugars w/o fats or carbs = insulin spike that easily takes up simple sugars
Hypothyroidism (general)
Hashimotos thyroiditis, subacute thyroiditis, diet reduced metabolic state, primary: thyroid gland is iodine def, dec CO, lethargy, dec affected appetite w/ inc weight secondary: pituitary is affected lithium OD gain, coarse hair, mental (TSH deficiency, pituitary tumor) (rare),congenit al errors of TH slowness, dry skin, slow tertiary: hypothalamus is pulse (brachycardia), affected (tumors, infiltrative dz) release/ synthesis cool/dry/ puffy skin, droopy (rare), eyelids, large tongue, +/most common causes? goiter, thinning of lateral 1/3 Autoimmune dz, radioiodine radiation exposure, of eyebrows, constipation, or thyroidectomy, pituitary iatrogenic cold intolerance, insufficiency (radioactive iodine tx or KIDS: same sx as adults surgery BUT poor linear growth, ablation), excess weight gain, & postpartum poor school performance thyroiditis underproduction of T3&T4 reduced production of T3 & T4 Failure to thrive! thyroid gland dysgenesis or agenesis - most common cause thyroid gland dysgenesis or agenesis
iodine def = elderly most common cause globally of hypothyroidism F>M, increased prevalence w/ age 10% of elderly
primary: low T3, T4; extremely hi TSH (compensation to increase TH) hi TSH/TRH could possibly cause prolactinemia secondary: low T3, T4; low TSH
Levothyroxine (Synthroid, 1.6ug/kg body weight)- pure T4; DOC for replacement/ suppression, keep TSH WNL, watch free T4 w/ sec/ tert hypothyroidism Liothyroxine (Cytomel) pure T3; used ONLY for acute/severe hypothyroid (Myxedema coma) Liotrix (Euthroid, Thyrola) mixture of T4/T3 in 4:1, no advantage Thyroid (USP) and thyroglobulin (Proloid) dried animal thyroid; not recommended
diabetes, atherosclerosis, slow titration of Levothyroxin in elderly to avoid complications w/ coronary heart disease
Congenital
impaired development of CNS & skeleton, severe mental retardation, short dyshormogenesis - deficiency or lingual thyroid stature, coarse facial absence of TPO features, protruding tongue & umbilical, +/- goiter if dyshormogenesis
newborn screen - confirm w/ TSH (extremely hi if no thyroid hormone present) & serum free T4
thyroid hormone (Levothyroxine) increases growth & mental development - if unsure, treat shortly after birth bc brain growth 8085% complete by 3y.o. treat moms if maternal thyroid deficiency
CRETINISM = mental retardation if not treated early!!! Signs?? Impaired skeletal/CNS development) risk of bleeding if removal of lingual thyroid
Hashimoto's most common cause of thyroiditis hypothyroidism in FEMALES goiter.
autoimmune destruction of the thyroid defect of T cells causes production of anti-thyroid antibodies that are cytotoxic to the thyroid gland initial thyrotoxicosis followed by hypothyroid state abrupt onset of thyrotoxicosis; progresses to hypothyroidism in 40-50% of patients
2nd most common cause of hypoT AFTER iatrogenic!
low T3, T4; hi TSH; positive thyroid antibodies (TPO)
Subclinical
Painful thyroid following URI or viral infection Painless thyroid
NO uptake on I-123 scan
transient - supportive care rarely progresses to & treatment of underlying overt hypothyroidism dz
postpartum
Disease Hyperthyroidism
Defining Characteristics overproduction of T3&T4 inc metabolic state, nervousness, insomnia, fatigue, irregular heart beat (afib), tachycardia, inc appetite w/ dramatic weight loss, heat intolerance, exopthalmos, +/- goiter, hyperhidrosis, alopecia, hyperdefecation, abnl LFTs, osteopenia, hi Ca, tremors, proximal myopathy, periodic paralysis, onycholysis (separation of fingernail)
Pathogenesis exaggerated T3 and T4 production causes suppressed TSH (negative feedback)
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications osteoporosis, bone fx
85% of the Graves dz cases caused (young F) by Graves see below toxic, 5-10% of pts will have nl T4 but multinodular exaggerated T3 (T3 toxicosis) goiter (elderly) - see pituitary tumors can sometimes below cause inc T3, T4, AND TSH! TH overdose (most common cause!) thyroid tumor, subacute thyroiditis, postpartum thyroiditis, painless thyroiditis amiodarone
hi T4, T3; undetectable TSH Thioureylenes (compensation to decrease (Propylthiouracil or Methimazole/Tapazole) TH) I-123 scan: hot nodules brain MRI if pituitary tumor suspected (hi T4/T3, hi TSH) should try & get I-123 scan on all hyperthyroid patients (not all thyrotoxic patients are hyperthyroid - i.e. subacute thyroiditis)
Graves disease
most common cause of spontaneous hyperthyroidism under 40 years old
autoimmune disorder resulting in the production of anti-TSH receptor antibodies (thyroid stimulating immunoglobulin IgG) that bind TSH-receptor and diffuse toxic goiter, mimics natural TSH; thus, exophthalmos (protrusion thyroid produces TH of eyeball from thickening of retro-orbital tissues), thyroid "stare" (stare from the spasm of levator palpebrae muscle form inc B-adrenergic stimulation), pretibial myxedema (orange peel appearance on lower legs from mucopolysaccaride infiltration: non-pitting edema), onycholysis, Afib (most common sx in elderly) amount of TH made is autonomous functioning related to mass of nodule "single" thyroid nodule
a/w HLA-B8 & DR3, other autoimmune d/o
F>M (7:1) 2% US women
FH
hi T4, T3; undetectable TSH, "cool down" with antithyroid drugs; 50% of pts positive TSI (thyroid will be cured w/ meds stimulated IgG), goiter alone possible T3 toxicosis (inc in med tx: propanolol T3 only) (tachycardia, inhibits Hot, diffuse nodule on I-123 conversion of T4 to T3), anti-thyroid meds scan (methimazole, PTU for pregnant women ONLY), GCs (inhibit T4-->T3) usually require radioactive iodine surgery also option
blindness and decreased ocular vision if exophthalmos not treated! Radioactive iodine --> hypothyroidism
Toxic adenoma
2% of hyperthyroid cases
low iodine intake I-123: hot nodule w/ complete to partial supression of paranodular thyroid tissue Propanolol + thioureylenes + large doses of Lugol's
Thyroid storm (Thyrotoxicosis)
tachycardia, fibrillation, shock, heart failure
Thyroglossal duct cyst
sudden acute exacerbation of thyrotoxicosis secondary to severe hyperthyroidism and upregulation of metabolism/ sympathetic nervous system mass in midline of neck + remnants that occur when duct does not sufficiently close thyroid tissue present
Lateral aberrant thyroid
lateral to sternocleidomastoid
usually metastasis from papillary thyroid carcinoma
histology: variable epithelium cyst lining (nondescript cuboidal, sometimes squamous) histology: lymphoid tissue + thyroid glands
Disease Goiter
Defining Characteristics enlargement of the thyroid gland
Pathogenesis in low iodine areas, TH cannot be produced so hypothalamus increases TSH secretion = increased growth of thyroid gland causes in developed countries: diffuse simple goiter, Graves, Hashimotos, subacute thyroiditis, multinodular goiter, malignancy, genetic
Etiologies endemic (iodine deficiency, goitrogens!), sporadic, familial
Epi
Risk factors endemic areas (Alps, Andes, Himalayas; iodine def = TSH = hyperplasia)
Lab/Imaging histology: large colloid lakes w/ involuted areas of variable appearance, surrounded by smaller thyroid follicles
Treatment Iodine if related to iodine def
Complications
Diffuse
diffuse, symmetrical enlargement Toxic (Graves disease) Non-toxic (simple)
diffuse non-toxic: diffuse hyperplasia w/o nodularity; usually related to goitrogens (Ca, Fl, veggies), may develop in multinodular diffuse toxic (Graves dz): a/w autoimmune dz
F>M
FH of Graves
euthyroid - nontoxic hyperthyroid - Graves gross: Graves - red, hyperactive appearing thyroid histology: Graves scalloping (clefts around colloid), inc # cells & hyperplasia I-123: hot nodules multinodular PE: can sometimes feel lumpy thyroid gland, but 25% of patients have nonpalpable U/S
Multinodular
nodular, lumpy enlargement Toxic (Plummer's dz) non-toxic (simple) toxic sx: unexplained weight loss, depression, Afib
autonomous function of nodular thyroid tissue --> hyperthyroidism (toxic)
older age
hypothyroidism if tx w/ anti-thyroid meds prevent sx BUT DO NOT radioactive iodine (although less CURE DZ!! common than Graves patients) Radioactive iodine +/surgery (only if trouble swallowing, compression of trachea) - surgery can sometimes be better option if VERY large
Thyroid nodules
benign / non- solitary or part of neoplastic multinodular goiter R/O malignancy by measuring TH & TSH - if abnl do fine needle aspiration (also done if nodule > 1cm) follicular adenomas uniform follicular pattern; no goitrous nodules (if present, think multinodular goiter), complete fibrous capsule, sharp demarcations, no vascular or transcapsular invasion!!!
occur in almost any thyroid disorder 50% - non-neoplastic colloid nodules 30% - adenomas (benign epithelial follicular neoplasms; slow growing, rarely fxnal) 10% - carcinoma 5% - benign cysts
carcinoma, benign hyperplasia
palpable nodules in 6% women, 2% men
usually euthyroid require fine needle aspiration cytology to define hyperplasia OR malignant epithelium I-123 scan: nl thyroid nod will have diffuse filling/uptake; "cold" nodules (no iodine uptake - VERY concerning for Ca) gross: if uniform tan/ gooey material w/o capsule - colloid nodule; capsule w/ complete integrity - adenoma; thick capsules - malignancy histology: uniform w/o transcapsular invasion (adenoma)
Disease
Clinical Variants Thyroid carcinoma
papillary - sporadic, PMH of neck radiation; slow growing, good prognosis follicular - more aggressive but good prognosis; common in iodine def countries medullary - arise from Ccells (parafollicular cells secrete calcitonin), neuroendocrine neoplasm (MEN IIa, MEN IIb, nonMEN) w/ amyloid deposition undifferentiated - no follicular/ papillary morph, elderly, rapid growth, local invasion, poor prognosis Malignant lymphomaelderly women, a/w Hashimotos thyroiditis
Pathogenesis normal follicular cells --> adenomas under influence of RAS oncogenes --> subset of adenomas progress into follicular carcinomas normal follicular cells --> papillary carcinomas under influence of RET mutations pre-existing follicular or papillary cancer acquires p53 mutation to become anaplastic carcinomas (hi grade!!)
Etiologies
Epi
Risk factors
Lab/Imaging histology: Papillary (fibrovascular core lined by epithelial cells; finger-like; enlarged, optically clear cells w/ intranuclear grooves; little orphan Annie's eyes Psammoma bodies); Follicular (hard to diff from adenoma; vascular &/or transcaps invasion; Hurthle cells - more agg lesions); Medullary (C- cell hyperplasia, amyloid deposition, neuroendocrine + stains - calcitonin, ectopic hormones) gross: transcapsular invasion (follicular!!); necrosis (malignant lymphoma)
Treatment thyroidectomy, radioactive iodine Thyroid replacement therapy if hypothyroidism results whole body scan post surgery serum thyroglobulin tumor marker after total thyroidectomy
Complications papillary carcinoma lymphogenic spread follicular carcinoma angio-invasion/ vascular spread to bone & lungs total thyroidectomy required exogenous hormone replacement
uncommon radiation to neck but increased incidence w/I genetic past 20 years, (medullary) F>M pre-existing young- mid thyroid disease age females (hashimotos (papillary) malignant lymphoma, Papillary (75- carcinoma) 80%), follicular (10- elderly (malignant 20%), undifferentiated lymphoma, undiff (1-5%), medullary (3- carcinoma) 5%)
Thyroiditis
Acute Chronic Hashimoto's thyroiditis
inflammation of the thyroid caused by bacteria or fungus a/w other autoimmune d/o: deficiency of suppressor T cells --> immunologic abnl (anti-microsomal autoantibody) --> thyroid destruction
very rare <1% F>M
immunocomp familial histology: lymphocytic thyroiditis, reactive follicular centers (germinal centers); destruction of thyroid follicles, Hurthle cells (abundant pink reactive cytoplasm), fibrosis gross: enlarged thyroid, bosselated (bumpy) w/ creamy surface from lymphocytes serum autoantibodies: antimicrosomal, antithyroglobulin, anti TSHR, blocking antibodies hyperthyroidism followed by hypothyroidism (if gland stops functioning) histology: granulomatous giant cells w/ lymphocyte infiltrate (no giant cells seen in Hashimotos!) I-123: no uptake (inflammation of thyroid responsible for hyperthyroidism) inc risk for thyroid carcinoma & malignant lymphoma
Subacute
uncertain - possibly post-viral DeQuervain's / granulomatous thyroiditis inflammation causes hyperthyroidism from rapid small goiter AND DIFFUSE PAIN!! (unable to release of TH palpate bc of pain), fever of TRANSIENT - complete unknown origin resolution over 2-6 months hyperthyroidism state --> hypothyroidism state (sometimes)
F>M
Fibrous
Riedel's thyroiditis woody/ stone hard thyroid gland
long-term inflammation --> fibrosis --> destruction of thyroid gland and adjacent neck structures clinically resembles malignancy
VERY rare
gross: woody hard area around periphery of thyroid gland
Disease
Clinical Variants Postpartum
Defining Characteristics painless thyroiditis appearing 1-2m postdelivery, lasts 2-5m goiter increases 1-2m postpartum, fatigue/ moodiness (hard to dx!!) hyperthyroidism state --> hypothyroidism state
Pathogenesis
Etiologies
Epi very common!!
Risk factors
Lab/Imaging
Treatment
Complications severe depression
high recurrence hi T3/T4 (hyperthyroidism), rate! low TSH, positive antithyroid antibodies; followed often by hypothyroid phase!
Multiple endocrine neoplasm
MEN1 (Werners syndrome)
recurrent stomach ulcers, hypercalcuria w/ nephrolithiasis, headaches, bitemporal visual field loss, hypercalcemia 3Ps: pituitary adenomas (prolactinomas most common), hyperparathyroidism (4 gland hyperplasia from 2ndary hyper-parathyroidism leading to hypercalcemia), pancreatic islet cell tumors (gastrinomas --> ZE syndrome-inc gastric acid secretion & PUD from gastrinoma; insulinomas --> hypoglycemia) adrenal hyperplasia
germline mutation in menin (tumor suppressor gene) chromosome 11 other early signs of menin mutation? Facial angiofibromas & collagenomas
Autosomal dominant
0.25% population all ages, no sex pref 80% manifest tumor by 5th decade first manifestation s occur earlier than in sporadic dz
dx: 2 or more of "3Ps" + relative w/ 1P 4 gland hyperplasia (sporadic dz only has single parathyroid adenoma) genetic screening if mutation known in the family
total parathyroidectomy pancreatic islet cell tumors (usually & autotransplant multiple, small, & benign) can become PPIs if gastrinoma; malignant ocreotide or pancreatectomy if hi surg failure & insulinoma recurrence necrolytic migratory erythema - if glucagonoma
MEN2A
medullary thyroid germline mutation in RET carcinoma or hyperplasia oncogene (tyrosine kinase of thyroid C cells + pheo- receptor) chromocytoma (adrenal medullary tumor) + parathyroid neoplasms (adenoma or hyperplasia)
path: medullary thyroid carcinoma will be immunoreactive for calcitonin
prophylactic thyroidectomy
some variants of MEN2A have Hirschsprungs dz (megacolon from lower intestinal obstruction) or cutaneous lichen amyloidosis (upper back)
MEN2B
Pheochromocytoma + thyroid medullary carcinoma (or C- cell hyperplasia) + mucosal neuromas (neural tissue nodules in GI tract or mouth) + marfanoid habitus hypercalcemia, pathological fractures, bone pain hyperparathyroid bone disease
germline mutation in RET oncogene
calcitonin secretion
prophylactic thyroidectomy
Osteitis fibrosa cystica
excessive bone resorption by osteoclasts related to parathyroid overactivity --> dissecting osteitis in cancellous bone --> osteoblastic bone formation (fibrous replacement results in weakened bone and scarring)
XR: thin cortex & bone cysts path: dissecting osteitis
Disease Hypocalcemia
Defining Characteristics tetany (neuromusc irritability, musc cramps, tonic-clonic seizure; elicited musc contractions w/ Chvostek & Trousseau signs), ocular abnl (cataracts, papilledema, pseudotumor cerebri), prolonged QT interval & nonspecific T wave changes, anxiety, confusion, depression, intracranial sx (basal ganglia calcification, parkinsonism), dental manifestations (dental hypoplasia, failure of eruption), macrocytic megaloblastic anemia, diarrhea
Pathogenesis hypoparathyroidism (insuff activity of parathyroid = low PTH, hypocalcemia), pseudohypoparathyroidism (active parathyroid gland but unresponsive end organs), vit D def/insufficiency, vit D dependent rickets I & II (genetic deficiency of 1-a hydroxylase prevents activation of vit D in kidney), end organ resistance to vit D; renal failure (unable to make RBCs, active vit D; can't reabsorb Ca or eliminate P = inc PTH) activating defects (GOF) in CaR of parathyroids(takes a lower calcium to induce PTH; would have nl PTH levels); PTH resistance inherited activating mutation of calcium-sensing receptor on parathyroid chief cells; results in constitutive supression of PTH release and low serum calcium levels
Etiologies low Mg+2, low albumin (binds calcium so can cause unadjusted low total calcium) meds (Lasix, calcitonin, antineoplastic agents, anticonvulsants, citrated blood products)
Epi
Risk factors
Lab/Imaging low total calcium, high phosphorus PTH deficiency - low Ca, low PTH PTH resistance or renal failure - low Ca, high PTH ALGORITHM: low PTH? hypoPTH (gland defect, no PTH production, prob w/ CaR); nl PTH? hypoPTH, transient hypoPTH; hi PTH? Renal failure, vitD deficiency (would mean PTH is less effective at raising calcium so parathyroids would continue to release more...)
Treatment acute - IV calcium gluconate chronic - calcium carbonate vitamin D - if PTH problem, give calcitriol; if vitD deficient, give cholecalciferol (precursor)
Complications
Familial hypercalcuric hypocalcemia
Hypercalcemia (general)
sx related to sites of calcium action/reg: ("stones, bones, groans, psychic overtones") - bone: fxs, osteoporosis, osteomalacia, osteitis fibrosa cystica -kidney: nephrolithiasis, nephrocalcinosis, polyuria - CNS: depression, seizures, obtundation, muscular contractions - EKG changes (shortened QT interval) - GI: gallstones, acute pancreatitis, peptic ulcers
parathyroid hormone related (primary or tertiary hyperparathyroidism - SEE BELOW) vitamin D related (vitD intoxication; granulomatous dz like sarcoidosis, TB) malignancies (ectopic hormone production - PTHrP; osteolytic metastases) Meds (thiazides, lithium, antacids) genetic (CaR mutations inactivating) hyperthyroidism
excess PTHrP (cancers) causes release of PTH
hi PTH? Hyperparathyroidism, familial hypocalcuric hypercalcemia
symptomatic - fluids followed by furosemide once volume is corrected; calcitonin IM/SC (acute relief), low PTH? Tumor induced bisphosphonates (PTHrP), granulomatous dz (slower relief); GCs (if myeloma, granulomatous or lymphoma, bone dz, or vitD toxicity), metastases, meds dialysis - last resort bone mineral density test for osteoporosis 24h urine calcium & creatinine clearance for kidney fxn
Hypercalcemia from malignancy
most common cause of symptomatic hypercalcemia PTH independent hypercalcemia FATIGUE, polyuria
humoral hypercalcemia of malignancy (HHM) - major cause of severe hypercalcemia, usually due to ectopic PTHrP osteolytic metastases: ectopic PTHrP from SCC, RCC, lymphomas, HTLV; vitD producing tumors (lymphomas), ectopic PTH tumors, local osteolysis (breast Ca or myeloma metastasizes to bone)
SCC - lung cancer, RCC, lymphomas. Local bone metastasis from breast Ca or myeloma
LOW PTH, hi Ca (nl feedback system, but hi calcium from hi PTHrP) often have low albumin from malnourishment/ weight loss MRI or CXR to find malignancy
Disease
Clinical Variants hypercalcemia from granuloma dz
Defining Characteristics PTH independent hypercalcemia
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Granulomas make 1aTB, sarcoid, hydroxyase = increased 1alymphomas, hydroxylase activity = increased fungal infection production of vitamin D = increased calcium absorption inherited inactivating mutation of the calcium-sensing receptor on parathyroid chief cells; results in constitutive release of PTH and high serum calcium levels CaR senses low calcium when the Ca levels are actually normal --> causes hi PTH, hi calcium Hispanic origin FH low 24h urine excretion of calcium benign condition that usually doesnt require tx
Familial hypocalcuric hypercalcemia
PTH dependent hypercalcemia
HyperPrimary parathyroidism
PTH dependent hypercalcemia most often asymptomatic hypercalcemia
lesions directly to the parathyroid gland cause excessive PTH release
parathyroid adenoma
25/100,000 cases in U.S.
hi PTH, hi Ca, hi 24h urine excretion of Ca
parathyroid adenomas = most common cause of asymp hypercalcemia; usually sporadic, solitary lesions Can also cause STONES, diagnosed incidentally; often have mutations in cyclin D1 BONES, GROANS, (promotes cell division), menin PSYCHIC OVERTONES (MEN1), RET (MEN2)
diffuse/ nodular Females 3:1 hyperplasia parathyroid carcinoma (rare)
path of parathyroid adenoma: small tumor w/ encapsulated growth pattern, lack of nl fat component of PT, uniform if do not meet surgical cells w/ round nuclei (tumor criteria, monitor blood nests w/ dense chromatin), tests every 6 months rare mitoses path of parathyroid carcinoma: much larger than adenoma; bland cytology (may have fibrosis, scarring within tumor nests, subtle infiltrative growth); local invasion & metastasis
parathyroid adenomas are treated by surgical excision IF criteria met (Ca > 11.5, reduced kidney fxn, T-score on BMD <-2.5, age <50)
brown tumors of hyperparathyroidism (reactive mass formed secondarily to microfractures and hemorrhages as a result of multinucleated giant cells and fibrous tissue influx) osteitis fibrosa cystica (see above)
Secondary
dialysis patients!
chronic hypocalcemia --> hyperstimulation of the parathyroid gland --> hyperplasia of parathyroid and increased/chronic release of PTH accumulation of mutations from secondary hyperparathyroidism hyperplasia leads to the development of calciumindependent lesion
renal failure vit D deficiency
PTH > 500 REQUIRES medical intervention
parathyroidectomy if PTH cannot be controlled w/ meds
Tertiary
possibly associated w/ duration of dialysis; can occur in post-kidney transplant patients
Disease Hypoparathyroidism
Clinical Variants primary
Defining Characteristics insuff activity of parathyroid gland = low PTH and hypocalcemia
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging low (or nl) PTH, low calcium, hi phosphate
Treatment slow infusion of IV calcium (too fast can cause cardiac probs + burns) oral vitD (if low PTH which means that 1ahydroxylase cannot be activated to make active vitD) recheck calcium levels in 3m (if rise in Ca, suggests transient hypoPTH)
Complications
dysfunctional or hypofunctional parathyroid gland usually related to an autoimmune process, infiltrative process (hemochromatosis, Wilson's dz decreased serum PTH (deficienct PTH secretion) copper, aluminum, breast cancer metastasis, granulomatous dz), or magnesium deficiency (chronic alcholism, malnutrition, TPN, diuretics - thiazides, furosemide, familial)
Iatrogenic
history of neck surgery, thyroidectomy, cervical lymph node dissection
removal of parathyroids from surgery (thyroidectomy), TPN, thyroid ablation w/ radiation
most common cause of hypocalcemia
Congenital
DiGeorge syndrome (pharyngeal pouch maldevelopment) posteriorly rotated ear, flat nasal bridge, hypertelorism (lots of space btwn eyes), small chin Velocardiofacial syndrome
absence of 3rd & 4th pharyngeal pouches, the embryological origin of parathyroids DiGeorge syndrome - defect in chromosome 22; 95% de novo mutation
agenesis/ dysgenesis of parathyroids; transient (maternal hypercalcemia shuts down baby's PTH), syndromes
digeorge 1:5500 (M=F)
if patient's calcium levels rise after 3m of meds, suggests transient hypoPTH
DiGeorge syndrome abdominal aortic arches, VSDs life threatening after birth; immune dysfxn (abnl thymus development)
Familial (APS-I)
candidiasis, hypoparathyroidism, Addison disease
recessive autoimmune regulator gene (AIRE) mutations cause autoimmune polyendocrine syndrome 1
Pseudo
increased serum PTH Type 1a = Pseudohypoparathyroidism (abnl biochem findings) + Albright's hereditary osteodystrophy (AHO) (short stature, obesity, brachymetaphalangia, calcifications, mental retadation)
end organ resistance to PTH (PTH resistance) due to production of abnl PTH molecule that does not properly interact w/ receptor (abnl alpha subunit of G protein - GNAS1 gene)
low Ca, hi phos, hi PTH, nl renal fxn, low 1,25(OH)2vitD, problems w/ other hormones that work through G proteins (TSH, LH, FSH) XR of hands: short metacarpals
Disease Vitamin D deficiency / insufficiency
Clinical Variants
Defining Characteristics rickets: bowed legs, kyphosis, enlarged epiphyses, metaphyseal flaring, thickened wrists from hi bone turnover, rickettic rosary (palpable nodules on ribs) osteomalacia in adults def = vitD < 50 mmol/L insuff = vitD < 75 mmol/L
Pathogenesis normal bone development involves mixture of osteoid (nonmineralized component of collagen, chondroitin sulfate, & osteocalcin) with mineralized component (calcium phosphate)
Etiologies
Epi
Risk factors
Lab/Imaging decreased 1,25(OH)2 vit D OR total 25(OH) vitD2/D3 better indicator bc longer half life low Ca, low phos (bc vitD increases GI absorption of Ca + phos; also nl PTH causes kidney excretion of phos), hi alkaline phosphatase; however, rickets dx REQUIRES radiographic changes XR: cupping/ metaphyseal flaring
Treatment
Complications bone disease/ inc fx (osteoporosis - bone resorption > bone formation), rickets/ osteomalacia (osteoid does not mineralize --> "soft bone"), cancer, CVD, T2DM, autoimmunity
1 billion limited worldwide sunlight exposure, inadequate dietary intake, kidney dz (increased vit D deficiency = dec calcium, excretion of phosphate absorption = poor phos + inability mineralization of bone --> to create active rickets in kids or vitD), GI dz osteomalacia in adults (dec absorption), nutritional vitD deficiency, def in vitD hypophosphatemic rickets, 25- enzymes/ OHase def; 1,25-OHase def receptors, (renal failure), resistance to resistance to calcitriol vitD
Hypophosphatemia
respiratory & cardiac arrest decreased absorption of (lack of ATP) phosphate (vitD def, vitD dependent rickets I&II, alcohol, refeeding syndrome) bone pain, weakness, pathologic fx increased urinary loss of phosphate (hyperparathyroidism, RTAs, DKA; oncogenic osteomalacia tumors that make FGF-23; Xlinked hypophosphatemic rickets - mutation in PHEX prevents FGF-23 degradation; autosomal dominant hypophosphatemic rickets FGF-23 resistant to PHEX degradation) transcellular (respiratory alkalosis, leukemia)
hi PTH hi FGF-23 (low P, low vitD3) low vitD3 PHEX mutation
low vitD3, low serum phosphate, & phosphaturia? Check MRI of head/chest/pelvis for tumor (suspect oncogenic osteomalacia), could also suggest PHEX mutation preventing FGF-23 degradation (suspect Xlinked hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets)
give VitD (increases phosphate & calcium absorption, preventing PTH action)
Hyperphosphatemia
increased intake (TPN, phosphate enemas) decreased excretion (usually chronic kidney disease, hypoparathyroidism) excess bone resorption transcellular shift (tumor lysis, rhabdo)
Disease Pituitary adenoma
Defining Characteristics microadenomas (usually secrete hormones) - <1cm; prolactinomas, corticotroph adenomas, somatotroph adenomas macroadenomas (usually present w/ mass effect without syndromic effect) >1cm - bitemporal heminopsia, diplopia (CN3, 4, 6 palsy), headache order of hormone disruption: GH--> LH/FSH -> TSH --> ACTH
Pathogenesis mass effect macroadenomas grow so large that impinge the optic chiasm, which supplies the medial aspects of the globe and responsible for lateral portions of visual field (lateral field deficits) evasion of apoptosis -> unlimited replicative potential > growth signal independence -> anti-growth insensitivity -> sustained survival -> adenoma formation
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications pituitary apoplexy pituitary adenoma infarction from expansion --> severe headache & loss of vision (MED EMERGENCY!! Interferes w/ ACTH secretion) pressure/mass effects, hypersecretion of hormones
MENI (menin most common mutation), in adults (40other mutations 50 y.o.; M=F) (CREB, Gs protein, loss of Rb, excessive growth factor production)
macroadenomas are histology: loss of cellular harder to manage (mass heterogeneity, loss of glandular structure (sheet effect) like proliferation, neurocytic rosettes around vessels, papillary config, or ribbon appearance), enlarged nuclei; if severe necrosis/ hemorrhage think apoplexy! MRI: homogenously contrast enhancing (no cystic components or calcifications)
Prolactinoma
galactorrhea, amenorrhea, decreased libido, infertility, amenorrhea/ hypogonadism, osteoporosis, reduced facial hair in men
adenomas that secrete prolactin occur in 20% of patients with MEN1 syndrome
30% of pituitary adenomas
increased serum prolactin (usually > 200 ng/mL) & positive immunohistochemistry for prolactin (brown = positive) possible decrease in FSH, LH; possible hypopituitarism depending on size of prolactinoma R/O secondary causes (kidney, liver tests; TSH; pregnancy test, med eval) MRI of pituitary for mass
Treatment IF macroadenoma, mass effect, fxnal compromise (infertility, galactorrhea); o/w monitor dopamine agonists (Bromocripitine, Cabergoline) for tx of microadenomas
mass effect can interfere w/ secretion of other pituitary hormones
prolactin inhibits gonadotropin release & steroid prod in end organs --> amenorrhea or secondary surgery if macroadenoma hypogonadism in w/ critical mass effect men (loss of vision, rapid progression, spread to osteoporosis ICA), young pt w/ potential for cure, no response/ recurrence (16%) tolerance for med tx, recurrence surgery - loss of anterior / posterior pit fxn (DI)
Nonfunctional
no clinical manifestations
Corticotroph Cushing's disease microadenoma that secretes (obesity, stria, HTN, acne, excess ACTH DM)
20% of pituitary adenomas 15% of pituitary adenomas
Disease
Clinical Variants Somatotroph
Defining Characteristics Gigantism (if adenoma occurs in childhood before closure of epiphyses) acromegaly (if adenoma occurs AFTER closure of epiphyses) - large feet, coarse/ enlarged /spongy hands, auditory probs, thickened skin/ lips, wide nasal bridge, furrowed brow), proportionally enlarged organs, arthritis, neuropathy
Pathogenesis adenoma that secretes excess GH GH over production leads to gigantism or acromegaly; most likely due to pituitary adenoma can also have mixed GH & prolactin secreting adenomas (better prognosis than GH adenoma alone)
Etiologies
Epi 15% of pituitary adenomas
Risk factors
Lab/Imaging elevated IGF-1 (even after age- matching to references) OGTT suppression test (hyperglycemia) results in sustained elevation of GH (nl the GH level would be reduced w/ hyperglycemia) impaired glucose intolerance insidious onset - check pictures of pt from years before
Treatment
Complications
usually macroadenomas acromegaly: requiring debulking surgery - 1st option! cardiomyopathy, obstructive sleep meds: somatostatin apnea, diabetes, analogs (ocreotide), GH colon cancer, increased malignancy receptor antagonists (Pegvisomant), panhypopituitarism dopamine agonists (if after radiation tx dual prolactin & GH (causes loss of GH, secretion) then FSH/LH, TSH, radiation for residual dz or ACTH) suboptimal response to surgery & meds
Gonadotroph Thyrotroph
excess secreted by adenoma could cause precocious puberty
5% of pituitary adenomas 1% of pituitary adenomas overgrowth of cells of one type, leading to hormone hypersecretion without presence of obvious tumor
Pituitary hyperplasia
Craniopharyngioma
suprasellar tumor
proliferative or neoplastic conversion of cysts in "intermediate lobe" --> ectopic remnants of pharangeal epithelium hemorrhagic mass in suprastellar space that impinges on CNS structures -> calcifications, squamous differentiation
somatic cell more mutations in B- common in catenin gene kids (ages 1016) 10% of all pediatric intracranial tumors
difficult to resect (due to radiation can cause oily substance secretion & pan hypopituitarism keratin) (lifelong hormone replacement therapy) Histology: usually don't see epithelium in the brain but surgery + radiation proximity to 3rd this has epithelium (from ventricle/ optic nerves/ Rathke's cleft) lined w/ optic chiasm/ basal lamina that create hypothalamus keratinaceous material (wet keratin nodules that large size, locally undergo calcification), invasive, recurrence cystic spaces w/ oily risk substance/ cholesterol MRI: cystic components + calcifications deposits
Rathke's cleft cysts
located within sellar space or extends into suprasellar space single cell layer (simple) cyst
hyperplasia of cystic structures of intermediate lobe of pituitary
histology: lined by single layer of columnar ciliated epithelium, everything else is cyst fluid
Pituitary carcinoma
aggressive lesions that invade soft tissue structure, vasculature, & bony structures
<5% of masses
Disease Germinoma
Clinical Variants
Defining Characteristics suprasellar tumor
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging histology: clear tumor cells w/ large nuclei, prominent nucleoli, positive lymphocytic infiltrate & granulomatous inflammation, positive for PLAP, c-kit, Oct4 markers, similar pathologic features as testicle/ovary neoplasms MRI:homogenous & compact suprasellar mass
Treatment
Complications
Pituicytoma
suprasellar tumor that resembles glial tumors
arise from posterior pituitary (pituicytes)
histology: stains positive for GFAP (glial fibular acidic protein - IF of glial cells) histology: large pink, lysosome filled benign tumor cells that PAS positive hi serum osm, low urine osm; urine osm < serum osm (DILUTE urine bc no ADH & H2O reabs; nl expect hi serum osm to cause inc urine osm) water deprivation test - once plasma osm > 295, give ADH; central cause of DI if low serum ADH but responsive to ADH ; nephrogenic cause if hi serum ADH but NOT responsive to ADH R/O psychogenic polydipsia (hi fluid intake & polyuria)- no ADH resp, low urine osm & serum osm surgical resection low, grade benign lesions
Granular cell tumor
suprasellar tumor
arises from posterior pituitary gland
ADH deficiency Diabetes Insipidus
excessive urinary loss of solute-free water excessive thirst/ H2O intake (polydipsia), polyuria (>2.5L/d), hypernatremia, hyperosmolarity
central causes: loss of posterior pituitary function --> deficiency of ADH nephrogenic causes: end organ resistance to ADH
acquired central (neurosurgery, head trauma, tumors, infiltrative dz, idiopathic) acquired nephrogenic (hypercalcemia, hypokalemia, lithium use, amyloidosis, Sjogrens) Congenital nephrogenic (defective V2R; aquaporin mutation)
Disease ADH excess
Clinical Variants Syndrome of Inapprop ADH (SIADH)
Defining Characteristics gradual onset of dilutional hyponatremia (mild sx: headaches, muscle cramps, nausea, lethargy; severe sx: AMS, seizures, coma, death!)
Pathogenesis inappropriate (nl/hi) concentration of ADH for low plasma osmolality --> water retention & hypo-osmolality despite euvolemic status
Etiologies malignancy (small cell lung para-neoplastic synd; non-pulm cancers), CNS d/o (mass lesions, inflam dz - SLE, meningitis, degenerative dz, subarach hemorrhage, trauma) drugs, pulm dz (TB, pneumo, mech ventilation), other (AIDS)
Epi
Risk factors
Lab/Imaging hyponatremia w/ inapp low plasma osm urine osm > plasma osm (would nl expect dilute urine if low plasma osm) exclude secondary causes of hyponatremia (hypovol, hypotension, generalized edema d/o, renal/ adrenal insuff, hypothyroidism) renal sodium excretion > 20 mmols
Treatment
Complications
Short stature
(general)
analyze growth velocity, final height prediction (mid parental height, bone age)
malnutrition (ask re: 24h dietary intake), systemic illness (chronic renal failure, congenital heart disease w/ hi Final ht = MPH +/- 3.9" output or cyanosis, anemia, males: (5"+ moms ht + IBD); skeletal dysplasia dads ht)/2 (estimate body proportions), females: (moms ht + dads chromosomal aneuploidy ht - 5)/2 (Turners syndrome), hormone const delay - nl growth deficiency/resistance, velocity, delayed bone age idiopathic genetic - nl growth velocity, nl bone age (-2sd) hormone probs - poor linear growth, adequate/ excessive weight gain, delayed BA, increased weight: height percentile
nl causes: genetic/ familial, const delay of growth, improper measurement abnl causes: poor weight gain, osteochondrodysplasia, genetic syndromes, hormone problems (thyroid def, GH def, GC excess)
90% of referrals are normal most common cause for failure to grow?? GC excess (Cushings)
blood or urine test: IGF-1 & WAIT - most improves w/ time; counseling, improve IGF-BP3, free T4 & TSH caloric delivery, GI/ genetics eval?? GH stimulation testing Bone age: XR of LEFT wrist HRT?? & hand (girls: 95% of ht at BA 13; boys: 95% of ht at BA 14.5)
Disease
Clinical Variants hypothalamic defect
Defining Characteristics GHRH deficiency
Pathogenesis
Etiologies hypothalamus (GHRH def, somatostatin excess), pituitary (GHRH receptors, GH1 gene to encode GH, transc factors like Pit-1, PROP1, HESX1); target (GHreceptors, intact Jak/Stat pathway, intact IGF-1 and IGFBP3 response systems) possible craniopharyngioma
Epi
Risk factors
Lab/Imaging GHRH def = low basal GH, IGF-1, & IGF-BP3 no GH released following indirect stimulation testing (hypoglycemia, a-2 agonist, L-DOPA) +GH released w/ direct administration of GHRH (if intact blood supply of anterior pituitary), ghrelin, or GHRP
Treatment
Complications
Pituitary defect
GH deficiency
low basal GH, IGF-1, & IGF- treat w/ GH until growth complete; may need as an BP3 adult also no GH released following indirect stimulation testing no GH released with direct admin of GHRH
End organ defect
GH receptor mutations (deletion, non-functional) prevents end organs from responding to GH
GH receptor mutations? (Laron Syndrome)
low IGF-1 levels, HI basal and stimulated GH levels low levels of GHBP (extracellular domain of GH receptor that has broken off) - suggest GH insensitivity rather than problem w/ GH
Hypopituitarism
(general)
tumors - craniopharyngioma, central defects in pituitary hormones (all or optic glioma, pituitary adenoma trauma - physical abuse, MVA partial) (usually posterior & anterior defects bc severed neural stalk) inflammation - histiocytosis, hypophysitis cranial radiation - usually knocks GH out first Idiopathic inborn errors of pituitary development - septic optic dysplasia (SOD) - incomplete development of hypothalamus, septum pellucidum, & optic nerves
congenital or acquired - use age of onset, medical hx, imaging, associated findings, & impairment of visual fields to assess suspect genetic cause if early onset, no hx of trauma/ radiation, distinct growth & hormone phenotypes, founder effect
Disease
Clinical Variants MPHD
Defining Characteristics Multiple pituitary hormone deficiency
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
consider transcription factors genetic - AR mutation involved in pituitary development multiple sibling involvement SHH - expect w/ normal parents holoprosencephaly; HESX1 a/w SOD; LHX3 & LHX4 involves loss of less hormones; Pit1 mutations - early & extreme growth retardation, PIT1 & PROP1 (PROP1 is spont puberty necessary for appearance of Pit1; PROP 1 promotes development of lineage cell PROP1 mutations - no precursors in anterior pituitary) pubertal stage, abnl rosy cheeks, severe hypothyroidism
Precocious puberty
(general)
signs of clinical puberty (breast/ testicular development and/or pubic hair)
increased sex steroids central or non-central (see below) causes of early menarche (vaginal bleeding) w/o other signs of puberty?? FOREIGN BODY, trauma, ovarian cysts, McCune Albright
caloric intake (excess adipose)
early maternal menarche, low birth weight, inc weight gain (obesity) in childhood, international adoption, estrogenic chemicals, absence of father in household, FEMALES
evaluate girls/boys showing clinical pub before 7y(white) or 6y (black) / 9.5y respectively Check urinary/GI tract if bleeding; Check estrogen / testosterone; Growth velocity? Growth chart? Significant weight gain? (more chol = more androgens) Check neuro/ fundoscopic exam; check for physical signs of puberty If child has muscle development, check testes size - think non-central cause if small (if central - enlarged testes bc stimulation w/ FSH/LH)
GnRH agonist (lupron)
advanced bone age early but finish treat underlying problem growing so end up (eliminate exposure to being smaller than agents, surgery for tumor/ expected cysts, treat hormone abnl like CAH/ hypothyroidism) ketoconazole - inhibits androgen synthesis
Central
gonadotropin - dependent (inc FSH & LH, inc testosterone or estradiol) idiopathic (>90% females, 45% males) CNS abnormality hypothalamic/ pituitary mass, cerebral malformation, injury/ head trauma Early exposure to sex steroids (inc bone age w/ estrogen or testosterone)
Disease
Clinical Variants Non-central
Pathogenesis gonadotropin - independent (decreased FSH/LH, increased testosterone or estradiol) autonomous gonadal activation- McCune-Albright Syndrome (GNAS activating; see below), activating mutation of LH receptor gene adrenal d/o - CAH, adrenal tumor (muscle development + small testes) exogenous exposure to sex steroids Tumor - ovarian cysts (Granulosa cell / androgen producing), Leydig cell tumors in testicle, hCG producing tumors in liver van Wyk-Grumbach syndrome (see below)
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
McCuneAlbright Syndrome
early non-central puberty + activating mutation in GNAS mutation in the gene that hyperthyroidism causes ovary/testicle to codes for the develop independently of TRIAD: non-central stimulation by gonadotropins - alpha subunit of the precocious puberty, caf- -> secretion of estradiol/ stimulatory G testosterone--> precocious au-lait skin findings, protein (Gsa) puberty hyperostosis fibrous dysplasia Excess estrogen exposure = increased growth velocity & marked advancement in skeletal maturity ovary will be hyperfunctional for some time but then involutes; once brain senses that bone age is appropriate, pulsatile GnRH & LH/FSH secretion will begin, normalizing puberty
XR: smoked out appearance on XR of femur
aromatase inhibitors (dec estrogen), SERM (tamoxifen - blocks estrogen receptor) however, tx is controversial as this d/o usually does not progress
Van WykGrumbach Syndrome
only condition w/ precocious puberty w/o bone age advancement (growth arrest)!! Primary hypothyroid + precocious non-central puberty
dec T4 = inc TRH = inc TSH & Prolactin TSH shares alpha subunit w/ FSH so FSH also increases = increased estradiol in ovary
Disease Turner Syndrome
Clinical Variants
Defining Characteristics Short stature, primary amenorrhea, infertility Clinical clues? Pterygium colli (abnl ear), cystic hygroma (fluid filled mass prenatal U/S), acral lymphedema (nail dysplasia, puffy feet), aorta coarctation (HTN, CHF, cardiomegaly, pulm edema AFTER ductus closes), cervical hypoplasia, congenital hip dislocation, horseshoe kidney, hi arched palate, shield chest, hypogonadism, sensorineural deafness, Madelung deformity, strabismus (cross eyed) secondary amenorrhea, hirsutism/acne, infertility, obesity, hyperlipidemia, insulin resistance Diagnosis REQUIRES 2 of 3 criteria: oligomenorrhea, any evidence of hyperandrogenism (clinical hirsutism, acne; biochem findings), PCOS appearing ovaries on U/S (>12 cysts, 2-9 mm) acanthosis nigricans
Pathogenesis phenotype that occurs in patients w/ one normal X chromosome & complete/ partial absence of the other X chromosome = 45X OR 46X, structurally abnl X OR mosaics lymphatics drainage prob --> cystic hygroma, non-pitting edema hi arched palate --> feeding/ speech problems, dental crowding gene dosage effect - SHOX (pseudoautosomal region) deficiency --> skeletal abnl & short stature
Etiologies
Epi
Risk factors
Lab/Imaging amniocentesis: abnl chromosomes karyotype: One X chromosome with absent 46th chromosome PE: signs of coarct & HF (crackles, displaced apical impulse, hepatomegaly, early systolic click), non-pitting edema (sign of lymph prob) Pelvic XR - maldeveloped head of femur, displaced from foramen - DISLOCATED HIP ECHO - bicuspid aortic valve Renal/pelvic U/S - horsehoe kidney, duplicated UT
Treatment short stature - GH replacement
Complications
paternal non- 1:2500 live female births disjunction structural chrom abnl (isochromosome = 2q's - long arms, no p short arm; ring chromosome) most common recognizable cause of spont Ab median age of dx? 15 y.o.
hypothyroidism, T1DM, T2DM, osteoporosis, premature ovarian failure - premature death add androgens when (related to CVD, appropriate for puberty coarct), aortic dissection, ovarian multi-disciplinary failure/ dysgenesis interactions w/ cardio, psych, ENT, progressive endocrinology, etc sensorineural deafness, probs w/ social intxns & visual/ spatial defects Y chrom mosaics - inc risk for gonadoblastomas --> dysgerminoma require ovary removal!! weight loss & exercise for insulin resistance & hirsutism (can also use OCPs) metformin for hyperinsulinemia & possible improved response to clomid ovarian wedge resection for hyperandrogenemia clomiphene, gonadotropins, or aromatase inhibitors for anovulation live birth rate better w/ clomid + met or clomid alone (NOT met alone) increased risk of endometrial cancer (unopposed estrogen), DM, CVD, obstetric risks, depression, anxiety, infertility
Polycystic ovary syndrome (PCOS)
androgens cause early follicular arrest & atresia --> oliganovulation, infertility, & cysts on ovaries androgens provoke accelerated GnRH pulsatility, causing enhanced release of LH and subsequent production of more ovarian androgens insulin resistance might also be underlying mechanism for PCOS - hyperinsulinemia might potentiate LH response to produce hyperandrogenemia
6-10% prevalence accounts for ~75% anovulatory infertility
FH
DX OF EXCLUSION: supportive data? Hyperandrogenism, oligoanovulation, polycystic ovaries on U/S, obesity, IR/DM, hi LH/FSH ratio
Disease Abnormal uterine bleeding (AUB)
Defining Characteristics any disruption from normal cycle (24-35d x 46d, 30 ml blood loss)
Pathogenesis structural or functional abnormality??
Etiologies
Epi 2nd most common reason for OB/GYN visits most common cause of adolescent hospital admissions
Risk factors perimenopause
Lab/Imaging Pregnancy test!!! CBC (R/O anemia, thrombocytopenia) TSH (hypo/hyperthyroidism a/w AUB) cervical cancer screening chlamydia (hi risk patients) screening for bleeding d/o (adolescents) endometrial bx (>40 y.o., prolonged anovulation) transvaginal U/S (hi risk for cancer/ hyperplasia if endometrial stripe > 5 mm) hysteroscopy (dx, tx symptomatic intrauterine pathology) Menstrual diaries
Treatment Anovulatory bleeding: progesterone (oral tx, Mirena IUD) - induces regular bleeding & prevents endomet hyperplasia (opposes estrogen), combined OCPs, estrogen tx (only if hemorrhaging w/ low hematocrit), D&C (hemodynamically unstable) Ovulatory bleeding: NSAIDs (dec prostaglandin), OCPs, Mirena IUD, GnRH agonists (preop pts), antifibrinolytics (tranexamic acid) surgery: endometrial ablation, hysterectomy
Complications
PALM-COEIM P (polyp), A (adenomyosis Ovulatory v. anovulatory?? Ask ), L (leioabout timing (ovulatory bleeding myomas) M oligomenorrhea - cycle more regular due to intervals > 35 days (malignancy, programmed shedding of polymenorrhea - cycle hyperplasia), C corpus luteum) intervals < 24d (coagulopathy menorrhagia - normal ), O (ovulat intervals but excessive flow absent menstrual flow during pill dysfxn), E free week of OCP - think or duration (endometrial), progesterone breakthrough metrorrhagia - irregular I (Iatrogenic), bleeding (use short interval of intervals, normal flow or M (Mullerian estrogen) duration anomalies) menometrorrhagia irregular intervals, excessive flow or duration
Polyps
intermenstrual spotting
Adenomyosis
painful periods
Leiomyomas (fibroids)
primarily benign but can convert to tumor (rare) submucosal fibroids (in uterus) have severe bleeding
benign growths, can cause intermenstrual spotting, can be hyperplastic in menopausal women endometrial glands that grow into the myometrium (muscle) of the uterus, making the uterus globular benign tumor from the smooth muscle of the uterus myometrium
diagnosed with pathology only!
most common lesion causing AUB in reproductive aged women obese, elderly, postmenopausal, PCOS
Malignancy
postmenopausal bleeding endometrial cancer - bleeding most likely due to atrophy - must R/O endometrial cancer ovarian neoplasms often functional tumors (granulosa cell, thecoma) von Willebrand factor, ristocetin often in adolescents or patients with chronic AUB cofactor certain meds (warfarin, heparin, NSAIDs, herbals - gingko, ginseng, motherwort)
Coagulopathy
20% w/ heavy menstrual bleeding have underlying bleeding d/o
CBC/platelets prothrombin time partial thromboplastin time
Ovulatory dysfunction
nl H/P/O axis, nl steroid hormones
local abnl prostaglandin synthesis, increased tissue plasminogen activator (TPA) activity, increased local fibrinolytic activity bleeding due to unopposed estrogen endometritis, hyperplasia PCOS
Endocrinopathy Endometrial
usually PCOS
Disease
Clinical Defining Characteristics Pathogenesis Variants Inflammatory bleeding without relation vulvitis, vaginitis, cervicitis, endometritis, salpingitis, PID to menses a/w signs of infections foreign bodies (children), coital lacerations, trauma implantation bleeding 1-2d following missed menses (often mistaken as menses)
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Iatrogenic Pregnancy bleeding bleeding + PAIN - think ECTOPIC!!
snowstorm pattern on U/S molar pregnancy gestational sac seen outside of the uterus ectopic pregnancy
Uterus S>D, quant b-hCG > 100,000 - think MOLAR ectopic pregnancy, molar pregnancy pregnancy! 20-25% of women spot/ bleed during 1st trimester Hypertension during pregnancy Chronic HTN hi BP before pregnancy, or <20 weeks gestational age systolic > 140, diastolic > 90 predating pregnancy or identified before 20 weeks gestation if PNC began at > 20 weeks and she has HTN > 12 weeks postpartum, considered chronic HTN (diagnosed post-hoc) Gestational HTN hi BP >20 weeks gestational age BP > 140/90, occuring after 20 weeks without proteinuria mosy common med comp of pregnancy 6-8% of all live births 17.6% of maternal deaths in U.S.
Preeclampsia
hi BP > 20 weeks AND PROTEINURIA
BP > 140/90, occuring after 20 requires weeks gestation with placenta!! proteinuria (> 300 mg/24h collection) severe: 1+ of following criteria (BP>160/110 >2x, 6 h apart while on bedrest OR proteinuria of >5g/24h OR proteinuria of >3g in 2 random urines >4h apart) vasoconstriction/ vasospasm [circul vasoconstrictors + endog vasoconstrictors -> endothelial damage (dec prostacyclin, inc TbxA2) --> primary DIC]
severe pre-eclampsia sx: oliguria of 500mL in 24h, cerebral/ visual disturbance, pulmonary edema or cyanosis, epigastric or RUQ pain, impaired liver function, thrombocytopenia (platelets < 100,000), fetal growth restriction
maternal starts w/ up & down BP, extremes of age progresses to >140/90, then proteinuria followed by 1st child signs & sx of severe preeclampsia; if left untreated, chronic HTN, will progress to eclampsia vascular disease, DM hx of HTN in pregnancy minority groups
DELIVERY!!
HELLP syndrome (>24wks): hemolysis, elevated liver enzymes, low platelets improper trophoblast implantation --> immunologic response Eclampsia mild or severe preeclampsia PLUS SEIZURES!!!
HELLP: liver hematomas, DIC If <32 weeks, give fetal risks: IUGR, oligohydramnios antenatal (decreased amniotic corticosteroids & stabilize w/ MgSO4 (anti- fluid = dec urine output from blood flow shunt seizures), antito brain/heart/adrenals hypertensives, & LD & away from kidneys), bedrest for 48h before placental delivering infarct/abruption, prematurity consequences, uteroplacental insufficiency, perinatal death maternal risks: CNS problems (stroke, seizures), DIC, C/S, renal failure, hepatic failure, death stabilization (MgSO4, antihypertensives), assessment for maternal sequelae, and delivery
cause of maternal mortality
Disease
Clinical Defining Characteristics Variants Atypical pre- vague RUQ or epigastric eclampsia discomfort, small headache, incidental thrombocytopenia new swelling of legs, general sick appearance
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Spontaneous abortion
1st trimester bleeding Threatened Inevitable - os is wide open, lots of blood missed/incomplete - some tissue still present Complete - uterus is empty and hCG levels drop off following day
aneuploidy - monosomy X0 or trisomy 16
50% of 1st trimester bleeding
Type & Cross - Rhogam if Rh-
usually no intervention is required; however, if tissue remains (missed) D&C or medical tx heavy bleeding? D&C
Ectopic pregnancy
pregnancy/ implantation of Chlamydia gestational sac OUTSIDE of the replicates uterus intracell & Bleeding + pain!! lyses cells Adnexal mass + tenderness interstitial tubal pregnancy most dangerous bc least rupture?? Unstable vitals, distensible! positive pregnancy test, Ampullary end of Fallopian diffuse tenderness, tube and abdomen most bleeding (low HCT) conducive to embryonic development 1st trimester bleeding
1-2% prevalence
prior ectopic, PID, surgery, endometriosis
Type & Cross - Rhogam Rh- Unstable? Send directly to OR Transvaginal U/S Certain ectopic? endometrial stripe w/ no Methotrexate (1st line!), gestational sac; gest sac in fallopian tube/ outside uterus surgery Blood in belly - ruptured ectopic Arias-Stella reaction hyperplastic endometrial cells; stroma with decidua but no chorionic villi / placenta= pregnancy but outside of uterus gross: decidual cast partially necrotic membranous tissue expelled from vagina
10% mortality w/ rupture INFERTILITY chronic pain
Placental abruption
3rd trimester bleeding AND PAIN!!! 10% have no bleeding (blood could be retained behind the placenta) increased uterine contractions
separation of placenta from uterus
15% of 3rd trim bleeding 1:120 deliveries
trauma, U/S NOT helpful, dx is smoking/ clinical (NO CERVICAL cocaine, EXAM!!) multiparity, HTN, prior abruption, AMA
immediate hospitalization, Fetal prematurity IV access/ fluids/ type & (Resp distress cross syndrome, intraventricular Deliver if unstable (vag hemorrhage, enterocolitis, or C/S) blindness), stable? Expectantly fetal anemia, manage fetal hypoxia (cerebral palsy, seizures), maternal hemorrhage shock, DIC (abruption)
fetal anemia, Disease Placenta previa Clinical Variants Defining Characteristics 3rd trimester bleeding PAINLESS bleeding Pathogenesis placenta covers the internal cervical os Etiologies Epi 10% of 3rd trim bleeding Risk factors Lab/Imaging Treatment Complications fetal hypoxia (cerebral palsy, seizures),
multiparity, prior NO CERVICAL EXAM!!! C/S, prior D&C, smoking, prior U/S 0.5% of births previa, AMA
immediate hospitalization, maternal hemorrhage IV access/ fluids/ type & shock, cross C/S delivery if unstable or term Stable & pre-term? expectantly manage, eventual C/S DIC (abruption)
Postpartum hemorrhage
blood loss with delivery
most loss after separation of placenta; control the contraction (involution) of uterus & coagulation/ thrombus formation
noncontracting uterus (UTERINE ATONY)
5% of deliveries
uterine atony = lack of involution or contraction down genital tract laceration genital tract lacerations caused by large baby, retained compound presentation, placental episiotomy, operative delivery, fragments or rapid labor coagulation disorders
uterine atony: hi parity, overdistention uterine atony - (twins, most common macrosomia), cause of post- prolonged labor, partum rapid labor, hemorrhage prolonged use of induction agents, chorioamnionitis, prior history retained placental frags: prior C/S, uterine curretage, accreta
evaluate uterine fundus bogginess? Inspect for lacerations if uterus is firm feeling evaluate the placenta & explore uterus
IV access/fluids/ type & cross immediately atony? Pitocin-like oxytocin, prostaglandins
Ovarian cancer Germ cell & stromal cell (more common in younger women) epithelial (most aggressive form, more common in older women) Endometrial cancer
abdominal discomfort & distention (usually advanced stage), dyspepsia, urinary frequency, weight loss, abnl bleeding, pelvic pressure, back pain, asymptomatic mass
most are spontaneous cases, hereditary although 5-10% have hereditary breast & component ovarian cancer (BRCA1) unknown etiology protective factors? Multiparity, OCP use, breast feeding [increased risk of ovarian cancer a/w increased ovulatory cycles, so events that decrease # cycles protective] estrogen sensitive neoplasm unopposed estrogenic stimulation of endometrium increased estrogen synthesis (obesity, granulosa cell tumors) decreased estrogen metabolism (hepatic dz) inapprop HRT (estrogen only)
Leading cause of death for gyn malig 1/70 women
FH of ovarian cancer, advanced age, nulliparity, North American/ North European descent, PMH of breast/ colon/ uterine cancer
CA-125 (low specificity, useful if hi clinical suspicion) + transvaginal U/S to assess pelvis (best in peri & postmenopausal women) palpable mass on pelvic exam
If mass on PE, increased CA-125, and suspicious U/S --> SURGERY (exploratory surgery, maximal tumor reduction, biopsies) + postoperative treatment w/ IV chemotherapy or clinical trials
no screening test so patients present at later stage (Stage III) -> higher mortality
primarily affecting peri/postmenopausal women
most common gyn malignancy in U.S.
protective factors? OCP, postmenopausal bleeding, leucorrhea (thick smoking (gross) white discharge), tamoxifen (breast cancer pain/pressure chemoagent) - selective endometrioid type - most estrogen receptor that has common histology type and antagonistic effect on breast BUT agonist effect on CURATIVE! endometrium
age > 60 obesity unopposed estrogen chronic anovulation (PCOS) tamoxifen use endometrial hyperplasia (atypical complex)
surgery - TAH endometrial biopsy perform if abnl bleeding + >4mm endometrial thickness on U/S; abnl bleeding + tamoxifen use; post-menopausal bleeding; change in bleeding pattern in women on HRT or perimenopausal
Clinical Variants Cervical cancer Squamous (80-90%) adenocarcinoma (10-20%) small cell & sarcomas (worst prognosis)
Disease
Defining Characteristics abnl bleeding, discharge POST-COITAL BLEEDING back/ flank pain, hematuria, dysuria advanced stages
Pathogenesis
Etiologies HPV 16 & 18
Epi globally, most common gyn malignancy (lower in U.S. bc screening) 3rd most common gyn malignancy
Risk factors
Lab/Imaging
Treatment Stage I-II A: radical surgery/ hysterectomy + additional cervical tissue Stage IIB - IV: chemo+radiation
Complications stage I - cervix Stage II - upper vag Stage III - lower vag each stage has A (vertical progression) and B (lateral progression) larger masses, more invasive/ vascularized, lymph node involvement = worse prognosis surgical comps? ureteral injury, fistulae, bladder/ rectal dysfxn, DVT, bleeding
low SES (access Pap smears - screen for to screening) dysplasia young age at 1st Colposcopy sexual exposure (duration of Biopsy HPV) CXR - R/O lung metastasis multiple sexual IVP - analyze kidney partners, function cigarette smoking, high risk male partner, persistent HPV/ HIV infection
Germ cell Ovarian Dys- dysplastic germ cells tumors of ovary germinoma (similar to testicular seminoma) usually NO hormone production
unilateral germ cell tumor
young women, often a/w pregnancy
gross: solid, yellow, lobulated/ septated tumor; no necrosis histology: large nucleus & nucleoli; lobular appearance
radiosensitive, treated malignant but good conservatively (R/O mixed prognosis germ cell tumor!!)
Endodermal sinus (yolk sac) tumor
young women
gross: solid tumor w/ multiple areas of necrosis histology: Schiller Duval body (central vessel surrounded by tumor cells), globules with alpha-feto protein AFP - hi but decrease postsurgery (unless some tumor remaining)
combo of chemo, radiation, & surgery improve 5y survival
malignant tumor
embryonal carcinoma polyembryoma Choriocarcinoma
histology: embryoid body
markedly hemorrhagic produces hCG!! +pregnancy test in men!
arise from trophoblasts gestational: arise from placenta & products of conception non-gestational: arise from germ cell tumor
gross: marked hemorrhage gestational: methotrexate sensitive, better histology: prognosis syncytiotrophoblasts that stain brown for hCG non-gestational: NOT responsive to monitor w/ hCG methotrexate, worse prognosis
Disease Ovarian Teratoma
Defining Characteristics benign teratomas? Brain & choroid plexus (nonfunctioning) sacrococcygeal teratoma sacral growth in newborns
Pathogenesis germ cell tumors that make somatic tissue
Etiologies
Epi
Risk factors
Lab/Imaging gross: - hemorrhage w/ hair, etc? think teratoma infarction - cystic teratoma - filled w/ yellow solidified sebum (nl in skin); some have teeth at risk for rupture - multiple glial nodules? Benign teratoma (brain)
Treatment
Complications torsion of cystic teratoma (acute abd pain resulting form vasculature strangulation --> teratoma hemorrhagic infarction) teratomas w/ teeth at risk for rupture
Immature
solid, cystic, or both solid - malignant
immature teratomas are arrested in embryonic development - BAD!!
gross: solid - hemorrhagic & necrotic histology: neuroepithelial rosettes (immature brain glial tissue, resembles brain tissue in newborns) postmenopausal teratoma SCC
Mature
solid or cystic (dermoid cyst or dermoid cyst w/ malignant transformation postmenopausal women) struma ovarii: benign but functioning thyroid in a teratoma
monodermal struma ovarii carcinoid (serotonin-like substances)
struma ovarii: looks like thyroid tissue but also has carcinoid appearance ovarian carcinoid in a teratoma? Monotonous w/o necrosis gross: soft, nodular tumor hysterectomy!! that is solid, yellow, & hemorrhagic histology: Exner bodies (small acinar arrangement w/ tumor cells surrounding gland)
check opposite ovary if similar appearance, check intestines for metastasis
Ovarian Granulosa cell tumor (GCT)
initially benign but usually produces estrogens (rarely androgens) FEMINIZATION estrogen can cause AUB in post-menopausal women; menometrorrhagia (irregular, excessive periods) in reproductive aged women; early puberty in young women
malignancy shown by recurrence > 15 years later a/w uterine endometrioid carcinoma (unopposed estrogen)
Ovarian Theca cell tumor
MOSTLY benign! Usually produces estrogens
gross: solid yellow mass WITHOUT necrosis! Histology: benign spindle shaped cells (Theca cells) that stain red for fat (steroid production) gross: solid, white firm mass histology: benign spindle shaped cells CXR: ipsilateral hydrothorax
Ovarian fibroma
usually benign but can produce Meigs syndrome (ascites, pleural effusion, benign ovarian fibroma)
Disease Sertoli- Leydig cell tumor of ovary
Clinical Variants
Defining Characteristics benign masculinizing tumor --> clitormegaly, hirsutism
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging histology large columnar cells (Sertoli cells, Leydig cells); Leydig cells have Reinke crystals (androgen producing) CXR: check for mediastinal masses in Klinefelters pts hCG & alpha-feto protein are markers for spread of germ cell or recurrence following orchidectomy
Treatment
Complications
Germ cell tumors of testes
(general)
testicular mass but may also arise in anterior mediastinum
germ cell tumors that present in chromosome prepubertal males may be 12 abnl benign (mature teratomas) or low grade malignant (yolk sac tumors) adult germ cell tumors = MALIGNANT!
90% of testicular neoplasms
15-34 year old males Caucasians cryptorchidism familial clustering testicular dysgenesis (Klinefelters)
radical orchidectomy + chemo/radiation
MALIGNANT in adults
Intratubular germ cell neoplasia (ITGCN)
preinvasive form of germ cell immediate precursor tumors lesion for all types of germ cell tumors of testis found as focal lesion in 2% of cryptorchid testis & biopsies performed for infertility testing asymptomatic, sometimes pain/ discomfort most common pure type, resembles spermatogonium
5% of contralateral testes of men who had orchiectomy for germ cell neoplasm
cryptorchidism, histology: enlarged nuclei prior germ cell neoplasm (contralaterally)
50% of men who develop ITGCN will develop invasive germ cell tumors w/I 5y
Seminoma
DO NOT BIOPSY!!! Risk spreading germ cell tumor
embryonal carcinoma
composed of primitive undifferentiated epithelia
best prognosis - 95% radical inguinal cure rate orchiectomy, followed by radiation to histology: fried egg cells like abdominal LNs spermatogonia gross: varigated appearance NOT radiosensitive; & hemorrhage respond to orchiectomy + post-surgery chemo histology: epithelial cells, no spermatogonia (no fried eggs) gross: tumors of the testis w/ cartilage, hemorrhage if mixed w/ embryonal carcinoma
Teratoma
composed of tissue components resembling normal or immature organ tissue can be associated w/ embryonal carcinoma or other components (yolk sac, choriocarcinoma)
Sex cord Sertolistromal tumors Leydig cell of testes tumors
usually benign; often hormonally active (may produce androgens & estrogens) Leydig cells --> testosterone (precocious puberty) Leydig cell or Sertoli cell tumors --> gynecomastia in adults
5% of testicular neoplasms
90% are benign!
Disease Squamous cell carcinoma of penis
Clinical Variants
Pathogenesis
Etiologies
Epi <1% of male cancers in U.S. More common in Asia, Africa, S. America
Risk factors
Lab/Imaging
Treatment
Complications
uncircumcised males > precursor lesion? Carcinoma in HPV age 40 w/ poor hygiene & situ = Bowen disease = solitary chronic penile infections gray or erythematous plaque related to HPV 16 phimosis - inability to Bowenoid papulosis - rare retract prepuce/foreskin progression to SCC SCC = slow growing, locally invasive lesion; metastasis may occur at inguinal & iliac LNs but widespread dissemination uncommon
poor genital Bowenoid papulosis - HPV related precursor lesion hygiene in uncircumcised (rarely progresses) men; Bowen disease -gray or erythematous plaque; risk of HPV 16&18 invasion 10% other HPV histology: loss of polarity, genital warts mitotic figures, disorganized growth that occupies full thickness of epithelium (rather than more abundant cytoplasm at top like nl); KERATIN PEARLS
Carcinoma of scrotum Periductal mastitis
topical exposure to coal tars/ soot inflammatory, benign lesion in large ducts of breast
development of inflammatory cells in the periductal area of breast
middle aged older women
histology: inflammatory cell infiltration, weakened duct tissue
Duct ectasia
sagging of the breast dilation of duct due to dried out non-bloody, gritty bilateral nipple discharge secretions NO PAIN
histology: dilation / stretch of duct w/ dried out secretions
No predisposition to carcinoma!
Papilloma
unilateral, non-milky nipple discharge from 1 duct orifice, +/- blood
proliferative lesion
gross: pale, moist papilloma from collecting duct histology: nodule that projects into the duct w/ proteinaceous secretions (pink lines), blood supply present (fibrovascular core), epithelial + myoepithelial layers present
small risk of carcinoma development
Papillary carcinoma
unilateral, bloody nipple discharge
clonal lesion (no myoepithelial cells) with vascular supply
~ 60 years old
histology: fibrovascular core, epithelial lining WITHOUT myoepithelial layer; overlapping nuclei
usually good prognosis bc bloody discharge is alarming enough to seek help
Disease Cysts (breasts)
Clinical Variants
Pathogenesis
Etiologies
Epi VERY common!
Risk factors reproductive aged women
Lab/Imaging gross: dark orange structures (cysts) that are firm & tender, swell during luteal phase of cycle; bumpy stroma from collagen response to hormones histology: pink secretions seen in TDLUs, expansion and interconnection of TDLUs; apocrine cells + calcifications - benign findings
Treatment aspiration if extremely painful
Complications recurrence
non-proliferative lesions arising dense firm breasts w/ from terminal ductule units palpable (sometimes tender) lumps & frequent exaggerated response of breast gross cysts stroma & epithelium to cycling of hormones during reproductive years hormones make TDLUs more edematous; cysts change monthly w/ each cycle; however, TDLUs do not dry out btwn pregnancies so always a baseline secretion that increases in luteal phase of cycle --> increased pressure and secretion build up --> cyst formation
Fibroadenoma
BENIGN solid mass that is movable within the breast tissue
non-proliferative lesions arising from terminal ductule units arise in TDLUs in response to hormones --> hypertrophy of lobules (stroma, ductules, ducts) --> fibroadenoma formation
teenagers African Americans
histology: sometimes large calcifications (sclerosis w/ age - benign!) needle core biopsy: sharp demarcation of lesion w/ characteristic feature of enlarged duct, ductules, & stroma
Phyllodes tumor Adenosis
more cellular lesion in women after age 40 lumpy breasts due to cyclical hormone changes Benign sclerotic collagenous material causes FIRM breasts
non-proliferative lesions arising from terminal ductule units proliferative lesions arising in TDLUs adenosis = increase in lobular units proliferative lesions arising in TDLUs proliferative lesions arising in TDLUs; increased number of cells WITHOUT MUTATION!!
> age 40
women age 3040
histology: very cellular stroma that grows in leaflike pattern usually picked up on mammogram due to calcification formation
MUST BE TOTALLY EXCISED usually does not require routine f/u - no RR of malignancy development
absolutely recurrent so excision required!
Sclerosing adenosis Usual hyperplasia
histology: proliferation of both epithelial & myoepithelial cells into the lumen (creates bridges), phenotypic mixture of cells (linear, oval, narrowed spaces) but no pattern of identical mutations mammogram: calcifications in the lobule unit spaces
very low probability of becoming malignant! Benign lesion w/ minimal risk of malignancy
Disease Atypical hyperplasia (ADH)
Clinical Variants (general) ductal, lobular
Pathogenesis
Etiologies deletions in chromosomes 16 &17 --> "Roman bridge" structure
Epi
Risk factors
Lab/Imaging
Treatment
Complications increased risk for DCIS or invasive carcinoma
proliferative lesions arising in non-obligate precursor TDLUs; consistent mutations lesion for DCIS (some capable of progressing into in certain chromosomes DCIS) begins w/ proliferation (usual hyperplasia) --> deletions in chromosome 16 & 17 --> atypical hyperplasia non-motile mass on breast exam atypical hyperplasia + persistent mutations --> low grade DCIS
excision of lesion w/ histology: has some needle core biopsy cytologic features of low grade DCIS; usual hyperplasia + clonal lesions like Roman bridges! SMALLER than DCIS; calcifications in lumen of spaces Complete excision + histology: monoclonal radiation population of low grade,mutated cells; round/ punched out spaces (Arches of Roman Bridge!); calcium phosphate crystals (stain purple), no myoepithelial layer! invasion present? small patches of monoclonal cells lacking myoepithelial layer outside of the main DCIS lesion mammogram: atypical pattern of calcifications (jagged + small round calcifications)
Ductal Carcinoma In Situ (DCIS)
Low grade
deletions in chromosomes 16 &17 --> "Roman bridge" structure
very hi risk for development into invasive ductal carcinoma (if not excised adequately w/ clean margins)
High grade
usually ER/PR negative & HER2/neu amplification mutation positive non-motile mass on breast exam
NOT related to ADH HER2/neu amplification mutations in duct epithelial -> high grade DCIS
histology: no punched out spaces like low grade; fast growth --> disintegration of nuclei; necrotic material in lumen (pink material representing disintegrating nuclei) = comedo necrosis; positive stain for HER2/neu overamplification mammogram: calcifications that form mold/cast in duct (linear calcifications) gross: linear pattern; necrotic material in the duct (yellow)
do NOT respond well to estrogen antagonists like tamoxifen respond to chemo like Herceptin (Trastuzumab)
hi risk of invasion!!! Recurrence w/I 3y if not adequately excised
Paget's disease of the nipple
UNILATERAL red/ scaly/ erosive nipple appear moist
DCIS in the ductal system leading to the nipple
histology: DCIS riding towards nipple in the duct; dilated blood vessels (hence, redness), scaly appearing surface, DCIS cells perforating the epithelial layer
AVOID corticosteroids
may or may not be invasive
Disease Infiltrating ductal carcinoma,
Clinical Variants Low grade
Defining Characteristics receptors for estrogen & progesterone non-motile mass
Pathogenesis low grade DCIS--> infiltrating ductal carcinoma, grade 1 over time due to digestion of basement membrane and acquisition of vascular supply
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications potential to invade lymphatic spaces!
gross: firm, immobile mass suppressed by antiw/ irregular spiculations estrogen drugs (tamoxifen) mammogram: spiculations (stars) @ periphery histology: infiltrating pattern w/ remnants of DCIS; fibrotic (lots of collagen! byproduct of vascularization); low grade nuclei, gland formation invasive into stroma
High grade
not estrogen/ progesterone responsive (ER/PR negative), positive HER2/neu amplification non-motile mass
progression of high grade DCIS to poorly differentiated lesions like infiltrating ductal carcinoma grade 3
determined by differentiation (gland formation), nuclear anaplasia, and mitotic figures histology: poor gland formation, necrotic cells, mitotic figures
Atypical lobular hyperplasia (ALH) Lobular carcinoma in situ (LCIS)
precursor lesion to LCIS!
histology: ductule spaces full of round cells
non-calcifying lesion so hard to find!!
progresses from ALH precursor!! ALL LACK E-CADHERIN = poorly cohesive!!
deletion of gene for Ecadherin adhesion molecules
mammogram: no calcifications histology: proliferation of round cells within the lobule (bag of marbles)
Infiltrating lobular carcinoma
diffuse spread within the progression from LCIS breast (lack of E-cadherin) no masses or calcifications (i.e. woman w/ consistent mammograms suddenly has a 2.5 cm carcinoma) low grade bc ER/PR positive and HER2/neu negative!! Induration might be felt on breast exam
10% of invasive breast carcinomas
mammogram: no calcifications - difficult to detect! Gross: looks like fatty fibrous breast but can't see lesion histology: tumor cells arranged in linear fashion or concentric circles (bull's eye)
responds to tamoxifen!!
bilateral risk!!! (if lesion in one breast, check same spot on the other brest w/ biopsy!)
Medullary carcinoma
firm, small round mass ER/PR negative, HER2 negative or positive
round infiltrating ductal carcinomas commonly seen in patients w/ BRCA1 or BRCA2 mutations
BRCA1/2
2-3% of infiltrating ductal carcinomas
histology: rounded carcinomas w/ lymphocytic infiltration!
pretty good prognosis but confused for fibroadenoma often!
Disease Mucinous (colloid) carcinoma
Clinical Variants
Defining Characteristics rounded periphery lesions that also resemble fibroadenomas (BUT fibroadenomas appear at younger age usually & would have been noticed in earlier mammograms) ER/PR positive
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications good prognosis if properly diagnosed!!
women ages 55- mammogram: round 60 years old calcifications (looks like fibroadenoma) gross: infiltrating mucinous (wet, sticky appearing) w/ hemorrhage histology: islands of DCIS lesions floating in mucin (clear); vasular supply related to the number of uninterrupted menstrual periods (hence more estrogen exposure) pregnancy is protective in the long-run estrogen exposure (endogenous or exogenous) hi risk mutations (BRCA1,2; PTEN, TP53) #1 cancer among U.S. women; #2 cause of cancer mortality in women increased age Caucasians (after age 45; before age 45, AA have higher risk) > AA> NA, Hispanic, Asian tamoxifen & raloxifene reduces breast cancer risk by 50%; increase bone density; however, a/w increased risk for thromboembolic events
Breast cancer
(general) see above for deets
BRCA1/2 mutations - FH breast cancer < age 50, FH of papillary ovarian cancer; triple negative (ER/PR, HER2)
staged based on tumor grade, ER/PR stattus, HER2 status, lymph node status (axillary lymph nodes first!!)
mortality early menarche, greatest in AA nulliparity, late women menopause, OCP (but decreased risk affects 1/8 for endo/ovarian women Ca), estrogen replacement tx, obesity, alcohol, FH
localized tumor - excision, greater number of radiation to primary site + axillary nodes = lymphatics, consideration worst prognosis of systemic tx presence of axillary partial mastectomy w/ or other LNs is the local radiation therapy most impt risk factor (preferred over radical for recurrence & mastectomy) mortality sentinel LN studies
Dysmenorrhea (general)
painful menstrual period, cramping lower abd pain (radiates to the back & legs), plus GI, neurological symptoms, & malaise A/w cyclical periods!!
primary / idiopathic - without pelvic pathology secondary - underlying pelvic pathology (endometriosis, ovarian cysts)
50% of menstruating women 5-10% dysmen affects QoL
OCPs NSAIDs for moderate pain
Disease
Clinical Variants Primary
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging PE: nl except some tenderness confirm cyclical nature of pain, R/O underlying pelvic pathology
Treatment prostaglandin synthetase inhibitors NSAIDs taken prior to or at onset of pain, continuously ever 6-8h to prevent reformation of PG No response to NSAIDs after 3-6 cycles? OCPs (suppress endometrial proliferation, thus dec PG synthesis) others? Tinge unit, paracervical block, uterine nerve ablation (last resort) spontaneous resolution post-delivery
Complications
appears within 1-2 yrs of incresaed endometrial menarche when ovulatory prostaglandin production cycles are established PGF2a + PGE2 hi in secretory Pain occurs few hrs prior endometrium due to decline of or just after onset of progesterone levels in late period, lasts 48-72h luteal phase suprapubic cramping, lumbosacral backache (radiates to anterior thigh), colicky pain (improves w/ massage, movement), rare n/v/d increased uterine tone + hi amplitude contractions = reduced blood flow = ischemic pain
Secondary
Chronic Pelvic Pain
(general)
underlying pathology: endometriosis, adenomyosis, fibroids, congenital uterine anomalies (bicornuate, septate, pain begins 3-5d prior to period, relieved by period non-communicating horn), cervical stenosis, endometrial onset polyps, PID less likely to respond to NSAIDs or OCPs multi-factorial non-cyclical pain > 6m GYN: endometriosis, pelvic adhesions, PID, adenomyosis,uterine myomas GI: IBS, IBD, constipation, colitis, diverticulitis Urologic: IC, chronic UTI, urinary calculi, radiation cystitis MSK: pelvic floor pain, fibromyalgia, low back pain, nerve pain occurs many years after onset of menarche
PE: abd & vaginal exam may reveal underlying lesion U/S of vaginal/abd, laparoscopy, hysteroscopy
analgesics treatment of underlying cause
15% of reproductive age women
h/o sexual or impt to do rectovaginal & physical abuse bimanual exam in these patients! PTSD Laparoscopy - nl in 35-40%, drug/alcohol endometriosis in 30%, abuse pelvic adhesions in 25%
multidisciplinary (bc 50% of women have usually multiple causes of comorbid psych pain) diseases (DEPRESSION!) include mental health provider (counseling + med tx way more effective than med tx alone!) 1. NSAIDs 2. consideration of narcotics 3. chronic pain meds (gabapentin, topamax, valproic acid, antidepressants)
Disease
Clinical Variants Endometriosis
Defining Characteristics pain worsens w/ age
Pathogenesis
Etiologies
Epi cause of chronic pelvic pain in young women 3-15% of general population; 2050% of infertile population
Risk factors FH, increased exposure to menstruation (early menarche, nulliparity), flow obstruction, obesity
Lab/Imaging PE: possible to find tender pelvic structures, fixed retroverted uterus, adnexal masses, nodularity along uterosacral ligament Laparoscopy - gold standard others? Elevated Ca-125, U/S
Treatment presumptive tx before laparoscopy (interrupt menstrual cycle) monophasic OCP (daily hi dose progestin) / vag ring/ patch for 3m NSAIDs, Depo-Provera, GnRH analogs (Lupron, Synarel, Zoladex) surgery? Laparoscopic destruction of lesions, bilateral uterosacral ligament resection, hysterectomy
Complications
endometrial tissues (glands & Endometrial stroma) that occur outside the retrograde severity of pelvic pain =/= uterus menstruation, lymphatic pathology by laparoscopy dissemination, Immunologic abnl cause inc vascular pelvic pain, infertility presence of circulating dissemination, autoantibodies, inc # peritoneal macrophages, dec direct invasion, uretotubal T-cell reactivity & NK activit most common area? Posterior cul-de-sac protective factors? Habits that in situ decrease peripheral estrogen (congenital) celomic (exercise, smoking) metaplasia, Wolffian duct remnants, Mullerian duct remnants infection, pelvic bands of scar tissue form between two pelvic organs --> surgery, trauma infertility & chronic pain
Pelvic adhesions (asherman's syndrome) Pelvic venous congestion syndrome
exclude other pathology, laparoscopy, consistent history
hi fiber diet (avoid stool buildup) surgical lysis (dense adhesions) surery, laparoscopy, pelvic vein embolization
pain worsens w/ prolonged incompetence of valves & standing, post-coital dilation of ovarian veins, other veins draining pelvis dull pelvic pain/ pressure/ heaviness - relieved by lying down +/- vulvar or upper thigh varicosities
women aged 20- CT or U/S diagnosis 45 w/ multiparity
Pelvic floor dysfunction
pelvic floor muscles myofascial pain usually involving levator ani
Interstitial cystitis (80%)
Sexually transmitted infections
(general)
syphilis: primary = chancre/ painless ulcer; secondary = rash, condyloma, alopecia, mouth lesions; active or latent disease
GC infects mucus glands endocervix (NO ECTOCERVIX involvement), endometrium, fallopian tubes, oral - minor salivary glands (mouth = gonococcal oral pharyngitis), septic vasculitis & arthritis, Granuloma inguinale: Klebsiella granulomatis; conjunctivitis (bilateral small painless papule that involvement in infants; can cause blindness) eventually forms beefyred granulomatous ulcer that bleeds easily; subq spread --> elephantiasis of external genitalia
19 million new bacteria cases/ yr (gonorrhea, chlamydia, syphilis, chancroid) viruses (HIV, HPV, HSV, hep A/B/C) parasites (Trichomona, pubic lice)
15-24 year olds MSM (LGV, CT/GC, HepC, syphilis) racial minorities HIV+
PE: examination of pelvic floor muscles --> tenderness and pain in bladder, vagina, vulva, or perineum NAATs more sensitive (however, not FDA approved for all receptive sites)
pain meds, physical therapy, trigger point injections, Botox injections
syphilis? Penicillin +/- HIV women: asymptomatic treatment if indicated dz --> reproductive health consequences (infertility, stillbirth, premature birth, congenital urethral cultures transmission - HSV, HIV, syphilis); cervical GN diplococci - GC cancer, PID (untreated DONOVAN BODIES: chlamydia) Granulosum inguinale; easily treatable HIV transmission PE: purulent d/c from os?? lues maligna GC; mucopurulent d/c from malignant syphilis in os?? CT immunocompromised GC: bartholinitis --> Bartholins cyst or abscess (if pus filled)
Disease
Clinical Variants Urethricitis
Defining Characteristics dysuria, urinary frequency, intermittent penile discharge painful meatus? HSV
Pathogenesis gonorrhea, chlamydia, Mycoplasma genitalium
Etiologies GC (5-20%), CT (15-40%), NGU (non gonoccocal urethritis - all other agents)
Epi
Risk factors
Lab/Imaging Gram stain: increased polys (>5 per HPF), GN intracellular diplococci (Gonorrhea - suff for dx in men only!) GC/CT NAAT
Treatment Azithromycin - 1g PO once if NGU infection OR doxycycline 100mg/ PO bid x7d
Complications Writer's syndrome Keratoderma blenorrhagica (autoimmune syndrome w/ rash after CT infection)
Cervicitis
frequently asymptomatic
chlamydia, gonorrhea, trichomonas, herpes, BV
chlamydia
recurrent or persistent infection (30% of pts) - retreat if non-compliant, conjunctivitis? a/w think Trichomonas or CT autoinoculation resistant ureaplasma or mycoplasma PE: purulent / mucopurulent azithromycin - 1g PO once OR doxycycline endocervical exudate; easily induced endocervical 100mg/ PO bid x7d bleeding NAAT for GC/CT & trichomonas or wet mount culture for trich/ BV
Genital ulcers
elevated edge lesion - CT syphilis, herpes, chlamydia (LGV), H. ducreyi (chancroid), Granuloma inguinale circular, VERY painful lesion, erythematous edge, HSV - white plaques, firm bilateral & tender hemorrhage/ erythema, LNs - HSV inflammation (causing vaginal firm, painless, demarcated d/c), swelling, + painful ulcers; edge, non-tender bilateral reactivation?? Hypopigmentation, scalloped/ LNs - syphilis "hamburger meat lesions" irregular shaped, painful lesion, tender & unilateral Chancroid - tender papule w/ erythema that becomes pustular LNs - Chancroid then ulcerated; bulboes appear in LN regions after resolution irregular shape lesion + of ulcers pseudobuboes (LNs) Granulosum inguinale Syphilis - PAINLESS ulcers; firm & volcano appearing Trich: frothy/gray smelly d/c; strawberry cervix Candidiasis: cottage cheese d/c BV: fishy odor Trichomonas, bacterial vaginosis vaginitis: vaginal D/C, vulvar itching, irritation, odor
majority due to HSV or syphilis noninfectious sources? Yeast, fixed drug eruption, psoriasis
Granuloma mostly in Caribbean HSV - 1/4 young people
underlying dz syphilis serology, herpes (immunocomp, culture/ PCR serology Crohns), residence, travel hx # partners
empiric treatment for most possible likely agent - clinical/ epi superinfection w/ staph or co-infection (HSV + syphilis) HSV - acyclovir (pt + partner) HSV = chronic lifelong infection; transmission thru subclinical shedding HSV2 - a/w risk of HIV acquisition
Vaginal discharge
Trich (15-20%), BV (40-45%; a/w sex), vulvovaginal candidiasis (2025%)
Trich: pH>4.5; wet mount: motile flagellated protozoa w/ many WBCs Candidiasis: pH<4.5; wet mount: few WBCs; KOH: pseudohyphae BV: positive KOH whiff test; wet mount: Clue cells
Trich: metronidazole, HIV increased HIV risk w/ screening trich BV: metronidazole
Genital warts Proctitis
HPV
HPV low risk types 6&11 MSM, women w/ rectal intercourse
inflamed rectum w/ blood gonorrhea, chlamydia, syphilis, herpes & pus mucoid anal discharge, rectal bleeding
Disease
Clinical Variants PID
Defining Characteristics lower abdominal pain AND uterine/ adnexal/ cervical motion tenderness, dysuria, purulent vaginal d/c
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging PE: severe PID can have swollen uterus/ tubes w/ extruded pus
Treatment
Complications tubal inflammation --> scarring & loss of function = tubal factor infertility, ectopic pregnancy, chronic pelvic pain NO USE OF IUD!!! IUD + PID = TUBAL ABSCESS FORMATION
Pelvic inflammatory disease chlamydia, 1M women/yr infection & inflammation of gonorrhea, BV uterus, fallopian tubes, ovaries, & adjacent tissues others: mycoplasma, anaerobes, HSV, actinomyces, mycobacteria (TB) disseminated gonococcal infection very uncommon (decline in etiologic strains for unk reason) complement deficiency patients younger, sexually active women
DGI
monoarticular septic arthritis of large joints; tenosynovitis/ dermatitis (rash); 1-3% w/ mucosal infection; fever/ chills septic vasculitis - pustula (pus filled vesicle)
Tubo-ovarian abscess
sepsis symptoms (fever, shaking chills, tachycardia, elevated WBC), lower abd pain, mild rebound, large tender adnexal mass
PID + IUD
vaginorectal exam: pus palpated btwn rectum & uterus gross: ovary, multiple thickened luteal cysts & abscess path: actinomyces if a/w IUD
IV antibiotics first followed by draining/ removal of abscess usually requires removal of uterus and ovaries bc fibroids present!
Pyosalpinx Hydrosalpinx
Fallopian tube filled with pus Fallopian tube dilated with watery fluid
gross: retort shaped path: villi of fallopian tube are pressed into a flat lining (short broad & thickened papillae) confirm low cortisol; check ACTH levels (primary v. secondary) ACTH stimulation test
Adrenal insufficiency
(general)
hyponatremia, hypercalcemia, weakness/ fatigue/ anorexia, weight loss, postural hypotension, nausea, diarrhea, myalgia/ arthalgia
loss of cortisol production hyponatremia- dilution of Na by excess free water (nl cortisol inhibits ADH prod); weight loss (acute = weight gain from edema & H2O retention) chronic adrenal insuff has diarrhea so H2O loss; hypercalcemia - unk; postural hypotension - no cortisol = vasodilation = syncope
GC replacement hydrocortisone, cortisone acetate, prednisone (less preferred bc long t1/2)
Addisonian crisis hypotension, fever, AMS, abd pain, joint pain - saline volume expansion, hi dose MC replacement (primary hydrocortisone IV insuff only) (achieves GC & MC fludrocortisone effects) adjust for surgery/ minor stress/ fever - double daily requirements
Disease
Clinical Defining Characteristics Variants Primary Symptoms above in gen (ADDISONS category + adrenal ) calcification (fungal/ TB cause), vitiligo (autoimmune attack of melanocytes), hyperpigmentation (ACTH binds melanocytes), hyperkalemia (loss of zona glomerulosa = loss of aldosterone = inc K+)
Pathogenesis
Etiologies
Epi 0.3% of TB patients Addisons; 85% of pts who die from TB have adrenal involv
Risk factors
Lab/Imaging HI ACTH (pit trying to stimulate adrenals but adrenals unresp) short cosyntropin test - IV ACTH will cause no change in cortisol secretion
Treatment chronic replacement of GC & MC
Complications hyperpigmentation does NOT resolve even post-tx
adrenal destruction --> unable autoimmune, to respond to ACTH --> insuff TB, adrenal leukodystroph infectious - TB, HIV, CMV, histo, y, hereditary/ candidiasis; adrenal idiopathic hemorrhage - WaterhouseFriderichsen syndrome, others?? HIV, trauma, coag d/o, antiphosph hemorrh syndrome; autoimmune: infarction, polyglandular autoimmine sarcoid/ I&II; hereditary: congenital amyloid, adrenal hyperplasia, adrenal hemochromato leukodystrophy/ sis, thrombosis myeloneuropathy; infiltrative: sarcoid, amyloid, hemochromatosis; iatrogenic: adrenalectomy, steroid synt inhibitors hypothalamic/pit dysfxn --> no ACTH produced or secreted --> no stimulation of adrenals --> insuff no ACTH = adrenal atrophy = adrenal insuff Stopping GCs suddenly will cause adrenal insuff - MUST wean these patients & test for HPA axis responsiveness HIV, iatrogenic (most common!!) prolonged GC treatment HP axis dz (tumors of pit, hypothalamus, infiltrative dz, trauma)
Secondary
NORMAL POTASSIUM LEVELS!!!! + symptoms above in general category
LOW ACTH (unable to produce so adrenals aren't stimulated) short cosyntropin test - IV ACTH will cause slight increase in cortisol secretion (suggests partial insuff) Long Cosyntropin test repeated ACTH infusion awakens the atrophic adrenals and shows cortisol secretion - reversal of atrophy proves secondary adr insuff gross: caseous necrosis histology: Acid fast stain for Mycobacterium tuberculosis bacilli (red fish) usually not biopsied but would see lymphocytic infiltration
Chronic replacement of GC
Adrenal tuberculosis
adrenal insuff (see above)
Autoimmune adrenal disease WaterhouseFriderichsen syndrome
adrenal insuff (see above) polyendocrinopathies; isolated autoimmune adrenalitis acute hemorrhagic necrosis /infarct of adrenal glands as a complication of DIC child presents w/ adrenal insufficiency + infection + pic of hemorrhagic adrenals a/w systemic more infection: common in children Neisseria meningitidis, Pseudomonas, H.influenzae, Staph
gross: hemorrhage of adrenals histology: massive extravasation of RBCs in cortex
Disease Polyglandular Autoimmune Disease (PGA)
Clinical Variants Type I
Pathogenesis
Etiologies autosomal recessive
Epi
Risk factors
Lab/Imaging
Treatment
Complications
adrenal insuff (see above) antibodies form to 17a & 21hydroxylase + mucocutaneous candidiasis (thrush) + hypoparathyroid disease AIRE gene mutation Other disorders? Pernicious anemia, alopecia, malabsorption, chronic active hepatitis CHILDHOOD
Type II
adrenal insuff (see above) unknown gene mutation but chromosme 2q33 linkage + thyroid problems (Hashimoto's), T1DM, & gonad disorders + vitligo ADULT ONSET
autosomal dominant
HLA B8 (DW3), DR3, DR4
Adrenal Leukodystrophy
abnl peroxisomal transporter = defective oxidation of very long chain fatty acids = progressive neurological accumulation of lipid in adrenal, brain, gonads, spinal loss cord Adrenal myeloneuropathy - later onset variant w/ slower progression (ABCD2 gene) 10% of all adrenal insuff cases
X-linked recessive mutation of ABCD1 gene (MALES only)
25-35% of "idiopathic" Addisons now known as mild ALD
neuropsychiatric testing MRI for prognosis
Congenital Adrenal Hyperplasia (CAH)
(general)
most common cause of ambiguous genitalia
enzymatic defect in steroid biosynthesis --> impaired cortisol secretion --> chronic ACTH stimulation --> adrenal gland hypertrophy --> overproduction of androgens/ testosterone
21adrenal insuff, ambiguous loss of 21-hydroxylase prevents autosomal hydroxylase genitalia, hirsutism, salt- formation of recessive deficiency deoxycorticosterone from wasting hypotension progesterone (no aldosterone made) and formation of 11NO CORTISOL OR ALDOSTERONE; EXCESS deoxycortisol from 17 hydroxyprogesterone (no TESTOSTERONE/ cortisol made) ANDROGENS!! shunts pathway towards formation of sex hormones (DHT, estradiol, etc)
most common of CAH!! 1:15,000
Cortrosyn stimulation testing = gold standard for dx - measures 17-OH progesterone & cortisol levels pre& post stimulation
surgery for females replace cortisol (hydrocortisone), replace aldosterone if needed (fludrocortisone)
Disease
Clinical Defining Characteristics Pathogenesis Variants 11B loss of 11B-hydroxylase adrenal insuff, severe hydroxylase HTN + ambiguous prevents formation of deficiency corticosterone & aldosterone = genitalia accumulation of deoxycortisone, which is able NO ALDOSTERONE & to bind aldosterone receptor CORTISOL; HOWEVER, DEOXYCORTICOSTERON and act as a powerful E STILL ABLE TO BIND mineralocorticoid = HTN MR 11B- hydroxylase also used to make cortisol from 11deoxycortisol, thus these patients will have adrenal insuff and accumulation of 11deoxycortisol pathway is shunted towards the androgens 17aadrenal insuff, ambiguous hydroxylase genitalia, sexual deficiency infantilism, primary amenorrhea, HTN NO CORTISOL OR SEX ANDROGENS; EXCESS ALDOSTERONE loss of 17a-hydroxylase affects adrenal production early in the steroid pathway; pregnenolone or progesterone cannot be converted into their subsequent forms, so no cortisol or sex androgens are made thus, the pathway shunts towards aldosterone production only 3B-hydroxysteroid dehydrogen ase II adrenal insuff, bilateral adrenal hyperplasia, ambiguous genitalia, salt wasting hypotension NO CORTISOL, ANDROGENS, OR ALDOSTERONE loss of 3B-hydroxysteroid dehydrogenase results in decreased production of all 3 groups of adrenal steroids, which include mineralocorticoids, glucocorticoids, and sex steroids the lack of cortisol secretion leads to elevated ACTH, which results in the bilateral adrenal hyperplasia
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
much less common
Disease Cushing syndrome/ disease
Defining Characteristics adrenocortical hyperfunction
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging hi 24h urine free cortisol (excess cortisol > capacity of CBG) - elev even @ midnight etiology? measure plasma ACTH (<10 - autonomous adrenal activity; > 200 ectopic ACTH tumor); petrosal sinus samples (detect gradients of ACTH lelves peripherally), suppression/ stimulation tests (pituitary adenomas will be suppressed w/ exogen ACTH; non-pituitary causes are NOT suppressed) (exogen CRF stimulates pituitary to make ACTH - if pituitary cause) adrenal CT if ACTH < 10 for adrenal sizes/ masses
Treatment adrenal disease: adrenalectomy (last resort) + radiation
Complications
adrenal androgen production - constitutive -> androstenedione production -- activation of > hirsutism, amenorrhea, cAMP virilization, & acne; excess Cushing dz (pituitary) v. cortisol binds aldosterone ACTH Cushing syndrome producing receptors --> HTN, edema, tumor in ant pit hypokalemic alkalosis central obesity (thin extremities), moon facies, (aldosterone stimulates K+ functional hirsutism, HTN, weakness, wasting); cortisol stimulates adrenal appetite --> obesity osteoporosis, hyperglycemia, peripheral cortisol --> insulin resistance neoplasm (adenoma, insulin resistance, impaired (not understood); protein LH/FSH release, increased wasting --> proximal myopathy; carcinoma) appetite, skin thinning, ACTH stimulates melanocytes primary decreased linear growth --> hyperpigmentation; cortisol adrenal tumors (kids), neuropsych probs, affects collagen --> thin skin, iatrogenic immune suppresion, skin stria; cortisol inc bone striae on abd, resorption --> osteoporosis, paraneoplastic erythematous face, oily renal stones (small cell lung hair, dorsocervical Ca) buffalo hump Cushing disease caused by ACTH producing microadenoma (maj), corticotroph cell hyperplasia, hypothalamic corticotrophin releasing hormone tumor ACTH induces adrenocortical hyperplasia ACTH producing adenomas still under negative feedback but new setpoint, requiring much more cortisol to stop secretion of ACTH --> bilateral adrenal hyperplasia 70-80% of endogenous Cushings Females 5:1
50% of ACTHproducing bronchial carcinoids suppress w/ dexamethasone pituitary disease: trans(exception to the nonsphenoidal resection + pituitary causes radiation being nonsuppressible) med tx: steroid synthesis petrosal sampling inhibitors (block risk for thrombosis & 11BHSD1); GR bleeding antagonists psych illness <--> (mifepristone), hypercortisolism adrenolytic drugs, inhibitors of ACTH release (carbergoline, pasireotide)
Pituitary ACTH production
gross: enlarged cortex of adrenal 20> plasma ACTH < 200 medical suppression w/ dexamethasone (presence of negative feedback still so urine free cortisol suppressed) - distinguishes Cushing dz from syndrome CRH stimulation test: elevated ACTH prod (if give CRH, still stimulates ACTH prod from ant pituitary - just at a new set point) plasma ACTH > 200 Imaging of other organ systems for masses
pituitary disease: transsphenoidal resection + radiation
post-surgery cortisol supplementation until HPA axis recovers panhypopituitarism from radiation therapy (90% patients over 10y time frame)
complications of transsphenoidal resection? Transient DI (disruption of post pit), CSF leak, meningitis
Ectopic ACTH
Carney complex
Cushing syndrome hypercortisolism + lentiginosis (spotty pigmentation) + cardiac myxoma, endocrine tumors (adrenal cortical, GH, or thyroid adenomas/ carcinomas, melanocytic schwanomas, testicular or breast ductal carcinomas
ovarian tumor or pancreatic tumor produces ACTH, overstimulating the gland and shutting down pituitary production of ACTH (HPA axis no longer under negative feedback) autosomal dominant gene heterozygous inactivating rearrangement mutation of regulatory subunit of PKA --> cortisol production & Cushing syndrome autonomous cAMP pathway stimulation downstream
treat underlying cancer
Clinical Variants Adreno-cortical (general) adenoma
Disease
Pathogenesis
Etiologies
Epi very rare
Risk factors
Lab/Imaging plasma ACTH < 10 (ACTH independent cause for hypercortisolism) need CT scan of adrenals for masses
Treatment adrenalectomy (last resort) + radiation
Complications panhypopituitarism from radiation therapy (90% patients over 10y time frame) Nelson's syndrome unrepressed growth of pituitary adenoma from hi ACTH levels (complication of adrenalectomy)
kids: most often functional - loss of heterozygosity involving autosomal tumor suppressor gene leading dominant -> Cushing syndrome + to activation of cAMP signal; mutation virilization succession of mutations cause progression from: adults: functional & nonhyperplasia --> adenoma --> functional; Cushing> carcinoma hyperaldosteronism > virilization
Conn syndrome
HTN, hypokalemia, alkalosis, hi urinary potassium
aldosterone-producing adrenocortical adenoma
F>M adenomas in kids usually occur at age <5
gross: solitary encapsulated nodules (yellow-tan on cut section), >1cm if macroscopic; adrenocortical nodules (<1cm, notencapsulated; multiple & bilateral) histology: lipid rich cortical cells; cannot determine if functional by visual inspection
Adreno-cortical carcinoma
usually functional in kids; excess cortisol shuts off a/w Beckwithfunctional or non-functional pituitary ACTH, causing adrenal Wiedemann in adults atrophy syndrome, La Fraumeni Cushing +/- virilization >> syndrome hyperaldosteronism (p53 mutation), & hemimost common cause of hypertrophy Cushings in kids
kids: ~4y.o. adults: ~45yo F>M very rare compared to adenomas
gross: large mass + hemorrhage + necrosis in cortical section (yellow) histology: sheets of eosinophilic to clear cells; hi nuclear polymorphism, atypical mitotic figures, necrosis of larger cells plasma ACTH < 10 (ACTH independent cause for hypercortisolism) need CT scan of adrenals for masses CXR: check for lung mass
adrenalectomy + radiation very poor prognosis (med survival ~2y)
Adrenal metastasis
adrenal mets from primary lung, breast, or kidney cancer Bilateral, nonfunctional adrenal masses in older individuals - THINK METS!
Secondary hypertension
(general)
resistant HTN (BP>140/90 w/ full doses of >3 meds + suddent onset + younger/older age at onset)
hyperaldosteronism, MC excess, pheochromocytoma, renal artery stenosis, renal disease, endocrine causes (Cushings, hypo/hyperthyroidism, OSA)
most common causes? Hyperaldosterone, renal dz
Disease
Clinical Defining Characteristics Variants Pheochromo onset of HTN at young age, cytoma episodic HTN, palpitations, tachycardia, tremor, weakness, pallor, anxiety (adrenergic stim), retinopathy, hyperglycemia, polyuria/ polydypsia, chest pain, nausea, hyperreninemia (orthostatic hypotension), ileus Classic triad?? Palpitations w/ tachycardia, headache, perspiration (drenching sweats)
Pathogenesis adrenal medullary (neuroendocrine) tumor arising from chromaffin cells = production of catecholamines = stimulation of alpha & beta receptors = inc BP, contractility, & HR = cerebrovascular & cardiovascular consequences
Etiologies
Epi
Risk factors
Lab/Imaging urinary catecholamine metabolites (vanillylmandelic acid, metanephrines) - might require rpt testing bc episodic nature of tumor Clonidine suppression testdistinguishes pheo from false positive inc in catech MRI/CT nodules? last option gross: gray-tan hemorrhagic mass > 1cm; bilateral in familial cases (a/w syndromes); displacement of cortex histology: polygonal spindle cells, nested pattern (Zellballen), extensive vascular pattern, variable nuclear pleomorphism aldosterone:renin ratio (nl<20; >20 suggests autonomous prod of aldosterone) confirm hyperald w/ oral salt loading --> should shut down aldosterone (if not suppressed, suggests autonomous prod of ald)
Treatment preoperative alpha-adrenergic blockers (lowers BP&catech surges; Phenoxy-benzamine, terazosin) B-adrenergic blockers (only start AFTER ablockers; used for tachycardia) SURGERY required!!
Complications 50% 5y survival in malignant tumors certain drugs can interfere w/ catecholamine assay so might need to change meds around
syndromes: rare MEN2, neurofibromatosis, usually adults (50y.o.) von HippelLindau, SturgeWeber
Rule of 10s: 10% a/w syndrome, 10% bilateral, 10% kids, 10% malignant Hyperaldost adrenocortical eronism hyperfunction Conn's syndrome - HTN, hypokalemia, alkalosis, kaliuresis; suppressed renin w/ severe HTN, hypokalemia, high aldosterone alkalosis, low renin, hi Renin nl converts aldosterone angiotensinogen to angiotensin I; ACE converts angI to angII; angII stimulates the adrenals to secrete aldosterone; aldosterone increases sodium retention and potassium excretion aldosterone producing adrenal adenoma, bilateral adrenal hyperplasia, hypertensive forms of CAH (11B &17a hydroxlase def), adrenal cancers 2-15% prevalence
adenoma? Surgery (curative) medical mgmt? aldactone, epleronone, amilioride (K+ sparing)
Glucocorticoid remedial hyperaldoste ronism
adrenal adenoma + HTN + translocation in which the gene autosomal hypokalemia involved in cortisol production is dominant transferred to the gene involved aymptomatic severe HTN in aldosterone production --> aldosterone being produced in child or young adult; in response to ACTH family h/o hemorrhagic stroke; profound ACTH DRIVES hypokalemia w/ thiazide ALDOSTERONE SYNTHESIS admin
RARE: <1% of hyperald cases
CT scan of abdomen bilateral adrenal vein sampling (aldo:cortisol > 4 suggests adenoma) FH hemorrhagic genetic testing for GRA stroke (uncont mutation on all pts w/ history HTN) of hyperald, strokes at young age, or onset of HTN at young age
lowest dose of longacting steroid (dexamethasone, prednisone) to control BP
Deoxycortic osterone HTN
deoxycorticosterone is made in the zona fasciculata in response to ACTH; elevated levels of deoxycorticosterone seen in adrenomas, adrenal carcinomas, or CAH thus, this MC is able to contribute to HTN
Disease
Clinical Variants Liddle syndrome
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging low renin & aldosterone (RAAS system not part of the etiology of this syndrome)
Treatment
Complications
autosomal severe HTN, hypokalemia, mutation in gamma or beta subunits of amilioride sensitive dominant low aldosterone & low renal sodium epithelial channels mutation renin in distal nephron --> ENaC channels stay open longer increasing Na reabsorption & decreasing Na excretion childhood: low birth weight, failure to thrive, short stature, severe HTN + hypokalemic alkalosis cortisol circulates at much higher levels than aldosterone; cortisol has equal affinity for MR
Syndrome of Apparent MC Excess (AME)
HTN normally prevented by 11BAME Type 1 - decrease or HSD2 by converting cortisol to cortisone, which is unable to absence of 11B-HSD2 bind MR; nonfunctional 11BHSD2 from mutations cause AME Type 2 - milder phenotype w/ expression as cortisol to bind MR and young age; milder alteration activate aldosterone response, despite generally in urinary products and decreased aldosterone activity HTN
AME type 1 - normal cortisol levels, normal ACTH feedback regulation (problem is with cortisol breakdown!!); hi urinary cortisol metabolites (elevated ratio of cortisol metabs: cortisone metabs)
BP control & tx of hypokalemia supression of cortisol w/ dexamethasone spirinolactone kidney transplant
Licorice
Virilizing syndromes
mineralocorticoid excess licorice contains glycyrrhizinic HTN acid, with active metabolite of glycyrrhetinic acid = potent HTN, hypokalemia, low inhibiot of 11B-HSD2 renin & aldosterone, increase in cortisol found in candy, chewing gum, metabolites & decrease in & chewing tobacco cortisone adrenocortical excess sex hormones hyperfunction
stop offending agent & BP reverts to normal
Sexual pain disorders
Dyspareunia
recurrent or persistent involuntary genital pain associated w/ sexual intercourse vulvodynia hypersensitivity to touch, erythema, pain w/ penetration
vulvovaginal atrophy - often results from menopause (loss of estrogen = loss of keratin & epithelial lining of vaginal wall = thinning, loss of lubrication & genital blood flow = tearing w/ penile penetration) vulvodynia/ vestibulodynia = inflammation of vulva or vestibule infection
vulvo/ vestibulodynia = hypersensitivity to yeast, allergic response, HPV, genital rash, autoimm, estrogen def inf = HSV, HPV, GC, CT, PID, UTI, BV, trich, candidiasis
vulvodynia = most common cause of dyspareunia
estrogen creams (unless contraind) if related to atrophy address etiologies - if not helpful, surgical excision of vestibule (which is mesodermal derivative so might be reacting differently to surrounding tissues) & reconnection to other tissues tx infections
Vaginismus signs? Unconcumated marriage, difficulty w/ pelvic exam, difficulty placing tampons
recurrent or persistent involuntary spasm/ contraction of muscles surrounding introitus prevent penile insertion -> personal distress;
childhood trauma
vaginal dilators, psychogenic therapy, muscle relaxatants
Disease Sexual desire disorders
Clinical Variants Hypoactive sexual desire disorder (HSDD)
Defining Characteristics persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity
Pathogenesis a/w menopause - reduced androgen production = reduced testosterone = decreased libido a/w OCPs - inhibition of gonadotropins = reduced production of estrogen & androgens + inc synthesis of steroid hormone binding globulin = reduced testosterone Dopamine = excitatory for sexual desire/arousal Serotonin = inhibitory for sexual desire/ arousal
Etiologies menopause (natural or surgical) meds (OCPs, SSRIs - inhibit pleasure pathways)
Epi
Risk factors menopause, OCP side effect??
Lab/Imaging
Treatment treat only if distressful! Flibanserin - although not FDA approved low dose testosterone Wellbutrin (Buproprion) blocks reuptake of dopamine; give in combo w/ SSRI to compensate for dec libido
Complications
Sexual aversion disorder
Sexual arousal disorder
persistent or recurrent extreme aversion to, and avoidance of, all genital sexual contact w/ appropriate sexual partner persistent or recurrent inability to attain or maintain an adequate lubrication - swelling response of sexual excitement
arousal is mediated by relaxation of arteriolar smooth muscles (NO, VIP mediated) in genitals that increases blood flow into clitoris and vaginal epithelium
psychogenic sexual trauma, poor relationship, drugs
possible female use for PDE-5 inhibitors (Sildenafil, tadalafil) to prevent the breakdown of cGMP
organic - DM, Dysfxn? Inadequate afferent PVD, metabolic syndrome, and/or efferent neural obesity transmission to sexual organs (psychogenic or organic) OR inadequate response of erectile & vaginal tissue (insufficient release of NO or VIP; downregulated smooth muscle receptors; insufficient second messenger regulation of relaxation)
Orgasmic disorder
Female Orgasmic Disorder
persistent or recurrent delay or absence of organsm following nl sexual excitement phase orgasmic capacity < reasonable for age, sex experience, and adequacy of stimulation
directed masturbation program (if lifelong d/o), relationship therapy (if situational d/o), education about sexual fxn & response, anxiety reduction techniques, testosterone/ DHEA/ local estrogen/ oxytocin
Disease Paratesticular disorders
Clinical Variants Hydrocele
Defining Characteristics painless enlargement of scrotum that transilluminates lymphatic obstruction
Pathogenesis accumulation of fluid in tunica vaginalis that surrounds testis congenital hydroceles: occur during first year of life as patent processus vaginalis fails to close, allowing fluid to enter & distend tunica vaginalis; a/w inguinal hernia acquired hydroceles: usually due to lymphatic obstruction from trauma, prior surgery, neoplasms, or infection of testis/ epididymis; a/w parasites (filariasis) in tropical parts of world
Etiologies congenital or acquired
Epi most common cause of scrotal enlargement usually 1st year of life congenital more common
Risk factors prior surgery, neoplasm/ inf of testis/ epididymis, trauma
Lab/Imaging gross: distended testis full of fluid; thin membrane so able to see veins & tunica vaginalis
Treatment
Complications
Varicocele
painless dilation & tortousity of veins more common on left side of scrotum (right spermatic vein drains into IVC at a narrow angle so less probs w/ drainage; left spermatic vein --> L renal vein = long column of blood that rests atop valves)
dilation of vein plexus in spermatic cord
10% of young adults
PE: veins engorge w/ blood when standing
a/w infertility (inc termpature in scrotum optimal spermatogenesis is more efficient at lower temps)
Spermatocele
cyst formation in epididymis hard, pea-sized nodules above the testis inflammation of epididymis enlarged & TENDER epididymis
small cysts that arise from efferent (testis --> meatus) ductal system of testis, particularly epididymis often arises from direct extesion of UTIs from prostatic urethra or prostate with advanced infection, testis may also become infected & difficult to distinguish from epididymis; fibrosis & chronic obstruction of epididymis duct may result --> infertility young men gonococcal & chlamydial infections older men E.coli, M. tuberculosis most common intrascrotal inflamm d/o gross: purulent exodate in the epididymis (above the testis) if gonococcal
NOT a/w infertility!! BENIGN!
Epididymitis
untreated gonococcal epididymitis --> epididymis abscess spread to testicles infertility if chronic scarring & obstruction
Testicular torsion
EXTREME PAIN that may occur spontaneously during sleep or be related to minor injury urologic surgical EMERGENCY!!
twisting of spermatic cord = compression of venous drainage = vascular engorgement & congestion = infarction of testis anomaly of testicular suspension - gubernaculum attached horizontally instead of at the bottom of the testis
2nd decade of life minor injury?
gross: necrotic testis, edematous spermatic cord
surgery to manually untwist spermatic cord
testicular infarction / necrosis if not surgically managed in time! Bilateral risk so gubernaculum is fixed on both testes
Disease Cryptorchidism
Clinical Variants
Defining Characteristics condition where one or more testis has not descended to its nl position in the scrotal sac
Pathogenesis usually arrested along the inguinal canal (dangerous bc this area is injury prone), sometimes the top of the scrotum, and even less commonly the abdomen
Etiologies
Epi 3% of male infants at birth
Risk factors
Lab/Imaging
Treatment
Complications if not repaired within 2 years --> testicular atrophy & fibrosis --> infertility (low sperm counts) INC risk of germ cell tumors (5-10x) - this risk never returns to baseline, even after orchiopexy
histology: atrophy of orchiopexy cryptorchid testis after 2y w.o treatment; fibrosis of seminiferous tubules
Orchitis
Bacterial Syphilitic
inflammation of testis
Mumps orchitis
extension of bacterial infection from epididymis inflammation of testis infiltration of lymphocytes causes obliteration of small blood vessels --> tubular atrophy & fibrosis enlarged & PAINFUL testis viral mumps infection --> lymphocytic infiltration --> edema & pain --> focal atrophy in 50% of involved testis Oligospermia: exogenous testosterone- dec spermatogenesis from inh of LH/FSH; lack of GnRH neuronsKallman's syndrome; congenital bilateral absence of vas deferens - CF, abnl mesonephric duct diff; Klinefelters - low testosterone, elev FSH immotile sperm: primary ciliary dyskinisia - Kartagener syndrome drugs: CCBs ovulatory dysfxn: anovulation (PCOS, androgen excess, low gonadotropins, hi prolactin, diminished ovarian reserve, primary ovarian insuff, hypothyroidism tubal/uterine dz: PID, appendectomy, TB, DES exp, hydrosalpinges, endometriosis Ovarian reserve: problems with hypothalamus GnRH; pituitary gland - lack of gonadotropins; systemic diseases that suppress spermatogenesis (those a/w fever) result in immature seminiferous tubules - no signs of spermatocyte differentation (resemble those of prepubertal testes), or decreased spermatogenesis
mumps 30% of postchildhood virus pubertal males w/ mumps 1/12 couples 35% - male factor, 35% tubal factor; 15%ovulatory dysfxn, 5%cervical factor; 10% unexplained scar tissue (Asherman's), submucosal fibroids, uterine anomaly, endometriosis, PCOS, Kallman's syndrome, CF, renal agenesis, Klinefelters, Turner syndrome sperm analysis (oligospermia, immotile sperm), ovulation detection (basal body temp chart, urine LH surge, endometrial bx, mid luteal serum progesterone >3ng/mL), eval anovulation (preg test, FSH/LH, OCPs, prolactin, TSH, androgens, Cushings, acromegaly, CAH), eval tubal/ uterine/ peritoneal factors (hysteroscopy, hysterosalpingogram, laparoscopy); ovarian reserve testing (Day3 FSH & estradiol, clomiphene challenge, inhibin B, AMH, antral follicle count) induce ovulation (meds = clomiphine - SERM; letrazole (aromatase inh); injections of FSH/LH or hCG) insemination (sperm is placed directly onto uterus near ovulation time) IVF other (gestational carriers, donor gametes, donor embryo, oocyte cryopreservation, ovarian transplant)
fertility usually preserved in unilateral infections
Infertility
Primary - no one year of unprotected prior preg intercourse w/o conception Secondary preg in the past
Male infertility
Supratesticular
above the testis results from abnormalities in organs that regulate hormonal & metabolic aspects of spermatogenesis
no gonadotropins
histology: anatomic seminiferous tubules but no active spermatogenesis; Leydig cells are indistinguishable from stromal cells
Disease
Clinical Variants Testicular
Pathogenesis disorders or lesions of testis itself varicoceles --> increased temperature = low spermatogenesis Cryptorchid testis can develop atrophy & peritubular fibrosis Klinefelters syndrome - atrophy of gonads --> fibrotic testis
Etiologies varicocele cryptorchid testis w/ scarring Klinefelters idiopathic
Epi most common cause
Risk factors
Lab/Imaging histology: IDIOPATHIC? Germ cell maturation arrest, germ cell aplasia (Sertoli cells only, no germ cells)
Treatment
Complications
Posttesticular
obstruction of excretory ducts, particularly the epididymis results in no spermatozoa in the ejaculate, despite being made properly in the testis
untreated epididymitis trauma vasectomy check morning testosterone start tx around 12y.o. (low watch out for levels, LH & FSH, prolactin, doses then dose hi and inappropriately every 2weeks) semen analysis normal gonadotropins!! (if testosterone cranial imaging, bone age, low testosterone, replacement - IM q 2w, U/S of scrotum & adrenals, would expect to have neuro exam (visual fields skin gels/ patch (cannot hi FSH/LH - suspect R/O pituitary lesions), be given as pill bc pituitary/ testicular size, karyotype, dangerous to liver!) hypothalamus med hx (anabolic steroids?), pathology) trauma (testicular or head) check other pituitary hormones and adrenals!
Hypogonadism (general)
testicular failure symptoms? Low testosterone in adulthood = dec libido, soft testes but nl size, dec strength/ muscle mass, dec body hair, gynecomastia, INABILITY TO FOCUS pre-pubertal = small testes, eunuchoidal skeletal proportions, hi pitched voice, dec muscle mass, delayed bone age, dec body hair
central defects - hypothalamus or pituitary problem w/ secretion of gonadotropins testicular defects feedback loop defects - HPG v HPA axes genetic defects - sex chromosomes, transcription factors biochemical defects - adrenal v. gonad androgen receptor defects
Hypergonad increased FSH & LH, nl pituitary & hypothalamus but congenital or otropic hypo- decreased testosterone = primary testicular failure acquired gonadism primary testicular failure either congenital or acquired Primary CONGENITAL (see below) - genetic abnormality (gonadal dysgenesis, Leydig cell hyperplasia, Sertoli cell only syndrome**, CAH); Vanishing testes syndrome Primary ACQUIRED Infectious (mumps, cocksackie B virus, echovirus, arbovirus), drugs (spironolactone - blocks test synthesis; cyproterene or ketoconazole - blocks androgen receptor), iatrogenic (chemo agents, radiation therapy to abdomen), trauma
Disease
Clinical Variants hypogonado trophic hypogonadism
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
testicle is functioning but congenital or decreased FSH & LH, acquired decreased testosterone = insufficient signal from central (GnRH, LH) failure pituitary or hypothalamus Secondary CONGENITAL: gene mutations (FSH/ LH deficiencies - PROP1), central midline defects (cleft lip palate, septo-optic dysplasia), Genetic syndromes (Kallman's, Prader Willi) Secondary ACQUIRED: brain abnl (trauma, infectious, tumors - craniopharyngioma), anorexia (malnourishment shuts down HPG axis), systemic illness, hemochromatosis, elevated prolactin (inhibits FSH&LH), obstructive sleep apnea
Gonadal dysgenesis
congenital hypergonadotropic hypogonadism
caused by abnormal karyotype (Klinefelters - 47 XXY), transcription factor deficiency (SF-1, SRY, SOX9), transcription factor excess (DAX1) karyotype abnl or transcription factor problems -> impaired development of testis --> dysgenesis
Klinefelter's Syndrome
congenital hypergonadotropic hypogonadism from gonadal dysgenesis increased limb length, decreased verbal IQ, "odd" impulsive behavior
47XXY --> impaired seminiferous tubules
1:10,000
prisoners
Leydig cell hyperplasia
congenital hypergonadotropic hypogonadism male pseudohermaphroditism
46XY but inactivating mutations of LH receptor --> female phenotype LH required for Leydig cells to produce testosterone Germ cell aplasia/ DelCastillo syndrome sertoli cells are not functioning --> impaired sperm production normal secondary sexual characteristics bc nl testosterone & LH levels
autosomal recessive mutations of LH receptor
Sertoli Cell Only Syndrome
congenital hypergonadotropic hypogonadism Male sterility without sexual abnormality & nl secondary sex characterisitics
nl testosterone & LH; HI FSH NO seminiferous tubules or sperm!
Disease Vanishing Testes Syndrome
Clinical Variants
Defining Characteristics congenital hypergonadotropic hypogonadism
Pathogenesis nl 46XY karyotype but absent testes (anorchia), due to prenatal testicular torsion or INSUL3 transcription factor defect regression of testes during 814w gestation de Morsier's syndrome --> absent septum pellucidum
Etiologies
Epi
Risk factors
Lab/Imaging low testosterone, hi FSH & LH
Treatment
Complications
Septo-optic dysplasia
congenital hypogonadotrophic hypogonadism optic nerve hypoplasia, potential hypopituitarism
Kallman's Syndrome
congenital hypogonadotrophic hypogonadism
problem w/ KAL gene (codes for adhesion molecule) = loss of migration of cells required to make GnRH
1:10,000 M>F 5:1
Hypergonadism
(general)
HYPOSMIA OR ANOSMIA (loss of smell) a/w hypogonadism bc same anatomic location as olfactory bulb androgen excess, acne, early pubertal development virilization, anger, small from excessive androgen testes secretion endogenous (central precocious puberty, adrenal gland abnormality, androgen secreting tumor) exogenous (anabolic steroids)
anabolic steroids
treat cause inhibit testosterone w/ GC (if adrenal cause), surgery (if tumor), or discontinuation of meds (if exogenous anabolic steroids)
often also have low HDL so at risk for CVD
Menopause
natural
final menstruation during oocyte atresia dimacteric phase (no menses for 1y w/ inc FSH) menstrual cycle changes: follicular phase shortens, inhibin is lower so FSH levels rise, perimenopausal women estradiol & progesterone can sometimes have irregular & heavy bleeding decrease --> irregular & anovulatory cycles reduced estrogen effects? Hot flashes, decreased androgen levels: atrophy (vaginal, uterus & androstenedione, testosterone, ovaries, urinary tract, & DHEAS leads to decreased breasts, hair, skin), estradiol levels osteoporosis, psychological changes, loss of cardioprotection & neuronal protection
occurs around age 50
early menopause? Smoking, surgery, genetics, radiation/ chemo exp, autoimmune, med induced (Lupron)
estradiol < 20 pg/mL; FSH > 50-100 hypothyroidism becomes more common endometrial bx if postmenopausal bleeding
treatment only if symptoms impact QoL; use lowest effective dose of HRT; can also use transdermal / transvag admin of HT to reduce blood clot risk
endometrial hyperplasia & cancer if continuous estrogen exposure w/o enough progesterone in perimenopausal women
Mirena IUD - lowest DEXA scans for osteoporosis systemic dose of progestin
contraind for HRT? Hormone sensitive cancer, unexplained uterine bleeding, acute androgen therapy - risks liver dz, hx of DVT/PE, uncertain but thought to confirmed CVD, be beneficial for dec libido uncontrolled HTN, migraine w/ aura or alternatives to HRT? TIA SSRIs, clonidine vaginal estrogen or lubricants for atrophy & dyspaurenia osteoporosis tx: estrogen, bisphosphonates, SERMs, calcitonin, calcium & vit D supplements, exercise
SSRIs, clonidine Disease Clinical Variants Premature Defining Characteristics Primary ovarian insufficiency Pathogenesis Etiologies idiopathic (maj), Turners syndrome, chemotherapy, familial, pelvic surgery, gonadal dysgenesis (46XY), galactosemia, pelvic irradiation Epi premature or primary ovarian insuff occurs <40 1% of women Risk factors Lab/Imaging vaginal estrogen or Treatment lubricants for atrophy & dyspaurenia osteoporosis tx: estrogen, bisphosphonates, SERMs, calcitonin, calcium & vit D supplements, exercise Complications
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Screening / Education daily glucose monitoring, realistic BG targets, healthy lifestyle (diet, ex), office visits q 3-4m for evaluation of retina, lower extremities, CV, & routine screening (A1C, TFTs, lipids) Prevention 1.autoimm 2. prevent dz in those w/ autoimm 3. intervene to preserve islet cells
OGTT = most sens way to dx pre-diabetes or diabetes (post prand gluc rises first) gluc monitoring & self-mgmt of insulin adjustments for stress, ex, sickness, diet CVD risk factors and complications screening
Screening / Education A1s are at low risk for IU demise; do not need antepartum surveillance or early elective induction A2s: antenatal surveillance w/ US & NST at 32 weeks until delivery, 2x/week PP: screen 612 wks w/ 75g 2h OGTT (DM if FBS >126, 2h > 200) pre-preg ex a/w lower GDM risk
prevent w/ early INTENSIVE glucose control
every patient over age 60 should have TSH checked! Increase levothyroxine dose by 30% in pregnant patients!!
recurrent parathyroid dz possible
Screening / Education rarely malignant
dopamine agonists limited during pregnancy (no progression of microadenoma during pregnancy despite estrogen stimulation) surgical debulking of macroadenomas prior to pregnancy bc can worsen
Screening / Education routine evaluation? Cardiovasc screen, anticipatory mgmt for aortic dissection, thyroid function, celiac screen, FSH/LH, renal & liver fxn, DEXA, psych consults, blood glucose/ fasting lipids, ENT/ audiology
expectant management & reassurance
Stages: I - ovaries only II - pelvis, ovaries III - abdomen, lymph nodes, superficial liver IV - outside of abdomen, parenchymal liver lower survival w/ higher stage
Screening / Education yearly paps beginning ages 21-29; if lowrisk, paps every 2-3yrs after age 30 if 3 normals in a row stop paps at 70y.o. if no abnl in last 10 years & 3nls in a row stop paps if hysterectomy & no h/o CIN2/3
continue to monitor other testicle if prior germ cell tumor!
yearly mammograms for women > age 40 breast exams q 3y for women 20-40; yearly age > 40 hi risk women yearly MRI of breasts
female screening- CT (sex active <24; at risk >25), gonorrhea / HIV/syphilis (at risk), cervical Ca (all sex active women w/ cervix) pregnant women - CT if at risk or less <24; syphilis, HepB MSM - yearly if sex active: syphilis, HIV, GC/CT, hep; selective males
screen women < 25 for chlamydia!
PROTECTIVE SEX!!
Gardisal quadrivalent vaccine
Screening / Education Chlamydia = leading preventable cause of tubal factor infertility
Screening / Education check testes regularly to screen for development of neoplasms, even after orchiopexy!
Pre-implantation genetic diagnosis (PGD) aneuploidy screen, single gene defect, HLA matching, sex selection
CVD & osteoporosis screening
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Aplastic anemia
all cell lines are down!!
premalignant condition w/ loss of Paroxysmal self renewal (affects the stem cell) nocturnal hemoglobinuria (PNH), Fanconi's anemia
BM: hypocellular (empty marrow), fat vacuoles only; hi power reveals lymphs only (suggest that whole myeloid line is gone) CBC: loss of all cell lines
sometimes immunosuppression helps restore cell lines allogeneic stem cell transplant
infections - unable to generate new lymphocytes
Myeloproliferative syndromes (MPS)
(general)
expansion in peripheral blood premalignant condition w/ = high counts of affected growth advantage and loss of myeloid line apoptosis; injury occurs at a level beyond stem cell splenomegaly mutations in tyrosine kinase --> increased proliferation but INTACT differentiation Chronic pre-malignant disorder caused by fusion protein (BCRmyelogenous ABL gene) formed via t(9;22) leukemia typically presents w/ [Philadelphia chromosome] (CML) whole dz is driven by mutation in splenomegaly + BCR-ABL (probs w/ adhesion so leukocytosis (nl plt & Hb) abnl myeloid cells leave marrow; inhibition of apoptosis; activation splenomegaly, of proliferation & differentiation via hepatomegaly if adv, early RAF-MEK-MAPK) satiety (big spleen/liver compresses stomach; good proliferative disorder of appetite but weight loss bc hematopoietic stem cells without early satiety) arrest in maturation; due to 3 phases of presentation: single molecular abnormality chronic phase (maj of patients; asymptomatic but abnl CBC), accelerated phase (symptomatic, difficult to control leukocytosis), blastic phase (acute leukemia, terminal & poor prognosis) only leukemia w/ thrombosis Essential 50% JAK2 nonfunctional platelets --> thrombomutation bleeding cytosis splenomegaly
CBC: all cells lines present & in excess; always hi WBC (leukocytosis) smear: increased lymphocytes, WBCs at every level of maturation Cytogenetics: t(9;22) FISH: fusion protein PCR: ABL-BCR gene flow is not diagnostic, BM bx does not need to be done; confirmed w/ karyotype/ FISH/ PCR
eradicated Philadelphia can progress to AML chromosome (causative (blastic phase) agent), prevent progression to blast phase (AML) mean survival of chronic phase = 4-6y targeted therapy against resistance to Imatinib by BCR-ABL via tyrosine kinase inhibitors (Imatinib/ cancer cells (pump drug out of cell, produce Gleevec, Dasatinib, more BCR-ABL, develop Nilotinib) mutations to prevent Allogeneic HSCT if resistant drug MOA) to imatinib
elevated platelet count (>450K) MUST R/O iron deficiency (iron studies), other MPDs (CML, PRV)
pegylated interferon suppresses abnl hematopoiesis
some patients transform to polycythemia vera some patients, over time, can develop myelofibrosis
Poly-cythemia elevated WBC, Hb, Hct, rubra vera platelet counts + aqua (PRV) induced pruritis splenomegaly, thrombosis
inappropriate absolute JAK2 mutation polycythemia (EPO independent colony growth) from mutation in JAK2/STAT pathway --> upregulated transcription of lineage specific myeloid genes for WBCs, RBCs, platelets (basically myeloid cell line expansion)
Diagnosis: Hb > 18.5 (males) or pegylated interferon 16.5 (females), Jak2 mutation, suppresses abnl hematopoiesis inc WBCs, inc platelets, low EPO, splenomegaly, thrombosis (common & unusual locations)
some patients, over time, can develop myelofibrosis
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Primary anemia, splenomegaly, myelofibrosis elevated or decreased WBC & platelets portal hypertension
fibroblasts prompted to make extra JAK2 mutation fibrous tissue --> filling of bone marrow w/ fibrotic tissue --> hematopoiesis then occurs at other sites (extramedullary hematopoiesis)
tear drop RBCs (dacrocytes), immature granulocytes, nucleated RBCs "dry tap" on marrow aspiration (scarring of marrow) hypercellular marrow + fibrous tissue
JAK2 inhibitors - useful for reducing spleen size and improving symptoms; not helpful for clone reduction
Myelo-dysplastic Refractory subacute presentation syndromes anemia (w/ or ("feeling bad") w/ anemia +/(MDS) w/o ringed neutropenia, sideroblasts) thrombocytopenia (1, 2, 3 cell lines affected) refractory anemia w/ anemia, bleeding, multilineage infections dysplasia refractory anemia w/ excess blasts 5q syndrome
premalignant condition where an radiation, cigarettes insult (damage to bone marrow) affects differentiation and maturation of myeloid line --> clonal hematopoiesis --> cytoplasmic & nuclear asynchrony -> immune dysregulation, altered cytokines --> decreased hematopoiesis & delivery of mature blood cells to periphery --> leukemic transformation apoptosis is shifted to bone marrow = inappropriate cell death before delivery to peripheral blood
prior chemo/ more common in radiation treatment elderly
Smear: abnormal segmentation Stem cell transplant of WBCs (Pelger-Huet immune suppression for the nucleus, hypogranular), hypolobated megakaryocytes small proportion of patients that have immune dysregulation & hypocellular BM bx: ringed sideroblasts, marrow excess blasts demethylation drugs like azacitidine
frequently progresses to AML (30% of cases) Prognosis depends on proportion of blasts in bone marrow, cytogenetic features, & number of cytopenias
Acute myelogenous leukemia (AML)
completely immunodeficient (pancytopenia)
mutation in early progenitor myeloid cell causes complete replacement of bone marrow with no normal lineages being made; anemia sx - fatigue, DOE, roaring in ears (Hb<6); low cells no longer have nl function WBC (feveres, infection), low (immature blasts); clonal, platelets (bleeding, bruising), proliferative, & arrested bone pain (wakes patient at differentiation --> impaired night), hyperviscosity production of nl blood cells (mental status change, vision, (stuck in progenitor cell phase) dyspnea, spont bleeding), chloroma (skin infiltration by cytogenic abnormalities leukemia) common - poor prognosis = chrom 5, 7, 8 or complex; exam: pallor, petechiaes, intermediate = nl karyotype; good ecchymosis, splenomegaly, = t(15;17), t(8;21) lymphadenopathy, gingival hyperplasia (monocytic leukemia), perirectal abscess, skin nodules
Primary: exposure to chemicals (benzene shoes, rubber), radiation, hereditary (Fanconi's, Down's) Secondary: chemotherapy, hematologic dz (CML, MDS)
1/150,000 bimodal age distribution (15-59)
CBC: possible hi WBC if driven by blasts, low or nl WBC if arrested development; low RBCs & platelets smear: Auer rods, blasts (all cells look alike), low platelets & RBCs, low WBCs if cells stuck in marrow; hi WBCs if cells are in blood BM bx: hypercellular, >3% primary granules flow cytometry: express CD13, CD33, CD117, HLA-DR+ FISH: t(15:17) prog&tx response - cytogenic & molecular markers; WBC # at presentation, age, subtype, LDH > 700, poor initial reponse to tx genetic profiling for intermediate risk patients
eradicate AML & restore hematopoiesis 1. induction therapy (anthracycline, cytarabine) 2. check therapy response, establish risk stratification 3. consolidation therapy 4. Observe patients; if poor prognosis while on consolidation therapy, HSCT
poor cytogenics or normal cytogenics but poor mutational risk profile - do not survive beyond 2 years & require transplant! Worse survival out of the leukemias hyperleukocytosis --> CNS injury & pulm leukostasis
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Acute lymphocytic leukemia (ALL)
malignant d/o of lymphoid progenitor cells that completely replace the marrow --> pancytopenia
higher SES, Down's syndrome, radiation exposure, late 2.8/100,000 common S/S: anemia (dec energy, infections, FH CHF), thrombocytopenia environmental - 2-3y.o. of (hemorrhage - mucosal; lack of pathogen exposure as an lack of exposure (peak autoimmune petechiae, bruising), infant, with subsequent delayed exposure to pathogens at time of to pathogens in incidence) dz leukopenia (infxn, fever), M>F slightly increased lymphoid proliferation -- infancy systemic involvement (fever, weight loss, malaise, > extremely robust response others - trisomy decreased activity), 21, high birth extramedullary involvement rate, ionizing (lymphadenopathy, hepatoradiation, "late" splenomegaly, bone/ joint common inf, pain- bilateral; CNS sx topo-isomerase chloromas, leukemic II inhibiters meningitis, renal failure, edema, skin or testicular masses)
stem cell gives rise to slightly more genetic mature lymphoid progenitor cell sensitivity to B that proliferates out of control cell hypersensitization (FH of autoimmune genetic & environmental dz) combination of etiologies
most common childhood malignancy
CBC - normocytic anemia w/ low retic count; thrombocytopenia, leukopenia, possible leukocytosis (malignant cells) Peripheral smear: blasts in periph blood (20% of pts do not have blasts in periphery at time of dx) BM morphology: hypercellular w/ monotonous cells resembling lymphocytes BM flow cytometry: blasts > 25% = confirmed dx; CD20 clonal population PCR: TEL-AML rearrangement LDH: elevated (marker of cell turnover) tumor lysis labs CXR, lumbar puncture (CNS?) LFTs, coag screen
prognostic factors - initial present (age hi risk if <1 or >10; WBC hi risk if >50,000); location of dz (hi risk if CNS positive), immunophenotype - T cell or biphenotypic higher risk; cytogenetics - favorable (TEL-AML), hyperdiploid; unfavorable (MLL - mixed leukemia, t(9;22)), 4w tx assessment - slow early responders or induction failure need intensification use of maintenance tx (administer low dose drugs 1.5-2.5y) - hallmark of ALL CNS prophylaxis
tumor lysis syndrome rapid cell death and turnover causes phosphorus and potassium to be released; calcium and uric acid can block kidneys oncologic emergencies: tumor lysis syndrome (renal failure), anterior mediastinal mass (T cell disease - block airway and compress SVC), hyperleukocytosis (cause sludging --> stroke, ARDS), sepsis
Chronic lymphocytic leukemia (CLL)
lymphadenopathy + elevated WBC/ ALC infections - decreased polyclonal immunoglobulins autoimmune disorders AIHA, ITP, Evan's syndrome
mutation in B cells post antigen exposure in the lymph node --> clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells; in the peripheral blood, these cells resemble mature lymphocytes neoplastic B cells do not differentiate into functioning plasma cells = hypogammaglobulinemia
3/100,000 per yr
MBL (monoclonal B cell Caucasian> lymphocytosis AA>Asian ) patients > age 60 most common overall leukemia & most common cause of general lymphadenopathy in adult > 60
flow cytometry: cell population CD19+ (B cells), CD5+ (T cells but occurs briefly in B cell development), CD23; poor prognosis a/w CD38+, ZAP70, CBC: extremely elevated ALC/ WBC (>5000 circulating cells w/ CLL phenotype) smear: high number of mature lymphocytes; smudge cells (fragile cells that have burst), RBC abnormalities (polychromatic, nucleated, microspherocytes - represent BM response) LN bx: well differentiated lymphocytes; diffuse primary & secondary follicles FISH: poor prognosis a/w 17p &11q deletion SPEP: hypogammaglobulinemia
important to observe asymptomatic patients!!
Richter's transformation (1% per year) - evolve into large cell lymphoma
treatment indicated if: Rai 3, 4; lymphocyte count doubles staging: <1y, B symptoms, high risk Rai 0 = low risk; lymphocytosis only, med molecular studies survival 14y Rai 1 = intermed risk; Treatment includes fludarabine or chlorambucil lymphadenopathy, med survival 7y in older patients Rai 2 = intermed risk; lymphadenopathy + HSCT for poor prognosis spleno/hepatomegaly; disease med survival 7y Rai 3 = anemia, med survival 4y Rai 4 = thrombocytopenia, med survival 4y
Monoclonal Bcell Lymphocytosis
precursor to CLL
6-15% of age relatives of (increased CLL patients CLL clones)
detectable clonal CLL cells at less than 5000
1.2-1.4% of MBL becomes CLL
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Plasma Cell Myeloma
fatigue, bone pain, renal dysfunction, hypercalcemia, recurrent infections w/ encapsulated organisms (H.influenzae, Strep pneumo)
plasma cell dyscrasia (B cell malignancies) common because germinal centers have such high error rates! malignant plasma cells --> 1. decreased normal immunoglobulins --> recurrent infections 2. marrow infiltration --> anemia, thrombocytopenia 3. bone destruction from the release of IL-1 (osteoclast activating factor) --> lytic lesions, pathologic fractures, osteopenia, hypercalcemia 4. monoclonal immunoglobulins + hyperviscosity of blood (decreased blood flow) + hypercalcemia + amyloid (light chains converted to amyloid) --> renal failure
MGUS
4.3/100,000 AA> Caucasians median age 66y.o.
CBC: low WBC, anemia, thrombocytopenia Chemistries: hypercalcemia, hi total protein but nl albumin, hi globulin Smear: Rouleaux formation of RBCs, +/- plasma cells Skeletal survey: compression fractures, osteopenia, lytic lesions SPEP: IgG kappa paraprotein present at high levels (monoclonal gammopathy) BM bx: plasma cells in bone marrow (>10%) DX REQUIRES: presence of serum/ urine M protein, clonal bone marrow plasma cells, organ/ tissue impairment (CRAB = increased plasma calcium, renal insuff, anemia, lytic bone lesions)
autologous transplant Thalidomide, lenalidomide, bortezomib most impt for remission rates & improved outcomes
incurable! Staged by Beta-2 microglobulin (total body burden of plasma cells) & albumin; cytogenetics for high risk mutations
Monoclonal Gammopathy of Undetermined Significance (MGUS)
precursor to myeloma!!! Fight infections fine bc normal polyclonal Ig's not decreased; no lytic lesions, hypercalcemia, or organ damage (CRAB); < 10% plasma cells in marrow autoimmune hemolytic anemia + ITP a/w ALPS, SLE (other autoimmune dz) malignancies arising from cells of lymphatic system (lymph nodes, spleen, thymus, MALT); can move to the bone marrow majority are B cell origin, very few are T cell origin
<10% plasma cells in marrow, observation <3g monoclonal protein, absent CRAB!
1/3 of MGUS patients progres to myeloma obligated to observe and follow these patients!!
Evan's syndrome
Lymphomas
(general)
painless swelling of LNs, B symptoms (unexplained fever, drenching night sweats, unexplained weight loss > 10% of body weight), constant fatigue, alcohol induced pruritis, reddened patches of skin
should always order HIV test if suspect lymphoma!!
Disease
Clinical Variants
Hodgkin's lymphoma
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
asymmetric lymphadenopathy (90% of cases - firm, rubbery, motile; supraclavicular, lower cervical), rare hepatosplenomegaly, extranodal manifestations (rare except in HIV+ or advanced stage), B symptoms (1/3 of cases), painful lymph node when drinking alcohol
contiguous LN involvement suggests spread via lymphatic system Reed Sternberg cell - releases cytokines that cause severe inflammation, fever, deranged immune system
bimodal age distribution (15-34; >50)
later exposure to EBV, HIV, iatrogenic immunosupp , higher SES
autoimmune cytopenias (ITP, AIHA), immune deficiencies anemia of chronic inflammation, elevated ESR, elevated LDH LN bx: Reed Sternberg cell (transformed post-germinal B cell w/ EBV transcripts present) Staging: PET scan + CT, bone marrow biopsy
Localized disease (Stage 1) - Ann Arbor staging: extended field radiation Stage 1 = single LN region; Stage 2 = 2 LN Stage 2,3 disease regions on same side of combination chemo + diaphragm; Stage 3 = radiation to residual areas LNs on both sides of diaphragm; Stage 4 = Stage 4 disease diffuse/ disseminated combination chemo cocktail involvement of extralymphatic organ (ABVD) If relapse occurs >1 year, retreat as new HL patient; if relapse occurs <1 year, chemo + autologous HSCT w/ treatment, 5y survival: Stage 1- 90%, Stage 2- ~90%, Stage 3 85%, Stage 4- 75% no treatment - death!! (mass effect, immune dysreg, profound anemia) secondary malignancies, CAD Ann Arbor staging: Stage 1 = single LN region; Stage 2 = 2 LN regions on same side of diaphragm; Stage 3 = LNs on both sides of diaphragm; Stage 4 = diffuse/ dissem involv of extralymphatic organ Indolent - survival mos yrs w/o tx; observation after chemo; incurable aggressive - survival wks - mos w/o tx; combo chemo outpt; >50% cure rate very aggressive survival days to weeks; combo chemo inpt; cure rate >50% 3% follicular lymphomas transform to aggressive forms
NonHodgkin's lymphoma
adults - diffuse large B cell lymphoma (AGGRESSIVE), follicular lymphoma (INDOLENT) kids - burkitt's lymphoma (VERY AGGRESSIVE), diffuse large B cell, lymphoblastic
spreads hematologically so random lymphadenopathy indolent / low grade - dec apoptosis; aggressive / intermediate grade - dec apoptosis, slightly inc mitosis; very aggressive / high grade - dec apoptosis, VERY inc mitosis
see risk factors
Fever neutropenia
Low risk
HIV a/w increased Burkitt's lymphomas, very aggressive plasmablastic indolent - usually present as lymphomas, diffuse lymphadenopathy & follicular lymphomas usually aggressive have translocation 14;18 (moves diffuse large B involve the BM Ig heavy chain next to Bcl-2 = cell lymphomas marked overexpression of Bcl2 = hepC a/w splenic marginal zone lymphoma; H. pylori a/w anti-apoptotic) MALToma - both respond to Burkitt lymphoma - B cell tx of infectious agent neoplasm w/ translocation 8;14 mycosis fungoidies - mature places heavy chain next to cMyc oncogene; endemic (Africa) T cell lymphoma --> disfiguring skin lesions --> forms a/w jaw swelling & EBV; Sezary syndrome (end non-endemic (a/w HIV, EBV stage) negative) Solid tumors, ALL/NHL in GN bacteremia from enteric remission, neutropenia < source (Pseudomonas) 7days, expected neutropenia < 10days, no localization
most common type of lymphoma; 4% of new malignancie s, rising incidence Burkitt lymphoma peaks in kids age 11; adults at age > 30 fastest growing malignancy !!
age (50-60 y.o.), environment al exposure (chemicals fertilizer, pesticides, solvents), chemotherap y, radiation, immune suppression, HIV/AIDS, autoimmune dz (Sjogrens, Hashimotos, RA, Celiac), infectious (HTLV1, EBV, human herpes virus 8, hepC, H.pylori)
LN bx: Diffuse large B cell large abnl lymphocytes that replace nl LN architecture, light chain restricted; follicular lymphoma - nodular/ follicular pattern, cytogenetics show t(14;18); Burkitt's lymphoma monomorphic cell population w/ vacuoles + c-myc rearrangement BM bx: not std of care, but if abnl lymphocytes automatically stage IV disease
CHOPR = Cyclophosphamide, hydroxy doxirubicin, oncovin (Vincristine), prednisone, rituximab If relapse, HSCT - 50% can be cured if respond to salvage + transplant
recommend observing indolent NHL like follicular lymphoma if asymptomatic; once symptomatic, use rituximab determine prognosis via IPI = (improves lifespan) inc risk is age > 60, performance status 2-4, elevated LDH, extranodal involvement, Ann Arbor stage 34
Ceftazadime (3rd gen cephalosporin)
Fever neutropenia
Disease
Clinical Variants
High risk
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
ALL/NHL in induction, AML, evidence of sepsis (chills), mouth sores (mucositis), high dose cytarabine, localized (central line, GI, rectum) require very aggressive antibiotic treatment!!
GN bacteremia (Pseudomonas), GP bacteremia (Staph, Strep) abdominal symptoms present? GN bacteremia (Pseudomonas), GP bacteremia (Staph, Strep), or Anaerobes unstable? Tachycardia, hypotension, respiratory distress perirectal abscess, port pocket infection
GN enterics, Staph/ Strep, Anaerobes other sources? HSV, varicella, dysphagia (fungal, CMV, HSV), yeasts/ molds
GN bacteremia: ceftazadime GP bacteremia: vancomycin abdominal symptoms: meropenum (anaerobes, Pseudo), vancomycin, +/tobramycin unstable: meropenum, vancomycin, amikacin (double coverage against pseudo)
Typhlitis
RLQ pain, obstruction, GI bleed, pneumatosis/ perforation abdominal pain in the setting of neutropenia = emergency!! electrolyte imbalance + renal failure
bacterial overgrowth syndrome in the intestine (usually cecum) --> increased risk of sepsis and GI manifestations
CT: thickened bowel wall from fluid/ air/ bacteria within the lumen
BSA management of constipation/ diarrhea
Tumor lysis syndrome
Normally, potassium load is excreted by the kidneys; however, the administration of chemotherapy causes the release of DNA, phosphorus, and potassium DNA gets further metabolized to uric acid via xanthine oxidase Calcium and phosphorus can complex & precipitate --> kidney stones & renal failure inability to excrete potassium --> cardiac manifestations
monitor coags pain mgmt, nutrition IV fluids + urate oxidase + hyperkalemia, IV calcium gluconade/ hyperphosphatemia, hypocalcemia, hyperuricemia chloride if seizure/ heart failure + amphogel + treatments for hyperkalemia
hypocalcemia --> muscle spasm, heart failure, seizures hyperuricemia & hyperphosphatemia -> renal failure hyperkalemia --> arrhythmias (sine wave, Torsaud's)
Hyperleukocytosis
WBC > 100K AML: 5-22% patients; clinically significant at > 200K -> CNS injury (cerebral hemorrhage, thrombosis), pulmonary leukostasis (similar to ARDS) ALL: 9-13% patients, significant at >300K; complications related to tumor lysis syndrome
treatment for tumor lysis tumor lysis syndrome, syndrome - hydration, urate neurological changes oxidase (stroke, CNS bleed), respiratory distress maintain platelet count > 2050K (dilutional effect w/ transfusion) exchange transfusion (plasmapheresis, double exchange)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Mediastinal mass
tripod position, accessory muscle usage - suggests airway compression (presents w/ cough, dysphagia, orthopnea, hoarseness, wheezing) SVC syndrome - obstruction of venous return to the heart -> compression, thrombosis, prevention of cerebral perfusion (presents w/ edema of upper extremities, head; AMS changes, acute respiratory changes - PE)
CXR!!
sedation is contraindicated!!
Spinal cord compression
back pain, decreased strength, increased reflexes, sensory changes, rectal tone petechiae (platelet dysfxn or severely low platelet counts), purpura (platelet d/o, coag d/o, nonhemostatic dz like Cushing's, collagen-vascular, scurvy, age)
chloromas = masses of WBCs in leukemia patients; can encroach on spinal column, causing paralysis
3-5% of newly diagnosed oncology patients platelets <150K Normal WBC & Hb? Check peripheral smear - nl RBC morphology, platelets nl or increased in size consider drug induced, ITP, infection induced, congenital thrombocytopenia - fragmented RBCs - consider hemolytic anemias (DIC, TTP) - clumped platelets - redraw in sodium citrate or heparin Abnl Hb & WBC? - bone marrow exam
Thrombocytopenia
dec platelet prod by marrow: primary: marrow failure (SAA), MPDs, lymphoprolif dz, MDS; secondary: meds, chemo, rad, alcohol, vitB12/ folate def, marrow infiltration, viral infxn (HIV, hep), liver dz (dec TPO) accelerated destruct of platelets: non-immune: DIC, TTP, HUS, vasculitis, abnl laminar flow, drug- induced platelet consump; immune: primary: ITP; secondary: HIT, glycoprotein antiplatelet Abs, CTDs, lymphoproliferative d/o, infxns, neonatal alloimmune thrombocytopenia, posttransfusion purpura platelet sequestration (spleen) dilutional thrombocytopenia (blood transfusions) pseudo-thrombocytopenia (clumping of platelets) Immune thrombo- Newly heterogeneous autoimmune primary immune-mediated cytopenia (ITP) diagnosed destruction of platelets in d/o characterized by: (<3m, mostly isolated thrombocytopenia, peripheral blood kids) no underlying cause, +/anti-platelet antibodies produced bleeding manifestations persistent by B cells adhere to platelets & (3m-1y) target them for destruction; mucosal bleeding, previously healthy, usually antibodies also inhibit chronic (>1y, follows infection megakaryocyte maturation/ mostly adults) proliferation, block release of platelets most kids spontaneously remit; most adults have chronic or persistent ITP
1.54/100,000 per year avg age 2050
CBC: platelets < 100K Smear: dec # platelets, large platelets BM bx: increased megakaryocytes; done only if suspect other abnl Check HIV & Hep serologies! Check for other autoimmune d/o: Anti-phospholipid antibodies, TSH, ANA
prevent/ stop bleeding if present increase platelet count (but not to nl levels, just enough to stop bleeding) maintain platelet count > 30K for stable hemostasis 1. steroids, IVIG, Anti-D if pt is Rh+ 2. splenectomy, immune suppression, chemo, rituximab, TPO receptor agonists
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Heparin-induced thrombocytopenia (HIT)
heparin attaches to platelet factor 4 (which is released from platelets); heparin + PF4 attaches to IgG to form immune complex immune complex attacks the platelet --> immune mediated platelet destruction & removal of platelets by splenic macrophages at same time, there is platelet activation, release of platelet granules, platelet aggregation, & activation of clotting cascade --> thrombosis & significant risk of VTE
pre-test clinical scoring system: 4Ts (thrombocytopenia: platelets fall >50% reaching nadir >20K; timing: clear onset btwn days 5-10; thrombosis: new thrombosis confirmed, skin necrosis, acute reaction; other causes: none apparent) - low score (<3 pts) a/w up to 1.6% +HIT assay, intermediate (4-5 pts) a/w 8-28%, & high (6-8 pts) a/w 21-100% HIT+ assay
requires IMMEDIATE thrombotic events!! discontinuation of heparin & use of alternative anti- Life & limb threatening coagulation therapy!! condition Treat thromboembolic event continue anti-coagulation after d/c from hospital thrombosis risk remains
Drug induced thrombocytopenia
Platelet sequestration
drugs induce antibodies or caused by direct antibody formation to drug OR drug+ lupus-like syndrome protein on platelet can form hapten, leading to platelet destruction splenomegaly hepatic cirrhosis w/ portal HTN (low TPO, splenomegaly) infiltrative diseases (MPD, Guacher's dz) Inflammatory dz (Sarcoid, TB) Hyperplastic responses (chronic hemolysis) blood & fluid resuscitation results in fall in platelet count generally, loss of at least 1-2 blood volumes occurs before significant decrease in platelet count becomes apparent after HbF decreased production of globin chains during hemoglobin transitions to HbA synthesis Deletion of 1 or 2 alpha genes rarely problematic bc gene (usually in African Americans as duplication an evolved protection against malaria) HbH disease - severe anemia + splenomegaly loss of all alpha genes = no HbF = Hb Barts = hydrops fetalis (fatal in utero) loss of 3 of 4 alpha genes = HbH disease loss of 2 of 4 alpha genes = alpha thalassemia minor loss of 1 of 4 alpha genes = alpha carrier state
thrombocytopenia
Dilutional thrombocytopenia
replete 1 unit of platelets per every 5-6 units of blood
Thalassemias
(general)
Alpha
Hb Electrophoresis: HbH Iron studies: normal ferritin Smear: target cells, microcytic, HbH inclusions CBC: mild anemia + significant microcytosis = alpha thal minor; low normal MCV but hematologically normal = alpha thal carrier
Disease
Clinical Variants
Beta
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
B+ has mutation that disrupts translation B0 has mutation that stops translation B0 = beta thalassemia major = severe transfusion dependent anemia, jaundice, hepatosplenomegaly, bone changes, growth retardation, infections, iron overload --> cardiac, liver, endocrine failure B+ = beta thalassemia minor = asymptomatic + splenomegaly
multiple mutations (promotor mutations, frame shift, splicing) --> abnl translation --> decreased production of beta globin chain (B+) or no production of beta globin chain (B0) excess alpha chains --> insoluble & precipitates producing inclusion bodies in RBCs --> membrane damage, spleen sequestration, & profound anemia marrow amps up to make more RBCs and expands --> frontal bossing, pathologic bone fractures & deformities
Beta thal major: blood transfusion Hb Electrophoresis: small amt or absent HbA; predominant HbF Smear: microcytosis, hypochromic, high RDW (very different cell populations) -----------Beta thal minor: anemia w/ elevated RBC count, more microcytic than anemic, nl RDW; increased HbA2 & HbF on electrophoresis
hemochromatosis (iron overload following blood transfusions) - require iron chelating agents cardiac dz, GI dz, & DM (from iron deposition on other organs)
Hypoproliferative anemias
(general)
decreased absolute retic count (<75,000) or corrected reticulocyte % (<2%) Microcytic, normocytic, or macrocytic (see below)
decreased production of hemoglobin/ RBCs
Microcytic anemias
(general)
corrected retic % < 2% MCV <80
anemia resulting from problematic hemoglobin synthesis
inadequate iron supply (deficiency or not free for utilization), abnl globin synthesis, abnl assembly of porphyrin ring inc blood loss (GI - colon Ca, excessive menstruation), dec iron intake (diet, iron malabsorp), inc requirements (pregnancy, lactation), unknown Smear: microcytic hypochromic RBCs Iron studies: low serum iron, inc TIBC, dec % sat, dec serum ferritin
Iron deficiency anemia
weakness, fatigue, dyspnea loss of iron > absorption of iron PE findings: pallor, angular stomatitis, glossitis, koilonychia (spoon nails), pica sx of underlying disease process
Disease
Clinical Variants
Anemia of chronic disease (ACD)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
underlying problem for >6 weeks activated monocytes & macrophages --> decreased RBC survival & blunted response to EPO --> EPO deficiency inflammation induces hepcidin release from liver --> inhibition of ferroportin on macrophage surface --> iron is locked in RES (metabolically unavailable) so cannot re-enter circulation to make new RBCs
chronic infections (TB, abscess, syphilis), neoplasms, chronic inflammation (arthritis, RA, gout)
2nd most common cause of anemia, hospitalize d patients!
Iron studies: low serum iron, low transferrin, low % saturation, high ferritin BM bx: increased RES iron storage
Thalassemia (SEE ABOVE SEPARATE CATEGORY)
autosomally inherited deficiency in rate of synthesis of nl globin chains
Sideroblastic require smear for diagnosis anemia
defect in heme synthesis --> accumulation of iron in mitochondria
most endemic high RBC & low Hb or low common malaria areas MCH monogeneti c d/o worldwide inherited defects Smear: dimorphic picture (normal RBCs+ hypochromic secondary microcytic cells) defects - preBM bx: ringed sideroblasts leukemia, (rings around nucleus & iron in drugs (INH), mitochondria) alcohol, lead CBC: high RDW poisoning Iron studies: high iron, nl TIBC, high ferritin
Normocytic anemias
(general)
corrected retic % < 2% MCV 80-94
anemia resulting from inadequate stem cells that become RBCs or decreased demand for RBCs Pregnancy pregnancy = pseudoanemia; dilutional - hormones secreted cause plasma expansion, causing renal failure measured hemoglobin to be slightly low renal failure = lower limit of creatinine clearance indicates severe kidney disease, resulting in less EPO production, thus less RBC & Hb production; EPO deficiency, shortened RBC survival, nutritional deficiency w/ dialysis
Metabolic
Disease
Clinical Variants
Endocrine
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
androgen deficiency testosterone stimulates EPO release from kidney; when androgen deficient, no testosterone to stimulate EPO Hypothyroidism = reduced thyroid hormone causes reduced metabolic rate & decreased need for O2 (thus Hb) adrenal failure = corticosteroid deficiency causes anemia
androgen deficiency hypothyroidism adrenal failure
Marrow replacement
damage to bone marrow --> fibrosis
infections, tumors, scar tissue aplastic anemia leukemia
Marrow failure
stem cells can't differentiate so they accumulate in primitive forms
CBC: normocytic anemia + alterations of other cell lines Blood smear: early WBC, RBC precursors; tear dropped RBCs = infiltration BM bx: fibrosis = myelofibrosis; fat cells / hypocellular = SAA; hypercellular homogenous blasts = leukemia
Anemia of chronic disease (ACD)
initially presents as normocytic anemia (as disease progresses, it becomes microcytic anemia)
Macrocytic anemias
(general)
corrected retic % < 2% MCV >94
anemia resulting from problematic RBC division, most likely due to abnormal DNA synthesis retics are not recognized by CBC as different RBCs so can cause increased MCV; must correct retic count with anemia!!! large RBCs from increased red cell liver disease, membrane (target cells) obstructive jaundice, post splenectomy mild increase in MCV due to increased lipid in membrane (usually normocytic though!!) bull's eye appearance on smear; Howell-Jolly bodies (inclusions in RBCs) suggest splenectomy
high reticulocyte count
Target cells
Severe hypothyroidism
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Megaloblastic corrected retic % < 2% anemias MCV >94
Acquired hemolytic anemias
(general)
Splenomegaly
problem with DNA synthesis folate def: THF (derived from folic acid) converts dUMP to dTMP; B12 def: jaundice, angular w.o folic acid, insuff substrate stomatitis (cracking at corners (thymidine) to support DNA of mouth), glossitis (beefy red synthesis tongue), neurologic irreversible probs B12 def: B12 converts (peripheral neuropathy, probs homocysteine to methionine via w/ posterior columns methyl group from THF; w.o B12, vibration, proprioception, conversion is blocked &THF is lateral corticospinal tract trapped as N-methyl THF, a probs - spasticity, dementia) metabolically useless substrate; methionine is used to make folic acid def: SAME myelin (no B12 = demyelination & hematologic & symptoms as neuropathy) B12D EXCEPT no neurological involvement!!! Folic acid def etiologies - inadeq dietary intake (chronic alcohol, elderly), inc requirements (pregnancy), imp absorption (liver dz, small bowel dz), def interconversion (drugs like MTX) represents destruction corrected retic >2% or (hemolysis) or loss of RBCs in 75,000 circulation (bleeding - GI or GU extravascular hemolytic tract) anemia - destruction of RBCs in RES--> increased increased retic count means indirect bilirubin, increased marrow is mounting a normal urobilinogenin in urine, high response to the anemia iron % sat; increased delivery of iron from RBC breakdown Immune mediated hemolysis products antibody and/or complement fixation to RBCs results in intravascular hemolytic phagocytosis by macrophages in anemia - RBCs burst apart splenic fenestrations, bone in the vessels --> hi plasma marrow, or liver Hb, hi urine Hb, high LDH, and iron-stained renal tubule cells spleen normally filters blood; if acquired extrinsic RBC RBCs are abnormal, the spleen will defect resulting in nonimmune mediated hemolysis collect the RBCs and destroy them in states of splenomegaly (infxn, malignancy), the spleen will filter the blood too effectively, removing normal RBCs from circulation = shortened RBC survival = increased retic count
vitB12 deficiency, folate deficiency, chemotherapy, myelodysplastic syndromes, hereditary defects in DNA synthesis B12D = vegans, absorption probs (low pancreatic enzymes, pernicious anemia, small bowel dz Celiacs, Crohns), liver dz, fish tapeworm
FH of autoimmune dz (B12d)
CBC: large RDW B12 injections / oral supplementation Smear: macro-ovalocytes, hypersegmented neutrophils, immature chromatin (more euchromatin than dark heterochromatin), large platelets Other tests: inc LDH, inc indirect bilirubin, inc TIBC B12D: low serum B12, nl serum folate, inc homocysteine, inc methylmalonate; autoantibodies to parietal cells/ IF/ thyroid if autoimmune Folate def: low serum folate, nl serum B12, inc homocysteine, NL methylmalonate
increased retic count isolated elevation of non-conj/ indirect bilirubin increased LDH decreased haptoglobins hemosiderinuria - intravascular hemoglobinemia, hemoglobinuria (rare) decreased measured RBC survival
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Fragmentatio acquired extrinsic RBC RBCs encounter an abnormal n hemolytic surface in circulation (heart valve, defect resulting in nonanemia immune mediated hemolysis fibrin deposits) --> shearing apart of the RBCs also a/w thrombocytopenia
valvular/ vascular prosthesis, severe AS, DIC, vasculitis, RA, SLE, TTP, HUS, hemangiomas, eclampsia, malignant hypertension, pulm HTN
systemic illness
Smear: schistocytes
Other acquired extrinsic RBC abnormalities defect resulting in noncausing immune mediated hemolysis acquired, nonimmune mediated
Physical & chemical agents (burns, bacterial infections) - breakdown of RBCs or membrane lipids Lipid abnormalities & hypophosphatemia - abnormal lipid deposition (liver dz) or dehydration from abnl fxn of Na/K ATPase (hypophosphatemia) Infectious agents - malaria, babesiosis
Smear: marble appearing RBCs (physical or chemical agents), acanthocytes (abnl lipid deposition w/ severe liver dz, low phosphate), infectious agents (malaria)
Alloimmune hemolytic anemia
acquired extrinsic RBC defect resulting in immune mediated hemolysis
transfusion acute transfusion reaction major blood group incompatibility -- reactions > preformed antibodies to RBCs; when transfused w/ these RBCs, the Hb goes up but then immediately falls (hemolysis) delayed transfusion reaction Hb increases but then begins to fall 7-10d later (hemolysis); pt made new antibodies that attacked the transfused RBCs
acute transfusion rxn activation of coagulation system, renal failure, & death
Autoimmune hemolytic anemia
Antibodies developed to self RBCs Warm antibody? Warm antibody - IgG or Idiopathic, IgG+Complement; hemolysis lymphoprolif d/o, autoimmune dz, warm or cold antibody AIHA occurs mainly in spleen infections Cold antibody - IgM antibodies so complement activation only; Cold antibody? hemolysis occurs in liver/ bone Infections, lymphoprolif d/o, marrow/ other RES sites idiopathic, paroxysmal cold hemoglobinurea (actually IgG mediated cold antibody AIHA) acquired extrinsic RBC defect resulting in immune mediated hemolysis
Smear: microspherocytes + increased reticulocytes, cold antibody AIHA has prominent agglutination or clumping of RBCs Coomb's test: Warm antibody (IgG or IgG+complement), Cold antibody (Complement only)
Warm antibody responsive to steroids & splenectomy Cold antibody unresponsive to steroids & splenectomy
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Drug induced acquired extrinsic RBC hemolytic defect resulting in immune anemia mediated hemolysis
Hapten-Penicillin type - Antibody Hapten against a drug that is bound to penicllin type? RBC --> IgG positive Coomb's Penicillins, cephalosporins, ceftriaxone Innocent Bystander type (most common!) - antibody against the Innocent drug forms an immune complex that adheres to RBC surface --> bystander complement positive Coomb's type? Sulfonamides, Autoimmune-Aldomet type (very quinidine, phenothiazines rare now since don't really use these meds) autoantibody to Rh Autoimmine components of RBC --> IgG Aldomet type positive Coomb's L-DOPA, aldomet for HTN
Inherited hemolytic anemias
(general)
corrected retic >2% or 75,000 neonatal jaundice, recurrent "hepatitis", personal or FH of premature gallstones/ anemias/ splenectomy/ or specific dz; chronic or recurrent symptoms that have not been adequately addressed
intrinsic defect in RBC leads to hemolysis gallstones? Increased Hb breakdown = inc indirect bili = inc bile salts = inc pigmented gallstones --> cholecystectomy problem w/ membrane? Hereditary spherocytosis, elliptocytosis, pyropoikilocytosis problem w/ hemoglobin? sickle cell anemia problem w/ enzymes? G6PD deficiency
Hereditary spherocytosis
hemolytic anemia (mild to severe) aplastic crisis w/ infection (ParvoB19), which stops RBC production for 7-10d (usually childhood presentation)
disorder in RBC membrane autosomal shaped causing "marble shaped" dominant, RBCs sometimes AR osmotic fragility - hemolysis at higher concentrations (membrane is already very leaky) abnl cytoskeleton proteins deficiencies in proteins that bind to spectrin (which is the foundation of the protein matrix)
Smear: microspherocytes, splenectomy helps with elevated retic count (looks just symptoms but morphological changes persist like AIHA so need Coomb's test to R/O)
Hereditary elliptocytosis
hemolytic anemia (mild to moderate) high phenotypic variability within families severe hemolytic anemia abnormal RBC shape with heat
abnl spectrin interactions with other matrix proteins
autosomal dominant
Smear: elliptical RBCs (if >20% = diagnosis)
Hereditary pyropoikilocytosis
major deletions in portions of spectrin molecule = abnormal fragments of RBCs
autosomal recessive
Smear: fragments of RBCs, worse w/ heat
Disease
Clinical Variants
Sickle cell disease
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
hemolytic anemia increased severity of infections (s. pneumo, meningitis) tissue infarction w/ organ failure (leg ulcers, stroke, nephropathy) severe pain episodes (bone degeneration from sickling --> arthritic pain & loss of function; sudden onset pain in extremities & back) Sickle cell carriers asymptomatic except when exposed to severe hypoxia or dehydration Hb SC dz - milder sickle anemia, mild probs in childhood so might present later in life
mutation in 6th position of beta globin chain where valine is substituted for glutamic acid = Sickle cells polymerize during states of deoxygenation, increased MCHC, acidosis, or increased temperature; polymerization makes RBCs rigid & unable to circulate well -> mechanical destruction in circulation, plugging of small vessels --> ischemia & pain severe infxns - fever inc sickling, inc S.pneumo (which can cause sepsis in these pts!), inc meningtiis Stroke - occlusion of large vessels sickle nephropathy - sickled RBCs disrupt vasa recta & glomeruli Leg ulcers, sickle pain Mature RBCs depend on anaerobic glycosis for ATP generation, reducing capacity (requires NADPH & NADH) a.a. substitutions, deletions, or insertions resulting in G6PD instability, In G6PD def, there is inadeq defective NADPH so Hb and proteins become oxidized and precipitate enzyme fxn, or in RBC --> inclusions of Hb that combos bind RBC membrane (Heinz bodies) occurs if immunocompromised patients receive blood that is not irradiated!!
8-10% of African Americans pain is the most severe complicatio n (disability, healthcare $)
Hb electrophoresis: HbS only (Sickle cell disease), HbS + HbA (sickle cell trait), HbS + HbC (Hb SC disease)
hydroxyurea - increases production of HbF to interfere w/ sickle cell polymerization & reduce frequency of sickle events pain mgmt - nonopiods (absolute dose ceiling), opiods (no abs dose ceiling)
stroke, sepsis, sickle nephropathy #1 cause of death? Acute Chest Syndrome
G6PD deficiency
can present w/ drug-induced hemolytic anemia (antimalarials, sulfonamides), Mediterranean favism, congenital nonspherocytic hemolytic anemia, neonatal jaundice, hemolysis w/ infxns or DKA
7-8% of African Americans, 10-15% of Mediterrane an heritage
Smear: bitocytes, staining of Heinz body inclusions
Transfusion associated GvHD
nearly uniformly fatal involves marrow, liver, skin, gut skin sloughing often due to ABO incompatability, most likely due to clerical error (misidentification of patient) Sx: fevers, chills, back pain, hypotension, n/v Delayed hemolytic transfusion rxn 3-10d after transfusion of blood that appeared compatible often asymptomatic w/ fever, mild jaundice, anemia
severely immunocompromise d; neonates
Transfusion reactions
Acute hemolytic transfusion rxn
intravascular hemolysis, complement mediated, IgM
STOP transfusion!! Flush w/ IVF Check CBC to monitor platelets & Hb, check renal fxn labs and coagulation studies
DIC, renal failure
antibody not detected preantibodies to transfusion (Anamnestic antibody Rh, Kidd, Duffy response) --> intravascular and/or minor antigens extravascular hemolysis
ARF, DIC
Disease
Clinical Variants
Febrile reaction
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
One degree Celsius rise in temperature to the febrile range cannot be distinguished from fever in acute hemolytic rxn so transfusion must be stopped!!
occurs from cytokine release from WBCs in the unit being transfused, antibodies to donor WBCs, or bacterial contamination
STOP transfusion!!
Septic reaction
Urticarial reactions
rash and/or itching ONLY reaction where blood can be restarted & work up is not mandatory
unit becomes contaminated w/ Platelets bacteria (much more likely to occur usually Staph in platelet units which are stored at room temp) RBCs - usually Yersinia enterocolitica, Citrobacter recipient is previously sensitized to soluble allergens in donor unit
3% of transfusions (second most common reaction) consider IgA deficiency!
Benadryl, then start transfusion again
Anaphylactic reactions
hypotension, chills, fever, dyspnea, n/v, diarrhea, urticaria
antihistamine, epinephrine, steroids, supportive care
Transfusion respiratory insuff, fevers, antibody mediated situation often FFP related acute chills, hypotension due to HLA antibodies present in transfusions lung injury the transfused product (TRALI) mimics ARDS but resolves w/I 48h Tranfusion fluid overload --> breathing associated problems circulatory overload (TACO) Iron overload liver/ cardiac/ endocrine problems occurs in patients w/ pre-existing cardiopulmonary compromise, perhaps a/w hypertension
#1 leading cause of death from transfusion
CXR: bilateral chest infiltrates does not improve w/ diuretics
improves w/ diuretics (UNLIKE TRALI!)
each unit of RBCs contains 200mg of iron; patients who are chronically transfused (sickle cell) have higher risk of iron overload transmission of Aspergillus mold from environmental source CT of head to check for dissemination to brain CT: characterisitc halo description of nodular infiltrate
chelation therapy (Exjade)
Aspergillosis
most popular fungal infxn in HSCT pts Colonization - non-disease state; Aspergilloma = mold fills lung cavity & releases spores; a/w colonization in CF patients Invasive disease pulmonary, sinusitis, tracheobronchitis, cutaneous, disseminated
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Mucormycosis
mold w/ high mortality rate Rhinocerebral nasocongestion, pain behind eye, proptosis, AMS Pulmonary - dyspnea, fever, non-productive cough, pleuritic chest pain
spores are inhaled and deposit on mucosa, then germinate and invade tissue; angioinvasion --> tissue necrosis
low incidence (1.7/100K)
neutropenia, immunocomp (HSCT, organ transplant, cancer, autoimmune dz), poorly controlled DM
MRI shows opacification of sinuses, brain edema & invasion CXR shows dense infiltrates; CT does NOT have halo infiltrates like Aspergillus Cx: grows very quickly, branching hyphae
Candidiasis
most common fungal infection in hospitalized patients variety of presentations - UTI, pneumonia, mucocutaneous (thrush, esophagitis, diaper rash), tissue, bloodstream
bloodstream infxn risk factors? Neutropenia, indwelling devices, hemodialysis, DM, AIDS, abd surgery, critical illness, neonate, age>65, TPN, broad spectrum Abs
if affects lung via hematogenous do not treat asymptomatic spread, can see lung abscesses UTI (unless prior to GU surgery, immunocomp, or white plaques on soft palate, neonates) esophagus symptomatic UTI hepatosplenic candidiasis amphotericin B or microabscesses in liver & fluconazole spleen seen on MRI (heme-onc pts only) dx? Blood/ mucus/ bx culture,
Qualitative (general) platelet disorders
platelets present in adequate acquired causes - meds, MPS, numbers but do not function systemic illnesses, renal dysfxn, properly cardiopulmonary bypass Congenital causes - granule disorders, absent/ dysfunctional adhesion receptors
DDAVP - synthetic derivative of ADH/vasopressin so causes release of VWF from endothelium (increases stickiness of plasma) anti-fibrinolytic agents block plasmin and prevent lysis of fibrin within clots
COX1 inhibitors
aspirin, NSAIDs bruising, bleeding
Aspirin = irreversible COX1 inhibitor; platelets do not synthesize new COX1 (anucleated) so reversal of aspirin effect depends on platelet half life (3-5d); after new platelets are made, function returns NSAIDs = reversible COX1 inhibitors; reversal of NSAID effect depends on half life of the drug
Clopidogrel (Plavix) Uremia (renal dysfxn)
irreversible inhibitor of ADP receptor, blocks platelet activation accumulated metabolites impair fxn of circulating platelets dialysis corrects platelet dysfxn
Disease
Clinical Variants
Glanzmann thrombasthenia
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
normal platelet count w/ mucocutaneous bleeding
absence or dysfunction of integrin aIIbB3, preventing platelet aggregation
mutation within the binding site of aIIbB3 or talin deficiency (talin nl exposes binding site)
PFA - no aggregation but will agglutinate w/ ristocetin
BernardSoulier syndrome Absence of platelet granules
thrombocytopenia w/ giant platelets
absence or dysfunction of platelet adhesive receptor (GP1b), preventing platelet adhesion dense granule def - patients will also have varying degrees of albinism alpha granule def - gray platelet syndrome
PFA - aggregation but no agglutination w/ ristocetin
PFA - loss of 2nd wave (no aggregation because deficiency of granules or dysfunctional granule release)
von Willebrand disease (VWD)
Dysfunctional granule release (general) VWF activity less than 30% certain conditions can also change autosomal the amount of circulating vWF; ie dominant = increased bleeding risk sympathetic response has increased vWF in preparation for injury hi vWF - stress, exercise, pregnancy, age, acute & chronic inflamm, DM, OCP use, malignancy, hyperthyroidism low vWF - hypothyroidism, blood type O significant bleeding history, decreased synthesis & plasma FH of inc bleeding or VWD, secretion of VWF; can also occur as a result of inc clearance low levels of VWF activity low factor 8 activity leading to hemarthrosis high circulating VWF but defective function
low agglutination with ristocetin
plasma derived factor 8 products w/ high concentrations of VWF DDAVP
Type 1 (7580%)
Type 3 (13%) Type 2 normal VWF levels but (qualititative; decreased VWF activity 15-20%) from: 1. decreased multimers circulating 2. decreased binding to factor GP1b 3. abnl binding to factor 8 4. dysfxnal hi affinity interaction w/ GP1b
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Inherited hemophilia
Hemophilia A = factor 8 deficiency Hemophilia B = factor 9 deficiency Bleeding into joints/ muscles, prolonged bleeds from lacerations or dental procedures, excessive bruising / hematomas, bleeding w/ surgery or trauma, intracranial hemorrhage, kidney / GU tract bleeding
defect in platelet surface thrombin generation (factors 9 & 8 are required to provide platelet surface for activation by factor 10)
X-linked 20-30% = spontaneous mutations
A = 1/10K male births B = 1/30K male births
replace missing clotting factor - recombinant release of stored factor 8 w/ DDAVP
60% of patients are severe - spontaneous bleeds 15% are moderate trauma/ surgery bleeds, occasional joint bleeds 25% are mild - major trauma/ surgery bleeds, rare joint bleeds 25% of hemophilia A pts will develop spontaneous antibodies to factor 8 other complications? chronic hemarthrosis w/ pain/ joint destruction, HCV, HIV risk
Acquired hemophilia
severe bleeding in pt w/ no auto-antibodies bind native factor known bleeding problems 8 in persons without congenital hemophilia bruising, mucosal bleeding, muscle bleeding
a/w autoimmune 1.4/1million conditions, pregnancy, mortality 6malignancy 20% (highest in elderly)
prolonged PTT, elevated mixing study (suggests inhibitor to intrinsic pathway factor)
control bleeding eradicate inhibitor w/ steroids, IVIG, rituximab
Lupus anticoagulant
thrombosis
looks like DVT
antibodies that inhibit phospholipid dependent coagulation; neutralized by presence of excess phospholipids
symptoms + factor 8 >10% that "titers up" with dilution titered up PTT post mixing!!!
Vitamin K deficiency
muscle bleeding, deep bleeds
blocks conversion of vit K dependent factors (2, 7, 9, 10, protein C, protein S) to activated forms --> bleeding
infancy, malabsorption, hyperemesis gravidarum, fasting, alcoholism, drugs (warfarin, Abs, salicylates)
intercerebral, GI, prolonged PT, prolonged PTT, asymptomatic? Oral or IM vitK umbilical, or ENT post mixing study corrects bleeding PTT active bleed? Emergency! Requires FFP then correct vitK
Liver failure
liver makes all coagulation factors (except VWF), anticoagulants (protein C & S), and TPO (stimulates platelet production) liver failure = deficiency of majority of coagulation cascade, splenomegaly, thrombocytopenia, bleeding
Factor 12 deficiency
Hageman factor NOT a/w bleeding
autosomal recessive
abnl PTT
NO TREATMENT!!
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Fibrinogen abnormalities
increased fibrinogen? Acute prevents stable formation of crossphase reactant, inflammation, linked fibrin clot OR overproduction of fibrin clots pregnancy decreased fibrinogen? DIC, liver dz, ascites, alcohol
deficiency? Abnl PT & PTT, prolonged thrombin time, abnl fibrinogen assay
Hemolytic Uremic Syndrome (HUS)
#1 cause of acute renal failure formation of clots in the glomerulus in kids acquired (90%) - infection (prodrome of bloody diarrhea --> classic triad - intravascular release of large vWF multimers = hemolytic anemia increased thrombosis) genetic (atypical HUS) - mutations (schistocytes), in complement pathway (factor H thrombocytopenia, renal normally suppresses C3b failure convertase; however, without factor H, convertase able to activate complement all the time --> thrombosis)
Smear: schistocytes from fragmentation
acquired? Supportive tx only Atypical? Poor prognosis w/ renal failure; cannot be transplanted (intrinsic dz)
clots generated in small vessels, turbulent flow shears RBCs, platelets consumed by thrombosis & shearing --> excessive thrombin generation & loss of compartmentalization (diffuse endothelial injury, loss of endothelium = loss of inhibition) Thrombotic Thrombocytopenic Purpura (TTP) pentad: hemolytic anemia (schistocytes), thrombocytopenia, renal insufficiency, neurologic changes, fever absent ADAMTS13 = large multimers of VWF formed that activate platelets = widespread thrombosis (primary hemostasis) Acquired - Ab formed to ADAMTS13 congenital - def ADAMTS13 sepsis, malignancy, trauma/ head injury/ burns, obstetric causes (eclampsia, retained fetus, abruptio placenta) others? AA, toxins, transfusion, immunologic elevated clotting times & decreased platelet count ELEVATED D-DIMER FFP transfusions but watch for volume cryoprecipitate to keep fibrinogen elevated platelet transfusions (keep platelets > 50K) ??heparin plasma exchange & vWF inhibitors
Disseminated Intravascular Coagulation (DIC)
bleeding + subclinical or clinical thrombosis sepsis patients!
uncontrolled activation of primary & secondary hemostasis, activation of fibrinolysis, consumption of factors & inhibitors, and evidence of end organ damage Cytokines, TF, LPS, hemolysis, acidosis, turbulence all contribute to factor activation, endothelial damage, & platelet activation
Disease
Clinical Variants
(general)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Venous Thrombosis
abnl formation of blood clot inside venous system (fibrin mediated) embolism - detached intravascular solid mass that is carried by blood to site distant from its origin Virchow's triad - endothelial injury (atherosclerosis, TTP, HIT, trauma) + abnormal blood flow (stasis from immobilization, stenosis) + hypercoagulability (thrombophilias)
age, comorbid Wells score conditions (OCP use, lower extremity U/S, CT of chest HRT, to R/O PE hospitalizati on, cancer, surgery) immobilizati on, burns, HIT, DIC, pregnancy persistent risk factors? Inherited thrombophilia, acquired thrombophilia s, obesity, CHF, nephrotic syndrome,
heparin (LMWH or UFH) UFH cleared by macrophages so no effect on kidney or liver + short half life; LMWH is fast acting and more predictable but renally cleared bridge with warfarin (at least 5 days overlap) before d/c heparin
anticoagulation continued if high risk of recurrence (i.e. no reason for VTE at time of diagnosis unprovoked VTE, type of underlying syndrome, gender - men, elevated D-dimer 1m after d/c warfarin) post-thrombotic syndrome (see below)
Superficial vein thrombosis (SVT)
generally benign & self limiting becomes more serious if extends into deep vein tender, palpable cord w/ surrounding erythema & heat
thrombosis in superficial vein
low dose heparin for at least 4 weeks
Deep vein thrombosis (DVT)
occlusion of deep veins in leg --> lack of venous return of blood --> congestion & pain
major risk of embolization to lungs (PE) and post thrombotic syndrome (PTS) 20-50% of pts w/ symptomatic proximal vein DVT common femoral or iliac vein DVT hi BMI prior ipsilateral venous thrombosis female older age regular use of compression stockings! (must be replaced every 6 months, worn daily for 2y after DVT)
Postthrombotic syndrome (PTS)
develops within 1-2 y of acute DVT; a/w poor QoL possible ulcer formation, lower extremity swelling, pain, itching, heaviness, edema, venous ectasia, hyperpigmentation, pain w calf compression worse sx w/ activity; better w/ rest
damage to venous valves (mechanical damage from clot & inflammation provoked by acute thrombosis)
Anti-thrombin deficiency
variable presentation but overall risk of thrombosis increased 15-20x
AT normally inactivates thrombin & factor X to shut down coagulation cascade; deficiency leads to increased thrombosis
1% of pts with VTE 1/250-1/500 prevalence
anti-thrombin activity assay low activity & low numbers of AT (type 1) or normal numbers but low activity (type 2) exclude acquired causes - liver disease, nephrotic syndrome
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Protein C deficiency
variable presentation but overall risk of thrombosis increased 15-20x
Protein C (along with Protein S) normally inhibit factors 5&8 of coagulation cascade
2-9% of patients w/ VTE
make sure patient has d/c warfarin for 2 weeks prior to testing Protein C prolonged PTT in protein C deficient plasma Prolonged PTT w/ protein S deficient plasma make sure patient has d/c warfarin and not on hormonal therapy or pregnancy APC sensitivity ratio = PTT in presence of protein C/ PTT in absence of protein C PCR based assay for specific mutation lupus anti-coagulant test (requires 2 tests since insensitive): prolonged clotting time that does not correct w/ mixing + clotting time that shortens w/ addition of phospholipid
Protein S deficiency
cofactor to activated protein C, enhances anticoagulant effect of protein C deficiency a/w increased thronbosis risk
3% of pts w/ VTE
Factor V Leiden
Heterozygotes - VTE risk increased by 5-7x Homozygotes - VTE risk increasd by 50x
mutation in factor 5 gene --> resistance to factor 5 inactivation by protein C
Acquired thrombophilia
Antiphospholipid syndrome (APS)
synergism w/ OCPs enhanced platelet activation & thrombosis (1+ episodes confirmed by imaging/ path) subsequent aggregation OR pregnancy morbidity (recurrent pregnancy loss) enhanced TF expression thru monocyte activation PLUS inhibition of protein C/S anticoagulant pathway high anti-B2 glycoprotein/high aCL activation of complement antibodies/ high Lupus anticoagulant
remission = residual leukemia burder below level of detection cure = remission beyond 5 years
better prognosis than AML COG - children's oncology group guarantees clinical research trial for every kid w/ leukemia
newborn screening = early diagnosis & prompt tx of infxns & comps informed reproductive decisions for sickle traits PCN prophylaxis birth to age 5
can be prevented if blood is irradiated for at risk patients!!
avoid transfusion of plasma containing products; wash products prior to future transfusion, premedicate; transfuse from IgA def donors if pt is IgA def declining incidence due to use of male only FFP
give VitK to all newborns as prophylaxis against hemorrhagic disease of newborn
Compression stockings IVC filters if contraind for anticoagulation
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Subdural hematoma
tearing of the bridging veins (low coup contra coup injuries pressure venous bleed that from MVA, falls, blood is often crescent increases w/ time) shaken baby shape over brain surface -syndrome > increased intracranial subdural space = deep to dura pressure (nowhere for extra mater btwn dura & arachnoid layers of meninges volume to escape) usually in shaken brains blood accumulates rapidly, forming a bulge between regions of dural attachment to bone --> increased intracranial pressure tearing of the middle meningeal artery (high pressure rapid bleed that separates dura from skull) epidural space = potential space btwn dura & skull; fills w/ blood or fluid w/ trauma blow to skull (baseball)
CT: best for acute bleeds MRI: best for subacute bleeds; shows blood spread out across the surface of the brain
Epidural hematoma
PE: lucid interval (delayed neurological signs) CT: best for acute bleeds MRI: best for subacute bleeds
Subarachnoid hemorrhage, intracranial hemorrhage Coup contra coup injury
sudden onset, "worse headache of life"
CT: blood in ventricles or other brain areas
ABCs, Neurosurgical consult
3 points of impact: 1) Car to brain hits skull then bounces back tree, 2) Skull to windshield, 3) to other side of skull (primary Brain to skull insult)--> brain bruising on both sides --> swelling & subdural hematoma (secondary insult) --> Increased ICP Falx cerebri Foramen magnum brain herniates from left to right side brain undergoes tonsillar/ cerebellar herniation
Brain herniation
Tentorium cerebelli (uncal herniation)
Hydrocephalus
Left (dominant) hemisphere lesion
inc ICP in foramen magnum (near cerebellum & medulla) --> herniation of cerebellum --> pressure against medulla --> compromise of basic homeostasis mechanisms --> respiratory arrest tentorium cerebelli separates primary or Uncus (bump protruding from medial temporal lobe) occipital lobe from cerebellum; inc metastatic tumors ICP in cerebral cortex --> uncal herniates through the herniation thru tentorium tentorium cerebelli cerebelli --> inc pressure impaired pupillary light midbrain & CN3 --> impaired pupillary light reflex reflex (ipsilateral dilated pupil), Cheynes-Stokes respirations, left decerebrate posturing, dec consciousness causes? 1) overproduction of CSF gradually inc ICP by choroid plexi, 2) not enough increased pressure & volume reabsorption of CSF by arachnoid granulations, 3) blockage of CSF of CSF --> increased flow ventricular volume, inflammation of underlying tissue, & decreased brain tissue right visual field deficit (hemianopsia), right hemiparesis (weakness), right hemisensory loss (numbness), left gaze deviation/ preference, aphasia
CT: no CSF space, severe vasogenic edema, ring enhancing masses, uncal herniation
normalize inc ICP by elevating head, intubating & hyperventilate, giving mannitol & dexamethasone (reduces edema; do NOT use if herniation due to ischemic stroke!) decompressive surgery
surgical placement of shunt to divert CSF from brain
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Right (nondominant) hemisphere lesion Medial midbrain syndrome
left visual field deficit, left hemiparesis, left hemisensory loss, left hemineglect, right gaze deviation/ preference ptosis, diplopia, anisocoria (uneven pupils), contralateral hemiparesis, contralateral UMN facial weakness CN3 palsy, damage to corticospinal tract (CL hemiparesis), and damage to corticobulbar tract (CL facial weakness) ipsilateral facial sensory loss, lateral medulla lesion causes contralateral body sensory problems with spinal trigeminal loss, ipsilateral ataxia, nucleus (IL facial sensation loss), dysarthria, dysphagia, +/spinothalamic tract (CL light hoarseness, hiccups, Horner touch & temp loss of body), syndrome inferior cerebellar peduncle (IL ataxia), nucleus ambiguus (dysarthria, dysphagia), and descending autonomic tracts (sympathetic - Horner syndrome)
Lateral medullary syndrome
infarct to the vertebral artery or posterior inferior cerebellar artery
Horner's syndrome
ptosis, anhidrosis & flushing of affected side of face, miosis (pupil constriction)
oculosympathetic pathway projects from hypothalamus to lateral tegmentum (MB, pons, medulla) to the intermediolateral cell column of the spinal cord; interruption in this pathway causes Horner's syndrome lesion affecting the corticospinal tract (CL weakness), dorsal column-medial lemniscus (CL loss of fine touch, vibration), and hypoglossal nucleus (IL tongue weakness) LMN lesion of facial nerve or nucleus --> peripheral ipsilateral facial paralysis with inability to close eye on involved side
lesion above T1 (Pancoast tumor, BrownSequard syndrome, late stage syringomyelia) infarct of vertebral artery or anterior spinal artery (posterior circulation) reactivation of viral inflammation of facial nerve by stress, emotional triggers?? Complication of AIDS, lyme dz, HSV, sarcoidosis, tumors, DM most common mononeuropathy
Medial medullary syndrome
contralateral weakness, contralateral loss of fine touch, ipsilateral tongue weakness
Bell's palsy
recent onset of unilateral facial weakness (weak forehead, unable to close eyes, weak lower face, unable to wrinkle forehead on same side as lesion, ipsilateral flattened nasolabial fold), impaired taste (dysguesia), hyperacusis on right
Cerebellar pontine angle tumor
unilateral hearing loss, peripheral facial weakness, possible development of horizontal diplopia
tumor impinges on pontomedullary junction, where CN 6,7,8 all exit
Disease
Clinical Variants
Locked in syndrome
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Basilar pontine infarction
bilateral facial weakness, inability to abduct both eyes, bilateral quadraplegia, extensor plantar responses
loss of CN6, 7, + bilateral corticospinal involvement, as well as UMN deficits
basilar artery supplies vasculature to majority of pons; infarction pt is awake & alert but quadriplegic and unable to knocks out both corticospinal speak, swallow, or breathe tracts, spinothalamic tracts, & posterior column tracts BUT preserves ascending RAS (so pt remains conscious) intact cerebral cortex that is unable to interact w/ external world Epilepsy (general) syndromes depend on age of onset, FH, MRI findings, predisposing factors, EEG dj vu, disconnection / out of findings, chronicity, clusters/cycles, severity body experience, olfactory/ gustatory hallucinations, behavioral arrest, unresponsiveness, amnesia, repetitive movements, wandering, confusion 2+ unprovoked seizures, generalized or focal 1-2% of population PMH of complex febrile seizures as a kid, head trauma, alcoholism, recreational drug use, encephalitis, develop delay, stroke, focal brain lesions FH of epilepsy Idiopathic (primary) relatively self-limited, medication responsive generalized > focal Childhood Absence Epilepsy absence seizures ("spacing idiopathic generalized epilepsy syndrome; genetic out") onset age: 3-8 y.o. frequent daily seizures normal development myoclonic (muscle twitching), GTC seizures onset age: 13-20 y.o. rare GTC, myoclonic seizures in AM normal development EEG: 3Hz spike wave good prognosis, resolves by teenage years no underlying pathology; normal development considered genetic usually med responsive but co-morbidities: some can be refractory and depression, anxiety, require lobectomy unemployment, loss of driving privileges, social stigma, relationships post-op complications: visual deficits, memory loss (Verbal > visuospatial)
Juvenile Myoclonic Epilepsy
idiopathic generalized epilepsy syndrome; genetic
seizures can be triggered by EtOH or lack of sleep
most FH common idioathic generalized epilepsy
EEG: 4-5Hz spike wave
lifelong valproic acid or lamotrigine exacerbated by AEDs like carbamazepine & phenytoin
requires lifelong treatment, medication responsive
Benign Epilepsy with Centrotemporal spikes (BECTS)
simple partial seizures or secondary GTC seizures onset age: 4-10 y.o. infrequent nocturnal seizures normal development
idiopathic localization related epilepsy syndrome
EEG: centro-temporal spikes
good prognosis remission by teenage years
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Symptomatic frequent seizures, difficult to structural or metabolic neurologic abnormalities control focal > generalized any type of seizures can occur (GTC, atonic, tonic) onset age: 1-6 y.o. very frequent seizures a/w mental retardation & abnormal MRI Temporal Lobe Epilepsy simple partial or complex partial seizures age of onset: ANY +/- cognitive dysfunction seizures occur most often during sleep! (most common in stage2 sleep so early in night) Seizure clusters (up to 20/night), occassional daytime events in 1/3 pts, +/recall, stereotyped behaviors, a/w frontal lobe lesions Can mimic non-REM sleep disorders (confusional arousals, night terrors, sleep walking) symptomatic localization related epilepsy syndrome; structural (abnl MRI) or unknown (nl MRI) EEG: temporal spikes MRI: mesial temporal sclerosis (scarred hippocampus) often refractory to meds, but poor prognosis for surgery can be curative (80- remission; often 85%) refractory to meds
LennoxGastaut Syndrome
symptomatic (structural or metabolic) generalized epilepsy syndrome
EEG: 1-2Hz slow spike wave
poor prognosis, very difficult to control
Nocturnal Frontal Lobe Epilepsy (NFLE)
mean age of onset 14y (mostly kids) 70% men
Carbamazepine or other AED Safe environment
Focal seizures
(general)
symptoms vary depending on location of seizure activity (i.e. temporal - hallucinations, dj vu; occipital - visual disturbances; motor cortex disruptive motor coordination) aura of any kind indicates focal onset of seizure
more common in adults (acquire risk factors; complex partial seizures)
MRI of brain with and without gadolinium EEG, asleep & awake
Simple partial no loss of consciousness (auras) variable S&S (motor, sensory, autonomic, psychic); if temporal lobe source - dj vu, olfactory/ gustatory hallucinations, epigastric rising sensation
small focal seizure (abnl electrical discharges)
Disease
Clinical Variants
Complex partial
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
loss of consciousness; lasts 1-2m automatisms (involuntary non-purposeful behaviors: lip smacking, repetitive arm movements, eye blinking), S&S can vary depending on area of seizure activity (aphasa if left temporal lobe, often occur at night if frontal lobe) amnesia post-ictal confusion or weakness convulsive seizure
focal seizure
focal brain lesion (tumor, AVM, abscess, old stroke, posttrauma, mesial temporal sclerosis, HIV dementia, Alzheimer's)
require brain MRI to look for causative agent EEG: focal spikes over epileptogenic focus
AEDs or if refractory to multiple meds, surgical resection
Secondarily generalized tonic-clonic Generalized seizures (general)
evolves from focal seizure to bilateral, convulsive seizure
Todd's paralysis (transient, post-ictal hemiparesis CL to seizure focus) more common in kids most common type of seizure
abnl electrical activity starts deep in the brain then simultaneously spreads to all areas of cortex loss of consciousness; lasts 1-2m; tonic (fall with muscular rigidity) followed by clonic (rhythmic jerking; fast jerks then slower jerks); cyanosis & ictal cry (respirations inhibited) lateral tongue bite common; bladder/bowel incontinence; postictal confusion
Tonic-clonic
Absence
brief loss of awareness; lasts 5-20s staring spells; subtle movements/ automaticisms (eye blinks, head nod), no aura no postictal period ALWAYS start in childhood & resolve before adulthood
2nd most common seizure
kids
EEG: 3Hz generalized spike & waves
AEDs: ethosuximide & valproic acid
often misdiagnosed as ADHD
Myoclonic
brief shocklke muscle contractions in head, shoulders, & upper extremities consciousness preserved, precipitated by waking
may progress to generalized tonic-clonic seizure
Clonic Tonic
Disease
Clinical Variants
Atonic
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
loss of consciousness, sudden onset & lasts few seconds (but very frequent in number!!)
kids
a/w developmental delay very difficult to treat (poor prognosis)
often a/w falls; can be subtle (head drop); "drop attacks" so injuries common Psychogenic seizures no tonic phase, clonic jerkings do not slow down like characteristic GTC seizure; very irregular movements last up to 45 minutes (normally seizures last 1-2m at most) Stroke (general) apopletic (sudden onset) 5SUDDENS (weakness/ numbness on one side, difficulty speaking or understanding speech, difficulty walking/ dizziness/ loss of balance, loss of vision in one or both eyes, severe headache) Act F.A.S.T. (face, arm, speech, time) 4th leading cause of death leading cause of long-term disability blacks are at higher mortality risk than other races; stroke at earlier age in blacks age, M>F, race (A.A.), geographic region (Stroke belt) CHF (poor heart fxn), cardiomyopathy (stasis of blood), HTN, afib, CAD, smoking, DM, EtOH, BMI Stat labs: CBC (severe anemia, thrombocytosis), chem panel (hypoglycemia?), PT & PTT (blood clotting d/o?), cardiac biomarkers (acute stroke pts at risk for MI), EKG (r/o cardioembolic source & afib), noncontrast CT scan of brain (nl CT proves ischemic stroke - cannot see acute ischemic change) IV t-PA if sx onset w/I 3h window (DO NOT give tPA if subacute ischemia or hemorrhage!!) do NOT treat high BP in acute ischemic stroke (unless above tPA criteria of 185/110) post-tPA mgmt? ICU, BP < 180/105, neuro checks for ICH, avoid meds that inc bleeding, aspirin after 24h no improvement w/ IV tPA? clot retrieval devices, intra-arterial tPA to site of clot, aspirin etiologic eval (DWI MRI, carotid duplex, TTE, young pts need sickle cell & hypercoag workups) clinical pic cannot reliably differentiate types of strokes! Prevention: HTN (ARBs, ACE-i), hyperlipidemia (statin), DM (HbA1c<7%), smoking (nicotine patch, bupropion), limit alcohol, diet hi in fruits/ veggies, aerobic ex (>20m, 3x/wk), avoid sympathomimetic agents (Claritin D) & estrogen conversion disorders EEG: normal brain activity throughout
Ischemic
lack of blood flow due to clots occluding artery (deprives brain of O2 & glucose needed for energy production) Large vessel causes: atherosclerosis, inflammation, arteritis Small vessel/ lacunar: lipohyalinosis, vasculitis, embolic Cardioembolic source: CHF, afib, cardiac myxomas Other causes: coagulopathies (Protein C, S def, AT3 def, sickle cell, myeloprolif d/o, DIC, TTP, elev homocysteine), aortic dissection
TOAST criteria 85% of strokes (atherosclerotic, small vessel/ lacune, cardio-embolic, other, cryptogenic) THROMBOEMBOLISM = MOST COMMON CAUSE! Cardioembol, atheroscl, hypercoag, arterial diss/ vasculitis, small vessel dz, hypotension
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Hemorrhagic In addition to SUDDENS, can bleeding into the brain tissues also have vomiting & (intracerebral hemorrhage) --> headache more than mass effect ischemic
aneurysms, arteriovenous malformations, uncont HTN, tumors, hemorrhagic conversion of infarct, amyloid angiopathy
10% of strokes
more fatalities than ischemic strokes
Subarachnoid hemorrhage
Headache more prominent in bleeding around the brain, into the aneurysms, 5% of SAH than ischemic subarachnoid space but not within AVM, idiopathic, strokes the brain tissue --> raised ICP, trauma hydrocephalus, vasospasms aphasia (loss of fluency, naming, comprehension, reading/ writing, repetition), left gaze deviation (loss of L FEF), R homonymous hemianopsia (loss of L optic radiations), R face & arm weakness > leg weakness CT scan -
Stroke syndromes
Left MCA stroke
Right MCA stroke
contralateral neglect (left hemineglect- denial of weakness, limb; visual/ auditory/ sensory neglect), right gaze deviation, left homonymous hemianopsia (loss of R optic radiations), left face & arm weakness > leg weakness aphasia? Apathetic, right leg weakness >> right arm weakness apathetic, left leg weakness >> left arm weakness posterior circulation stroke (vertebral artery, PICA) produces lesions in brainstem PICA supplies the inferior portion of the cerebellum & lateral portion of medulla MRI: hyperintensity in inferior cerebellar territory
Left ACA stroke Right ACA stroke
Vertebral crossed signs (ipsilateral artery / PICA face numbness + stroke contralateral arm & leg numbness), vertigo, dizziness, n/v, Horner's syndrome (ptosis, misosis, anhidrosis), ipsilateral ataxia
Basilar artery stroke (locked in syndrome) see above for basilar pontine infarction
Quadriplegia or hemiplegia, nystagmus, crossed signs, vertigo, diplopia, n/v, ipsilateral ataxia
basilar artery infarct produces lesions in the perforators that feed the brainstem; the amount of perforators affected correlates w/ symptoms
MRI: hyperintensity in brainstem
Disease
Clinical Variants
Lacunar syndromes
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
pure motor hemiparesis (if affects internal capsule), pure sensory stroke (if affects thalamus), or sensorimotor stroke (if between internal capsule & thalamus) ataxic hemiparesis, clumsy hand dysarthria (weak hand + slurred speech)
small (<1.5 cm diameter), deep infarcts in territory of the deep penetrating arteries pure motor hemiparesis affects internal capsule & corticospinal tracts
long standing HTN --> lipohyalinosis --> ischemia
CT: small round hypodensity (darker) in deep white matter or subcortex from infarct of penetrating arteries
Tremor
(general)
involuntary rhythmic oscillating movements
alternating or synchronous contraction of reciprocally innervated antagonist muscles
Rest tremors occur during rest Postural tremors Kinetic (action, intention) tremors occurs while body part is maintaining posture against gravity occurs during goal-directed movements
Parkinsons, Essential tremor, drugs (lithium, valproic acid, neuroleptics, stroke), rubral (stroke, MS) Parkinsonism
most common movement disorder
essential tremor, physiologic (caffeine, stress, meds, drugs) MS, stroke
check meds!!
Rigidity
Mixed tremor combination of above tremors; rugral tremor (slow, occurs at rest, posture, & action) Task specific occur during specific tasks tremors like writing, playing musical instruments increase in resistance to passive movements stiffness but not major disability "lead-pipe" "cog-wheeling"
Parkinsonism
Akinesia/ bradykinesia
slowness / fatigue or arrest in ongoing movements interferes w/ all activities and very disabling
Parkinsonism
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Dystonia
involuntary sustained muscle contractions that produce twisting/ squeezing movements & abnl postures; may be stereotyped or repetitive; usually action induced & worsen w/ stress/ fatigue can be a/w tremor (jerky) blepharospasm (invol closing of eyes), use of "tricks", generalized dystonia usually begins in legs contractions stop during sleep
co-contraction of muscle agonists & antagonists
generalized genetic origin (DYT1), kids
kids generalize dystonias
Ashkenazi jews (DYT1)
genetic testing not very helpful bc low penetrance any pt w/ dystonia needs to be tested for Wilson's disease (24h urine copper, eye exam for KF-rings) and given tx trial of Levodopa (check to see if Levodopa-responsive!)
Anticholinergic drugs - well tolerated in kids but difficult to use in adults muscle relaxants, PT - less useful? Pallidal DBS - indicated in DYT1 generalized dystonia, cervical dystonia, tx refractory dystonias; slow onset of effect Botulinum toxin - indicated for focal dystonias
specific dystonias? Writer's focal dystonias - adults cramp, DYT1 generalized dystonia (AD w/ low penetrance) excessive use, focal adults dystonias DYT1 - early onset; likelihood of dz Primary is 0 if no sx onset by age 26 dystonias focal dystonia - action dependent Wilson's (related to overuse of muscle) disease Doparesponsive dystonia
Chorea
excessive, spontaneous movements that are irregularly timed, nonrepetitive, & randomly distributed involves multiple body parts
Huntington's chorea tardive dyskinesia (iatrogenic Levodopa in PD pts) Tourette's syndrome, OCD, excessive blinking
Tic
repetitive, brief, rapid, involuntary, purposeless, & stereotyped movements can be suppressed temporarily by the pt
Myoclonus
rapid, shock-like, arrhythmic & repetitive involuntary movements generalized, focal, multifocal lasts milliseconds in duration negative myoclonus (asterixis) - muscle becomes silent --> jerky flaps; result of liver/renal disease, metabolic d/o, or drugs
Alzheimer's disease, prion disease, drugs
Disease
Clinical Variants
(Parkinsonis m)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Parkinson's disease
inc output from basal ganglia = tremor at rest, rigidity inhibition of cortex (cogwheeling), bradykinesia/ akinesia (masked face, freezing, difficulty getting up from chair,no arm swing, difficulty turning), gait d/o (festination/ shuffling, post instability, freezing, no arm swing), flexed posture, NO voice tremor Other S&S: sialorrhea (drooling), hypophonic speech (fast, low volume), dystonia, autonomic dysfxn, sleep probs, depression, micrographia early signs? trouble maintaining plan of action, hyposmia
PD, strokeinduced (rapid, stepwise prog), PSP (abnl eye movements), drug induced (symmetric), toxins (MPTP), drugs (neuroleptics), Wilson's dz, neurodegen d/o
high risk of falls! Dyskinesia/ dystonia from Levodopa tx
PD
bradykinesia + one of cardinal features (rigidity, resting tremor, postural instability)
loss of cells in SNc = fast loss of dopamine (oxid damage, mitoch damage, inflamm, protein aggregation) = change in striatum anatomy (loss of asymmetric mode of onset, medium spiny neurons) unilateral tremor possible that PD ascends: BS to SN to cortex slow progression - 15y to develop Low dopa ultimately affects NOT seen in PD: cerebellar transmission (inc basal ganglia output @ putamen = abnl firing signs, early autonomic patterns = disrupted cortical failure, gaze palsy, early processing), striatum anatomy, dementia other organs (cardiac denervation, oropharyngeal muscle dysfxn) genetic? young onset, rapid progression sporadic? susceptibility loci
sporadic M >= F (>80%), genetic (<20%) 5-24/ 10^5 incidence genetic suscept (inc w/ aging + environm pop) factors
old age, MPTP, toxin exposure (herbicides, heavy metals, wood preservs), head trauma possible protective factors? Caffeine, smoking, antiinflamm drugs
Path: SN & red nucleus look pale, Lewy body formation Histology: Lewy bodies in SNc (composed of alpha synuclein & found in Lewy neutrites)
1. protect neurons late stage? Orthostatic (exercise), 2. treat sx (mild - hypotension, aspiration, amantadine; tremor dementia anticholinergics; depression anti-depr, anxiety - benzos; severe sx - dopamine agonists, LDOPA/carbidopa) too many side effects or ineffective? Surgery/ DBS directed at thalamus, internal segment of globus pallidus, or STN treatment of non-motor sx: depression, sleep d/o, orthostatic hypotension, etc.
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Essential tremor
Action/ kinetic tremor (goes unknown away with rest) - present 5x risk increased if first degree throughout ENTIRE relative w/ ET movement exaggerated by fatigue, stress, & caffeine; diminished w/ alcohol location: upper extremities > head > voice > leg/ chin often asymmetric
1-6% of population (most common movement d/o) bimodal age of onset (peaks in early adult & later adulthood) M=F
FH
beta blockers (propanolol) more rapid progression in younger patients & those without head primidone (precursor of tremor (head tremor GABA receptor binding =better prognosis) barbituates) - try first in elderly patients! side effects of BB bradycardia, dizziness; Surgery - but some contraind in DM & interventions do not last depression very long side effects of primidone - cognitive effects (fuzzy memory)
Progressive supranuclear palsy
shock/astonished look on face, square wave jerks during fixation & saccadic intrusions during pursuit, unable to move eyes vertically, slow optokinetic nystagmus (occurs when following an object w/ eyes), hyperreflexia, "drunken stumbling" intact Doll's eye maneuver suggests intact brainstem
Parkinsonism disorder that presents with cardinal features + eye movement abnormalities (gaze palsy)
fall very early in dz course!
Wilson's disease
facial dystonia w/ retraction of mouth, Keyser-Fleischer rings in eyes (sunflower cataracts), fixed dystonia (does not improve w/ tricks)
Cerebellar syndromes
Ataxia
Inferior olive sends information directly to the Purkinje cells, which normally inhibit the deep cerebellar nuclei (output system of cerebellum); in ataxia, the Purkinje cells become disinhibited, therefore the deep cerebellar nucli are abnl eye movements (gaze- hyperexcitable evoked nystagmus, impaired smooth pursuit - jerky acquired (primary) = idiopathic saccades, inability to late onset cerebellar degen, MSA, suppress vestibulo-ocular autoimmune (paraneoplastic reflex by fixation) degen, anti-GAD65, gluten ataxia); (secondary) = hypothyroidism, stroke, MS, tumor, vitE def, toxic loss of coordination, dysmetria + dysrhythmia, dyssynergia, abnl regulation of movement speed/ force/ distance (movement delay, dysdiadochokinesia) inherited (AD, AR, Mitochondrial, X-linked, inborn errors) - a/w inc genetic repeats
MRI of head, TSH, B12, vitE, anti-GAD, anti-gliadin, antitissue transglutaminase, ?ceruloplasmin, antithyroglobulin, genetic testing (depending on phenotype)
symptomatic tx of ataxia PT, ?chantix, ?riluzole reduces deep cerebellar nuclei hyperexcitability symptomatic tx of assoc sx swallowing, spasticity, pain, depression disease modifying tx lithium for SCA1, dantrolene for SCA2, HDAC inh & antioxidants for FRDA
Disease
Clinical Variants
Toxic syndromes
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
chronic alcohol history? Midline cerebellar atrophy, legs & trunk >> arms, speech spared
Alcohol can cause midline atrophy EtOH, lithium, of cerebellum AEDs (phenytoin, Acute lithium toxicity can lead to carbamazepine, permanent cerebellar damage oxcarbazepine), amiodarone autosomal dominant disease w/ large degree of phenotypic variability & hi genetic anticipation
MachadoJoseph Disease (MJD) = SCA3
ataxia, dysarthria, mild ophthalmoplegia, periocular or perioral fasics, dystonia neuropathy, motor neuron disease, dystonia, parkinsonism Neuro: ataxia, dysarthria, areflexia (loss of reflexes),extensor plantar responses, loss of vibration/ position sense, others (nystagmus, weakness legs>arms, blindness, hearing loss, incontinence) cardiomyopathy, glucose intolerance/ DM, scoliosis, pes cavus
Friedreich's ataxia (FRDA)
autosomal recessive ataxia with strong founder effect (IndoEuropean races) mutation in frataxin (trinucleotide repeat GAA); inc repeats = inc clinical severity Spinal cord pathology: loss of dorsal colums, spinocerebellar tracts, corticospinal tract Peripheral nerves: damage to dorsal root ganglion CNS: affects brainstem & cerebellar nuclei heart: fibrotic cardiomyopathy (hypertrophic)
sx onset in late childhood/ adolescence
most Indocommon European inherited races ataxia (1/3050K)
supportive (balance, orthotics) anti-oxidants? HDAC inhibitors?
Anti-GAD ataxia
stiff person syndrome, cerebellar ataxia, downward nystagmus, adult onset epilepsy, or autoimmune encephalitis - sx vary w/ spectrum of anti-GAD antibody burden
autoimmune process where antibodies are made against GAD65 --> CNS disease and pancreas diseases like DM
MSA
Multiple Systems Atrophy = Parkisonism + cerebellar ataxia + autonomic dysfunction Axial/ midline wide stance & gait, nodding midline problem in the cerebellum ataxia tremor, nystagmus syndrome Appendicular dismetria, random alternating problem with cerebellar inputs & ataxia movements, discoordination outputs (peduncles) syndrome w/ limb motor dexterity superior peduncle - midbrain middle peduncle - pons inferior peduncle - medulla
death within 5-10y
Disease
Clinical Variants
slowly progressive, degenerative neuropsychiatric d/o
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Huntington's disease
90% adult onset; duration of 15-30+y dx requires FH or genetic confirmation + typical choreic movements cognitive decline: slow thinking & distractibility, impaired visual spatial abilities, impaired memory, attention deficits, impaired executive fxn emotional disturbances: depression, impulsivity, irritability, OCD, anxiety, psychosis, personality/ beh change movement d/o: eye movement abnl, chorea, dystonia, bradykinesia
Autosomal dominant mutation in the huntingtin gene, leading to unstable expansion of CAG repeats (nl < 26) in the polyQ area Htt role unknown? Protein folds incorrectly --> aggregation --> dysreg transcription & abnl RNA prod, mitoc dysfxn, & oxid damage; protein is cleaved & forms polyglutamine fragments (toxic!)
AD inheritance 5-10/100K w/ hi penetrance huntingtin gene mutation
FH
histology: substantial loss of medium spiny neurons in basal ganglia striatum, intranuclear inclusions w/ mutant Htt aggregates pathology: severe atrophy of caudate nucleus (but also atrophy of other brain regions) MRI: inc CSF (due to atrophy) FH & typical movement disorders; genetic testing if FH unknown
NONE - progressive & fatal discuss end of life issues manage symptoms & social support Movement d/o: PT, OT, speech & swallowing therapy, tetrabenazine if chorea affects ADLs Attention deficits: one task @ a time, avoid meal distractions disorganization: routine, to do lists, step by step instructions decision-making: simple choices, no open ended ? depression: antidepressants, psychotx early in dz impulsivity: remove temptations (guns, alcohol, keys), mood stabilizing meds clinical trials
Juvenile onset
Multiple Sclerosis (MS)
Relapsingremitting (80%), primary progressive (10%), secondary progressive, progressive relapsing
bradykinesia prominent & early (chorea less prominent), rigidity, tremor, seizures, dystonia, myoclonic jerks, school failure,behavioral probs Charcot's triad (SIN: Scanning speech, Intention tremor/ Incontinence/ Intranuclear ophthalmoplegia, Nystagmus) bladder/ bowel probs (constipation, urgency, incontinence), cognitive difficulties, depression, fatigue, muscle rigidity/ stiffness, hemiparesis, hemisensory loss, vision changes (optic neuritis = sudden loss of vision), pain, ataxia, hemiparetic gait (circumduction, semi-flexed arm) dx: mult lesions in time & space
10% of Huntington's is juvenile onset
autoimmune inflammation & demyelination of axons, interrupting the flow of electrical impulses in the CNS negative sx (weak/numb) - due to loss of conduction (low # Na channels) --> nodal widening & disbursed electrical current = dec safety factor & instability of demyelinated axons
gen predisposition + abnl immune system (EBV, low vitD, smoker) --> abnl attack on CNS
leading cause of nontraumatic disability in young adults 70% women, 8500-10K new cases per yr
Th1 cells secrete IFN-y & Th17 cells secrete IL-17 & Il-23, recruiting remission occurs (sx microglial cells improvement) when: inc Na+ that display channels, dec inflamm & NO, & glial ensheathment; remyelination myelin; B cells make Abs -(but shorter internodes than nl) >demyelination positive sx (tingling, Lhermitte's) - & axonal transection hyperexcitable response to demyelination
females, geography (inc risk if far from equator), vitD def, smoking, EBV+, FH, HLA-DRB 1 gene
MRI of brain: white plaques in CNS CSF analysis: Inc IgG & oligoclonal bands from B cells (suggests BBB breach) Evoked potentials: slowed (loss of myelin) histology: loss of myelin, hypocellular
Vitamin D supplements (lowers dz severity), manage sx
avg lifespan 65y men more likely to develop chronic progressive form of disease a/w other autoimmune dz like thyroiditis & psoriasis With every 1 clinical event, on average, there are 5-10 new lesions More attacks = more brain damage = more brain atrophy inflammatory dz --> neurodegenerative dz
age of genetically onset: 15-50 protected? Eskimos, Native Americans, Hungarians
Glatiramer acetate (GA)mimics myelin so it is attacked instead of actual myelin on axons OR beta-IFN - reduces the # of circulating & activated T sx exaceberated by temperature cells by dec MMP generation & fever Natalizumab - SAM inhibitors (blocks a4 integrin, preventing T cell migration across BBB) Fingolimod blocks T cells from leaving LN IV steroids for relapses
Disease
Clinical Variants
(general)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Dementia
acquired, persistent, severe impairment of multiple areas of higher brain functions (>2 deficits in memory, language, praxis, visuospatial skills, executive fxn, emotions, personality) cog complaints: altered consciousness, difficulty performing tasks/ finding words, disorientation in familiar locations, misplacing objects in weird places, repeating ?, loss of initiative, inappropriate clothing, disregard for personal appearance, personality change
characterized by acquired memory impairment + performance impairment in functional domains (language, visuospatial skills, identification skills, executive skills)
AD, FTD, Lewy body dementia, CJD, low B12, HIV, neurosyphilis, organ failure, hydrocephalus, subdural hematoma, MS, PD, TBI, pseudodementi a, TB, depression, brain tumors, vascular infarcts
increased incidence w/ baby booming population 50% of people >85 have dementia
history, neuro exam, blood tests (B12, thyroid, syphilis, HIV), imaging, clinical features (genetics, CSF), neuropsy testing Montreal cognitive assessment or MMSE logical memory (read a paragraph then talk about what was read), word recall (immediate & delayed), naming test (line drawings) executive fxn (connect the dots, clock drawing) visuospatial (intersecting pentagons)
very vulnerable to delirium
Alzheimer's disease
memory loss
dramatic loss & degeneration of amyloid accumulation -> neurons containing ACh neuron injury--> 90% of AD is sporadic- with age, tau release -> AD clinical amyloid clearance mechanisms slow down; amyloid aggregates symptoms forming oligomers --> BetaFAD: APOE4 amyloid deposits in neuritic plaques --> neurotoxicity & AD gene, presenilin sx genes, APP mutations tau protein accumulates in neurofibrillary tangles, which correlate w/ sx & degree of dementia 10% of AD has familial form: early onset (<65y.o.), autosomal dominant w/ 100% penetrance (mutations in APP, presenilin-1, presenilin 2, or ApoE4)
most common type of dementia F>M
age, Down syndrome, head trauma, depression, HTN, hypercholesteremia , hi homocysteine , low B12/ folate protective? Education, exercise, Med diet, NSAIDs, statins, red wine
CT: mesial temporal atrophy PIB: increased amyloid burden CSF: measure biomarkers like beta-amyloid & tau protein (predicts MCI conversion to AD) pathology: brain atrophy, neurofibrillary tangles, senile amyloid plaques
symptomatic? AChE inhibitors (donepezil, galanthamine, rivastigmine), memantine Neuroprotective? VitE
Lewy Body dementia
dementia + Parkinsonism (bradykinesia/ rigidity) + psych sx (hallucinations, delusions, depression, anxiety), fluctuating cognitive state (attention/ arousal), other features (REM behavior d/o, autonomic dysfxn, neuroleptic sensitivity, rapid progression compared to PD, poorly tolerated dopaminergics) distinguished from PD bc dementia begins at around same time as dementia sx
thought to be an intermediate syndrome between AD & PD decreased cortical ACh & striatal dopamine formation of amyloid plaques, neurofibrillay tangles, & Lewy bodies cortical Lewy bodies & Lewy neurites widespread in DLB (correlate w/ dementia severity); asynuclein = major component of Lewy bodies
at risk genes? APOE4, mutation in alphasynuclein
10-20% of dementia M>F age of onset? 5080
FH
cannot be distinguished neuropathologically from Parkinson's dementia
d/c anticholinergics, lower doses of dopaminergics AChE inhibitors, antidepressants, atypical antipsychotics
Disease
Clinical Variants
Frontotemporal dementia
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
syndromic dx
TDP-43 (normally a nuclear transcriptional regulator) undergoes translocation to form Behavioral variant FTD (bvFTD) - 3 of following: early hyperphosphorylated disinhibition, early apathy, cytoplasmic inclusions in FTD early loss of sympathy/ empathy, early ritualistic Tau can also become behavior, hyperorality/ diet hyperphosphorylated --> changes, exec deficits w/ microtubule dysfunction sparing of memory & visuospatial fxns FUS unclear Primary progressive aphasia (PPA) - semantic dementia, non-fluent variant, intermittently fluent w/ word finding pauses autosomal dominant mutations in MAPT and progranulin TDP a/w ALS Tau a/w PSP
histology: Frontotemporal lobar degeneration w/ lesions displaying Pick bodies (intracellular, aggregated tau protein), immunoreactivity to TDP-43 or FUS MRI: frontotemporal atrophy (bvFTD), subtle left atrophy (PPA)
Delirium
FTD plus - FTD + ALS or PSP Progressive falls early in disease course; supranuclear abnl eye movements palsy inability to sustain, direct, or appropriately shift attention - due to CNS process or another organ system affecting CNS
drugs/ toxins (EtOH intox/wd, sedatives, opioids, anticholinergics), endocrine (hypo/hyperthyroidism, hypo/hyperglycemia), electrolytes (hypo/hypercalcemia, impaired attention (waxes & hyponatremia), nutritional (thiamine), organ system dysfxn wanes) (CHF, MI, pneumonia, COPD, PE, large variability in the level of pancreatitis, renal failure, UTI), infectious (meningitis, arousal, +/- visual hallucinations, autonomic encephalitis), vascular instability (hypertensive encephalopathy, SAH, SDH, ICH), head trauma, epileptic seizure
I WATCH DEATH (infection, withdrawal, trauma, CNS path, hypoxia, deficiency of vitamins, endocrinopathy, acute vascul insult, toxins, heavy metals) brain mets (melanoma, colon, breast, prostate, renal transitional cell)
strongly associated with morbidity & mortality
dementia patients
see patient serially over time to evaluate fixed/fluctuating sx Psych mental status exam (ABC STAMP LICKER - appearance, behavior, cooperation, speech, thought, affect, mood, perception, level of consciousness, insight, cognition, knowledge, endings suicidal/ homicidal, reliability) MMSE or MoCA, UDS, CT scan (r/o head trauma), CBC, CMP
Consciousness
Awake & alert fully aware of self & environment Lethargic mildly depressed consciousness, easily aroused to wakefulness Obtunded moderately depressed consciousness, aroused w/ stimulation to answer questions but lapses back without verbal/ tactile stimuli Stuporous deeply depressed consciousness, aroused by vigorous & repeated stimuli (require these stimuli to respond)
Disease
Clinical Variants
Comatose
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
cannot be aroused to consciousness despite stimuli used decorticate posturing (flexor)- damage to upper midbrain decerebrate posturing (extensor) - damange to lower midbrain/ upper pons Cheynes- Stokes resp - liver failure or toxic insult to brain Central neurogenic hyperventilation - midbrain lesion apneusis - ischemic stroke to pons cluster breathing - lower pons lesion ataxic breathing - medulla lesion
total absence of awareness of self & environment (lack of sleep/wake cycles, lack of consciousness) impaired RAS in the brainstem or diencephalon OR damage to BOTH cerebral hemispheres from structural or metabolic/toxic injury
BS: trauma, brainstem stroke/ hemorr Both hemispheres: bilateral subdural hematomas, large/ lots brain tumors, inc ICP, degen dz metab/toxic: hypoxia, ischemia, hi/low gluc, hi/low Na+, hypo-thyroidism, drugs, liver failure, hypercarbia, sepsis, meningitis
Neuro exam!! Respiratory patterns, pupillary light responses (loss suggests struct damage), eye movements (Oculocephalic testing, oculovestibular), & motor responses (posturing) EEG can suggest various causes (liver failure, seizure, drugs) MRI to r/o reversible causes Glasgow coma scale assessed for eye opening, verbal output, & motor response to pain (lower score = more comatose)
Brain oriented ICU - balance cerebral metabolic supply with cerebral metabolic demand and minimize cpds that worsen neuro damage
within a few months, patients either die, end up in vegetative state, or recover (various degrees)
Persistent vegetative state (PVS)
wakefulness without awareness intact sleep/wake cycles, eat food placed in mouth, smile/cry, fixates visually on objects or orients head to auditory stimuli, non purposeful limb movements actions have no cognitive content
brainstem functions without cortical function glucose in cerebral cortex is greatly reduced, to a degree incompatible w/ consciousness
hypoxic ischemic encephalopathy (most common cause of PVS)
pathology: diffuse laminar necrosis of cerebral cortex w/ extensive hippocampal involvement
>3m of PVS, functional recovery is rare
Minimally conscious state (MCS)
severely altered consciousness w/ minimal but definite behavioral evidence of self or environment reproducible evidence of awareness (speech,yes/no responses, purposeful behaviors like following commands) emergence: functional interactive communication and/or functional use of two different objects
hypoxic ischemic encephalopathy, TBI, stroke, neurodegen dz, metabolic d/o, tumors, congenital or developmental d/o
can be permanent or transitional state
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Brain death
documented loss of irreversible loss of all brain & consciousness (coma) + no brain stem function brain stem reflexes + apnea NO motor/facial responses to pain (nail bed pressure, sternal rub, nasal tickle), absent pupillary response, round/ oval pupils, no doll's eye or caloric testing movements (eyes stay fixed in skull), absent corneal reflex, absent cough response to bronchial suctioning REPEAT CLINICAL EXAM!
Brain stem reflexes (pupillary light, ocular movements, facial sensation & motor responses, pharyngeal/ tracheal reflexes)
medical record documentation: etiology & irreversibility of condition, absent brainstem reflexes, absent motor response to apnea test (no respirations at pain, rpt neuro exam, absence of respiration w/ hi CO2>60 mmHg) pCO2, justification & results of confirmatory tests, time confirmatory tests (cerebral angiography, EEG, transcranial of death (time last test is completed) doppler u/s, isotope angiography) if pt cannot reliably undergo clinical testing components
apnea test should be done last (risk of pneumothorax, arrhythmias, & hypotension) confirmatory tests have hi rates of false negatives so done if clinical exam cannot be performed properly!
Axonal polyneuropathy
(general)
usually affects both sensory AND motor fibers symmetric & distal: Stocking-glove distribution (Legs>arms), absent ankle jerks chronic (if acute, think about vasculitis)
Metabolic, majority of endocrine (DM), polymeds/ toxins, neuropathy nutritional (B12 def), connective tissue (SLE, Sjogren's)
HbA1C or 2h GTT, TSH, B12, serum protein electrophoresis (multiple myeloma), ESR/CRP
Diabetic peripheral neuropathy
burning pain, reduced pin prick & temp sensation absent ankle jerks symmetric distal pain/ burning, mild weakness, +/autonomic involvement (postural hypotension, arrhythmias, bowel/bladder probs)
involves small C fibers (pain), as well as sensory large fibers (vibration, mechanical sensation)
30% prevalence among diabetics
poor glycemic exclude other causes (meds, control DM, neuropathic control, toxin exposure, combordities) pain mgmt (Neurontin, advanced Lyrica), foot care! age, HTN, NCS, HbA1C, autonomic testing longer duration of DM, dyslipidemia, smoking, heavy alcohol intake, HLA DR3/4
7x increase for diabetic foot ulcers on soles of feet! Charcot's joints (severe diabetic neuropathy + osteopenia --> calcification of vascular smooth muscle & degen of bones --> changes in navicular bone of foot -> dysmorphic feet (requires joint fixation/ surgery to repair)
Myelinopathy
(general)
inflammatory cells attack myelin -- acquired: acute > segmental demyelination in both GBS, chronic CIDP moderate -severe weakness sensory & motor fibers --> eventual total demyelination w/ normal muscle bulk Inherited: CMT areflexia, hypertrophic nerves motor> sensory symptoms
NCS: conduction block (20% drop in amplitude btwn proximal & distal sites)
Disease
Clinical Variants
GuillainBarre Syndrome (GBS)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
ACUTE ascending weakness, absent reflexes, can involve CN7 (facial paralysis) & autonomic dysfxn (cardiac irregularities, HTN, hypotension) PRECEDING ILLNESS (often GI - Campylobacter jejuni; CMV, EBV, HSV, influenza, mycoplasma), immunization, recent surgery or renal transplantation may be a/w Hodgkin's dz, SLE, HIV?
immune mediated process (T cells)--> inflammation & demyelination of peripheral nerves & motor fibers of ventral roots
most common cause of acute generalized paralysis 0.61.9/100K all age groups
no familial or NCS: absent F-waves & occupation conduction block triggers CSF: elevated protein w/ nl identified amount of cells (however, CSF will be nl during first 48h so does not necessarily exclude GBS) MRI if suspect spinal cord involvement
IV Ig, plasma exchange NO CORTICOSTEROIDS! Admission to ICU if autonimic dysfxn
majority of pts recover; 15% have NO residual deficits, 50-65% are restored 2/3 normal fxn, 10% have persistent severe weakness mechanical ventilation a/w 15-30% mortality
Myasthenia gravis (MG)
fluctuating weakness of VOLUNTARY muscles --> diplopia, ptosis, difficulty swallowing/ breathing weakness may fluctuate in intensity throughout the day nl pupillary responses insidious onset, exacerbated by menstrual period/ pregnancy
blocks of neuromuscular transmission due to AUTOANTIBODIES binding to AChR on postsynaptic membrane --> 1) decrease in number of available receptors, 2) less surface area due to architectural change of postsynaptic membrane --> less ability to depolarize the membrane --> chronic muscle weakness AChR antibodies lead to destruction of the AChR by activating complement fixation OR inducing endocytosis of receptors (similar to botulinum toxin)
occurs at all HLA-DR3 ages women
Elevated level of serum AChR antibodies (sensitivity 80-90%) CT scan of chest to R/O thymoma NCS - decreased muscle response to repetitive stimulation increased strength following administration of AChE inhibitor
Anti-cholinesterase drugs can be a/w thymic provide symptomatic benefit tumor, thyrotoxicosis, RA, SLE steroids if poor response to AChE inhibitors aspiration pneumonia, myasthenic crisis --> thymectomy (symptomatic respiratory weakness benefit or remission) considered in all pts <60
Motor neuron (general) diseases (anterior horn cell dz, motor neuronopathies)
PAINLESS weakness & atrophy
progressive course!
cramps, fasciculations NO sensory loss, NO ptosis or eye movement probs
cell dz, motor neuronopathies)
Disease
Clinical Variants
Poliomyelitis
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
1-2d nonspecific viral prodrome (many pts get better), minority of pts get meningo-encephalitis (fever, nuchal rigidity, back pain, AMS, +/- paralysis 310d later)--> paralytic poliomyelitis - myalgias & cramps --> rapidly progressive paralysis (asymmetric, limbs & trunk; spares CN 3,4,6) & autonomic dysfxn post-polio syndrome slowly progressive weakness, occurs ~35y after initial illness; LMN signs: muscle weakness & atrophy, fascics, hyporeflexia
neurotropic enterovirus w/ predisposition for ventral horn in spinal cord & motor cranial nerve nuclei --> LMN destruction
fecal oral route poliovirus, Coxsackie virus, echovirus, enterovirus, Japanese encephalitis virus, rabies virus, West Nile virus
new cases eradicated in U.S. but cases of post-polio syndrome
CSF: neg in early stages, w/I 2w supportive treatment - pleocytosis (inc WBCs) w/ lymphocytic predominance, elevated CSF protein Stool/ throat viral cultures; elevted serum antibodies WNV - IgM antibodies or RNA in CSF
Spinal Muscular Atrophy (SMA)
SMA1 - Infantile/ WerdnigHoffmann; first 6m of life--> hypotonic (floppy) infants w/ prox weakness & areflexia, tongue fascics, abd breathing, ventilatory failure; can't sit independently SMA2 - intermed form; age 618m, sits independently but can't walk; orthopedic deformities, > survival than SMA1, tongue fascics/ areflexia/ prox weak/ hand tremor SMA3 - Juvenile form/ Kugelberg-Welander; onset >18m, nl life expectancy, prox weakness, areflexia, tongue & limb fascics SMA4 - adult onset, rare, prox weakness X-linked bulbospinal muscular atrophy adult onset, bulbar & proximal weakness, lower extremity weakness very disabling - wheelchair dependency ANDROGEN INSENSITIVITY - gynecomastia, impotence, testicular atrophy, infertility increased incidence of DM
progressive hereditary diseases of anterior horn cells & select motor cranial nerve nuclei SMN (survival motor neuron) 1 on chrom 5 is deleted; severity of SMA depends on #SMN2 copies available (more SMN2 = less severe dz)
4-10/100K SMA1 = most common motor neuron dz
Kennedy's disease
mutation of androgen receptor gene on X chromosome
mostly males median age 44
Disease
Clinical Variants
Amyotrophic Lateral Sclerosis (ALS)
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
LMN signs: weakness, atrophy (first dorsal interosseous muscle, tongue, paraspinal), hyporeflexia, muscle cramps, fascics UMN signs: spasticity, hyperreflexia, jaw jerk, Hoffman sign, Babinski's sign no cognitive deficit! ASYMMETRIC weakness, local spread, NO sensory/ autonomic/ eye movement abnormalities (spares CN 3,4,6 & Onuf's nucleus)!! non-motor sx: involuntary, unprovoked laughing & crying; depression & anxiety
progressive disorder of voluntary motor system - upper & lower motor neuron dysfxn cause unknown?
90-95% sporadic; 5-10% AD
1/100K avg age = mid 50s M:F 3:2
Pathology: degeneration & death of motor neurons; UMN death of Betz cells (cortical spinal tract); LMN - death of anterior horn cells
Riluzole - prolongs survival (2-3m); must monitor LFTs during tx Nuedexta helps bulbar sx
no cure - progressive & fatal variable dz course - if initial rapid presentation then rapid progression 50% die w/I 3-4y 20% live 5+y 10% live 10+y FTD in 5-20% MOST COMMON CAUSE OF DEATH? Respiratory dysfxn (restrictive pattern; sx? Inability to lay flat, frequent nighttime arousal, EDS, exertional dyspnea) Cardiovascular disease (HTN) and stroke risk!! Increased rates of mortality
Thought to be a continuum that eventually converge to have ALS (i.e. progressive muscular atrophy is LMN and primary lateral sclerosis is UMN; ALS is in the middle of these two)
U.S. prev = 30K
El Escorial criteria (should not spasticity managed by be used to preclude clinical dx) baclofen SSRIs, benzos for depression/ anxiety PT/OT/Speech therapy bipap for breathing nutrition
Sleep apnea
10% prevalence by age 3540
AGE, obesity
C-PAP lifestyle modifications
Insomnia
(general)
difficulty maintaining sleep 3Ps: predisposition to insomnia (decreased homeostatic drive or (older adults) pressure for sleep; anxiety/ depression/ stress/ worry about difficulty falling asleep sleep), precipitating factors (young adults) (acute stressors - illness, life events, prescriptions/ herbals/ OTCs), perpetuating factors (poor sleep hygiene, counterproductive efforts to solve sleep issues) sudden onset of sleep (sleep attacks); inability to stay awake during the day & sustain wakefulness fragmented sleep (unable to maintain sleep) sleepiness, hallucinations upon falling asleep or awakening, sleep paralysis, cataplexy (can be triggered by emiotions; sudden intrusion of muscle atonia; most specific finding!) loss of hypocretin cells in the hypothalamus --> loss of major excitatory influence to areas necessary for wakefulness AND loss of inhibition to PPT so early REM sleep & cataplexy --> poorly consolidated states of thalamocortical arousal (wakesleep instability) normal sleep homeostatic mechanisms but more fragmented episodes of sleep w/ REM sleep occurring right at the onset of sleep molecular mimicry & certain infections?
most prevalent sleep sx F>M
behavior based tx: improved sleep hygiene, relaxation/ breathing exercises, get out of bed if cannot sleep, restrict time in bed to night, daytime light exposure & physical activity
Narcolepsy
1/2000 people
Polysomnogram: short nocturnal REM latency, signs of disruptive nocturnal sleep, periodic leg movements
Behavioral strategies: short/scheduled naps, consistent sleep/wake schedule, exercise, good sleep hygiene, avoid alcohol/ caffeine/ nicotine Multiple Sleep Latency Test (MSLT) measures the amount before bed of time it takes to fall asleep; EDS treatment: Modafenil latency period < 8 minutes suggests narcolepsy cataplexy tx: Sodium oxybate(date rape drug), CSF sample lacking SSRIs, TCAs, SNRIs hypocretin HLA testing: HLA DQB 10602
obesity (hypocretin system also related to leptin, ghrelin, insulin, & thyroid hormone)
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Restless leg syndrome (RLS)
urge to move legs, uncomfortable leg sensations, onset/worsening of symptoms at rest or inactivity, relief with movement, worsening at night
disorder of the emotional motor system throught he ventromedial medulla; sensory dysfunction ascends to the brain in the spinothalamic tract Brain deficits in IRON --> RLS (unable to retain or mobilize iron from periphery to brain) Multiple SNPs in 2 of 4 genes are related in a dose dependent fashion to # PLMs (not severity)
most often familial (AD) pregnancy, iron & B12 deficiencies, anemia
10% of U.S. FH, women, population pregnancy, iron def 12 million anemia, Americans Northern have European moderate- descent severe RLS
R/O secondary causes (iron deficiency, diabetes, uremia)
Dopaminergics
oral or IV iron repletion polysomnogram NOT indicated! when iron def confirmed Check for medication aggravators (benadryl), careful FH, psych screening (hi # affected pts have anxiety/dep), neuro exam (USUALLY NL!), serum iron/ ferritin/ B12/ TSH, ambulatory actigraphy for PLMs
higher rates of mood disorders (depression, anxiety, panic disorder) increased rate of CVD (autonomic arousals occur w/ PLMs)
Rapid Eye (general) Movement Sleep Behavior Disorder (RBD)
"acting out" dreams, vivid lack of atonia & presumed lack dreams w/ good recall, violent of suppression of movement themes & behaviors common during REM sleep (injury to self or bed partner) Dx? At least one of sleep related injury, disruptive behavior by hx, or abnl REM sleep behavior by PSG AND REM sleep without atonia AND not better explained by another d/o Occurs during 2nd half of sleep (REM sleep), nightly, speech & dream recall? behavior changes depending on dream content, a/w neurodegen dz or narcolepsy
mostly men > 50y.o. (unless antidep related)
Physical measures to ensure safety: remove dangerous nearby objects, bedrails, soothing alarm Change anti-depressants to wellbutrin Pharm tx: Clonazepam, Melatonin
RBD is dangerous!!!
Acute onset
Iatrogenic (anti-depressants) Withdrawal - Alcohol (chronic EtOH --> downregulation of GABA -> delirium tremors that look like RBD); Barbituates/ benzodiazepines structural lesions - Pontine lesions (ischemia, hemorrhage, tumor, demyelination, inflammation); limbic cortex (limbic encephalitis)
Chronic form most common RBD
associated with neurological disease - young patients (hypocretin def --> narcolepsy); older patients (alpha synucleinopathies - PD, MSA, LBD), idiopathic
Idiopathic RBD a/w future neurodegenerative dz
Disease
Clinical Variants
Confusional arousals
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Non-REM arousal disorders
overlapping spectrum (confusional arousals most basic, sleep walking adds Sleep terrors motor activity, & sleep terrors add fear & Somnautonomic activation w/o ambulism memory of event) (sleep walking) Occurs during 1st half of sleep (N3 stage), infrequent (1-3x/m), no recall
incomplete arousal from slowwave sleep (N3) resulting in dissociation between behavioral state (wake) and EEG (sleep)
disorders of childhood if occur in adulthood, consider occult cause of arousal (OSA)
safe environment avoid triggers (sleep deprivation) Clonazepam (reduces behaviors)
Migraine
(general)
trigger (somehow involves vascular serotonin, substance P, and/or neurokinin A) --> activation of trigeminal vasculature system in brain (trigeminal nucleus caudalis) --> dilation of blood vessels (throbbing & pain)
28 million Americans 18% women, 6% men peak age: 25-55 y <10% able to fxn during HA
Consider Echo to R/O PFO, polysomnogram, imaging if headache persists/worsens
Migraine Abortive therapy (take as soon as symptoms start!) - Triptans (avoid if vascular comorbidities, hemiplegic variants, basilar migraine, or pregnant); NSAIDs, Triptan/ NSAID combo, Tramadol, Antihistamines (pregnant women), opiates Vitamin prophylaxis VitB2 (reduces pain, edema), Mg2+, feverfew Prophylaxis based on comorbidities w/ headaches: AED (Topamax, Gabapentin, valproic acid), Anti-HTN (propanolol, CCB), Antidepressants (TCAs, SSRIs, SNRIs) IV DHE if continuous headache (need EKG before using - inc stroke/ MI risk) regular lifestyle/ sleep, exercise, stress mgmt, avoid triggers (chocolate, etc)
Common migraine
At least 5 attacks with: attacks lasting 4-72h, 2+ characteristics (unilateral location, pulsating quality, mod/severe pain, aggravation/worsen w/ physical activity), nausea/vomiting OR photo/phonophobia cannot attribute to another d/o
Classic migraine
common migraine + "AURA" - visual, dysphasia, hemisensory deficits (neurological deficits reversible >5m but <60m)
inciting event in visual cortex --> lack of blood flow at that point --? Neurologic change --> positive or negative visual phenomena
Hemiplegic migraine
Basilar migraine
Cyclical vomiting migraine
migraine symptoms w/ fully Familial - genetic w/ basilar sx reversible motor weakness (ataxia) often present & aphasia Sporadic - not present in 1st or 2nd degree relative Aura w/ 2 of following affects brainstem, or location of reversible sx (dysarthria, basilar artery vertigo, tinnitus, hypacusia, diplopia, visual sx simultaneously in temporal & nasal fields of both eyes, ataxia, dec consciousness, bilateral paresthesias), NO motor weakness vomiting at least 4x/h for 1h, symptom free between attacks can last 1h-5d
FH
if symptoms persist, imaging at ER!
Disease
Clinical Variants
Benign Paroxysmal Vertigo of Childhood
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
multiple episodes of severe vertigo, occurring wihtout warning & resolving spontaneously after minutes to hours a/w nystagmus or vomiting, unilateral throbbing HA may occur nl neuro exam & EEG frontal headache accompanied by pain in regions of face/ ears/ teeth resolves within 7d after remission or tx of rhinosinusitis
Sinus headache
headache attributed to rhinosinusitis
Evidence (clinical - purulence, nasal obstruction, hyposmia, fever; imaging) of acute or chronic rhinosinusitis
90% of sinus headache patients have MIGRAINE!!
Medication overuse headache
also called rebound or drug-induced headache
chronic overuse of medications HA >15d/m + regular overuse of drugs used for prevents prophylaxis from being effective in headaches acute HA >3m + HA developed/worsened during med overuse + HA resolves within 2m after d/c meds episodic HA that occurs >15d/month, lasts 30m-7d, pressing/tightening (nonpulsating), bilateral, mild or mod intensity, NO n/v, no photo/phonophobia
Ibuprofen, Goody's powder, tylenol
reduce offending agents consider IV abortive therapy if difficult for pt to endure pain
Tension headache
non-pharm prophylaxis: spinal manipulation, neck exercises, therapeutic touch/ self massage/ stretching regular lifestyle/ sleep, exercise, stress mgmt Sumatriptan injection or nasal spray (>90% effective), indomethacin, consider prednisone Oxygen therapy DHE - IM, subq, IV Prophylaxis: Verapamil, Topiramate, Melatonin, Lithium carbonate Surgery: central parasympathetic interruption, sensory trigeminal interruption, radiofrequency thermocoagulation
Trigeminal Autonomic Cephalgias
Cluster headache
severe unilateral orbital/supraorbital/ temporal pain lasting 15m180m (EXTREME INTENSITY EXCRUCIATING UNILAT HA) associated with one of the following signs on the painful side: conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead/facial sweating, miosis, ptosis, eyelid edema freq attacks: 1 every other day to 8x/d
Chronic Paroxysmal hemicrania
At least 50 attacks of severe unilateral orbital/ supraorbital/ temporal pain lasting 2-45m 5x/d, no predilection for night attacks a/w lacrimation, nasal congestion, conjunctival injection, rhinorrhea, ptosis
Disease
Clinical Variants
Hemicrania continua
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
non-remitting, remitting pain 24/7 w/ +/- autonomic sx, exacerbations w/ coexisting migraines or cluster HA, "foreign body" sensation in eye, ice pick HA
Indomethacin
Conjunctivitis
(general)
affects both palpebral & epibulbar conjunctiva!!
Bacterial
purulent; pain but NO blurry vision; bilateral Lids stuck in the AM hyperpurulent?? N. gonorrhea
microbes, viruses, toxins, allergens, tear deficiency S. aureus, Strep pneumo, H.flu, Pseudomonas, N. gonorrhea
usually resolves w/I 4-5d or sooner if use warm compresses topical antibiotic If N. gonorrhea as causative agent REQUIRES systemic antibiotics & lavage ADENOVIRUS: Eye exam: conjunctival follicles (lymphoid aggregates)- Cool compresses, topical decongestants or artificial adenovirus tears; refer if severe pain or decreased vision
Viral
watery exudates, starts monocular, URI +/- sore throat, fever pre-auricular lymphadenopathy - pink eye HSV - dendritis ulcers w/ fluorescein stain seasonal itching of eyes, white mucus of eyes swollen lids, watery discharge, hay fever sx #1 cause of inflamm blindness in U.S. Honey-crusted lesions on erythematous base (looks like impetigo) near mucocutaneous junction (eye, lips, nose) herpetic lesions following dermatome (trigeminal distribution) - ophthalmic + nasociliary lesions feel "pain behind the eye"
Adenovirus pink eye HSV
Allergic
IgE mediated ocular surface disease affecting mucus membranes (eyes & nose)
OTC lubricants & decongestants, cool compresses, topical antihistamines fluorescein dye or Rose bengal stain shows DENDRITIC ulcers Acyclovir, steroids
HSV keratitis
HSV destroys corneal epithelium and periodically bifurcates --> dendritic corneal ulcers --> recruitment of antibodies --> scarring of corneal --> blindness & recurrence even in corneal grafts
Herpes Zoster Ophthalmicus
Acyclovir
Blepharitis
chronic inflammation of lid a/w seborrheic dermatitis leading margins --> swollen or closed to hyperkeratosis of basilar Meibomian glands epithelium leading to problems w/ Meibomian glands foreign body sensation, burning, itching crusts on lashes - Staph blepharitis
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Stye
Chalazion
acute infection of the eyelid; small, tender & painful, warm granulomatous inflammation involving the Meibomian gland of eyelid usually self-limiting
S.aureus
NOT infectious - lipogranuloma
Dacrycystitis
purulent material through the infection of lacrimal sac region, punctum
Dacryoadenitis Orbital cellulitis
prominent eye lids
inflammation of lacrimal gland
previous facial trauma obstructing the nasolacrimal passage infxn, inflamm, granulomatous hospitalization
usually spread from infection in the periorbital redness & swelling often secondary to ethmoid air cells or maxillary sinusitis, impaired/painful sinuses EOM, proptosis fever, proptosis, periorbital swelling, ophthalmoplegia (impaired eye movements)
Subconjunctival hemorrhage
hemorrhage/ blood in the conjunctiva, PAINLESS SELF-LIMITING
inadvertent rubbing or Valsalva maneuvers -->small vessel hemorrhage in the substantia propria of conjunctiva
trauma, blood thinners
if associated w/ trauma emergency! Otherwise, get better on own
Scleritis
red eye but able to see sclera vessels deep, throbbing pain worse w/ touch bleeding INSIDE the eye = OPHTHALMIC EMERGENCY! (increased IOP) White blood cells layering out INSIDE the eye = OPHTHALMIC EMERGENCY!
inflammatory condition in the front Wegener's, RA, of the eye infections
Hyphema
bleeding of iris or ciliary body vessels usually due to blunt ocular trauma --> blockage of aqueous outflow w/ RBCs --> increased IOP
tear of iris or sphincter muscle
Hypopyon
corneal abrasions (contact lenses), previous surgeries, septic emboli denuded epithelium from abrasion -> irregular fibers/ scarring in stroma --> vision loss topical antibiotic
Corneal abrasion
evident w/ Fluorescein dye
Orbital fracture
associated with blunt trauma to the eye edema & ecchymosis of eyelids & periorbital region (raccoon eye), vertical diplopia
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Optic neuritis
inflammation of the optic nerve blurry vision or loss of vision, PAIN on eye movement, central scotoma
MS
F>M ages 15-45 (younger population)
fundo exam: normal or swollen corticosteroids disc (nl if retrobulbar optic neuritis); 3m later, optic pallor MRI: acute inflammation of optic nerve; white matter lesions & plaques if MS fundo exam: swollen disc
Anterior Ischemic Optic Neuropathy
PAINLESS, permanent visual loss
ischemia to optic nerve head
DM, HTN, giant M=F cell arteritis older population (age>50) intracranial ANY age mass lesions, hydrocephalus, meningeal processes, idiopathic, venous thrombosis
Papilledema
painless, BILATERAL usually spares central vision until late peripheral vision lost early
disc edema from raised ICP
fundo exam: bilateral swelling of optic nerve heads Workup of bilateral disc edema + headache: 1. CT scan to r/o acute bleed; if nl, get brain MRI 2. abnl MRI? Hydrocephalus, mass, venous thrombosis; nl MRI? 3. get LP; if abnl - meningitis, spinal cord tumor; nl + hi pressure idiopathic intracranial hypertension; nl + nl pressure no raised ICP Vascular risk factors (smoking, HTN, hi cholesterol) ESR/CRP normal (giant cell less no acute treatment likely) secondary prevention of workup for source of emboli cerebral & ocular infarcts antiplatelets, carotid (carotid U/S or CTA, EKG, endarterectomy, mgmt of cardiac echo) vascular risk factors
Central retinal artery occlusion
sudden, PAINLESS loss of vision in ONE eye, RAPD "curtain coming down" transient
embolization of plaque material from ipsilateral carotid artery or ophthalmic artery
suspect giant cell arteritis if elderly person c/o sudden pallor of optic disc, "cherry vision loss + temporal headaches red" macula Central retinal vein occlusion sudden, painless loss of vision, swelling of optic disc, engorged retinal veins with hemorrhage Open angle: bilateral, painless, night blindness, scotomas and loss of periperal vision --> tunnel vision & blindness; exam shows increased cup:disc ratio Angle closure: severe pain a/w photophobia & blurry vision, red eye with cloudy cornea, abnl light reflex, fixed/non-reactive pupil late stages will have loss of central vision too hypercoagulable state
DM & Chronic HTN
Glaucoma
progressive optic neuropathy that meds 1/50 adults is usually a/w increased intraocular (steroids), pressure trauma, uveitis, tumors, cause depends on if open angle or neovascul angle closure: prolif (retinal open angle glaucoma: vein occlusion, decreased rate of aqueous outflow diabetic into the canal of Schlemm retinopathy, angle closure glaucoma: carotid occlusive narrowing of anterior chamber dz) angle aqueous continually being made by ciliary body + insufficient filtration out of the trabecular meshwork --> increased IOP & axonal death (infero/superotemporal axons affected first) --> enlarged optic cup
FH (6x risk) A.A., Hispanics, elderly
penlight test: shadow produced on nasal side (bc iris is domed up blocking the light across the iris); do not dilate this patient's pupil!!
Pilocarpine systemic carbonic anhydrase inhibitor to lower pressure enough for surgery iridotomy or ididectomy
blindness!!!!!
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Uveitis
pain + blurry vision, miotic inflammation of uveal tract (iris, pupil, adhesions btwn iris & ciliary body, choroid) --> WBCs in the aqueous humor anterior lens capsule, red eye + photophobia most common cause of permanent vision loss in ELDERLY degeneration of maculr retinal pigment epithelium
sarcoidosis, ulcerative colitis, ankylosing spondylitis FH, Caucasians, females, light eyes, smoking, heart dz, HTN, UV light exposure, poor nutrition, AGE
check CXR for hilar adenopathy if suspect sarcoid!
Macular degeneration
vitamin therapy to prevent progression from dry--> wet?? (at least eat healthy!!)
CMV retinitis
dry type: thinning of retina & formation of yellowish white slow, progressive loss of deposits (drusen) fine vision (inability to see centrally, unable to see faces) wet type: extension of dry type Drusens (yellow deposits) if where neovascularization of choroid vessels --> subretinal dry; hemorrhages if wet hemorrhage --> death of retinal cells, blind spots & distorted vision most common cause of blindness in AIDS cotton wool exudates + retinal hemorrhages #1 cause of worldwide blindness opacity of the lens
Cataracts
congenital (rubella) adult (agerelated)
epithelial cells of lens capsule constantly divide --> thickening/ hardening of lens over time --> cataract formation
advanced age, DM, infection, corticosteroid use
cataract extraction procedures (most common smudges on retroillumination - surgery in U.S.) subcapsular white cortical cataracts - DM
glare with bright lights, unable white cortical to drive at night - think cataracts posterior subcapsular (DM) posterior subcapsular cataract (DM, steroid use) Malignant tumors of the eye Retinoblastoma - kids, white eye reflex malignant melanoma adults "near sightedness" = unable to see far Enucleation
Myopia
focal point falls short of the retina so the focus of light is now in the vitreous cavity --> blurry vision all uncontrolled diabetics have blurry vision bc glucose enters the lens --> osmotic change in the lens --> myopia
concave lens - causes parallel light rays to diverge, moving the focal point back to the retina
Hyperopia
"far sightedness" = unable to see close
Astigmatism
eye is smaller than normal so rays of light strike the retina BEFORE they come into focus abnormalities in cornea and/or lens causes the eye to lose it spherical shape
convex lens - pulls the focal point forward back onto retina glasses or toric contact lens
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
Presbyopia
"wise old owl has presbyopia"
loss of ability to accommodate, which normally occurs when you look at something close normal accommodation occurs when the ciliary muscle constricts, making the lens fatter & moving the focal point to the FRONT of the retina (instant myopia) (accomodation --> pupil constriction as object moves closer to eyes) with age, the lens proteins become stiffer
ages 40-50
reading glasses
Rubiosis iridis
Blood vessels seen in the iris Neovascularization of the lens/ iris occuring when the retina undergoes ischemia --> increased increased IOP VEGF --> increased blood vessels in abnormal areas of the eye
neovascular glaucoma, DM (proliferative diabetic retinopathy), central retinal vein occlusion
Ectropion
red eye + abnl conjunctiva epithelium red eye + eye infection usually
eye lid turns outward exposing the tear film and causing red eye eye lid turns inward disrupting the corneal epithelial cells and tear film causing red eye & infection (usually from eyelashes scratching cornea) hi glucose levels -> inc aldose reductase --> inc sugar alcohol by products --> loss of pericytes in endothelium of retina --> outpouching of blood vessels & bleeding/edema of retina
Extropion
Diabetic retinopathy
(general)
requires abnl glucose for 10-12y #1 cause of new adult cases of blindness 1. weak blood vessel walls 2. edema 3. neovascularization 4. bleeding
>70% of pts HbA1c > 7.0 w/ uncont DM uncontrolled HTN, renal dz, pregnancy, anemia longer duration of DM
tight glycemic control + control of HTN + laser therapy
Nonproliferative
lipid exudates + microaneurysms macular edema --> dec visual acuity
lack of retinal capillary endothelial integrity --> microaneurysms + fluid/ protein/ lipid exudates
trypsin digest microaneurysms, capillary drop out
macular edema (If exudates accumulate in central retina)
Proliferative
increased microthrombus formation --> retinal ischemia --> neovascularization of iris & release of VEGF--> neovascularization into vitreous retina cavity --> hemorrhage of these weak vessels --> retinal pre-retinal or vitreous detachment hemorrhage profound vision loss
Disease
Clinical Variants
Pathogenesis
Etiologies
Epi
Risk factors
Lab/Imaging
Treatment
Complications
HTN retinopathy
av nicking, cotton wool spots (if infarct in nerve fiber layer), hard exudates (infarct in deeper retinal layers), macular stars, hemorrhages are not present unless GRADE 4 HTN retinopathy painless, FLASHING lights/ falling stars/ FLOATERS followed by shadow in periphery vasculitis affecting medium-sized temporal headache + transient, monocular visual vessels loss in ELDERLY SUSPECT THIS DX W/ ANY systemic symptoms (weight NEURO-OPHTHALMOGIC loss, fatigue, headache, scalp COMPLAINT IN ELDERLY tenderness, jaw claudication, PATIENT!!!! hi ESR/CRP) 25% pts have ischemic complications involving eye & orbit (ischemic optic neuropathy, choroidal ischemia, central retinal artery occlusion, diplopia, cerebral ischemia, ocular ischemia) age >50 (usually 70s,80s) abnl ESR/ CRP (suggests systemic process) start IV steroids STAT if suspect this dx follow pt for corticosteroid side effects (BMD, etc)
Retinal detachment
Temporal (giant cell) arteritis
temporal artery bx to confirm Corticosteroids for 2y can save the other eye! dx
any diagnosed seizure? No driving or operating heavy machinery, swimming, bathing in tubs, ladders until seizure free avoid alcohol, sleep deprivation urge AED compliance f/u MRI
Framingham stroke risk score (age, untx SBP or tx SBP, DM, smoking, CVD, Afib, LVH) 2ndary prevention? Antiplatelet tx (aspirin if atheroscl, small vessel dz), anticoag tx (coumadin if cardioemb, hypercoag), carotid endaterectomy if stenosis lifestyle mods >> meds
PD progresses within 15-20y timeframe
genetic testing not done in unaffected children at risk!
w/I 15y of dx: 80% of pts have functional impairment, 50% are unable to walk, 70% are unable to work
patient autonomy
must talk to family members about what to expect as brain dead testing is done (spontaneous movements after brain death) give family the option to withdraw care! Organ donation
inactivated polio vaccine!
progression & life expectancy ~ age of onset
nutritional & caregiver education end of life decisions hospice
Concerned about use of OCP, stroke/ HTN/ OSA risk in migraine patients
VERY CONTAGIOUS!!! Avoid social contacts!
comprehensive eye exam for everyone after age 40 early eye exams if FH
smoking cessation wear sunglasses, get eye exams, eat healthy, control vascular dz
prevention involves controlling comorbidities
T1DM: dilated eye exam q 3-5y within dx & yearly afterwards T2DM: dilated eye exam @ time of dx, yearly afterwards
Bacteria
Classification
Gram +/-
Morphology
Characteristics
Streptococcus pyogenes
GAS
Catalase neg Facultative anaerobe hyaluronic capsule Cocci in pair/chains (mucoid appearance) strongly B-hemolytic Bacitracin susceptible
Staphylococcus aureus
Cocci in grape-like clusters
Catalase + Coagulase + (good test to distinguish S. aureus from other Staph) Facultative anaerobe Beta-hemolytic Mannitol + Yellow colonies (CoPS)
N. gonorrhea
Intracellular diplococci associated with neutrophils
Oxidase+ grows w/ CO2
Virulence factors
Diseases
Strep throat M surface protein (anti(pharyngitis) phagocytic; Rheumatic fever superantigen; >90 Impetigo types) Strep TSS Glomerulonephritis SPEs (superantigens SSTIs that superstimulate T Cellulitis cells --> inflam Erysipelas cytokines) NF CA-MRSA: SCCmec type IV cassette w/ methicillin resistance; PVL (toxin that kills leukocytes by forming SSTIs pores in their Cellulitis membranes); PFGE NF type USA 300 SSI Endocarditis General: Catalase + Pericarditis (anti-phagocytic), Pyomyositis clumping Meningitis factor/techoic acid/ Food poisoning proteins A&B TSS (adherence), lipases (abscess formation), leukocidin (lysis of phagocytes), MANY toxins! Resistant to human serum - Por1A
Population
Disease
Risk factors
Transplant patients
Age UV exposure Type 1- 3 skin Duration of immunosuppressants Skin cancers Intensity of immunosuppressants HPV Hx of skin cancer CD4 lymphopenia
Skin break Human bite (mouth pathogens) Cat bite/puncture Dog bite/puncture Fresh water Salt water/fish Aquarium Spa/ hot tub Trauma Cirrhosis & salt water Edema
Pathogen Eikenella corrodens Pasteruela multocida C. canimorsus Aeromonas hydrophilia Erysipelothrix rhusiopathiae Mycobacterium marinum Psuedomonas aeruginosa Gas gangrene Vibrio vulnificus Streptococci
S P A C E K
Nosocomial Infections Serratia Pseudomonas Acinetobacter Citrobacter Enterobacter Klebsiella

Skin Cancer Guide: Actinic Keratoses, BCC, SCC, Melanoma

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Skin Cancer Guide: Actinic Keratoses, BCC, SCC, Melanoma

Uploaded by

Copyright:

Available Formats

Disease

Actinic Keratoses (AK)

Hypertrophic AK (thickened), pigmented AK, actinic chelitis (lips)

sun exposure immunosuppression genetic conditions

Histology? Surface changes at epidermis

Most common precursor to SCC

750,000 new cases/yr, growing incidence among younger ages (30-40s)

male, older age, fair complexion, tendency to burn, outdoor occupation

Basal Cell Nevus Syndrome (BCNS)

Loss of taste (and ultimately anorexia) is a side effect of tx

Squamous Cell Carcinoma (SCC)

250,000 new cases/yr; growing incidence among younger ages (30-40s)

Heart/lung transplant recipients Chronic lymphocytic leukemia XP

Arise from melanocytes

can be sporadic or familial

Giant Melanocytic Nevus

Relative risk for melanoma depends on size of CN

Xeroderma pigmentosum (XP)

High rate of MM, SCC, freckles

Major risk factor for nonmelanoma and melanoma skin cancers

Inherited disease causing generalized scaling and thickened skin

Excess stratum corneum due to altered epidermal differentiation

Excess stratum corneum from low epidermal turnover

Genetic defects w/ keratin (arginine at position G of alpha-helix heptad is mutated)

Premature stop codon in collagen VII genes

Epidermolysis bullosa acquisita Bullous pemphigoid (BP) Bullous pemphigoid

Autoantibodies against BPAG1 and/or BPAG2

Mucus membrane pemphigoid

red line along gingivial sulcus (white picket fence), no scarring

Autoantibodies against BPAG2, laminins, integrins

Ocular cicatricial pemphigoid Pemphigus Pemphigus vulgaris

side effects of steroids; high fatality w/o tx

Pemphigus foliaceus Ectodermal Dysplasia N/A

Albinism Vitiligo Keloid Panniculitis onychomycosis Dermatitis

side effects of steroids

Atopic Dermatitis (AD)

Stasis Dermatitis (SD)

Often require hospitalization for tx of Can be complicated by LSC venous ulcers

Lichen Simplex Chronicus (LSC)

Contact Dermatitis 1. Irritant 2. Allergic (ACD)

People living in warm/ humid climates have higher bacterial carriage

Pityrosporum folliculitis Bacterial folliculitis Bacterial folliculitis

Follicular centered inflammation on chest or back

Inflammation of hair follicle due to fungal colonization/infection

Histology? Massive infiltration of neutrophils around hair follicle

Do NOT give topical steroids!

Clinical (pustules/papules w/ hair follicle in middle) Gram stain/Cx

Hot tub folliculitis

Exposure to Pseudomonas in water that has not been sufficiently chlorinated

Bullous impetigo (S. aureus) Impetigo Impetiginized eczema (2ndary inf)

Small vesicles/pustules, erosions w/ golden honey-colored crust

Increased incidence in SE, day care settings

Childhood Crowded areas Heat/humidity

Clinical (honey crust) Gram stain/Cx

Furuncle (smaller) Furuncles/ Carbuncles Carbuncle (larger!)

Chronic S. aureus carrier Folliculitis Obesity Immunodeficiency

Clinical Gram stain/Cx

Culture w/ sensitivity testing

NO beta-lactams, possible adjunct therapy Use Bactrim or clindamycin

Erythromycin & methicillin resisitant

Filamentous fungi (Microsporum, Trichophyton, Epidermophyton)

Verruca plantaris Condylomata acuminata Filiform warts Verruca plana