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Disease

Actinic Keratoses (AK)

Clinical Variants

Hypertrophic AK (thickened), pigmented AK,


actinic chelitis (lips)

Nodular (can be pigmented in darker pts)


Basal Cell Carcinoma
(BCC)

Superficial (more scaly, less thick)


Morpheaform (scarring, loss of pigment;
MORE AGGRESSIVE)

Basal Cell Nevus


Syndrome (BCNS)

N/A

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

Defining Characteristics

small, raised scaly spots on chronically sun-exposed skin;


scattered, thick erythematous patches

Pathogenesis

UV induced mutations in p53 cause unrestrained growth and


damage to repair genes prevents tumor rejection

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

TONS of BCCs as child, megaloblastomas, palmar pits, bifid


ribs, frontal bossing of scalp

Asymptomatic until fast growing --> painful, grows faster than


BCC, ulceration/ verruca-like, common in transplant pts,
metastatic potential

Etiologies

Epidemiology

sun exposure
immunosuppression
genetic conditions

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)

Risk factors

Lab/Imaging

Treatment

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

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

Deficiency in patch (negative regulator of Shh) causes


constitutive action of positive regulator (Shh), increasing
incidence of BCC

Vismodegib (targets Shh to


decrease tumor size; but still
residual tumor so perhaps
development of resistance)

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)

250,000 new cases/yr;


growing incidence
among younger ages
(30-40s)

Complications

Most common precursor to


SCC

Loss of taste (and ultimately


anorexia) is a side effect of tx

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

Heart/lung transplant recipients


Chronic lymphocytic leukemia
XP

genetic mutations (MC1R


mutations- red hair &
predispose to B-raf mut;
familial loss of p16)
less common than other skin cancers (BCC>SCC>>MM)

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!)

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

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

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

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)

later detection and higher stage


associated with higher mortality
Pts with p16 mutations have
increased risk of pancreatic
cancer too!

Braf inhibitors (PLX4032) prolongs survival but not curative

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

Benign Nevi

Dysplastic Nevi

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)

Congenital Nevi

Giant Melanocytic Nevus

Present at birth or within first year of life; important to monitor


changes in size/color/symmetry

Xeroderma
pigmentosum (XP)

N/A

marked increase in skin malignancies at young age,


photosensitivity, impaired DNA damage repair systems

Arise from melanocytes

can be sporadic or familial

b-raf mutations

Relative risk for melanoma depends on size of CN

N-ras mutations

Prophylactic removal during teen


years; staged surgical removals if
large

At least 10 DNA repair


defects

New tx include mimics of


photolyases (enzymes in other
organisms that repair CPDs)

Defective NER (nucleotide excision repair);


accumulation of oxidative and DNA damage
Determined by total UVB energy absorbed (ind of duration)

Sunburn

N/A

Inflammation, erythema

Inflammation (cytokines, histamine, prostaglandins, serotonin)


cause redness; increased adhesion protein expression -->
immune cell recruitment

Failed or incomplete
repair of thymine dimers
--> mutations in p53
(higher risk for nonmelanoma skin cancers)

Change in existing melanin (immediate pigment darkening


caused by redistribution of melanin - IPD, persistent pigment
darkening- PPD)
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

Ichthyosis

Psoriasis

N/A

Inherited disease causing generalized scaling and thickened skin

Excess stratum corneum due to altered epidermal


differentiation

Localized scaly plaques, can be raised; less prone to infections


(abundant AMPs)

Excess stratum corneum from low epidermal turnover

mutations in filaggrin
(which binds to keratin)
causes
bundling/collapsing of
keratin fibers

Histology?
Endothelial swelling, decreased langerhans, neutrophil
recruitment, apoptotic keratinocytes (bright pink)
areas of hyperplasia (thickened stratum corneum,
epidermis, dermis)

High rate of MM, SCC, freckles

Major risk factor for nonmelanoma and melanoma skin


cancers

Disease
Epidermolysis bullosa
(EB)

Clinical Variants
(General)

Defining Characteristics
blisters on hands and feet

Pathogenesis

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)

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

Complications

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
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
Blistering in the lamina lucida

Can be lethal in early childhood

sometimes defects w/
collagen 17 or B4/a6
integrins

Subepidermal blistering w/ scarring


Dystrophic (Recessive-RDEB or DominantDDEB)

Epidermolysis bullosa acquisita

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

Premature stop codon


in collagen VII genes

Severe scarring

Autoantibodies against
Collagen VII

Significant scarring

Bullous pemphigoid (BP)


Bullous pemphigoid

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

Autoantibodies against
BPAG1 and/or BPAG2

Autoantibodies against
BPAG2, laminins,
integrins

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

Ocular cicatricial pemphigoid

severe ocular disease, symblepharon (fibrous bands where


eyelid fuses to conjunctiva)

Severe inflammation of the eye causes thick & fibrous scarring


that fuses with the eye conjunctiva as symblepharon

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
Possible blindness as skin covers
cornea if no aggressive treatment

Pemphigus
Pemphigus vulgaris

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]

Chronic 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

Subacute dermatitis

Lichenification and spongiosis with crusting on surface

Pemphigus foliaceus
Ectodermal Dysplasia
N/A

Albinism

N/A

Vitiligo

N/A

Keloid
Panniculitis

N/A
N/A

onychomycosis

N/A

Dermatitis

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

General
Acute dermatitis (eczema)

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)

side effects of steroids; high


fatality w/o tx

Immunosuppressants,
corticosteroids

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

Hypersensitive, twitchy skin - overreaction to various stimuli,


causes skin to turn red--> white when scratched; same
"twitchiness" also seen in lung/nasal membranes

Atopic Dermatitis (AD)

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

Once child outgrows


AD, can have asthma/
allergies later; higher
prev in developed
countries suggest
environmental factor

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)

20% of children, 1% of
adults
"childhood eczema"; 2More common if parent has AD
3x more common now;
more developed
countries

Hygiene hypothesis? overreaction upon antigen exposure due


to "too clean" of environment

Lichen Simplex Chronicus (LSC)

Acne

Tinea versicolor

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

Contact Dermatitis
1. Irritant
2. Allergic (ACD)

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

Seborrheic Dermatitis

variation of dandruff, can be on scalp/face

N/A

N/A

hyper- or hypopigmented patches with readily inducible scale;


chest & back; warm/moist environment; usually asymptomatic
but may be pruritic

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

Probably all of these!


Abnormal circulation in skin comprises the skin barrier, causing
dryness and inflammation --> itch --> LSC & SD

Stasis Dermatitis (SD)

Complications due to abnl barrier


function of skin or abnl immune
response?

Often require hospitalization for tx of


Can be complicated by LSC
venous ulcers

Venous insufficiency

Can complicate other types of


dermatitis

Histology? Acanthotic
1. irritant - not allergic,
but burned/inflamed by
substance (occur in
anyone exposed)
2. Allergic - allergy
response (poison ivy,
does not occur in
everybody)

Patch testing

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

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)

People living in warm/ humid


climates have higher bacterial
carriage

Do NOT give topical steroids!

Possible scarring

Disease

Clinical Variants

Pityrosporum folliculitis

Defining Characteristics

Follicular centered inflammation on chest or back

Pathogenesis

Inflammation of hair follicle due to fungal colonization/infection

Etiologies

Epidemiology

Hot tub folliculitis

Follicular centered pustules or erythematous papules that are


slightly pruritic and/or tender

Diffuse folliculitis

Bacterial infection of hair follicles transmitted from direct


contact with infected person or autoinoculation

Exposure to Pseudomonas in water that has not been


sufficiently chlorinated

Lab/Imaging

Treatment

Complications

People living in warm/humid


climates

Histology? Massive infiltration of neutrophils around hair


follicle

Responds to anti-fungal tx

Do NOT give topical steroids!

S. aureus, occlusion of
non-dermatologic areas

Chronic S. aureus carrier


Irritation
Shaving
Occlusion

Clinical (pustules/papules w/ hair follicle in middle)


Gram stain/Cx

Topical Abs
Oral Abs (if extensive, recurrent)

Abscess formation

Bacterial folliculitis
Bacterial folliculitis

Risk factors

Hot/humid environment
AB use
Immunosuppressant
Hi sebum prod

Pseudomonas
aeruginosa

Clinical

Self-limited Sx usually don't require


tx
May give Ciprofloxacin if needed

Bullous impetigo (S. aureus)


Impetigo
Impetiginized eczema (2ndary inf)

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

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


crust

Superficial bacterial infection of epidermis caused by S.


aureus, GAS; highly contagious (direct contact)

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, GAS

Increased incidence in
SE, day care settings

S. aureus

Localized? Topical antibacterial


cream (Mupirocin)

Childhood
Crowded areas
Heat/humidity

Clinical (honey crust)


Gram stain/Cx

Chronic S. aureus carrier


Folliculitis
Obesity
Immunodeficiency

Clinical
Gram stain/Cx

Widespread? Oral Abs


(Dicloxacillin, cephalexin,
erythromycin, etc)
Drainage (hot compresses or
surgical)
Oral Abs (dicloxacillin,
Cephalexin, Bactrim)

Rare

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

CA-MRSA

asymptomatic --> fatal

Dermatophytosis

Tinea pedis (athlete's foot)


T. unguium (onychomycosis)
T. cruris (jock itch)
T. corporis/faciei (ring worm)
T. capitis (cradle cap)

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

Verruca vulgaris

Verrucus (bumpy/rough), hyperkeratotic skin colored papules;


usually asymptomatic unless 2ndary infection/inflammation

Filamentous fungi
(Microsporum,
Trichophyton,
Epidermophyton)

Often none
Humid/occluded skin
Common infection even
Atopy (eczema)
in healthy hosts
Immunodeficiency
TOPICAL STEROIDS

HPV 2, 4

VERY common
20% of kids have at
some time

HPV 1

Common in adults

Verruca (warts)

Condylomata acuminata
Filiform warts

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

Verruca plana

Pinkish warts common on hands/face

Verruca plantaris

Molluscum Contagiosum N/A

Herpes Simplex Virus


(HSV)

Varicella Zoster Virus


(VZV)

HSV-1 (classically oral)


HSV-2 (classically genital)

Umbilicated (central), small, dome-shaped, pink papules

PAINFUL, TENDER grouped vesicles or erosions on


erythematous base; prodrome (tingling); can occur on lips,
finger (Whitlow), genitals

Increased prevalence
as SSTI, furunculosis;
can cause infections in
Pts lack typical risk factors
pts typically lacking
RFs for MRSA
(hospital/prison/ sports)

HPV

Children
HIV
Sexually active young adults

Superficial poxvirus infection of epidermis only transmitted via Molluscum


skin to skin (considered STD in young adults)
contagiosum virus

HSV infection of keratinized skin/mucus membranes


transmitted skin-skin, skin-mucosa (possible STD)

PAINFUL, DERMATOMAL vesicles, crusted papules,


erosions often in unilateral fashion

(Shingles)

NOT contagious (represents reactivation state) but patients


with varicella zoster can transmit chicken pox to those who
have never had it

Varicella zoster virus

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

Lifetime risk of 10-20%

Topical anti-fungals (Azoles,


TOPICAL STEROIDS CAN
allylamines: naftifine, terbinafine) MAKE WORSE!!!
Oral anti-fungals (azoles,
allylamines, griseofulvin) for
hair/nail infections

Nail disfigurement (rare)


Alopecia

Spontaneously resolution (SLOW)


Histology? Hyperkeratosis of epidermis and granular
layer, inward bending of rete ridges, papillomatosis
(fingerlike projections of epithelia)

Clinical
Crush prep
Bx (rare)
Histology? Henderson-Patterson bodies (eosinophilic
inclusion bodies)

None - pretty ubiquitous virus

Clinical
Tzanck prep (cannot distinguish HSV from VZV)
Direct fluorescent antibody (CAN distinguish HSV from
VZV)
Viral culture
Bx (rare)

advancing age
immunosuppression
Stress!

Clinical
Tzanck prep
DFA (distinguish HSV from VZV)
Viral Cx
Bx (rare)

Latency phase, asymptomatic shedding

Erythromycin & methicillin


resisitant

Use Bactrim or clindamycin

Clinical
Bx (rare)
DNA testing to determine type of HPV present

VZV goes latent after active infection/vaccination in the ganglia


until risk factors cause reactivation of varicella zoster virus
N/A

Often none
HIV
Organ transplantation

Culture w/ sensitivity testing

NO beta-lactams, possible adjunct


therapy

Various OTC tx modalities that


aren't all that effective
(Salicylic acid, imiquimod, duct
tape)

possible some HPV types are


cancer-forming

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

Potential risk for wide-spread


dissemination
Neonatal transmission
POST-HERPETIC NEURALGIA

ORAL ANTI-VIRALS ASAP!! (w/I


first 48-72h)

dissemination
transmission of varicella (chicken
pox)

Topical creams (scabicides)

Scabies

N/A

Carbuncles w/ pus present? Think S. aureus


Cellulitis
Diffuse erythema w/ no pus? Think GAS

Eryisipelas

Diabetic foot ulcers

N/A

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

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)

Raised, sharply demarcated erythematic lesions, commonly


seen on face; acute onset

Acute infection caused by GAS entering the upper dermis

Group A Strep

Infection by S. aureus or B-hemolytic Streptococci


Often polymicrobial infection with enterococci, obligate
anaerobes, P. aeruginosa, and/or Enterobacteriaceae

Necrotizing fasciitis (NF)

Polymicrobial

Gas gangrene
(myonecrosis)

N/A

Deep incisional (fascia/muscle)


Organ/space

EMPIRICAL KNOWLEDGE (cx not always positive, low


sensitivity of needle aspiration cx)

Initial break in skin from trauma or surgery causes advancing


infection to fascial and/or muscle compartments

Less common in
children
Aerobic + Anaerobic
bowel flora

Rapidly progressive, toxemic infection in previously injured


muscle (blunt trauma), edema, crepitus (gas bubbles),
brown bullae; abrupt pain

Blunt trauma causes non-viable tissue to lose blood supply,


creating anaerobic environment for spore-forming, gram
positive rod bacteria to infect injured muscle

Can be early onset or take 5-14 days

Adverse infection associated with hospitalized patients who


have undergone recent surgery

treatment of fomites and close


contacts

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

Rare (psychological burden?)

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

clindamycin
Unasyn (ampicillin + SulbactamIV)
GAS, S. aureus, or
anaerobic
streptococci

Initially presents with cellulitis, blood-filled bullae,


ecchymosis, systemic toxicity, elevated CPK

Superficial incisional
(subq space)
Surgical Site Infections
(SSI)

Mineral oil prep? Mites with oval gray eggs and fecal
pellets

Less common than


cellulitis

Chronic

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

Previous cutaneous damage


(trauma, ulceration, fissured toe
webs, inflammatory dermatoses)
Obesity
Edema (venous insufficiency,
lymphatic obstruction)

Histology? Mites (ovals) in stratum corneum

More common in
infants/ children/ elderly

Acute

Monomicrobial

Nursing home residents


Children
Hospitals
Close contact areas

NSAIDs
Diabetes
Venous insufficiency
Completely normal hosts
Abdominal Surgeries
Decubitus ulcers
Perianal ulcers
Bartholin abscess
IVDU
h/o severe penetrating trauma
or crush injuries

Inherent risk with clean


contaminated, contaminated,
or dirty-infected operative
wounds

Possible CA-MRSA infection


associated with worse outcomes

Extensive debridement, surgery


Monomicrobial - clindamycin +
penicillin G

Usually bacteremic
30-60% mortality

Polymicrobial - Ampicillin,
clindamycin, and ciprofloxacin
Aggressive surgical debridement
XR shows edema and gas in soft tissue
PCN + clindamycin

Prophylactic superficial
antisepsis
Perioperative ABs
Incision & Drainage

Spontaneous (hematogenous)
gangrene from Clostridium
septicum in pts with GI
malignancies or neutropenia

Disease
Osteoporosis

Clinical Variants
N/A

Defining Characteristics
BMD T-score < -2.5, increased incidence of fractures

Pathogenesis

Etiologies

skeletal disorder characterized by compromised bone strength


(bone density & bone quality- arch, turnover, mineralization,
damage accum) predisposing a person to increased risk of
fracture

Loss of bone
trabeculae
(microarchitectural
deterioration)

With age, lose trabecular volume, #, thickness, connectivity

Genetic predisposition

Decreased estrogen is related to high bone turnover that


results in stressful micro-cracks and loss of bone density

Estrogen deficiency
activates immune
response

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

Epidemiology

Risk factors

Lab/Imaging

Age
Postmenopause
FH of osteoporosis

Treatment
Low dose Ca/VitD
Estrogen
calcitonin
raloxifene (estrogen Ag in bone,
Antag in breast)
Bisphosphonates -Alendronate,
Zoledronic acid (Reclast)

Adjustable RF?
Excessive alcohol
sedentary lifestyle

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

Anti-RANKL Ab - Denosumab

Increased RANKL

Anabolic agentForteo (teriparatide) - transient


PTH = bone formation
Odanacatib - Cat K inh
Sclerostin Ab

Polyostotic
Paget's disease
Monostotic

Autosomal recessive infantile malignant (ARO)

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 #)

Osteopetrosis
Autosomal dominant (Albers-Schonberg)
(ARO)

Spine sclerosis with sandwich vertebrae (rugger jersey


spine), variable penetrance/ severity
Disproportionate (big head, small body), pectus excavatum,
lumbar lordosis, nail hypoplasia (missing nails)

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

Carbonic Anhydrase II
deficiency

Progressive Diaphyseal
disease

Camurati-Engelmann

Endosteal hyperostosis
Sclerosteosis

Van Buchem

Worth type

Fibrodysplasia ossificans
N/A
progressive (FOP)

Osteomyelitis

Acute

Chronic

Hematogenous

gradual appearance of symmetric hyperostosis on periosteal


and endosteal surfaces of long bones

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

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)

Age
200,000 cases in U.S.
(~3% prev)
5-20% w/ symptoms
M>F

Bone scan? show sclerotic dz

Bone overgrowth due to Infancy


loss of osteoclast
resorptive fx
Late childhood/
adolescence onset

Mutation in CAII renders the cell unable to generate protons


from CO2 and H2O, causing loss of osteoclast resorptive
function and generalized disease

Bone overgrowth due to


loss of osteoclast
resorptive fx

mutation in TGF-B1, a latency protein that is a normally a


chronic sequesterer and inhibitor of TGF-B in bone

Unregulated TGF-B
causes overstimulation
Variable age, severity,
of osteoblasts and
course
excessive bone
formation

Osteoclast number, anemia labs

hypercalcemia tx if know pt will be


immobilized

Bone marrow transplantation

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]

hypercalcemia (immobilization)

Cranial nerve compression -->


blindness, deafness

Fractures, osteomyelitis, possible


nerve compression

XR? Dense orbital ridge, sclerotic skull base, hypoplasia


of facial bones, dense vertebrae w/ preservation of TVP

Recurrent fractures in lower


limbs

UA - check for RTA


Measured in erythrocytes

Glucocorticoids for pain relief

Autosomal recessive inheritance

Deactivating mutation in
SOST (Wnt inhibitor)

Dutch ancestry (Afrikaners)

Nl OC
Possible inc alk phosphatase
Possible optic atrophy, facial
nerve palsy, deafness

Deactivating mutation in
SOST (Wnt inhibitor)

Autosomal recessive inheritance

Mutation in LRP5,
prevents binding of
DKK1 (Wnt inhibitor)

Autosomal dominant inheritance

Patients usually die of R heart


failure, Pulmonary HTN

Excessive BMP
stimulation -->
increased osteoblast
formation

NO BIOPSY!!!!
Require wheelchair by 3rd
decade
More common in kids

XR? Moth eaten appearance of bone

Ortho surgeries

Kids- S. aureus, GBS


(infants), CoAN staph
Elderly- S. aureus,
Gram-

Nl OC
Possible inc alk phosphatase

Assess response after tx with ESR, CRP

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

IVDU- S. aureus, P.
aeruginosa, Serratia

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

Contiguous

Osteosarcoma!! (10% of older


pts) - but no inc in non-skeletal
malignancy!

Death by 10y.o. if not treated

Sickle cell- S. aureus,


Salmonella

increasing pain, skull/mandible/ small bones hand/ long


bones/feet, mild fever, minimal drainage

Fractures

XR? Rugger jersey spine

Immunocomp - fungi
IV DRUG USERS? Sternoclavicular joint, SI joint, pubic
bones

Advanced disease? Use


osteoporosis drugs
(bisphosphonates, since they too
kill osteoclasts)

Spinal cord/nerve root


compressions

Autosomal recessive

untreated acute osteomyelitis

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)

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)

sx? NSAIDs, COX2 inh, PT,


surgery for fx

Pagetic bone is hemorrhagic so


activity needs to reduced before
surgery

gout (23% of pts w/ gout have


paget's)

Mutation/defect in cathepsin K, so osteoclasts can no longer


function properly in bone resorption

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

Occurs over weeks/months/yrs; necrotic bone w/ loss of


vascular supply, swelling

Histology? Woven mosaic bone


adult disease (~60y.o.)

Onset in infancy, early


Bone overgrowth due to
childhood
loss of osteoclast
resorptive fx
Very rare!

TALL, heavy, Dutch ancestry, syndactyly, pain w/ point


pressure on long bones

Elevated bone-specific alkaline phosphatase (overactive


osteoblasts, >2x inc)

More common in people


from British Isles,
Caucasians

Most people are asymptomatic

Possible polymicrobial
(see diabetic foot ulcer
bacteria)
Mixed gram+/-,
anaerobes

MOST common in
adults

Chronic skin ulcers (arterial


sclerotic dz), trauma, diabetes,
post-op ortho surgery, chronic
edema

Imaging hard to interpret bc surrounding soft tissue inf

Revascularization

Bone scan sometimes reveals contiguous spread from


ulcer site

Amputation/ surgical debridement

Bone sample for culture

Abs for 4-8wks (Avoid empiric ab


tx)

Disease
Septic arthritis

Clinical Variants

Defining Characteristics

Pathogenesis

Etiologies

Epidemiology

Acute bacterial
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

Disseminated gonococcial infection (DGI)

Bactermic form:
Dermatitis that coincides w/ pustules/papules that are
sometimes hemorrhagic; centrifugic distribution, fever,
tenosynovitis, polyarthalgia/arthritis

S. aureus
Streptococci
GN rods

Other infectious diseases causing arthritis

Mycobacteria (Tb)
Lyme disease
Fungi
Rubella, mumps,
parvovirus

Arthritis associated with gonococcal bacteremia

Neisseria gonorrhoeae

F>M
declining incidence

Localized form:
purulent arthritis (1,2 joints)
Acute onset joint pain, effusion, erythema, warmth, fever

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)

Lab/Imaging

Treatment

Tap joint? Elevated WBC


Gram stain & cx

Sexually active young adult


Timing associated with menses
Pts w/ terminal complement
deficiencies

Cultures from mucosal sites

IV ceftriaxone

XR? Lucency at bone/cement interface, loose cemented


prosthesis

One-step procedures (remove and


replace prosthesis at same time)

Synovial fluid aspiration? Elevated WBCs w/ increased


neutrophils

Two step procedures


(debridement, removal, then
replacement later)

Joint replacement

Complications

Joint drainage (serial taps, open


procedure)
Systemic Abs 2-4wks

Synovial fluid Cx may be negative if biofilm formation


usually biofilm-forming pathogens
Hematogenous seeding from variety of sources (skin, resp,
dental, UTI)

Late (>2y)

S. aureus,
Streptococci, Gram rods, enterococci,
anaerobes, fungi (rare)

Ehlers Danlos Syndrome


(EDS)
Classical

Rising incidence w/
increased joint
replacement surgeries

Risk factors
Recent trauma (animal/ human
bites)
Immunocompromised
RA/gout/sickle cell
IVDU

Skin & joint hypermobility (Beighton's score >5 for joints),


atrophic scarring (not well healed), easy bruising,
smooth/velvety skin, hypotonia & decreased motor development

Sonication of removed prosthesis for cx

long term Ab (3-6m) for all


Clinical exam for manifestations

1/5000 individuals;
classical form is most
common

Mutation in collagen type V (COL5A1, COL5A2), disrupting


structural integrity of connective tissues

debridement and retention (stable


joint w/ early inf)

Beighton score
Autosomal dominant
baseline echocardiogram for kids <10 y.o.

Tx manifesting sx
Low-resistance exercise to increase
muscle tone
Vit. C & D, Ca supplem
Avoid high impact force

Evaluate clotting factors


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)

Autosomal dominant inheritance

Clinical & FH only


No genetic testing

Mutation in collagen type I (COL1A1, COL1A2) causes


abnormal processing of amino terminal ends

Autosomal dominant inheritance

Clinical genetic testing


Very severe - dissection of carotid
artery, arterial/digestive/ uterine
fragility or rupture

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

Clinical genetic testing

Dermatosparaxis

Severe skin fragility, sagging/redundant skin, large hernias Deficiency in type I procollagen N-peptidase

Autosomal recessive
inheritance

Clinical findings only (no genetic test!)

Kyphoscoliosis

Generalized joint laxity, severe hypotonia and scoliosis at


birth, scleral fragility, rupture of ocular globe

Mutation in PLOD1 causes decreased lysyl hydroxylase in


dermis and loss of connective tissue cross-linking capabilities

Decreased lysyl
hydroxylase

Autosomal recessive
inheritance

Clinical genetic testing

N/A

Extremely tall (arm span longer than height), long fingers,


dilated aortic root, ectopia lentis-dislocated lens, pectus
carinatum OR pectus excavatum

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

Abnl Fibrillin protein

Celiprolol (cardioprotective)

80% develop significant med


probs by age 40
Sudden death (median age 48)

Marfan Syndrome

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

Clinical exam tests? Walker Murdoch wrist sign,


Steinberg thumb sign

3 collagen genes:
COL2A1, COL11A1,
COL11A2

Autosomal dominant inheritance


Genetic testing
Multiple family members affected

Point mutations with


dominant-negative
Prev? 6-7/100,00
effects cause structural
defects in collagen

Most autosomal dominant


inheritance

Currently testing use of angiotensin


II type I receptor antagonist
(Losartan)

Type 1 - mild sx, fx w/ minor trauma, no bony deformities,


bluish-grey sclerae

Type I
Osteogenesis Imperfecta Type II
(OI)
Type III
Type IV

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

XR? Wormian bones


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

Achondroplasia

N/A

Osteoid Osteoma

Benign

Defining Characteristics
Short stature w/ disproportionately short arms/legs,
macrocephaly, frontal bossing, mid-face hypoplasia, hypotonia
in infancy, delayed developmental milestones

Pathogenesis

Etiologies

Epidemiology

Mutations in FGFR3 genes cause excessive signaling of


FGFR3, resulting in impaired chondrocyte fx w/I epiphyseal
growth plates

Risk factors

BENIGN

Osteochondroma

Osteosarcoma

Benign

Osteoblastic
Fibroblastic
Chrondroblastic
Telangiectatic
Parosteal
Periosteal
Central low-grade
Secondary

(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

Complications
Compression of spinal cord/
upper airway obstruction
increased risk of death in infancy

Histology? central nidus of woven, hemorrhagic bone


surrounded by reactive sclerosis

Males age 10-25

Remove to prevent recurrence

CT? sclerotic bone on outside w/ pinpoint middle nidus

>2cm? Osteoblastoma
Benign

Treatment

Dominant inheritance pattern

Pain in femur/tibia/vertebrae @ night, relieved by NSAIDs

Chondroma /
Endochondroma

Lab/Imaging

Residual bits of cartilage that were displaced during


development

XR? Popcorn calcifications


Histology? Benign cartilage

Occurs when bits of cartilage from the physis that get


incorporated into the bone begin to grow, producing a stalk in
the bone

Histology? Cartilage cap, bone marrow inside

None - benign
If cartilage cap >1cm, start to
worry about development into
chondrosarcoma (RARE)

Autosomal dominant disease


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)

Kids: occurs around knee


Adults: axial skeleton
M>F

Neoadjuvant therapy (Chemo


before surgery)

Histology? Periosteal rxn

Occur in the metaphysis, knee pain/swelling (loss of


ROM),weight loss (disseminated), pathologic fx w/ nl activity

80% of metastases are to the


lungs

Tumor resection, prosthesis


MRI? Soft tissue extension
CT? metastases

Trunk/pelvis/long bones; pain, swelling, resistant to


radiation/chemo (low blood supply/growth), possible
dedifferentiation (abrupt transition from low--> high grade
tumor)

Chondrosarcoma

VERY VERY RARE


M>F
Adolescents/ young
adults

XR? Popcorn calcification

Surgery only

Histology? "small round blue cell 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

Duchenne MD

Pseudohypertrophy (large calves), scoliosis, lumbar


lordosis, protuberant abdomen, toe walking, Gower's sign,
mental deficits

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.

Becker's MD

Variable onset (5-15y.o.), similar symptoms as DMD but later


onset and less severe

X-linked recessive mutation resulting in decreased dystrophin Decreased dystrophin

1/30,000 live births

Similar histology to DMD

Longer life expectancy (40-60y.o.)

Myotonic dystrophy type I

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

Maternal anticipation
Autosomal dominant inheritance associated with trinucleotide
(increases number of
CTG repeats in myotonin-protein kinase gene on C19
CTG rpts)

5-20/100,000 live births

Clinical exam

Multisystem disorder; possible


complete heart block

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

McArdle's disease

exercise intolerance w/ premature fatigue in anaerobic ex,


stiffness/weakness in exercising muscles relieved by rest;
rhabdomyolysis w/ intense ex, second wind phenomenon

myophosphorylase deficiency, preventing the breakdown of Defect in glycogen


glycogen to glucose (glycogen cannot be converted to G6P) breakdown

Carnitine palmitoyltransferase II deficiency

Recurrent rhabdomyolysis in adults after prolonged exercise


or fasting, proximal weakness later in life

Deficiency in enzyme required for transport of LCFA from


cytosol to mitochondria

Ewing sarcoma
Muscular dystrophy

Congenital Myopathy

M=F
35-60 y.o.

Metabolic myopathy

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

Most common MD,


especially in children
1/3000 live births

Asymptomatic but affected


mother --> drastic increase in
trinucleotide rpts

Autosomal dominant
defect in ryanodine

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)

Histology? Abnormal deposits of glycogen


Diagnosis needed to treat pts and
avoid recurrent hospital
admissions for renal failure

nl CK and EMG; dx requires direct measure of muscle


CPT or genetic testing

M>F

Maternal transmission, extra-muscular manifestations (in


tissues/organs w/ high met rates)
Furrowed brow, high-arched eyebrows
Mitochondrial myopathy

Histology? Ragged red fibers representing abnl


excess mitochondria

Abnormal amounts of mitochondria


Progressive External Opthalmoplegia (PEO) - ptosis,
opthalmoparesis
MELAS - stroke <40, encephalopathy, RRF, lactic acidosis
MERRF- myoclonus, epilepsy, ataxia, ragged red fibers

Inflammatory myopathy

Histology? Perifascicular atrophy, inflammation of


dermal-epidermal jx (interface dermatitis)

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)

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

Elevated muscle enzymes


Myositis specific Abs (Anti Jo-1- worse prognosis, Anti
Mi-2 -better prognosis)

F>M
Kids (more calcinosis)
& adults

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)

Increased risk of malignancy in


+/-4 yrs before/after dx
corticosteroids
Methotrexate, azathioprine (LT)
IV immunoglobulins

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)

Cell mediated immune response within the muscle


(endomysial inflammation) involving T cells &
macrophages

Histology? CD8+ T cell/mo infiltration in NORMAL


looking muscle!

Inclusion body myopathy

Most common acquired myopathy >50y.o; Distal and


asymmetric weakness of finger/wrist flexors, knee extensors,
ankle dorsiflexors

Histology? Centrally-placed nuclei, red-rimmed


vacuoles (fibers w/ holes in them)

Toxic Myopathy

Myopathy from following "toxins": Alcohol, Statins, Colchicine,


Glucocorticoids, AZT

Myopathies from
systemic dz

Myopathy associated with following systemic diseases:


Hypokalemia, Hypophosphatemia, Critical illness myopathy, or
endocrine disorders (thyroid dz, parathyroid dz, adrenal
disorders, hypopituitarism, acromegaly)

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)

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)

Pain perception
thresholds decreased
(abnl neurochem)

Fibromyalgia (FM)

Soft tissue pain disorder

F>M
Extremely unlikely in
pts <50y.o.

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)

Can be associated w/ Giant cell


arteritis

Peak onset
30-55y.o.

Corticosteroids (Should be RAPID


response if right dx)

Clinical dx

Clinical? Should not see weakness! Dramatic


pain/tenderness at pressure points

Prev? 4% of population
F>>M (10:1)

Elevated ESR/CRP
Thrombocytosis (hi platelets)
Nl CPK
Anemia of chronic dz
Negative ANA, RF

Corticosteroids

First degree relatives w/ FM (8x


higher risk!)
Mutations in serotonin gene

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)

Interstitial lung disease


Diaphragm/ intercostal
weakness --> resp arrest
Cardiac rhythm disturbance

Disease

Clinical Variants

Defining Characteristics

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]

Rheumatoid Arthritis

Fusiform swelling, SPARES THE DIP JOINT!

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)

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

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

Systemic sx (fever/malaise, poor energy, weight loss, tissue


damage in other organs)

Treatment

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

W/ age, side chains in cartilage shrink and hold less water =


less resilience & more dessication = stress fx & fissures

Osteoarthritis

Degenerative joint disease

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)

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.

SPARES MCP joints!!


Chondrocytes try to make new collagen but there is a shift
towards collagen 1, 3, 10 --> shortened proteoglycans (less
H2O retention)

Focal loss of articular


cartilage followed by
hypertrophism of
underlying bone and
formation of
osteophytes at joint
margin

Older individuals

Trauma
Infection
Crystsal dz
Neuropathy

Nl ESR/CRP/platelets
Nl hematocrit
<2000 WBC in joint fluid
XR? Osteophytes (bone spurs), asymmetric joint
space narrowing, NO PERIARTICULAR
OSTEOPENIA!

Acetaminophen
NSAIDs
Eventual joint replacement surgery

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

Disease

Clinical Variants

Episodic monoarticular
Gout

Polyarticular
Tophaceous gout

Defining Characteristics

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)

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)

Systemic Lupus
Erythematosus (SLE)

Pathogenesis

Etiologies

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

Epidemiology

Prev? Males
5-28/1000; females 16/1000

Hyperuricemia, tophi

Equal incidence after


menopause!
M>F (5:1)

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

Risk factors

>6.7mg/dL solubility of
monosodium urate crystals
Paget's, Psoriasis
certain cancers
excessive alcohol intake
Co-infection of joint

Lab/Imaging

Complications

NSAIDs- Indomethacin (acute pain


relief)
ALWAYS TAP JOINT & CULTURE FLUID! (yellow
parallel crystals)
XR? Nl mineralization, punched out erosions w/
sclerotic borders, overhanging edges

Age onset? M 40-50; F


postmenopause

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)

Treatment

Colchicine (acute pain relief,


prophylactic w/ LT meds)
Probenecid (chronic gout)

Initial tx for chronic gout can


actually increase the severity/freq
of acute attacks so take
prophylactic colchicine
simultaneously

Allopurinol (chronic gout)

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

Others?
Antimalarials (hydroxychloroquine)

Accelerated atherosclerosis

Systemic corticosteroids for serious


complications

Prev? 1/2000

Immunosuppressants for steroidresistance

Chronic fatigue!
Raynaud's
periungal erythema
Cutaneous vasculitis (palpable purpura)
Seen w/I first few months of life
Neonatal lupus

Mom w/ lupus

erythematous pathces that form blanchable rings on


head/neck

Drug-induced lupus

Lack skin findings, systemic arthalgias/inflammation

Thrombocytopenia
Anti-rho antibodies

congenital heart block

Positive ANA

induced/triggered by procainaminde, hydralazine, quinidine

Scleroderma (SS)

Major organ involvement!

(General)

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

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

Lung impairment (dyspnea on


exertion, cough, pulmonary
fibrosis)

Positive ANA, Anti-Scl-70 (nucleolar pattern ANA), Anticentromere

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

Diffuse

Pulmonary fibrosis (caused by


fibrosing alveolitis, pulmonary
vasculopathy)- early onset

PFTs detect poor gas exchange


XR? Interstitial fibrosis
CT? ground glass opacities in lung

Crackles w/ inhalation
Onset of skin changes w/I 1 year of Raynauds
Truncal & acral skin involvement

SRC histology? Sheared RBCs, narrowing of lumen, wall


fibrosis
SRC - anti-RNA pol III

SRC? ACE inh


GERD? PPIs
MSK? NSAIDs, PT, low dose
steroids (but watch renal!)
Raynauds? Smoking cessation
Lungs? Heavy immunosuppression

Anti-Scl-70 Ab

Dysphagia, GERD (from fibrotic


esophagus)
Scleroderma renal crisis (SRC) malignant hypertension, renal
insufficiency, microangiopathic
hemolytic anemia - tx ACE inh

Tendon friction rubs


Localized skin involvement (distal/upper extremities), nail fold
involvement, slower pace of progression
Limited (CREST)

Anti-centromere Abs
Calcinosis, Raynaud's (long duration), Esophageal
dysmotility, Sclerodactyly, Telangiectases

Localized cutaneous SS

morphea (erythematous plaques that are proximal, skin


discoloration/firmness/induration)

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)

Histology? Nl epidermis but extensive collagen


deposition & loss of epidermal appendage structures

Scleroderma + one or more features of other connective tissue


disease
Overlap syndromes

Anti-RNP Abs
Mixed connective tissue disease (MCTD) - SLE, SS,
polymyositis, & positive anti-RNP
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)

Ankylosing Spondylitis

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)

Immunosuppressants only help


peripheral arthritis
TNF inhibitors relieve axial arthritis

M>F
Age onset? 20s

HLA-B27

XR? Fuzzy, hard to trace bone margins of SI joint,


bamboo spine (syndesmophytes- new bone formed in
inappropriate location cause fusion through T-spine)

HLA-B27

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)

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

Classic - DIP joints of hands & feet


Arthritis mutilans w/ sacroilitis

Psoriatic Arthritis

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


(see AS path)

Pneumonia, loss of flexion at back

Disease

Clinical Variants

Defining Characteristics

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

"Can't see, can't pee, can't climb a tree"

Reiter's / Reactive
arthritis

Inflammatory bowel
associated arthritis

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)

M=F
young adults

HLA-B27

Spontaneous recovery, but can have


recurrences

(See AS path)

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

Complications

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

Screening / Education

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

Screening / Education

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

Screening / Education
Adjustment of risk factors (excessive
alcohol, sedentary lifestyle)

Prophylactic bisphosphonate
treatment prior to surgery!!!

Screening / Education

Stay active!!

Screening / Education

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

Screening / Education

Screening / Education

Avoid sun exposure, use sunscreen!

Counsel on posture, stretching,


spinal extension exercises
high risk for traumatic fractures

Screening / Education

Disease

Clinical Variants

Defining
Characteristics
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

Etiologies

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

Pulmonary Edema

Obstructive lung
disease

Emphysema, chronic
bronchitis, asthma

Restrictive lung
disease

Parenchymal lung
reduced lung volumes
disease (interstitial lung
dz); nonparenchymal
(chest wall disorder;
muscular weakness; less
shifted towards RV)

abnl accumulation of fluid in


the lung outside of the
vasculature

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

Risk factors

Lab/Imaging

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)

ability to move air


out of lungs is
impaired so takes
longer

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

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

Epidemiology

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

Treatment
Resolution?
Hydrostatic: intact
alv epithelium pumps
fluid out w/ Na/K
ATPase;
tx underlying cause;

Permeability: alv
epithelium injured so
takes longer to
resolve; tx primary
injury cause, manage
fluid balance,
supportive care

Complications
increased hospital
stay (leading to other
comorbidities) and
high mortality for
permeability edema

Disease

Clinical Variants
Intra-thoracic obstruction

Defining
Characteristics
Plateau on expiration

Pathogenesis

Etiologies

Equal pressure point has


variable migration depending on
transmural pressure; reduced
airflow during expiration

Ppl > Paw during


expiration reduces
airflow and causes
aw collapse; nl
inspiration
asthma

Epidemiology

Risk factors

Lab/Imaging

Tracheal lesions, PFT: plateau in exp


tracheal tumors, limb
tracheomalacia,
tracheal
inflammation,
mediastinal
lymph nodes

Treatment

Complications

Disease

Clinical Variants
Fixed lesion

COPD

Emphysema
(blow a balloon up and
release it? No air flows
out bc loss of elastic
recoil)

Defining
Characteristics
Plateau on inspiration &
expiration

Pathogenesis

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

A1AT deficiency
panacinar emphysema

DOE, cough, wheezing,


early presentation

Chronic bronchitis

typically presented as
overweight, cyanotic,
edematous, productive
cough, dyspnea at rest

Etiologies

Epidemiology

Risk factors

large tumor

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

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)

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

Lab/Imaging

Complications

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

alpha1antitrypsin
deficiency, FH
of A1AT def,
smoke, dust,
kerosine, PiSZ
smokers

Treatment

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)

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)

hoarseness =
common side effect of
steroids
Could require oxygen,
pulmonary
rehabilitation, lung
volume reduction
surgery, and/or lung
transplantation
cor pulmonale

Disease
Asthma

Clinical Variants

Defining
Characteristics

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;

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

Treatment

PFT: exp arm has


concavity; FEV1/FVC
<70 but other values
highly variable;
significant
bronchodilator
response (loss of
FVC, FEV1,
FEV1/FVC; nl DLCO)

Complications

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

Clinical Variants

Defining
Characteristics

Pathogenesis

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)

Risk factors

Lab/Imaging

Treatment

Complications

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)

Autosomal
recessive mutation
in gene hydin
failed dynein
motors or central
pair assembly =
cilia paralysis

(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

Flail chest

Lung bullae

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

Pneumomediastinum

gas in the interstices of


mediastinum

Pneumopericardium

Air in the pericardial


space (around heart);
muffled heart sounds

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

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!)

Bind and fixate the ribsPoor prognosis due to


ineffective ventilation

Emphysema

CXR: bilateral balls of


air

Tracheo-bronchial
tree/ esophagus
rupture from
trauma/ prolonged
vomiting

CXR: air along L heart


border, continuous
diaphragm sign

Fistula btwn 2
structures;
Ventilators

Pneumoperitoneum

Pulmonary nodules
(<3cm); pulmonary
masses (>3cm);
consolidation (think
pneumonia)

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)

Tension? Hi RR, HR; low


BP (due to low venous
return), trachea shifts to
opposite side

Lung cavities

Epidemiology

PIO2:FIO2
2,3-DPG

Acute
Chronic

Primary cilia
dyskinesia (PCD),
immotile ciliary
syndrome,
Kartagener
syndrome (KS)

Pneumothorax
(atelectasis - partial
collapse of lung,
collapse of alveoli)

Etiologies

Infection; vasculitis;
tumors

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

Disease

Clinical Variants

Atelectasis

Defining
Characteristics
Mediastinum pulled
towards affected side
on CXR

Alveolitis

Pathogenesis

Etiologies

Epidemiology

Obstructive Atx of
whole lung?
Cancer, mucus
plug, foreign body

CXR: Complete
Opacification
Hemithorax;
consolidation

infiltration of lymphocytes &


monocytes expands the
interstitium

Viral, mycoplasma
pneumoniae,
hypersensitivity
rxns

Histology: thickened
septa due to
infiltration of
inflammatory cells;
empty alveolus
space

Kidney, heart, liver 1.5 million pleural


failure
effusions yrly

CXR: Complete
Opacification
Hemithorax; blunted
costophrenic angle,
meniscus sign (upside
down U), loss of nl
structures at lung base

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

malignancy, PNA/
Infxn, PE, post
surgical

transudative pleural
effusion

Treatment

Complications

TB (global cause)
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

decreased pleural pressure


(atelectasis, trapped lung) - fluid
moves into lung

Hepatic hydrothorax

Lab/Imaging

Collapse of alveoli or partial lung


--> VQ mismatch hypoxemia
(perfusion, low ventilation) OR R->L shunt hypoxemia

either spontaneously resolves or


persists (if persists, leads to
interstitial fibrosis)
Pleural effusion

Risk factors

liver related pleural effusion due cirrhosis, liver


to high portal pressure (from
failure
cirrhosis usually)

diuretics

do not attempt
pleurodesis!!

Beta blocker to
decrease portal
pressure

ascites
RUQ

transplant

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

Clinical Variants

Empyema

Malignant Pleural
effusion

Defining
Characteristics

Pathogenesis

Etiologies

Epidemiology

Exudative pleural effusion Infection (collection of pus) in


pleural space

Exudative pleural
effusion

Risk factors

Lab/Imaging

Treatment

Complications

CXR: distinguish from Drainage


neoplasm (which
always appears
spherical) - empyema
will look different
based on viewing
position

hematogenous metastases to
parietal pleura

2nd most common


cause for
exudative effusion

cancer cells erode through


visceral pleura

Thoracentesis: gross
pus or positive gram
stain, pleural fluid
cultures
(always
low
pleural fluid
cytology

pleurodesis

positive in 60-80%

high recurrence rate,


usually represent an
advanced malignancy

possible pleural bx

cancer cells occlude lymphatics

Chylothorax

Exudative pleural
effusion

disruption of thoracic duct or LN


dissection; represents high lipid
content in pleural space

trauma or
CANCER!

turbid, milky white


pleural effusion; does
not smell (empyema), no
pus

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

Defining
Characteristics
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

Pulmonary venoocclusive disease


(PVOD)

Valvular diseases,
systemic dysfunction,
diastolic dysfunction

Etiologies

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

Epidemiology

Risk factors

20-30 y.o.

Lab/Imaging
histology? Intimal/
smooth muscle/
adventitia
hypertrophy &
formation of
plexiform lesions

F>M (2:1)

Treatment
see PAH

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)

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

see PAH

mPAP >= 25
PWP > 15

increased mPAP and PVR due


to vasomotor constriction or
pulmonary vascular remodeling

no meds approved
for this population

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

see PAH

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

(WHO Group 1')

Pulmonary arterial
hypertension from
Left heart disease

Pathogenesis

(WHO Group 2)

Pulmonary arterial
hypertension from
lung disease/
hypoxia
(WHO Group 3)

Chronic
Thromboembolic
Pulmonary HTN
(CTEPH)
(WHO Group 4)

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

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

Complications
High mortality without
treatment (median
survival 2.8 yrs) - cor
pulmonale

Disease

Clinical Variants

Defining
Characteristics

Pulmonary arterial
hypertension w/
unclear or
multifactoral causes

Pathogenesis

Risk factors

Lab/Imaging

Treatment

Complications

Chronic
myeloproliferative
dz, splenectomy,
sarcoidosis, LAM,
pulmonary
langerhans cell
histiocytosis,
glycogen storage
diseases, hyper/
hypothyroidism,
end stage renal dz

see PAH

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

Hepatopulmonary
syndrome

Secondary to liver
disease

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

decreased effective
minute ventilation =
PaCO2 > 45
(hypercapnia)

Epidemiology

miscellaneous diseases that all


cause PAH

(WHO Group 5)

Hypoventilation /
Hypercapnia

Etiologies

hypoventilation = acute CO2 =


pH = O2

Physiologic
causes? Hypoxia,
acidosis, irritants
(P.E., inhalants),
CHF (J-receptors)
Non-physiologic
causes? Pain,
anxiety,
psychogenic

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)

sepsis, PE,
pregnancy

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

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

Defining
Characteristics

Pathogenesis

FIO2;
hypoventilation;
diffusion
impairment; VQ
mismatch; shunt (RL), altitude induced
hypoxemia

General

hypoventilation induced
hypoxemia

Etiologies

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

VQ mismatch hypoxemia increased A-a gradient,


nl PaCO2 (unless severe
hypoxemia), respond to
increased FiO2

disease process causes


amplification of VQ mismatch,
where composition of alveolar
gas varies in different lung
regions, causing hypoxemia

hi ventilation, low
perfusion (PE)

Right to Left Shunt


hypoxemia

blood moves from right side of


heart to left side of heart without
being oxygenated (extreme form
of VQ mismatch)

anatomic shunt
(intracardiac
shunts, pulmonary
AV malformations,
hepatopulmonary
syndrome)

severe hypoxemia that is


not readily fixed with
increased FiO2,
increased A-a gradient, nl
PaCO2

low ventilation, hi
perfusion
(pneumonia, PECHF, ALI/ARDS,
atelectasis,
pulmonary fibrosis,
COPD)

physiologic shunt
(atelectasis,
pneumonia,
ALI/ARDS)
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

Epidemiology

Risk factors

Lab/Imaging

Treatment

Check A-A gradient

usually corrects with


small doses of O2
(FiO2); correct with
drug antagonist
(opoid antidote)

patients respond to
increased FiO2

Complications

Disease
Acute respiratory
failure (ARF)

Clinical Variants

Defining
Characteristics

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

Pulmonary
embolism

Pathogenesis

loss of capillary volume

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

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

Lab/Imaging

at-risk dx?
Direct lung
injury (aspiration
of GI contents,
pulmonary
contusion,
pneumonia/
sepsis); indirect
lung injury (nonpulm sepsis,
abdominal
trauma, multiple
fx, hypertransfusion)

300<PaO2/FiO2<200
CXR: bilateral
infiltrates
ABG: worsening CO2
and O2 levels despite
increased oxygenation

ILD

DLCO
gross: thickened
pulmonary arteries
(white macaroni)
DLCO

600,000 PE, 1
same as those
million silent PE; for DVT
3rd most common
CV disease in US

Treatment
manage underlying
cause

Complications
mortality ~30-40%,
long recovery time

provide supportive
care
restore oxygenation
to better levels
(PaO2 of 55-60, O2
sat 88-90%)
intubation & low tidal
volume mech
ventilation if
necessary

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

Clinical Variants

Deep Vein
Thrombosis

Defining
Characteristics
swollen leg, tenderness in
leg near deep veins,
unilateral swelling >3cm,
unilateral pitting edema

Pathogenesis

Etiologies

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

Epidemiology

Risk factors

Lab/Imaging

2 million cases,
1/1000 per yr;
M>F, blacks more
affected

Trauma, spinal
cord injury, ortho
surgery, Gyn
surgery, critical
care

Well's criteria: >3 pts


= high risk (75%
chance of DVT), 1-2
pts (moderate risk), <1
pt (low risk)

Prox/ pelvic DVT?


Catheter-directed
thrombolysis

Complications
AVOID giving anticoagulation
prophylaxis to spinal
surgery patients

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

Virchow's triad: vessel wall


damage, venous stasis
(stagnant blood coagulates),
increased blood coagulability
(cancer, Factor V Leiden)

Pulmonary fibrosis

Treatment

DLCO

increased membrane thickness,


increased VQ mismatch
hypoxemia, increased diffusion
limitations (fibrosis prevents O2
movement out of alveoli and into
capillary)

histology: blue-pink
color as collagen
deposits develop
fibrosis; thick, stiff
looking alveolar
spaces; temporal
heterogeneity
(normal septum next
to disease septum)

chronic inflammation = increased


cytokines = induced fibroblast
secretion of collagen = fibrous
scarring

gross: honeycombing
(bumpy cobblestone
pleura; tethering of
fibrin); traction
bronchiectasis (dilated
bronchi)

Obesity
hypoventilation
syndrome

"Pickwinian's syndrome"

Acute
Laryngotracheitis

"Croup"

DLCO

morbid obesity,
sleepiness &
hypoventilation during
day, hypercapnia,
cyanosis,
hypersomnolence

increased capillary blood volume

sound horrible but


ventilating ok

inflammation of larynx, trachea

viral

Parainfluenza viruses 1-3 are


most common agent (>75%)

extrathoracic
obstruction

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)

weight loss

cor pulmonale
difficult to reverse

less common? RSV, influenza,


adenovirus, herpesvirus (more
severe illness)
preceded by coryza-like
illnesses/URIs before croup
onset

uncommon in kids
< 6m (maternal
Abs)

Clinical dx, can make


child worse by trying
to get CXR

peaks btwn 1824m

CXR: steeple sign


(narrowing of
subglottic region)

most common
cause of upper
airway
obstruction in
kids

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

Clinical Variants

Epiglottitis

Defining
Characteristics

Pathogenesis

dyspnea, stridor, tripod bacterial cellulitis of superior


glottis structures
position

Foreign Body
Aspiration

Bronchiolitis

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

sudden cough/ wheeze


after eating or playing
(although sometimes
onset may be insidious)

typically objects are aspirated


down the right main bronchus
because shorter and straighter
than left bronchus

persistent cough or
wheeze,
current/persistent
pneumonia, decreased
breath sounds, delayed
air entry

intrathoracic obstruction

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

Etiologies
reduced
vaccination rates

Epidemiology

Risk factors

can occur at any


age, but most
common in kids <
5 y.o.

Treatment

other organisms cause more


gradual onset but slower
recovery

peanuts,
popcorn,
hotwheels, any
small toy

"Beefy red" &


swollen epiglottis w/
bronchoscopy

secure airway!!

CXR: hyperinflation
of affected airway
(air trapping) OR
completely nl CXR!!

remove foreign
object

Atelectasis w/
aspiration

RSV, followed by
parainfluenza

caused by RSV --> necrosis of


airway epithelium --> influx of
inflammatory cells --> release
of inflammatory mediators =
edema = narrowing of airways

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

Childhood wheezing Transient early wheeze

Non-atopic wheeze

Complications

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

B-hemolytic streps (A, B, C)


Staph aureus

foreign objects

Lab/Imaging

early wheezing but sx


resolve btwn ages 3-5

lower lung fx earlier in life associated w/ viral respiratory RSV, rhinovirus


that improves w/ age;
tract infections
generally resolves by
age 6

NOT FH of
asthma
reduced lung fx
before
respiratory
event
(prematurity, day
care, prenatal
maternal
smoking, post
natal smoking
exposure)
preschool age
kids

Many develop
recurrent wheezing
that may be
associated with
persistent
abnormalities in
lung function

Disease

Clinical Variants
Ig-associated wheeze
(asthma)

Defining
Characteristics
Wheezing before age 6

Pathogenesis

Etiologies

Epidemiology

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)

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

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

Injury results in inflammation &


tissue remodeling in lung - if
uncontrolled, tissue progresses
to fibrosis & scarring of lung

Lab/Imaging

FH of asthma,
allergy, elevated
IgE @ age1,
early
sensitization to
mold, obese
females,
maternal
prenatal smoking

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

Cystic fibrosis

Risk factors

>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)

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)

Most common life- 1/3200 births in


shortening genetic whites
dz in Caucasians
30,000
Americans,
60,000 cases
globally;

Treatment

Complications

inhaled
corticosteroids

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

Disease

Clinical Variants

Idiopathic Interstitial Idiopathic Pulmonary


Pneumonias
fibrosis

Defining
Characteristics
Chronic, progressive,
fibrosing, interstitial

Pathogenesis
"repeated cycles" of epithelial
activation or injury by some
unknown agent

Etiologies
Unknown?

limited to lungs!
Dyspnea (insidious but
progressively worsening);
non productive cough
(difficult to control),
clubbing, decreased
breath sounds, bilateral
crackles

Epidemiology

Risk factors

high mortality!!

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

DDx? Other ILD,


connective tissue dz (RA,
scleroderma),
occupational exposure,
meds (MTX, bleomycin,
nitrofurantoin)

Desquamative interstitial
pneumonia (DIP)

Acute interstitial
pneumonia (AIP)
Respiratory bronchiolitis
interstitial lung disease
Cryptogenic organizing
pneumonia (COP)
"Bronchiolitis obliterans
organizing pneumonia"
BOOP

Chronic onset of dyspnea


& cough; sometimes
clubbing

localized or diffuse

M>F, mean age


45 y.o.

consequence of infection or
inhalational injury

a/w CTD, drugs,


idiopathic

No FDA approved
med tx

Complications
About 50% survival
after 2 years dx; 1520% 5 yr survival

steroids
HARMFUL!!
treat GERD
Enroll in clinical
trials
Evaluate for lung
transplant
O2
supplementation,
pulm rehab,
vaccination for
flu/pneumonia, tx
comorbidities,
maintain BMI

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

CTDs

CT: multiple patchy


consolidations;
sometimes GG

fibrous plugs filling airway


into alveoli

chronic onset of dyspnea varying degrees of inflammation


& cough; sometimes fever & fibrosis w/I alveolar walls,
temporally uniform

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

>90% of cases
involve
smokers!

responsive to
steroids!! (~6m)

Histology? Fibrous
plugging of airway

sometimes present w/
fever (after which Abs
don't help)
Lymphocytic interstitial
pneumonia (LIP)
Non-specific interstitial
pneumonia (NSIP)

Lab/Imaging

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

Defining
Characteristics

Drug-induced ILD

Hypersensitivity
Pneumonitis
(extrinsic allergic
alveolitis)

Sarcoidosis

Farmer's lung
Pigeon breeder's lung
Humidifier lung

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

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)

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)

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!

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

Treatment

Complications

remove responsible
drug!

Non-smokers

Microbial agents
(bacteria, fungi,
amoeba, atypical
mycobacteria),
Animal proteins
(bird antigens), low
& high MW
chemicals

Histology:
bronchiocentric
lymphoplastic
infiltration, poorly
formed nonnecrotizing
granulomas,
mutlinucleated giant
cells around
bronchioles,

must stop
exposure!! Only
then will steroids be
effective

may progress to
chronic HP w/ end
stage fibrosis &
honeycombing

spontaneous
resolution but
management differs
based on location of
involvement

should always stain


tissue bx with acid
fast for bacilli to
avoid missing TB
(early TB looks very
similar to sarcoidosis)

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)

Unknown?

3x higher
incidence/ severity
in African
Americans

Some genetic
component (HLA
II on
chromosome 6
short arm)

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

glucocorticoids if
worsening pulm sx,
worse lung fx,
changes in CXR; 612m
lung transplant if
stage 4

Disease
Pneumoconsioses
(occupational lung
dz)

Clinical Variants
Asbestosis

Coal workers
pneumoconiosis
Silicosis

Berylliosis

Anthracosis

Community acquired
pneumonia (CAP) Typical pneumonia
(Pneumococcal
pneumonia)

Defining
Characteristics

Pathogenesis

Etiologies

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
diffuse fibrosis

general

Risk factors
industries that
mine, fabricate,
or install
asbestos
(roofing,
insulation,
brakes,
shipyards)

Lab/Imaging

Treatment

Histology: alveolitis &


development of giant
cells, interstitial
fibrosis

Complications
amphibole body a/w
mesothelioma
asbestos exposure
also increases risk for
bronchogenic
carcinoma, benign
pleural plaques
(marker of asbestos
exp), and
mesothelioma

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

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

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

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

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, 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)

Strep pneumo can invade the


blood stream and enter joints
(septic joint) or meninges
(menigitis)

CAP - Atypical
pneumonia

Epidemiology

CXR: lobar
consolidation, pleural
effusions sometimes

Strep pneumo is #1
cause of meningitis in
all age groups

blood cx positive in
20% of patients

can also cause other


clinical syndromes
(bacteremia, otitis
media, sinusitis,
bronchitis, bacterial
peritonitis, bone/joint
infs, endocarditis)

Macrolides
(arithromycin),
doxycycline, 3rd
gen
Sputum gram stain:
cephalosporins,
many neutrophils,
sometimes
gram+ cocci in pairs fluoroquinolone
& chains

Increased rate of blactam resistance


(altered PBPs)

Mycoplasma
pneumoniae,
Legionella,
Chlamydia
pneumoniae, viral

Disease

Clinical Variants
Legionella

Defining
Characteristics

Pathogenesis

Pontiac fever - acute,


self-limiting flu-like illness;
high attack rate among
exposed

Enters alveolar macrophages


thru coiling phagocytosis,
multiplies in the phagosomes,
reaches critical mass, then lyses
the macrophage

Legionnaires' dz - mild
respiratory dz to severe,
life-threatening
pneumonia; HI fever,
malaise, myalgias,
anorexia, headache,
diarrhea, dry cough,
hyponatremia, pleural
effusion

transmitted to humans via


aerosolization of
contaminated water
Cell mediated immunity = host
defense

Etiologies

Epidemiology

L. pneumophilia = rare in healthy


children, young
Gram negative,
aerobic, non-spore adults
forming,
unencapsulated
bacilli

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)

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

Chlamydia pneumoniae

>1/4 of
no seasonal
pneumonias in
variation
school-aged kids

CXR: patchy infiltrates Empirical tx

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

focal pneumonia caused by


inhalation of aerosols of birth
products from sheep, cattle,
goats, cats, rabbits
lymphocytic response due to
intracellular nature of organism

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)

CBC: nl WBC
cell cx not really tried
PCR/NA techniques
(Future)

person to person droplet


spread
Coxiella burnetti (Q fever) often asymptomatic

Complications

histology? interstitial
& alveolar infiltrates
of macrophages

doxycycline,
macrolides,
fluoroquinolones
NO B-lactams!!

immune mediated
systemic
manifestations
(Derm- SJS, CNSencephalitis, Heme hemolytic anemia,
MSK- myalgias,
arthalgias, etc)

Disease

Clinical Variants
Viral pneumonias

Defining
Characteristics

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

Complications

CMV?
Adenovirus?
Immunocompro Exudates w/ necrosis
mised individuals & hemorr; intranuclr
inclusions w/ blurred
nuclr membrane smudge cell;

difficult to detect but may diffuse alveolar damage &


precede bacterial
necrosis caused by CMV, HSV,
pneumonia
adenovirus, or measles virus

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)

Necrotizing
Pneumonia (Lung
Abscess)

focal infiltrates

fungal pneumonia that invades


immunocompromised hosts with
CD4 T cell count <200 (presence
of PCP = AIDS dx)

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
mised pts (AIDS,
transplant,
cancer, steroids)

Histology? Looks
bubbly with widened
alveolar septa due to
inflammatory cells;
characteristic cysts
seen w/ silver
staining

Immunocompro
mise; transplant

antimicrobial
Gross: cavitation
(gangrene of lung) w/
surrounding fibrosis,
pus filled
CXR: abscess
formation

scarring --> fibrosis


R/O carcinoma
extension into brain,
hemorrhage

Histology: alveolar
space filled w/ PMNs

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

Defining
Characteristics

Active TB

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

Atypical
Mycobacteria

M. avium intracelluaire
complex (MAC)

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

Complications

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

1.5 million
deaths/yr; 2nd
leading cause of
death after HIV;
#1 cause of death
in HIV pts

HIV
poor, crowded,
poorly ventilated
settings
malnutrition

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)

RIPE = Rifampin,
isoniazid,
pyrazinamide,
ethambutol for 6-9mdrug susc TB

Lots of undetected TB
cases globally so
need single point of
care test (GeneXpert RT-PCR $$)

start on 4 drugs if
suspicious of TB,
once have
susceptibilities, can
cut back to 2 drugs (4
drugs - 2m, 2 drugs 2m)

MDR-TB (resistance
to at least INH + RIF)

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

most cases in
Asia & Africa
HIV epidemic is
driving TB
coinfection

immunosuppress
ed (TNF-a
inhibitors,
prednisone)
recent inf w/
latent TB (<2y)
substance abuse
DM, renal failure,
cancer, chemo,
silicosis, fibrotic
changes on CXR

HIV, COPD/other
lung dz

Hot tub lung, pre-existing


lung conditions
susceptible; especially
aggressive in AIDS pts
(feverish, night sweats,
weight loss)

Granulomatous
fungal diseases
(very similar to TB
clinically,
pathologically)

Cryptococcus

granulomatous
inflammatory response

caused by Cryptococcus
neoformans, which is an
encapsulated yeast and
transmited to humans via
inhalation of soil & bird
droppings

dimorphic: mold in
the cold, yeast in the
heat!
GEOGRAPHIC
localization
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

opportunistic
infection!

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)

Multi-drug therapy

non-AIDS pts rarely


become infected (but if
so, productive cough +/weight loss/fever)

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

nl & immunoHistology: calcified


Ohio &
Mississippi River compromised pts necrosis,
unencapsulated
valleys
organisms seen w/
silver stain inside
alveolar
macrophages,
narrow based
budding if
replicating

XDR-TB (resistance
to INH, RIF, +
fluoroquinolones/
injectable Abs)

DIFFICULT TO
ERADICATE

Disease

Clinical Variants
Coccoidoidomycosis

Defining
Characteristics
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

Blastomycosis

Pathogenesis

Etiologies

inhalation of spores from


Coccidiodes immitis causes
delayed type hypersensitivity to
the fungus

Inhalation of spores from


Blastomyces dermatitidis,
Pulmonary, skin, & bone producing various dz
presentations
lesions
broad based budding

Epidemiology

Risk factors

Lab/Imaging

Southwest &
Western US

Histology? Large
organism containg
secondary
component
(spherule w/
endospores) multiple budding

Southeastern &
south central US

Histology? Broad
based budding
CXR: UL involvement

Treatment

Complications

Spontaneous
resolution, or can
persist as a chronic
lesion

pulm sx (productive
cough, chest pain,
abdominal pain, night
sweats, chills, anorexia,
weight loss)
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

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!!

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)

Foreign Body
Granulomas

Diffuse pulmonary emboli

Localized parenchymal
mass

entrapped foreign material (not


blood clot!) in pulmonary
vasculature

tissue reaction to foreign


material, commonly seen with
aspiration pneumonia or lipoid
pneumonia (lipid in the lung)

talc from IVDU


Iatrogenic (indwelling catheter,
IV line, silicone
from breast
implants)

IVDU

Histology?
Multinucleated giant
cells, birefringent
(polarized light will
show talc)

Histology? Lipids in
alveoli cause
formation of
granulomas

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

Disease
Influenza virus
(Orthomyxoviridae)

Clinical Variants

Defining
Characteristics
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

Complications

Oseltamivir/Tamiflu
(tx, prophylaxis)

More complications &


mortality in elderly

Tamiflu allergy?
Zanamivir/Relenza

EXCEPTION: deaths
from H1N1 were
middle aged adults

Tamiflu resistant flu


subtype?
Amantadine,
Rimantadine

primary viral
pneumonia,
secondary bacterial
pneumonia, otitis
media, Reye's
Syndrome (aspirin
+flu), myopericarditis,
?encephalitis

Disease

Clinical Variants

Parainfluenzae virus
(Paramyxoviridae)

Defining
Characteristics

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

20% of resp infs in young children


kids, very few in
adults

Laryngotracheobronchitis
(Croup)

Treatment

Complications

No specific antiviral
no vaccine
supportive care

Bronchiolitis (RSV first,


then parainfluenza)
Less common cause of
pneumonia
Respiratory
Syncytial Virus
(RSV)
(Paramyxoviridae)

severe lower respiratory


tract disease in infants

droplet transmission and direct


contact

bronchiolitis,
bronchopneumonia,
bronchitis in older
children/adults

community
outbreaks in late
fall to early
spring

clinically indistinguishable illnesses similar to RSV;


from RSV
coinfection w/ RSV =
severe illness
upper & lower
respiratory tract
infections
50% of inf are
asymptomatic

Adenovirus

seasonal (winter/spring) pattern


where it is transmitted by close
contact

elderly,
immunocomp,
young children

spread by droplet nuclei, fecaloral route, and can persist for


some time in the environment

Molecular detection w/
PCR

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

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)

PCR

Immunocomp:
pneumonia,
gastroenteritis,
hemorrhagic cystitis,
hepatitis, interstitial
nephritis

Common cold

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

significant resp
pathogen in
transplant pop

incubation period of 2-8


days; viral shedding for
1-2 weeks or longer

Human
metapneumovirus
(paramyxoviridae)

severe inf risk


diagnosed via Cx,
increased w/ kids antigen detection,
who have cong PCR
heart failure,
underlying pulm
dz, premature
birth

Rhinovirus
(Picornaviridae)

30-50% of common colds

circulate in spring,
summer, early fall

PCR

Coronavirus

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

circulate in fall,
winter

PCR

severe lung dz in lung


transplant pts

Disease
Sleep apnea

Clinical Variants
Central Sleep Apnea

Defining
Characteristics

Pathogenesis

cessation of airflow during


sleep due to cessation of
respiratory effort as result
of decreased ventilatory
motor output

nl - reset of CO2 setpoint


during sleep (transient period PaCO2 is below apnea threshold
= min vent = PaCO2 to apnea
threshold = minute ventilation

nl or slightly lower PaCO2


levels during the day,
chronic hypercapnia @
night

Chronic hypoventilation =
impaired CO2 drive since have
hi PaCO2 levels = cyclical sleep CHF (CheyneStokes,inc
onset central apnea ( apnea
feedback delay)
time, arousal)

Cheyne-Stokes
respiration

Obstructive Sleep Apnea

Etiologies
hi altitude (longer
periods of sleep
apnea)

Increased
hypersensitivity/
loop gain (from
oversensitive
medulla,
exaggerated output
to resp muscles, or
overefficiency of
lungs in gas
exchange)

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

Obesity (narrow
airways), large
neck, thick tongue,
URIs, nasal trauma
negative
oropharyngeal
press (small
pharyngeal cavity,
hi pharyngeal
compliance,
decreased upper
aw muscle activity)

Risk factors

Lab/Imaging

Treatment

Complications

maintain resp drive


(respiratory
stimulants theophylline,
progesteron;
increase metabolic
acidosis by
alkalinizing urine best for altitude
induced)

hypercapnia,
chronic
hypoventilation

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!!)

sleep onset -> apnea -> hypoxia,


hypercapnia, acidosis -> arousal
from sleep -> resumption of
airflow -> return to sleep -> cycle
starts over

Epidemiology

treat underlying
conditions (CHF CPAP mask)

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

Screening / Education

Screening / Education

Screening / Education

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

Screening / Education
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

Screening / Education

Screening / Education

Screening / Education

Screening / Education
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)

Screening / Education

Screening / Education

Screening / Education

Screening / Education
DVT prophylaxis
(intermittent sequential
compression device adherence issues; anticoagulation - LDUH,
LMWH heparin, factor Xa
inhibitors)

infection control practices


at home mandatory!!
(must clean everything)

Screening / Education
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)

Screening / Education

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)

Screening / Education

Screening / Education

Screening / Education

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

Screening / Education

Screening / Education

Screening / Education
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)

Screening / Education

Screening / Education
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!!

Screening / Education

RSV prophylaxis
(Synagis, mAB) - high
risk infants/premies

vaccination w/ oral live


attentuatd virus for
military recruits

Screening / Education

Disease

Clinical Variants Defining Characteristics

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)

Pathogenesis

Etiologies

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

Epidemiology

Risk factors

Lab/Imaging

diastolic
murmur across
tricuspid;
systolic
murmur across
pulmonic =
more severe

Treatment

Complications

septal occluder

right heart failure;


Afib; pulmonary
hypertension
(increased amt of
blood in RH and
PA)

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

increased preload on right heart


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)

Patent ductus
arteriosus

Right to left
shunts
(de-oxy blood
flows into
systemic circ)cyanotic!

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

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

Tetralogy of Fallot cyanotic skin during


crying/feeding

congenital abnl from the incomplete


closure of intrauterine cnxtn btwn pulm
artery & aorta --> decreased pulmnary
blood flow

4 parts:
1. LARGE VSD
2. PS (RVOT obst)
3. RVH
4. AO override
Eisenmenger

Vascular/
Valvular
congenital
disease

Bicuspid aortic
valve
pulmonic stenosis late peaking systolic
murmur
parasternal lift
big "a" wave

Down
syndrome;
maternal alcohol
intake;
trauma/MI
(muscular
defect)

rubella,
premature birth,
high altitude

CXR: inc cardiac


silhouette
(displaced apex
from LVVO)

HF, Eisenmengers
(deoxy blood in left
heart from PA -->
aorta movement
causes PA
hypertrophy = inc
PA press = unoxy
blood in left heart =
cyanosis)

Angiogram: blood
moves from PA
into aorta

increased right
heart pressure
(valsalva,
exercise)
pushes more
blood across
PFO & into LA!

septal occluder

CXR: hyperlucent
lungs (lack of blood
getting to the
lungs)

more severe PS = more RVOT obstruction

L-->R shunt that eventually reverses to R->L (acyanotic --> cyanotic shunt w/
increased pressure)

narrowing of pulmonic valve blocks blood usually part of


from leaving RV --> increased afterload on tetralogy of
RV --> RVPO --> RVH
fallot
Noonan's
syndrome

DVTs, MI, &


cryptogenic stroke!!

central cyanosis,
clubbing,
hypoxemia, growth
retardation,
polycythemia
(thrombosis, CVA),
PH, paradoxical
embolus

Disease

Tachycardia

Clinical Variants Defining Characteristics

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)

Systemic Arterial Primary /


Hypertension
Essential
(idiopathic)

asymptomatic
systolic BP

Pathogenesis

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

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

Hypertensive
Emergency

renal (abnl BUN,


creatinine, UA),
renovascular,
coarct,
endocrine
(pheochromocyt
oma, Cushing's,
PTH disease),
drugs, obstruct
sleep apnea

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

Epidemiology

RA/LA dilation; 3-4% of pts > 70


SA node
years old
inhibition;
hyperthyroidism

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)

Secondary (about
5% of HTN)

Malignant
Hypertension

Etiologies

Renal disease,
accelerated mild
HTN

Cocaine!

60 million
Americans

Risk factors

Lab/Imaging

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

Treatment

Complications

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

Disease

Clinical Variants Defining Characteristics

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

Pathogenesis

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

Etiologies

Epidemiology

uncontrolled
HTN (95%),
bicuspid aortic
valve, Marfan's,
AMA pregnancy,
Turner
syndrome,
coarct

Risk factors

cocaine,
pregnancy

Lab/Imaging

EKG
CT w/ contrast
TEE (intimal flap)
CXR (wide
mediastinum bc
now have 2 aortic
lumens --> aortic
dilation)

Treatment

Complications

nitroprusside
(lowers BP) & beta
blockers (lowers
shear stress) until
EMERGENCY
surgery

50% of patients w/
proximal AD will die
w/I 48h

bleeding into
pericardium, infarct,
shock

can also present w/ stroke,


MI, tamponade

distal dissection

Aortic
transection
Abdominal
Aortic
Aneurysms
(AAA)

Peripheral
Vascular
Disease

AR, pericardial
effusion w/
tamponade

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)

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

trauma
Marfan's,
syphilis,
idiopathic,
atherosclerosis
(cholesterol +
angiotensin II)

6% of individuals tobacco use,


> age 70
FH, M>>>F,
white middle
aged men,
age

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

Endovascular
repair (catheter
based, stent
material), open
surgical (graft
material)

progressive
aneurysm
expansion despite
tx

Duplex US:
increased stenosis
& velocity; used to
check intervention
success

risk factor
modification,
aspirin, control of
DM/BP/ chol,
exercise

life expectancy
reduced 10 years
in patients w/ PVD

CT angiography:
anatomic vessel
narrowing

ACEI, antiplatelet
(aspirin,
clopidogrel)

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

amputees
(asymmetric
reversal of
blood flow)

tobacco use, hi
chol, HTN,
DM, obesity,
sedentary,
male gender,
age

surgery:
endarterectomy,
bypass,
thrombectomy,
ligation; catheterdirected

increased risk for


death from stroke,
MI
decreased ABI =
increased risk of
mortality
HEMORRHAGE w/
procedures

Disease

Clinical Variants Defining Characteristics

Carotid Artery
Disease

symptomatic? Stroke, TIA


(amaurosis fugax transient monocular
blindness, transient
weakness)

Pathogenesis

Etiologies

atherosclerosis of internal carotid artery:


pieces of plaque embolize and enter
internal carotid artery --> brain

Epidemiology

Risk factors

recent MI
unstable
angina
uncompensate
d CHF
severe valvular
dz (aortic
stenosis)

Lab/Imaging

duplex US:carotid
artery bifurcation
CT angiograph stenosis of carotid

Treatment

symptomatic:
treat/ surgery if
stroke involves
<1/2 or 1/3 of
hemisphere;
asymptomatic:
operate once
stroke risk >
surgery risk

Complications

50-75% stroke -->


carotid stenosis!!
BP control impt
for pre& postoperative status
(o/w inc risk of
stroke & hyperperfusion syndrome poor BBB)

Meds: statins,
plavix, BBs

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

Aortic
regurgitation
(AR)

radial- femoral asynchrony; distal to subclavian; pressure overload -->


leg fatigue
LVH

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

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

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)

rib notching (large


intercostal artery
erodes rib)

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

HTN

ACUTE AR =
surgical
emergency!! Use
vasodilators
(nitroprusside;
decrease
afterload) while
waiting
CHRONIC AR =
reduce afterload;
surgery if
symptomatic

Disease

Aortic stenosis
(AS)

Mitral
regurgitation
(MR)

Clinical Variants Defining Characteristics

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

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)

Pathogenesis

Etiologies

SYSTOLIC PROBLEM but DIASTOLIC


DYSFXN
endothelial disruption (leaflet injury from
atherosclerosis calcification or wear & tear)
--> entry of inflamm cells & lipids -->
sclerosis --> stenosis

increased age,
bicuspid valve,
rheumatic heart
dz

blood flow across AV impeded during


systole (inc afterload)--> LVPO-->
concentric LVH --> dec compliance of LV
(inc LVEDP) --> LA hypertrophy & diastolic
dysfxn

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

Epidemiology

Risk factors

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)

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)

Lab/Imaging

Treatment

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)

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

Complications

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

Disease

Mitral stenosis
(MS)

Clinical Variants Defining Characteristics

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

Pathogenesis

Etiologies

Epidemiology

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

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)

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

PE: giant "a" wave,


diastolic rumble that
increases w/ inspiration at
tricuspid area, OS at
tricuspid area

RHD, carcinoid
syndrome, RA
myxoma

Tricuspid
Stenosis

pulmonary
hypertension
from MS or RHF

extremely rare!

Risk factors

Lab/Imaging

Treatment

Complications

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;

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

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

Disease

Clinical Variants Defining Characteristics

Pulmonic
Stenosis

PE: giant "a" wave,


parasternal lift, soft P2/ES
that increases with
inspiration, systolic murmur
@ pulmonic listening area

Pulmonary
Regurgitation
Left ventricular
hypertrophy

PE: hi pitched diastolic


blowing murmur
sustained apical impulse
normal placed PMI
palpable S2 (presystolic
component)

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

Complications

congenital
(Tetralogy of
Fallot), carcinoid
syndrome

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

Acute
Pericarditis

Pericardial
effusion

Clinical Variants Defining Characteristics

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

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

Pathogenesis

Etiologies

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

Silent or symptomatic?
1. volume of fluid
2. rate of fluid accumulation
3. compliance of pericardium

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)

Epidemiology

Risk factors

Lab/Imaging

Treatment

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)

idiopathic,
malignancies,
radiation, viral
causes, TB

Fluid analysis to
R/O malignancy

treat underlying
disorder (dialysis
for uremia)

TTE: pericardial
collections
(quantifies volume
of fluid, determines
if ventricular filling
is impaired, &
guides pericardiocentesis)

NSAIDS,
colchicine if
chronic pericarditis

Observe
asymptomatic
effusions
pericardiocentesis
for therapeutic
drainage &
analysis

EKG: electrical
alternans (QRS
pericardial window
complex height
procedure
varies from beat to
beat)

Complications

Disease

Clinical Variants Defining Characteristics

Cardiac
tamponade

CC: breathlessness
(decreased CO & max
increased EDPs =
increased press in alveoli);
low output state (shocklike), hypotension,
tachycardia

Pathogenesis

Etiologies

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

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

BECK'S TRIAD:
Hypotension, increased
JVP (elevated venous
pressure; deep "x", flat
"y" - decreased filling of
ventricles), muffled heart
sounds

Epidemiology

Risk factors

Lab/Imaging

catheterization =
gold standard

Treatment

Complications

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)

pulsus paradoxus
(decreased systolic BP of
>10 w/ inspiration)
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

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

CXR: calcified
pericardium
Catheterization:
elevation &
equalization of
pressures, dip &
plateau in early
diastole, y descent
in RA, discordance
in RV & LV
pressures w.
inspiration
calcification of the tunica media, the
muscular coat of the artery

intermittent
episodes of
HTN?

thickening of the arteriole wall that results


in some degree of ischemia

marker of HTN;
common in
diabetes

age > 40-50

can have effusiveconstrictive


pericarditis
(tamponade
physiology -->
effusion drainage -> constriction
physiology)

Disease

Clinical Variants Defining Characteristics

Atherosclerosis

vulnerable, hi risk plaques?


Large extracellular lipid
content, thin fibrous cap,
high content of
inflammatory cells
(lymph/monocytes)

Pathogenesis

Etiologies

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

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

Prinzmetal angina uncommon, episodic,


occurs at rest

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

Epidemiology

Risk factors

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

AS

high LDL, low


HDL, FH,
waist
circumference
(W>35; M>40),
smoking, HTN,
prior known
CAD

Lab/Imaging

pathology: gross
large arteries
(yellow spots =
foam cells; fatty
streaks; friable
cracks/ fissures)

stress test: ST
depression
(ischemia) & area
of ischemia
(suggests anatomic
stenosis)
Resting EKG
CT angiography
Cardiac cath if +
stress test

Complications

myocardial
ischemia,
claudication; sites
for thrombus
development (mural
thrombus in aorta
common in HTN,
smoking men);
abdominal aortic
aneurysm

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)

histology:
increased
proliferative SMCs
and fibrous tissue;
does not look
vulnerable bc lipid
core is far from
lumen & thick
fibrous cap

coronary artery vasospasm, not much


atherosclerosis & no thrombus/plaque
formation

Treatment

if top of plaque
ruptures, lipids are
released into
circulation and
activate
thrombosis -->
ischemia, MI
other complications
if embolization of
plaque material
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

MI @ sites of
unremarkable
lesions
single occlusion =
diffuse disease
CABG decreases
risk for rpt
interventions

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

Clinical Variants Defining Characteristics

Unstable angina
pectoris

Pathogenesis

Etiologies

Epidemiology

Risk factors

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!)

Lab/Imaging

Treatment

Complications

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

Subendocardial
MI

ischemic
cardiomyopathy

most susceptible to
ischemia bc farthest away

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: 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)

EKG: do not
always elicit
changes; non-Qwave MI
elderly patients

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

Disease

Clinical Variants Defining Characteristics

Sudden death

Dyslipidemia

Pathogenesis

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

(General)

Epidemiology

pediatric presentation w/
chronic abdominal pain
(pancreatitis),
hepatomegaly, xanthomas
abnl high LDL
(heterozygote LDL > 200;
homozygotes LDL > 500)
cutaneous manifestations
(xanthelasma, corneal
arcus, thickened Achille's)

Risk factors

Lab/Imaging

autosomal
dominant
mutation in
LDLR

1 in 500

low triglyceride diet


nutrition referral

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

autoimmune dz
(SLE, RA,
dermatomyositis),
meds/toxins,
infections

Histology:
fibrinoid necrosis
&
leukocytoclastic
vasculitis
(neutrophils!)

premature vascular dz

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

Complications

increased LDL:HDL
predicts higher risk
for CV event

DIET, genetic
errors of
metabolism,
metabolic
causes (insulin
resistance pre diabetes;
hypothyroidism
hormones),
drug side
effects,
smoking

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

Treatment

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

Familial Hyperhigh fasting triglyceride


chylomicronemia levels and low LDL levels

Familial Hypercholesterolemia

Etiologies

aggressive + early increased risk for


tx (combo therapy CV event even at
young age
of statin +
cholesterol
absorption
inhibitor); niacin;
LDL apheresis

Disease

Clinical Variants Defining Characteristics

Cutaneous
vasculitis

purpuric lesions, nonblanching, ulceration/


necrosis seen sometimes
(vascular damage &
ischemia)

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

Complications

lower extremity vasculitis from blood &


extravasated erythrocytes that infiltrated
the tissue

lower legs = primary site

Giant cell
(temporal)
arteritis

Large vessel vasculitis

not well understood

scalp pain/tenderness
distributed along
temporal artery, visual
disturbances/blindness (if
opthalmic a involved),
polymyalgia rheumatica
in upper neck/shoulders

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

"hunched over elderly


person w/ lateral
headache"

high dose
corticosteroids for
months (reduce
inflammation and
prevent
subsequent
sequelae)

Elevated ESR/CRP

Takayasu arteritis Large vessel vasculitis


(aorta & subclavian a)

aorta & major branches become inflamed


w/ granulomatous infiltrates so arteries do
not distend or carry pulse wave

Pulseless disease, low


blood pressure, ocular
disturbances, carotid
tenderness

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

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

unpredictable
course: rapid
progression +
quiescent stages

Disease

Clinical Variants Defining Characteristics

Kawasaki disease medium vessel vasculitis

Pathogenesis

not well understood

multisystemic sx
(polymorphous skin
eruption, erythema of
conjunctiva/oral
mucosa/tongue
"strawberry tongue",
cervical
lymphadenopathy, edema
in hands/feet,
desquamation of
fingertips/toes)

Etiologies

may be a/w
strep/ staph
infection

Epidemiology

Risk factors

pediatric
presentation

Lab/Imaging

anti-endothelial
antibodies
ANCA negative

small vessel vasculitis

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)

other multisystemic
manifestations?
Cutaneous, middle ear,
peripheral nerves, CNS,
ocular, oral cavity (midline
destructive lesions)

small vessel vasculitis


Multisystemic disorder
(fever, cardiac
involvement - arrythmia,
ventricular insufficiency,
coronary arteritis,
peri/myocarditis),
pulmonary infiltrates (noncavitating), renal
glomerulonephritis)

approximately 50%
of cases will have
CV involvement

MI in kids!!

ELK: Ear/nose/throat
(URI, saddle nose
deformity), Lung (cough,
hemoptysis, cavitary
necrotizing lesions),
Kidney involvement
(hematuria, proteinuria)

Allergic
granulomatosis
(Churg-Strauss)

IV IgG and
aspirin to reduce
inflammation and
avoid sequelae

Complications

lifelong risk for


coronary artery
aneurysm

CV INVOLVEMENT!
(myocarditis --> CHF,
coronary vasculitis -->
ischemic dz/infarct,
aneurysms)
Wegener's
granulomatosis

Treatment

histology:
vasculitis w/
necrotizing
granulomatous
inflammation

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

Clinical Variants Defining Characteristics

HenochSchonlein
purpura

small vessel vasculitis

Pathogenesis

not well understood

Multisystemic disorder
(cutaneous purpura w/
leukocytoclastic vasculitis,
abdominal pain - bloody
stools, melena; arthalgias,
renal glomerulonephritis)

Etiologies

Epidemiology

possibly
children <10
infection or drug y.o., M>F
related

Risk factors

Lab/Imaging

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)

not well understood

possibly
Adults
infection related
(strep), drug
related?

Elevated ESR,
anemia, renal
failure
UA: hematuria,
proteinuria

Multisystemic vasculitis
(cutaneous purpura,
abdominal pain,
pulmonary involvement!!!
- hemoptysis,
intrapulmonary
hemorrhage, renal
glomerulonephritis,
myalgias)

p-ANCA or cANCA positive

pulmonary involvement
distinguishes from PAN

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

Treatment

Complications

Disease

Heart failure

Clinical Variants Defining Characteristics

(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!

Systolic heart
failure

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)

reduced EF (LVEF < 4050%) = impaired


contractility w/
progressive dilation &
eccentric remodeling

Pathogenesis

Etiologies

Epidemiology

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)

Ischemic
cardiomyopathy
(atherosclerosis!
!)

5 million
Americans have
CHF, 1 million
hospitalizations/
yr

impaired contractility, volume overload


(increased sodium = inc total body water),
& pulm congestion

CAD, HTN,
dilated CMP,
valvular dysfxn

Risk factors

Lab/Imaging

CXR: cardiomegaly
if chronic HF
(cardiac
remodeling)

impaired relaxation =
elevated LVEDP; nl LV
volume, concentric
remodeling, EF > 50%

Afib (atria become


inflamed/scarred/
dilated) - use
cardioversion!

low CO
conditions
("cold, wet"):
valvular dz,
dilated CMP,
HTN, CAD

triad of meds
(carvedilol - BB;
lisinopril,
spironolactone)

thin walled,
dilated ventricle

diastolic dysfxn (abnl distensibility,


relaxation, or filling of LV) +
signs/symptoms of HF

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)

Complications

development of
kidney failure (nl
creatinine = 1) most impt
negative
prognostic factor!

Elevated BNP (nl


<100)

hi CO
conditions
("warm, wet"):
hyperthyroidism,
anemia, AV
fistula, Paget's,
Beri-Beri

decrease afterload
= improved SV =
less ischemia; =
reduced preload =
reduced
remodeling

Almost all pts w/ systolic


dysfxn have comcomitant
diastolic dysfxn
(impaired relaxation)

Diastolic heart
failure

Treatment

hypertensive
CMP, HOCM,
amyloidosis
hypertrophied,
enlarged,
thickened
cardiac
myocytes

increased
prevalence w/
age

requires clinical
evidence of
impaired RV
relaxation or LV
passive stiffness:

no treatment, just
symptom relief

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

presence of
symptoms = worse
prognosis
high comorbidity
burden (usually
elderly patients w/
dHF)
majority of dHF
patients die from
non-cardiac causes

Disease

Cardiomyopathies

Clinical Variants Defining Characteristics

Heart failure w/
normal EF
(HFnEF)

60% of HF patients have


nl EF

(General)

any disease of the heart


muscle, leading to
decreased fxn

Hypertensive
cardiomyopathy

dilated, thick heart on


ECHO

Familial dilated
cardiomyopathy

increased diastolic
pressure (>85 or 90)
dilated LV (nl 4-5cm)
causes poor systolic fxn
(can barely contract)

Pathogenesis

Etiologies

Epidemiology

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)

Risk factors

Lab/Imaging

Treatment

Complications

elderly women
w/ HTN, DM,
or both, CAD,
Afib

african
americans

autosomal dominant mutation in


myosin heavy chain or troponin T

younger age (20- multiple family genetic testing


30s)
members
affected

PE: displaced PMI, S3

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

Clinical Variants Defining Characteristics

Restrictive
cardiomyopathy

sx of CHF (dyspnea,
volume overload, edema)
very difficult to
distinguish from
pericardial constriction

Left Ventricle
Noncompaction

decreased LV function,
increased LV dilation

Pathogenesis

non-dilated, non-hypertrophied LV w/
advanced diastolic dysfxn (thin walled,
stiff ventricle that can't relax during
diastole)

Etiologies

Epidemiology

Risk factors

idiopathic
infiltrative dz
(amyloid,
sarcoid)
prior radiation

Lab/Imaging

Treatment

Complications

ECHO: huge, thin


dilated atria w/
normal appearing
ventricles and
normal systolic
function

stiffness in ventricle causes chronically


elevated atrial pressures (dilated atria)
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)

increased risk for


LV dilation, CHF,
thromboembolic
events

sarcomeric mutations but also other


nonsarcomeric mutations implicated
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

Non-neoplastic Thrombi
Cardiac masses

autosomal dominant sarcomeric


mutation (B-myosin heavy chain, myosin
binding protein C, troponin T) that causes
LV hypertrophy in absence of another
identifiable cause

Infective
endocarditis

family history
of HCM/SCD

SAM associatd
MR (systolic
anterior motion
of MV)

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

normally TB will affect the


pericardium but there is
potential for it to appear as
a myocardial lesion

1 in 500 adults

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)

post-MI thrombus, paradoxical embolus


(thrombus from a DVT enters systemic
circulation via PFO)
Tuberculoma

LVOT
obstruction

hypercoagulable
states; Afib (or
other rhythm
disorders)

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

Disease

Primary cardiac
tumors

Clinical Variants Defining Characteristics

(General)

Pathogenesis

Etiologies

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)

Epidemiology

Risk factors

Lab/Imaging

very rare

Treatment

Complications

delayed dx bc mimic
many dz that impair
cardiac fxn

clinical manifestations:
most common pediatric cardiac tumor?
impaired cardiac fxn, fever, Rhabdomyoma
inc ESR, emboli
most common malignant cardiac tumor?
Angiosarcoma
Cardiac myxomas most common primary
tumor

cytokine
associated (IL6)

found most commonly in


LA
possible MV dysfunction;
usually solitary (if multiple,
could be syndromic
association); systemic
manifestations (fever,
malaise, ESR)

Carney/LAMB/NAME
genetic syndromes w/
myxomas

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

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

embolus (stroke, GI
infarct, distal
toe/finger infarct)

Disease

Clinical Variants Defining Characteristics

cardiac
rhabdomyomas

most common pediatric


tumors

Pathogenesis

Etiologies

Epidemiology

can occur spontaneously but often caused tuberous


by tuberous sclerosis
sclerosis

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

Lab/Imaging

Treatment

Complications

macroscopic:
circumscribed
ventricular mass
(not encapsulated),
white-yellow &
waxy appearing

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)

Primary cardiac
sarcomas

Risk factors

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

Clinical Variants Defining Characteristics

Pathogenesis

Etiologies

Epidemiology

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

often asymptomatic
unilateral calf swelling
(large clots overwhelm
lymphatics); calf
tenderness, positive
Homan's sign (inflamed
venous wall), venous
cords

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

Risk factors

Lab/Imaging

Treatment

Complications

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!

highly
metastatic
cancers?
Melanoma
intermediate
metastatic
cancers?
Breast & lung
cancers, RCC,
leukemia/
lymphoma,
sarcomas
low metastatic
cancers?
Prostate, GI,
hepatocellular,
pancreatic,
ovarian

pregnancy,
male gender,
African
Americans

Disease

Clinical Variants Defining Characteristics

Pulmonary
embolism

dyspnea, pleuritic chest


pain, cough,
apprehension, syncope,
rales/crackles,
tachycardia, diaphoresis/
hemoptysis (if severe!)

Pathogenesis

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
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)

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)

3. PH w/ lung dz

pulmonary arterial hypertension (primary) PAP > 25 mmHg, normal PCWP (<15;
general pulm hypertension has ANY wedge
press), always elevated transpulmonary
gradient

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

mediators: increased activity of


vasoconstrictors (endothelin 1), reduced
activity of vasodilators (prostacyclin, NO)

Etiologies

pulmonary
artery
obstruction;Chro
nic pulmonary
hypertension w/
recurrent
emboli;
paradoxical
emboli (PFO,
ASD); chronic
thromboembolic
dz

stiffened LV
causes inc LA
pressure = inc
PAP (#2)
sarcoidosis,
hyper/
hypothyroidism,
renal dz (#5)
idiopathic (#1)

Epidemiology

3rd most
common CV
illness in US;
25% mortality if
untreated

Risk factors

Virchow's
triad

Lab/Imaging

ECHO: RVPO
(large PE)
spiral CT: best!

Treatment

anticoagulants

Complications

decreased CO and
BP --> Vtach, Vfib
pulseless activity to
heart

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)

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

Screening /
Education

Screening /
Education

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)

Screening /
Education

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!

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

50% maternal
mortality w/
subsequent
pregnancies if
CM persists
avoid combined
oral
contraceptives
increased risk of
recurrence!

Screening /
Education

Screening /
Education

Screening /
Education

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

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

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

Screening /
Education

competitive
sports restriction

common cause
of SCD in
athletes

Screening /
Education

competitive
sports restriction

ALL first degree


relatives need to
be screened
Screening of
adolescents &
competitive
athletes q 1218m
Screening of
adults q 5y

Screening /
Education

Screening /
Education

Screening /
Education

DVT
prophylaxis mechanical,
medical (anticoagulation!unfractionated
heparin,
LMWH)

Screening /
Education

Disease

Clinical Variants

Defining Characteristics

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)

HSV

(General)

Maxillary infection --> midface


(facial veins) --> cavernous
sinus thrombosis
Primary oral herpetic lesions (12% of infected)

Pathogenesis

dental plaque/host interaction

Etiologies

systemic diseases (ChediakHigashi, chronic


granulomatous dz,
neutropenia, DM, HIV)

Epidemiology

Risk factors

Lab/Imaging

Treatment

Complications

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-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

HSV

Young children

Self-resolving +/- acyclovir

Hospitalization for
dehydration

HSV

40% of U.S. population

prophylaxis w/ acyclovir

immunocompromised have
more widespread lesions

?? Not known

20-60% of population

self-resolving +/corticosteroids

can become a functional


problem if large

surgical + adjunct
radiation/chemo

prognosis related to stage


(overall 5y survival 20-60%)

sometimes prodrome present


(tingling prior to lesion)
Aphthous stomatitis

occurs on movable mucosa


(labial/buccal mucosa, soft
palate, floor of mouth)

stress induced; associated with Crohn's


disease

High SES,
immunocomp
(more severe)

appear round or oval with yellow


center and erythematous border
Behcet syndrome

Oral Squamous Cell


Carcinoma

Premalignant oral
lesions

multiple oral, genital ulcerations


+/- relatpsing iridocyclitis (eye)

Ulcerative,
exophytic, plaque
like

Leukoplakia

Erythroplakia
Oral/ sinonasal
melanoma
Ameloblastoma

Salivary gland
neoplasm

(general)

HLA types B5, B27, B12

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)

tobacco!! Can also have a


synergistic effect w/ alcohol;
Plummer-Vinson syndrome,
betel leaf (India), HPV

oral hyperkeratosis or callous but some


degree of dysplasia

M>>>F; 5th-6th decade; age, tobacco use


2-4% of all U.S.
malignancies

increased risk for 2nd


primary tumor

VERY common

VERY uncommon
VERY rare compared to
cutaneous melanoma
most common
odontogenic neoplasm

surgery often causes


functional impairment
1-17% of the dysplastic
lesions can transform to
malignancies

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

Disease

Clinical Variants

Pleomorphic
adenoma

most common type of benign


salivary gland neoplasm

Warthin tumor

85% occur in parotid


Most common bilateral tumor

Mucoepidermoid
carcinoma

Adenoid cystic
carcinoma
Paranasal sinus
neoplasms

Squamous cell
carcinoma
Adenocarcinoma

Gastroesophageal
reflux (GERD)

Barrett's esophagus

Eosinophilic
Esophagitis

Candida esophagitis

Defining Characteristics

Pathogenesis

Etiologies

Epidemiology

Risk factors

F>M

contain salivary and lymphoid tissue

M>F

acute dysphagia and food


impaction

odynophagia (painful swallowing)


+ dysphagia

candida

histology: large deposits of


mucin

40% 5y survival but gradedependent prognosis

histology: perineural invasion

high recurrence rate

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)

erosive esophagitis/ reflux


esophagitis (inflamm of
esophagus from stomach
contents)
esophageal strictures
(narrowing due to
inflammation)
esophageal
adenocarcinoma
Barrett's esophagus (see
below)

histology: intestinal
metaplasia (columnar
epithelium + Goblet cells +
villus pattern development)
endoscope: salmon colored
mucosa above Zline

Barretts --> dysplasia ->


esophageal
adenocarcinoma

uncommon

10% of population
globally; 15-44% of
Americans affected
monthly

diet, obesity, CT
disorders,
CVD/asthma (bagonists), DM

more common in middle


to older aged Caucasian
men

hx of atopy
(asthma, allergic
rhinitis, eczema);
younger men

infiltrative disorder -possible that certain


foods trigger eosinophilic infiltration of
esophageal body

Complications

smoking!!!

extremely aggressive; minor


glands; invasive growth
pattern
Maxillary sinus most frequently
affected

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)

Treatment

varied histopathology

commonly in parotid
most common malignant
salivary neoplasm (60-90%
occur in parotid despite parotid
glands nl having benign lesions)

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

Lab/Imaging

immunocomp
(HIV, chemo,
chronic steroid
use - asthmatics)

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

PPIs, steroids (oral flonase),


mast cell inhibitors, allergy
referral

anti-fungals (Fluconazole)

Disease

Clinical Variants

Viral esophagitis

Defining Characteristics

Pathogenesis

odynophagia (painful swallowing)


+ dysphagia

Etiologies

Epidemiology

Herpes, CMV

Risk factors

immunocomp
(HIV, chemo,
chronic steroid
use - asthmatics)

Lab/Imaging

Treatment

Complications

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

Esophageal
adenocarcinoma

GI stromal tumors
(GIST)

smoking, alcohol [synergistic


effect] --> mutations in p53

most common type


worldwide

HPV, chronic esophagitis;


dietary carcinogens (aflatoxin)

6/100,000 in U.S.

GERD, Barrett's

begin in the muscularis propria


(interstitial cells of Cajal myenteric plexusi) of
esophagus, stomach, or
intestine; then protrude through
submucosa & mucosa into
lumen

more common now due


to Barrett's

metastasis (middle
esophagus --> mediastinal,
paratracheal LN; lower 1/3
esop --> perigastric, celiac
LNs; upper 1/3 --> cervical
LNs)

gross: irregular, ulcerative


lesion in middle 1/3 of esop;
polypoid SCC occur in upper
1/3

Caucasians

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

hemorrhage & sepsis


tracheo-esophageal fistulas

histology: glandular structures


eroding through esophageal
wall
gross: umbilicated ulceration at surgical resection
organ surface
large tumors & metastases
treated by Imantinib
(Gleevec)

mutation in c-kit

bleeding
Small cell carcinoma

Primary esophageal
motility disorders

Melanoma
Achalasia

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

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

inflammatory infiltration of myenteric


plexus --> defective NO --> chronic
excitation --> chronically closed LES

Esophageal varices

life threatening bleeding

variceal rupture produces massive


hemorrhage into esoph lumen

cirrhosis, portal hypertension

Esophageal
lacerations (MalloryWeiss tears)

bleeding (hematemesis)

longitudinal tears at the GE junction from


severe retching or vomiting

alcoholic binge

endoscopy: pinhole opening


of LES
gross: enlarged venous
channels @ GE junction;
ruptured submucosal veins
chronic alcoholics;
acute illness w/
increased
vomiting

endoscopic sclerosing or
banding
most patients have coexisting hiatal hernia
(stomach slips into
esophageal hiatus)

Disease

Peptic ulcer disease

Clinical Variants

gastric, duodenal

Defining Characteristics

NSAIDs cause mostly gastric


ulcers (worse with food)

Pathogenesis

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

Gastritis

Acute gastritis

sudden inflammation of stomach transient mucosal inflammatory process


lining
due to numerous etiologies
asymptomatic or variable
epigastric pain, n/v

Chronic gastritis

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

Adenomatous

Gastric
adenocarcinoma

less severe symptoms than


acute gastritis but persistent

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

(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

Etiologies

increased gastric acid


secretion (nl in gastric ulcers,
30% increase in duodenal
ulcers);

Epidemiology

5-10% lifetime
prevalence

H. pylori & NSAIDs!!

Risk factors

Lab/Imaging

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

Treatment

Complications

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)

Alcohol, NSAIDs, ischemia

histology: overwhelming amt of


inflammatory cells; intestinal
metaplasia (Goblet cells); can
sometimes see H. pylori w.i
gastric gland

H. pylori, autoimmune
gastritis, chronic alcohol
abuse, radiation, post surgical

10% of chronic gastritis

associated with Peutz-Jegher


syndrome (intestinal/gastric
polyps + peri-oral
pigmentation), FAP (fundic
gland polyps; adenomatous
polyps in large intestine that
become adenocarcinomas)

F>M

found most commonly in


people 50-60y.o.

usually progress from atrophy and


intestinal metaplasia (commonly in the
background of chronic gastritis)

increased risk of dysplasia


and adenocarcinoma w/
intestinal metaplasia

histology: regenerative, dilated


gland but not neoplastic

larger size lesion


= increased risk
adenocarcinoma
environmental factors
(H.pylori, hi nitrate/nitrite diet,
hi smoked/salty diet, smoking,
lack of fruits/veggies, low SES)

leading cause of cancer


death globally, more
common in Japan, Chile,
China, Russia

host factors (chronic gastritis,


intestinal metaplasia,
adenomatous gastric polyps,
Barrett's esophagus, partial
gastrectomy, Menetrier
disease)

M>F; usually >50 y.o..

Genetic factors (+FH, HNPCCDNA mismatch repair gene


mut; familial gastric cancer
syndrome- E cadherin mut;
autoimmune gastritis)

Staging: depth of invasion


(Tis = in situ; T1 = lamina
propria/submucosa; T2 =
muscularis propria; T3 =
serosa; T4 = adjacent
structures)

Disease

Clinical Variants

Intestinal type

Defining Characteristics

most common type


slightly better prognosis than
diffuse type

Pathogenesis

Etiologies

a/w: intestinal metaplasia from


environmental factors; chronic gastritis;
and adenomatous polyps

Epidemiology

older patients w/
known risk factors

Risk factors

Lab/Imaging

Treatment

Complications

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

Gastric lymphomas

Gastric carcinoids

usually diagnosed at a high


stage so worse prognosis
(plus easily invades due to
lack of adherence molecules)

MALT lymphoma

Low grade

Diffuse large B-cell


lymphoma

high grade

symptoms depend on
hormones being produced
often secrete gastrin

E-cadherin mutations (CDH1 gene) -->


loss of cell adherence

younger patients with


no known risk factors
besides perhaps
genetics

gross: thick stomach wall,


enhanced ruggae (linitis
plastica morph), flatter
lesions

M=F

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

VERY rare

gross: hypertrophy of gastric


folds

chronic inflammation --> lymphoid stimulus H. pylori


--> clonal proliferation of small B
lymphocytes --> development of
lymphoma
arise de novo or in MALT lymphoma

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)

rare in stomach (more common


in SI & lungs)
patients can present w/
duodenal ulcers, diarrhea if ZE
Menetrier Disease

Malrotation

weight loss, diarrhea, peripheral


edema
hypochlorhydria (low gastric
acid in stomach)
most common congenital GI
malformation

excessive secretion of TGF-a


(transforming growth factor), causing
diffuse hyperplasia of foveolar epithelium
of body/fundus of stomach

?? Unknown

M>F; 30-50 y.o.

1% of congenital
population (incidence
ranges from 1/6000 1/200)

majority are asymp

majority diagnosed w/ 1
year of life but some go
undetected until
incidental find on GI
imaging/surgery

Older kids/adults: intermittent


vomiting, abd pain, volvulus,
pancreatitis, enteropathy,
peritonitis
bilious emesis IMMEDIATELY
following birth = hi grade
obstruction

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)

M slightly more than F

Newborns: bilious emesis, late


stage signs (hematemesis,
hematochezia, tenderness/pain,
peritonitis, shock = intestinal
necrosis) = very poor prog

Intestinal atresia

increased risk of
adenocarcinoma

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!!

Abd distention = mod grade


obstruction

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

Hirchsprung's
disease (aganglionic
bowel)

Defining Characteristics

Pathogenesis

Etiologies

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)

Epidemiology

1/5000

Risk factors

positive FH
sometimes

M>F in short segment;


M=F in long segment dz

Lab/Imaging

rectal biopsy - ganglion


cells? HD pts have no
ganglion cells and nerve
hypertrophy

Treatment

resection of aganglionic
segments

Complications

lifelong implications
15% of HD babies have
other associated
congenital anomalies :(

Barium enema: determines


transition area where no
contraction/distention

high complication risk postsurgery: strictures,


impactions, soiling,
constipation

anorectal manometry:
differentiates normal v. abnl
functioning bowel by recto-anal
inhibitory reflex

starts @ birth (unlike funct


constip) and rarely has fecal
soiling (unlike funct constip
again)
Gilbert syndrome

Crigler Najjar
Syndrome

Type 1

Type 2

Elevated indirect
(unconjugated) bilirubin;
benign - asymptomatic
jaundice
elevated indirect (unconjugated)
bilirubin

precipiated by fasting, stress,


EtOH

Prevalence ~ 5%; M>F

family history

increased indirect bilirubin

none

completely absent UDP glucoronyl


transferase activity

severe/fatal
elevated indirect (unconjugated) reduced UDP glucoronyl transferase
bilirubin;
activity
less severe (Arias syndrome)
neonatal jaundice
(unconjugated
hyperbilirubinemia) -->
kernicterus (toxic
encephalopathy)

Neonatal
hyperbilirubinemia

reduced UDP glucoronyl transferase


activity causes impaired conjugation of
bilirubin

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

Hepatitis B

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)

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

contaminated food products


(fecal-oral)

U.S. - horizontal transmission


of body fluids (IVDU, needle
stick- HCW, unprotected sex;
MSM)

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

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

increased ALT (liver damage)

NO risk for chronic


infection or cirrhosis!!!

IgM - suggests new/acute


infection
IgG persists to provide total
immunity

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

Defining Characteristics

Hepatitis C

Hepatitis D

Pathogenesis

Etiologies

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)

enveloped ssRNA virus known as a delta


agent because only propagates in the
presence of Hepatitis B!!

IVDU, blood transfusion

other: needlesticks in HCW,


vertical transmission, nonsexual household contact,
sexual transmission

Epidemiology

Risk factors

Lab/Imaging

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

Treatment

Complications

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)

treat hepatitis B to get rid of


hepD

Transmitted via blood or sex (usually


exposed to HepB & HepD at same time)
Hepatitis E

non-eveloped ssRNA virus that is


transmitted via fecal-oral route and can
be detected in stool/bile/liver;

contaminated food products


(fecal-oral)

CAN BE FATAL IN
PREGNANT WOMEN!!!

does NOT cause chronic infection


(Alcohol) hepatic
steatosis

occurs w. moderate-marked
EtOH intake
asymp in most cases
clinical presentation:
hepatomegaly, elevated liver
enzymes
REVERSIBLE!

Alcohol hepatitis

acute onset following binge


drinking

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)

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

also increased peripheral catabolism of


fat, which causes fatty acids to be
delivered to the liver where they
accumulated (steatosis)
gross: steatosis typically
present (represents hx of
alcohol abuse), +/hepatomegaly (unless cirrhotic)

excessive alcohol increases formation


of toxic metabolites, overwhelming liver's
metabolic ability; mitochondria & MT
dysfunction

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

Alcohol-related
hepatic cirrhosis

10-20% risk of death

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

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

benign course usually

not really understood

?? Liver enzyme elevation


(loss/death of hepatocytes so
not really too many left to be
injured)

increased HCC risk

decreased liver synthetic


function tests
gross: decreased size, diffuse
nodularity, brown/ green
pigmentation (bile stasis)

IRREVERSIBLE!!

histology: marked fibrosis,


regenerative nodules, variable
inflamm infiltrate, bile stasis;
trichrome stain identifies
collagen
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

>900 drugs implicated; many drugs have


cholestatic or hepatocellular signature
toxicity (after which they cause elevated
liver enzymes)

unpredictable timeline of DILI


presentation; can mimic
autoimmune hepatitis

metabolic: accumulation of toxic


metabolites in hepatocytes; steatosis;
autoimmune (methyldopa); mitochondrial
toxicity (HIV meds, amiodarone)

[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

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

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)

Hy's law: >10% of patients w/

>900 drugs implicated; many drugs have

death or transplantation, even


after cessation of drug

toxicity (after which they cause elevated


liver enzymes)

unpredictable timeline of DILI


presentation; can mimic
autoimmune hepatitis

metabolic: accumulation of toxic


metabolites in hepatocytes; steatosis;
autoimmune (methyldopa); mitochondrial
toxicity (HIV meds, amiodarone)

Clinical Variants DILI


Defining
Characteristics
cholestatic orPathogenesis
hepatocellular signature
+ jaundice
progress to
Idiosyncratic
(individualized;
immune-mediated)

[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)

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

steatosis --> steatohepatitis -->


cirrhosis

"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;

Autoimmune hepatitis

pediatric or young adult


presentation w/ liver disease

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

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

monitor LFTs in patients taking


INH

patients w/ comorbidities like


HepB, hepC are at greater risk!

20% prevalence in U.S. metabolic


syndrome

elevated ALT (AST/ALT <1)


U/S: increased echogenicity
from fatty infiltrate

weight loss & metabolic


control (treat DM w/
metformin, treat dyslipidemia
w/ statins)

biopsy: steatosis, inflammation,


fibrosis

central obesity, hepatomegaly


Wilson's disease

Adults
Risk factors
obesity
malnutrition
pregnancy
other drugs
alcohol
hx of DILI
genetics
PMH of liver dz

gene defect responsible for copper


autosomal recessive
transport --> decreased biliary excretion of inheritance
copper --> increased copper deposition
throughout body --> increased oxidative
stress & damage

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)

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

lifelong chelation
liver transplant is curative

increased 24h copper excretion


in urine

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)

increase immunosuppression 87% remission within 3y of


(prednisone, combo therapy) treatment

histology: interface hepatitis,


hepatic rosettes (small gland
like clusters of surviving
hepatocytes within
inflammatory infiltrate),
variable fibrosis depending
on dz stage

Primary Biliary
Cirrhosis (PBC)

Primary Sclerosing
Cholangitis (PSC)

autoimmune disorder
characterized by progressive
destruction of intrahepatic bile
ducts (microscopic injury)

aberrant immune response directed at own


biliary epithelial cells (small bile ducts)

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

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)

histology: bile duct destruction


w/ mononuclear cell
inflammatory infiltrate

8.5/100,000

elevated ALP, mild elevations


in transaminases

M>F
avg age of dx 40

majority of patients have IBD


(UC)

MUST exclude other dx


elevated ALP, nl or mildly
elevated transminases, IgM,
hypercholesterolemia, fat
soluble vitamin deficiency
(ADEK), anti-mitochondrial
antibody (AMA)

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

Glycogen storage
disease

Tyrosinemia

Clinical Variants

GSD-1

type 1

Defining Characteristics

Pathogenesis

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

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)

severe liver dz in young infants


(bleeding problems - unable to
produce clotting factors; FTT)

defective enzyme (FAH) causes buildup of


toxic metabolite FAA; FAA is converted to
another toxin SAA

Etiologies

Epidemiology

Risk factors

Lab/Imaging

uric acidosis, lactic acidosis,


elevated triglycericides
liver biopsy (measure amt of
glucose-6-phosphatase)

newborn screening (elevated


tyrosine --> repeat and check
for urine SAA)

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

Hereditary
hemochromatosis

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

family history

IV augmentation therapy (antienzyme therapy) - helps lung


fxn but not liver disease
(malformed protein is still
being produced)

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

monitor serum ferritin or


transferrin saturation

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

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

NTBC (inhibits buildup of


toxic substances)

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)

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);

Cirrhosis

nutritional management
(continuous night feeding via
ng tube; uncooked corn starch
before bed; frequent feedings)

dietary (reduce protein


intake)

Gaucher's disease, progressive hepatomegaly,


Fabry's disease, Tay- splenomegaly, loss of
Sach's disease
developmental skills, abnormal
facial features

Alpha1- antitrypsin
deficiency (A1AT)

Complications

liver transplant when dietary


treatment fails or when
adenomas develop

neurological problems, renal


involvement
Lysosomal storage
disease

Treatment

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

frequent phlebotomy to
remove RBCs (and hence
drop iron levels)

cirrhosis, HCC, diabetes


(toxicity to pancreas),

(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

decompensated

Defining Characteristics

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Cirrhotic changes +
SYMPTOMS

no biopsy needed (imaging +


symptoms sufficient)

compensated signs + jaundice,


ascites, asterixis (hepatic
encephalopathy)

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)

Treatment

chronic ascites? Minimize


sodium diet; diuretics,
paracentesis (especially if
ACS), TIPS (if refractory
ascites)
early antibiotics if SBP

Complications

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

hepatic
encephalopathy

neurologic & psychiatric


dysfunction in presence of
decompensated cirrhosis

conversion of ammonia (which is not


eliminated by dysfunctional liver) to
glutamine --> astrocyte swelling & altered
neurotransmission

cirrhosis (increased
resistance in sinusoidal space)
Other causes? Portal/ splenic
vein thrombosis,
schistosomiasis, venoocclusive disease, Budd-Chiari

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)

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)
Cirrhotic
cardiomyopathy

Hepatopulmonary
syndrome (HPS)

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

Disease

Clinical Variants

Portopulmonary
Hypertension
(PPHTN)

Defining Characteristics

pulmonary hypertension in the


setting of decompensated
cirrhosis --> right heart failure

Pathogenesis

Etiologies

Epidemiology

Risk factors

unk?? Vascular injury/ inflammation


mediated by serum factors abnormally
persist in hepatic outflow

Lab/Imaging

ECHO (screens) + RH
catheterization (confirms)

transudative pleural effusion


resulting from ascites tracking
across diaphragm into negative
intrathoracic space

accumulation of ascitic fluid in pleural


space, particularly right hemithorax -->
right sided pleural effusion

CXR

dyspnea, hypoxemia
Variceal hemorrhage

hematemesis, hematochezia

Complications

Diuresis, prostaglandin
therapy if acute RV failure
Liver transplantation does not
immediately reverse PPHTN
(so patients must continue
prostaglandins) - difference
btwn HPS & PPHTN

RHF, ascites, pulm edema,


peripheral edema

Hepatic hydrothorax

Treatment

significant portal hypertension causes


back flow of blood to gastroesophageal
plexus --> varice formation --> rupture -->
potentially fatal hemorrhage

endoscopy

Thoracentesis

respiratory faulure

diuretics

spontaneous bacterial
empyema

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

Hepatorenal
Syndrome (HRS)

functional renal failure in


presence of decompensated
cirrhosis

Annular pancreas

incomplete rotation of ventral


pancreatic bud

splanchnic vasodilation--> decreased


effective arterial blood volume (per the
kidneys) --> compensatory mechanisms
by kidneys --> functional renal failure

terlipressin (splanchnic
vasoconstrictor)

structurally normal kidneys


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

infants: n/v, FTT, feeding


problems

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

can have strictures/


obstruction in duodenum

failed fusion of dorsal and ventral


pancreatic ducts

5-7% of population

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

Ectopic pancreas

associated with other


congenital anomalies (Down
syndrome, duodenal
atresia, congenital heart
defects,
tracheoesophageal fistula)

endoscopic or surgical
sphincterectomy, stent
placement

1-2% of population

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)

Congenital pancreatic
cysts

Cholelithiasis
(gallstones)

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)

very rare!

surgical resection if
symptomatic

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

no intervention if
asymptomatic

FFFF (fat, female,


40s, fertile)

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

Biliary colic

Acute Cholecystitis

Clinical Variants

Defining Characteristics

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

Pathogenesis

Etiologies

Risk factors

intermittent obstruction of cystic duct; may


or may not have gallbladder inflammation

chronic obstruction of gallbladder outlet by


gallstone --> bile stasis --> severe
inflammation --> damage to gallbladder
mucosa

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

Choledocholithiasis

Epidemiology

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)

Lab/Imaging

U/S gold standard diagnosis

1/3 of patients with


gallstones

cholelithiasis

Treatment

Complications

recurrent? Elective
cholecystectomy +/intraoperative cholangiogram
to clear out any stones in bile
duct if needed

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

majority of people have no


complications

Elevated WBC, mild jaundice


(slightly elevated bili), slightly
elevated AST/ALT/ALP

gallbladder empyema
perforation (distention,
ischemia, pericholecystic
fluid collection --> abscess)

If U/S is questionable, proceed


with HIDA scan (would not see
any radioactivity in gallbladder diagnostic of acute
cholecystitis)

mild hyperbilirubinemia,
elevated ALP, transient
AST/ALT spike would suggest
passage of stone into
duodenum

diabetics can have


gangrenous cholecystitis

ERCP + cholecystectomy
(unless high risk patients these will have ERCP +
URSA to dissolve the stones)

U/S - identifies common bile


duct stones in 50% of patients

Cholangitis

Charcot's triad (fever, RUQ


pain, jaundice)
Reynold's pentad (charcot's +
altered mental status +
hypotension)

Gallstone ileus

Mirizzi Syndrome

Irritable Bowel
Syndrome (IBS)

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)

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!!

ERCP - diagnostic &


therapeutic
elevated WBC, bilirubin, ALP
positive blood cultures

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

Acute pancreatitis

Clinical Variants

Defining Characteristics

epigastric pain (severe,


persistent) that radiates to
back or left scapula
n/v, possible jaundice (if stones
in common bile duct),
tachycardia
self-limiting!!

Chronic pancreatitis

weight loss, n/v, anorexia,


abdominal pain (although some
patients are relatively painless),
maldigestive diarrhea
(steatorrhea, azotorrhea),
pancreatic diabetes

Pathogenesis

Etiologies

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)

gallbladder stones that have


migrated to become obstructed
in the Ampulla of Vater
(pancreatic duct + common bile
duct)

insult (gallstones, alcohol) --> loss of


protective mechanisms --> proenzyme
activation --> digestion of pancreas -->
acute changes --> ischemia --> release of
inflammatory mediators --> systemic
response (sometimes if severe)

alcohol
idiopathic
other (drug induced dideoxyinosine/DDI, 6mercaptopurine/
azathrioprine), iatrogenic ERCP, sphincter of Oddi, high
lipids, infection, pancreas
divisum, autoimmune, CF,
trauma, neoplasm)

Epidemiology

Risk factors

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

Lab/Imaging

Gallstone pancreatitis?
Elevated bilirubin, liver
enzymes, lipase/amylase,
WBC, + gallstones on
imaging

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)

Structural: dilated pancreatic


duct or dilated side branch of
pancreatic duct on imaging;
calcium deposits throughout
pancreas head (ERCP, CT,
U/S)

visceral dull pain that localizes


and becomes severe
somatoparietal pain in LLQ

antibiotics, surgical resection


of affected colon

constipation, diarrhea, fever

Acute mesenteric
ischemia

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

superior mesenteric artery


embolus

endoscopy: huge ulcers due to


loss of blood supply

nonocclusive mesenteric
ischemia

diarrhea, vomiting, melena

Abdominal Aortic
Aneurysm (AAA)

pain out of proportion to


findings
acute sudden onset severe midabdominal "tearing" pain
pulsatile, tender abdominal
mass
lightheaded, diaphoresis, nausea

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

no damage to pancreas;
majority of patients do NOT
have any complications

supportive care, IV fluids,


pain meds

Functional: parenchymal
changes denoted by
secretin/CCK test
Acute diverticulitis

Complications

abdominal pain + elevated


lipase/ amylase

Autoimmune pancreatitis?
Swollen pancreas on CT,
+ANA, +IgG4

autoimmune pancreatitis? Lymphocyte


infiltration causes fibrosis of pancreas -->
pancreatic dysfunction

Treatment

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

Benign liver
neoplasms

Clinical Variants

Cavernous
hemangioma

Hepatic adenoma

Defining Characteristics

most common benign liver


neoplasm

Pathogenesis

Etiologies

Epidemiology

Risk factors

vascular tumor defined by the proliferation


of blood vessels

most patients who have these


benign neoplasm of hepatocytes
present with hemorrhaged
hepatic adenoma - sudden RUQ
pain

Lab/Imaging

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

women of childbearing age


who have used OCPs

age, OCPs

histology: multiple large


vascular channels (full of blood
or thrombosed)
histology: no inflammatory
infiltrates; glycogen, no bile
ducts visible
gross: very bloody mass

Treatment

NO needle biopsy (could


cause bleeding!)

Complications

possible that they could


spontaneously rupture but
very rare

surgical excision after > 910cm

Bleeding risk!! (especially


subcapsular adenomas)
Common cause for sudden
peritoneal hemorrhage in
young women
increased risk for HCC

Non-neoplastic
hepatocellular
nodules

Hepatocellular
carcinoma

often mistaken for neoplasms

[FYI: most common


malignant neoplasm
of liver? Metastatic
carcinomas from
GI/colon, breast,
lung]

result from vascular malformation after


local vascular injury or AVM

women of
reproductive age

most common primary malignant


neoplasm

cirrhosis
hemochromatosis

silent hepatomegaly (if noncirrhotics), rapid increase in


liver size, worsened ascites,
increased pain

chronic HBV or HCV


chronic alcoholism
aflatoxin exposure
hemochromatosis

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

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)

Adenocarcinoma of
gallbladder

Cystic pancreatic
neoplasms

Pancreatoblastoma

more common than


cholangiocarcinoma

serous cystic
neoplasms
mucinous cystic
neoplasms

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

histology: formation of
haphazard glandular
structures

CIRRHOSIS PATIENTS DO
NOT HAVE INCREASED
RISK!
usually occurs in presence of
gallstones

gross: dilated duct lumen from


obstruction
Hispanics, Native histology: malginant lesions
Americans
have loss of cell polarity,
eccentric nuclei, &
hypochromatic areas;
resembles glandular structures

females; generally benign

Female

Females

Female

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)

prognosis best if single


tumor is <2cm in size and
good liver function

Disease

Clinical Variants

Pancreatic ductal
adenocarcinoma

Defining Characteristics

Pathogenesis

Etiologies

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%)

Epidemiology

4th leading cause of


cancer death

distributed most commonly in pancreas


head, but time of diagnosis, they have
metastasized to liver, LNs, peritoneum

Pancreatic Acinar
Cell carcinoma

rare malignant tumor

Risk factors

Lab/Imaging

Treatment

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

arise from acinar cells - secrete digestive


enzymes

poor prognosis but slightly


better than ductal
adenocarcinoma

tumors secrete lipase/ trypsin/


amylase
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

Pancreatic Islet Cell


Neoplasms

Clostridium dificile

Giardia lamblia

(Flagellate)

a/w fever, dehydration,


tachycardia
majority of cases are
asymptomatic
1-2 week incubation period

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)

Entamoeba
histolytica

Apicomplexa
parasites

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

Cryptosporidium
parvum

self-limiting watery diarrhea (can sexual & asexual stage


be very mild)

Isospora belli

immunosuppresed have chronic


refractory illness w/ high
recurrence rate

Microsporidia

Enterocytozoan
bienusi

2% of all pancreatic
tumors

Antibiotic use,
hospital setting,
elderly,
chemotherapy,
surgery,
Ulcerative colitis

contaminated water supplies; found worldwide


streams, ponds (near
reservoirs - beavers, muskrats)

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

daycare, camping stool microscopy for O&P

metronidazole or tinidazole
[toxicity/ side effect =
disulfuram effect = nausea
and severe symptoms]

daycare centers

immigrants & travelers to


developing world

stool microscopy &


immunoantigens

metronidazole for
trophozoites; paranomycin
for cysts

liver abscess aspirate =


"anchovy paste" - rust colored
contaminated surface water or global
water supplies

contaminated fruits & veggies

fungal organisms that produce pathology


when spores are inhaled or ingested

malignancy determined by
hormone secreted, size of
tumor, & aggressiveness

gross: abundant blood supply


(unlike adenocarcinomas which
are more white/ yellowish)
histology: monotonous
appearing

mostly tropical regions

Cyclospora
cayetanesis

Complications

mostly tropical regions

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)

extra-intestinal
manifestations (amoebic
liver/lung/ brain abscess)

self-limiting watery diarrhea (can


be very mild)
immunosuppresed have chronic
refractory illness w/ high
recurrence rate

Disease

Clinical Variants

Defining Characteristics

Microsporidia

Strongyloides
stercoralis

Other nematodes

Encephalitozoon
intestinalis
(Nematodes)

Ascariasis

Enterobiasis

Trichuriasis

Hookworm

Cestodes/ flatworms

Blood flukes

Taenia solium
Taenia saginata
Echinococcus
Diphyllobothrium
latum
Schistosomiasis

Liver flukes

Clonorchis sinensis

E. coli

Fasciola hepatica
ETEC (Traveler's
diarrhea)

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

Etiologies

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

whipworm
colitis (bloody stools), rectal
prolapse
major contributor to global
malnourishment

invades & destroys colon mucosa, causing


colitis & rectal prolapse

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

Lab/Imaging

Treatment

histology: polar tubules

ALB (albendazole), FMG


(fumagillin)

serology

IVERMECTIN (binds to
glutamate-gated chloride
channels causing parasite
paralysis & death)

biopsy would show adult


worm burrowing in small
bowel

Complications

immunocomp at
risk for
hyperinfection
syndrome

poor sanitation
places

stool exam +/- eosinophils

ALB (albendazole- inhibits


polymerization of tubulin &
tubulin dependent glucose
uptake), MBZ (mebendazole)

daycare!!!

scotch tape - characteristic


eggs

ALB, MBZ

stool exam +/- eosinophils

700 million people


affected; primarily
developing countries

PORK
BEEF
DOG, SHEEP
FRESHWATER FISH
FRESHWATER
RAW FRESHWATER FISH

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

WATERCRESS
contaminated food & water

hydration; antimotility
meds; fluoroquinolones
(CIPRO)

food, water, & person-toperson transmission

typhoid fever

contaminated human sewage

Salmonella
typhimurium

self-limited acute enterocolitis;


6-48h post-food ingestion &
lasts 3-7days

contaminated food with animal


waste

watery stools, abdominal


cramping, n/v

poor sanitation
places

tropical areas

infects cecum & colon


acquired through skin, after which the
worm uses teeth to attach to lungs & small
bowel mucosa

high worm burden --> significant


blood loss, low albumin, and low
nutrients
cysticercosis --> epilepsy

Risk factors

barefeet

ingestion of eggs

Salmonella typhi

Salmonella
enteritidis

Epidemiology
global

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

EHEC (SHEC; E.coli hemorrhagic colitis (bloody


O157:H7)
diarrhea)

Salmonella

Pathogenesis
fungal organisms that produce pathology
when spores are inhaled or ingested

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]

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

Food Poisoning

Clinical Variants

Defining Characteristics

Pathogenesis

Etiologies

Epidemiology

Risk factors

Lab/Imaging

Treatment

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.

nonenveloped dsRNA virus

fecal-oral; possible airborne


spread

600-850K deaths/ year


globall

antigen assays, RT-PCR,


culture

rehydration

winter season
Vomiting, fever, watery diarrhea
--> dehydration & electrolyte abnl
Norovirus

Small bowel
obstruction

Large Bowel
Obstruction (colonic)

most common cause of


foodborne outbreaks
investigated

relatively low infectious dose so easy to


spread from person to person

sudden onset N/V; short lasting


watery diarrhea
acute onset, intermittent
abdominal pain; vomiting
(bilious, fecal), obstipation,
abdominal distention

cruise ships

supportive treatment only

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)

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

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

CT, barium studies, XR

benign colonic strictures?


Thinner stool
malignant colonic strictures?
Hematochezia, iron def anemia,
weakness, weight loss, vomiting,
insiduous onset

Bowel ileus

fecal-oral; aerosol-vomitus;
fomites; contaminated food

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

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

XR/CT: presence of gas in


stomach, SI, colon + dilated
small bowel
no mechanical obstruction!!

cecal volvulus - NO
COLONOSCOPY; cecostomy,
resection
NPO until symptoms resolve;
NG tube; correct electrolytes;
limit narcotics; get patient
moving out of bed!

Complications

Disease

Clinical Variants

acute colonic pseudo


obstruction

Inflammatory bowel
disease

Defining Characteristics

Etiologies

Epidemiology

Crohn's disease

RLQ pain, weight loss,


arthritis/arthalgias, watery
diarrhea

Ulcerative colitis

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

Risk factors

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

Caucasians
Ashkenazi Jews;
SMOKING in
Crohn's disease
NSAIDs
genetic
predisposition

complicated diverticulitis perforation, abscess,


fistulization
uncomplicated - inflammation
w/o complications; MAJORITY
of cases
LLQ pain & tenderness; low
grade fever

Complications

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

CBC: microcytic anemia; low


albumin (if weight loss),
elevated ESR/CRP, stool
culture to R/O infection;
endoscopy w/ bx

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

endoscopy: mild (erythema,


preserved circular muscles);
moderate (edema,
inflammatory cell infiltrate,
bleeding/ ulcerations); severe
(denuded mucosa, blunted
haustrations, thickend w/
inflamm material)

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)

250,000 cases per year


in US
ages 10-30

western world

induction of remission?
Steroids, 5-ASA (reduce
prostaglandins)

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)
Maintenance of remission?
5-ASA, 6MP/AZA, biologics

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

M>F

Diverticulitis

Treatment

CARD15/NOD2 mutation - a/w ileocolonic


dz; early onset; early surgery; early
recurrence post-surgery; familial CD

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

Diverticulosis

Lab/Imaging

critically ill patients dilation of ALL segments of


colon

severe abdominal distention


with absence of stool/gas
passage

inflammatory; obstructing;
fistulizing/microperforating
subtypes

Acute appendicitis

Pathogenesis

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

Screening /
Education

certain foods or trauma


can precipitate the lesion

cancers a/w HPV have


better prognosis though!

Screening /
Education

Screening /
Education

Prognosis determined by
depth of invasion

Prognosis determined by
depth of invasion

aggressive behavior
determined by size and
number of mitoses

Screening /
Education
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

Screening /
Education

Screening /
Education

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)

Screening /
Education
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)

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education
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

Screening /
Education

Screening /
Education

Screening /
Education

bottled beverages; avoid


ice & uncooked food

cook ground beef; avoid


food cross
contamination; hand
wash after all animal
contact; diaper hygiene
at pools

Screening /
Education

live, oral vaccines for


infants (Rotarix)

Screening /
Education

Disease

Clinical
Variants

Fanconi's
Syndrome

Secondary
causes of
hypertension

Liddle
syndrome

Congenital
adrenal
hyperplasia

Pseudohypoaldosteronism
Type I

Gitelman
syndrome

Bartter
syndrome

Defining Characteristics

Pathogenesis

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]

(listing)

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

21-hydroxylase life-threatening hyperkalemia,


deficiency
profound metabolic acidosis,
hyponatremia, severe volume
depletion

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

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Cystinosis (auto
recessive; most
common cause in
childhood)

autosomal dominant
disorder

autosomal recessive
disorder

usually diagnosed @ birth w/ NBS

synthetic aldosterone
infusion

check magnesium because


hypomagnesemia can cause
refractory hypokalemia

replace K, Mg losses;
restore intravascular
volume w/ salt

autosomal recessive
disorder

autosomal recessive
disorder

genetic defect in NKCC co-transporter in TAL autosomal recessive


of loop of Henle, causing volume depletion
disorder
and aldosterone production

Complications

Screening /
Education

Disease

Clinical
Variants

Hyponatremia

Defining Characteristics
seizures (neuro emergency) or
can be gradual onset (intact
neuro exam)

Pathogenesis

Etiologies

Epi

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

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)

Hypernatremia

Central
diabetes
insipidus

Nephrogenic
diabetes
insipidus

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

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]

water loss (insensible loss from skin, lungs;


renal loss from DI, osmotic diuresis; GI loss,
loss into cells from seizures, severe exercise,
rhabdomyolysis)

complete,
partial

polyuria, dilute urine,


hypernatremia

Congenital

high urine output (20L/day),


bladder enlargement &
obstruction (from attempts to
retain urine), hypernatremia

Acquired complete,
partial

polyuria, dilute urine,


hypernatremia

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

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

partial central DI - can


also use chlorpropamide,
carbamezipine, or
clofibrate
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!)

osmotic diuretics like glucose, mannitol, urea


electrolyte abnl (hypercalcemia,
hypokalemia)

thiazide diuretics + low


sodium diet (decreases
overall urine output by
keeping mild volume
depletion state and
increasing PCT
reabsorption)

Screening /
Education

Disease
Edematous
states

Clinical
Variants
CHF

Defining Characteristics
edema

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

Nephrotic
syndrome

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

(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

Congenital
Nephrotic
Syndrome

Membranous
nephropathy

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

Primary glomerular
disease

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

vast majority are


primary/ idiopathic

UA
24h urine protein
albumin blood test, lipid panel
renal biopsy w/ immunofluorescence

thrombosis, thromboembolism (loss of


anticoagulant
factors)

most
common in
Finland

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)

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)

resistant to most
treatments; severe cases
require bilateral
nephrectomies and
subsequent lifelong
dialysis

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)

death secondary to
sepsis
other complications hyper-coagulopathy,
infection, stroke

Screening /
Education

Disease

Clinical
Variants
Minimal
change
disease

Defining Characteristics
normal biopsy findings EXCEPT
diffuse foot process effacement

Pathogenesis

Etiologies

most
common
nephrotic
syndrome in
kids

epithelial cell (podocyte) injury

insidious onset in o/w healthy


kids; proteinuria w/ preserved
kidney function
Focal
Segmental
Glomerulosclerosis
(FSGS)

important to distinguish from


minimal change dz!!!

primary /idiopathic

little tendency for spontaneous


remission
(general)

hematuria (gross, microscopic,


+/- RBC casts in UA),
acute renal failure (azotemia increased BUN; oliguria),
HTN,
+/- proteinuria,
+/- edema,
usually secondary to acute GN

Acute poststreptococcal
GN (postinfectious 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

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

Lab/Imaging
Creatinine: nl (nl GFR)

Treatment

similar to EASS

Complications

steroids (90% resolution) <5% develop


chronic renal failure

LM: nl glomerulus
IF: none
EM: diffuse foot process effacement
(fusion)
50% have renal
failure in 10y
20% rapidly
progress to ESRD in
2y
recurrence in 2550% of transplants

IF: none
EM: diffuse foot process effacement
+ focal/segmental sclerosis of
glomerulus

RBC casts in urine, mild


proteinuria, periorbital edema,
mild-mod HTN

Membranoproliferative
GN Type I
(MPGN1)

Risk factors

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)

secondary (HIVcollapsing variant of


FSGS; heroin use,
HTN, reflux
nephropathy,
unilateral renal
agenesis/ dysplasia;
primary
glomerulopathies,
SCC, renal
transplant, diabetic
nephropathy,
obesity)

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

Nephritic
presentation

Epi

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

<1% of kids do not


improve, become
severely oliguric,
and develop rapidly
progressive GN

EM: sparsely distributed


subepithelial humps, mesangial
immune deposits
IF: starry sky for IgG, C3

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)

Screening /
Education

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

Etiologies

Epi

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)

Risk factors

Lab/Imaging

Treatment

Complications

Screening /
Education

atherosclerosis
(AAA, MI, PVD);
amputation; HTN;
CVA, stroke;
retinopathy,
peripheral
neuropathy,
infection,
nephropathy

year 2: kidney
enlarges,
increased GFR

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

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

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)

IF: linear IgG appearance along


glomerular capillary loops
histology: cellular crescents
(parietal epithelial cell proliferation)

similar to expt anti-GBM dz


Goodpasture's dz: anti-NC1 domain Abs
cross react w/ pulmonary BMs, causing
rupture and pulmonary hemorrhage
Systemic
diseases w/
renal
manifestations

Diabetes
mellitus diabetic
nephropathy

Systemic lupus
erythematous lupus
nephritis

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

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

25.8 million
children and
adults in the
U.S.

renal
involvement
30-90% of
SLE patients

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)

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

leading cause of
kidney failure
papillary necrosis
(acute
pyelonephritis seen
more in DM but also
PN w/ obst and
NSAID abuse)

year 5: GFR
drops and
plateaus
year 15-25:
steady decline in
GFR (leading to
massive
proteinuria)

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

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

Epi

precipitating immune
reaction (PCN,
microbes- Strep,
heterologous
proteins, tumor
antigens)

Risk factors

Lab/Imaging

Treatment

Complications

histology: leukocytoclastic vasculitis


(fibrinoid necrosis, transmural
arteritis, fibrinoid arteriolitis); acute
necrotizing GN (segmental fibrinoid
necrosis of glomerulus w/ +/formation of cellular crescents)

kidneys: leukocytoclastic
vasculitis and acute
necrotizing (and often
crescentic) GN

Wegener's
Classic triad (acute necrotizing
granulomatosis granulomas of ENT, lungs hemoptysis; necrotizing
vasculitis of small & med
vessels; acute
necrotizing/crescentic GN)

autoantibodies directed against proteinase-3


affecting both small and medium sized
vessels

M>F

histology: transmural arteritis +


granulomatous vasculitis

avg age 40;


peak incid in
50y.o.'s

C-ANCA
mimics TB -necrotizing
granulomas, cavitary lesions
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

Screening /
Education

Disease

Clinical
Variants

Glomeruloneph Experimental
ritis
acute serum
sickness
(similar to
human poststreptococcal
GN)

Heymann
nephritis
(idiopathic
membranous
nephropathy in
humans)

Hyperkalemia

Defining Characteristics
single injection of Ag (acute
antigenemia)
stereotypical course
self-limited, short duration

Pathogenesis

Etiologies

Epi

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

IgA
asymptomatic & persistent
Nephropathy
hematuria (gross or micro), +/(IgAN, Berger's proteinuria; mesangiopathic dz
disease)
usually manifests as slow
insidious progression towards
ESRD

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

EKG abnormalities (can be life


threatening - SCD), weakness
(diminished reflexes, strength),
respiratory failure from
diaphragm paralysis

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)

Complications

Screening /
Education

bx: foot process effacement,


subepithelial deposits w/ regular
periodicity and spike formation
(chronic antigenemia)

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

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

Treatment

IF: IgG mesangial deposits + starry


sky pattern

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

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

Lab/Imaging
biopsy: diffuse proliferative GN
(>50% of glomeruli have lesions),
heavy mononuclear infiltrate,
endothelial cell swelling,
subepithelial humps

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

In situ formation of immune


complexes

Risk factors

IF: granular IgG and C3 deposits


along capillary loops with relative
periodicity

EM: NO dense deposits (Immune


complexes planted in each ind
anionic site; unable to aggregate)
IF: linear IF for IgG along capillary
loops

most
common GN
in developing
world
(Western
Pacific rim)

crush injuries

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)

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)

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)

transtubular K+ gradient (nl 6-12; if


hyperkalemic and TTKG is hi suggests extra-renal etiology)

Disease

Clinical
Variants

Hypokalemia

Defining Characteristics

Pathogenesis

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

Etiologies

Epi

Risk factors

If HTN, think about


conditions w/ inc
aldosterone
secretion (renal
artery stenosis,
hyper-aldosteronism,
Liddle's syndrome)

Lab/Imaging

Treatment

Complications

EKG shows U waves after T waves

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
TTKG > 4 suggests renal loss

if normal BP, think


about diuretics,
Gitelmans, Bartter
syndrome, vomiting

Chronic Kidney
Disease (CKD)

Diabetes,
HTN

CVD = leading
cause of death
decreased life
expectancy

Renal agenesis unilateral

normal function but late


complications of
glomerulosclerosis

failure to form ureteric bud or induce


differentiation of metanephrogenic blastema

sporadic inheritance 1/1000


births; 3:1
M:F

minority of cases due to involution of


dysplastic kidneys
bilateral

in utero demise or death shortly


after birth due to renal or
pulmonary insufficiency (Potter
syndrome)

sporadic inheritance 1/4000


births; 2:1
M:F

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

Renal
hypoplasia

unilateral - no problems

very rare

bilateral - variable degree of


renal insufficiency, hypertension
<6 pyramids (nl 10); kidney
weight < 50% of expected
weight for age
Renal atrophy

diminutive kidney

less likely to be hypoplasia


more likely to be caused by renal artery
atherosclerosis, especially in adults

Screening /
Education

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)

Disease

Clinical
Variants

Renal ectopia

Defining Characteristics

Pathogenesis

kidney in abnl anatomic location


(NOT T11-L1)

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

sporadic (very rarely 1/900


familial)

Complications
increased risk of UTI
from stasis

simple - pelvic,
subdiaphragmatic, thoracic

increased risk of
injury

crossed - with or without fusion


a/w other GU malformations
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

sporadic

1/400-600

incidental finding during imaging,


surgery, autopsy

slight risk of
infections, kidney
stones, and renal
pelvis tumors

unable to migrate out of pelvic cavity


because inferior mesenteric artery blocks
them
Renal tubular
acidosis

Type I (DT)

normal anion gap acidosis;


moderate renal failure (GFR 2050), impaired NH4+ and
phosphate excretion

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-

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]

UAG > 0 (not much NH4+)

requires high doses of


HCO3- to correct!!

UAG > 0 (not much NH4+)

fix hyperkalemia - usually


fixes the acidosis (if not,
minimal HCO3- needed)

urine is not maximally acidic


(pH > 5.3), severe serum
acidosis (HCO3- <10),
hypokalemia

Type 2 (PT)

Type 4

normal anion gap acidosis;


moderate renal failure (GFR 2050), impaired NH4+ and
phosphate excretion

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

increased risk of
Wilms tumor
(isthmus)

Problems in proximal tubule prevent


reabsorption of HCO3- and the formation of
ammonia from glutamine --> acidosis

Screening /
Education

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Lactic acidosis Type A LA

high anion gap acidosis

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)

Type B LA

high anion gap acidosis

decreased L-lactate destruction

Diabetic KA

high anion gap acidosis

urine nitroprusside test detects


acetone and acetoacetate

Alcoholic KA

high anion gap acidosis

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)

spot urine to determine if chloride


sensitive or chloride resistant [Ucl >
20 mEq/L implies chloride resistant
met alk]

Ketoacidosis

Metabolic
alkalosis

Benign renal
neoplasms

Papillary
(cortical)
adenoma

Angiomyolipoma

a/w long term hemodialysis


and papillary RCC

usually one large mass; if


multiple mass - suggests
tuberous sclerosis!!
Can present w/ pain or hematuria

Oncocytoma

usually unilateral, but if multifocal


or bilateral - think syndromes

benign neoplasm composed of thick walled


blood vessels, smooth muscle, and fat

Complications

liver disease, ETOH,


renal failure,
metformin, salycilate
OD

serum ketone test detects Bhydroxybutyrate (DKA - 75%; AKA


>90%)

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

Treatment

chloride supplementation
reverses the alkalosis (if
chloride sensitive)

hi FP rate for Ucl > 20 so check Uk (if


< 30, replete K+ and rpt Ucl) and
HTN (if no HTN, recheck Ucl)

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

pathology: small (<5 mm diameter),


well circumscribed lesions

<1% of renal
tumors

histology: angioma + myoma +


lipoma

histology: finger like projections


(fibrovascular projections)

usually in
adults

uniform population of pink cells

4-7% of adult
renal
epithelial
tumors

loose fibrous stroma mixed w/I


tumor cells

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

< 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)

Screening /
Education

Disease

Clinical
Variants

Malignant renal (general)


neoplasms

Defining Characteristics

Pathogenesis

Etiologies

"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

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

Epi

Tumors arise from proximal OR distal


convoluted tubules

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

partial nephrectomy
(nephron sparing
surgery)

metastases
(LUNGS, lymph
nodes, liver, bone,
adrenals,
contralateral kidney,
brain, heart, spleen,
intestine, skin)

smoking,
obesity in
women,
HTN, VHL
disease
(develop
RCC in 50%
of cases),
hereditary
RCC w/o
VHL,
tuberous
sclerosis

Hereditary
papillary renal
cell cancer
Hereditary
leiomyomatosis
RCC

increased risk of clear cell RCC


retinal angiomas, CNS
hemangioblastomas,
endolymphatic sac tumors,
epididymal tumors,
pheochromocytomas, pancreatic
cysts, renal cysts, clear cell RCC

radical nephrectomy
cryoablation (small
tumor, poor surgical
candidates)

high grade tumors will actually


appear darker from increased nuclei,
atypical mitotic figures, and spindle
cell differentiation

males 3:1

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

adults (7% of smoking


primary renal
cancers)
phenacetin
nephropathy
70% males
thorotrast
mean age 70 radiologic
dye

mutations promote transcription of vascular


growth factors --> unusual vascular tumors
20% de novo mutations (neg FH does not
R/O VHL!!)

increased risk of papillary type 1


RCC

benign skin leiomyomata, benign autosomal dominant w/ close to 100%


uterine fibroids, aggressive type penetrance for SOME manifestation of
2 papillary RCC
syndrome

histology: clear tumor


(intracytoplasmic lipids &
glycogen), very round nuclei, pale
cytoplasm, highly vascularized
(chicken wire vasculature)

path: hemorrhagic (sometimes


necrotic) appearance

autosomal dominant mutation in VHL gene


(3p25); variable expression & reduced
penetrance

increased risk for papillary type 2 FH gene codes for fumerase hydratase
RCC
enzyme;

pathology: very fatty (yellow)


appearing lesion

10-20% of
adults RCCs

horseshoe
kidney
von Hippel
Lindau (VHL)
syndrome

Screening /
Education

65,000
cases, 13500
deaths in
U.S.

cyclophosph
amide

Inherited
disorders of
RCC

Complications

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

M>F

hereditary papillary
carcinoma (VERY
rare)

Treatment
hereditary? CT imaging
to monitor dz
progression; nephron
sparing surgery, radical
nephrectomy,
cryotherapy (if not
surgery candidate);
screen family members

usually > 50
y.o.

associated with trisomy 7, trisomy 17, or


loss of Y chromosome!!

Lab/Imaging

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)

Rising
incidence

Papillary renal
cell carcinoma

Risk factors

10-16% risk
RCC

Fuhrman nuclear
grading system
(Grade IV - bad!!)
- prognostic
combined w/
staging (see
above)

Disease

Clinical
Variants

Defining Characteristics

Birt-Hogg-Dube variable risk for oncocytoma


fibrofolliculomas, pulmonary
cysts, renal cysts, RCC, colon
cancer, spontaneous
pneumothorax

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

Familial Renal
Oncocytoma
Lynch
Syndrome
Wilms' tumor
(nephroblastom
a)

increased risk for oncocytoma


increased risk for CRC &
endometrial/ovarian cancer;
transitional cell pathology
most
common
kidney tumor
of childhood

pediatric - 90% < age 6


presents as large abdominal
mass

nephrectomy and/or
chemotherapy

very aggressive, a/w


poor prognosis
lung metastases
(cough) or
traumatic rupture

1/8K-10K

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)

Tuberous
sclerosis

histology: triphasic (blastema,


epithelium, stroma); very
multinucleated, + mitotic figures

no gender
preference

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)

increased risk for


RCC (clear cell or
others)
a/w ADPKD

if see angiomyoplipomas on
kidneys - think tuberous
sclerosis!
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

infection
ulceration
adeno-carcinoma
squamous cell
carcinoma

bladder is on outside of patient


(no skin covering bladder mesenchymal defect)

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

older men
younger
women of
reproductive
age
immunosupp

non-infectious:
chemo, radiation,
trauma

histology: thickened urothelium,


infiltration of histiocytes/PMNs

broad spectrum Abs,


removal/treatment of
obstruction

death - esp if no
access to HC
(developing world)
pyelonephritis!!!

Screening /
Education

Disease

Clinical
Variants

Schistosomiasi
s

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

Etiologies
Schistosoma
hematobium common in Egypt
(water borne
parasite; lodges in
pelvic veins around
bladder)

Epi

Risk factors

Africa &
Middle East

Lab/Imaging

Treatment

histology: pink cytoplasm & granules


represent eosinophils; squamous
metaplasia w/ Schisto oval
cystoscopy

squamous cell
carcinoma

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

Polypoid
cystitis
Malakoplakia

Cystitis cystica
et glandularis

Squamous
metaplasia of
bladder

common incidental finding;


mostly benign

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

Bladder cancer (general)

Urothelial
carcinoma in
situ (CIS)

malignant

Urothelial
papilloma

schistosoma
infection (globally)

presence of cytotologically malignant cells


regardless of quantity

noninvasive flat cancer


hematuria

immunocomp,
women

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

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%)

as grade increases, the cells become more


discohesive and can end up in urine

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)

Screening /
Education

hydroureter,
hydronephrosis,
bladder ulcers,
bacterial infections,
renal failure

later changes - fibrosis w/ lymphocytes,


histiocytes, foreign body granulomas,
dystrophic calcification; squamous
metaplasia leads to squamous cell carcinoma
Hemorrhagic
cystitis

Complications

histology: hemorrhage of bladder

may require cystectomy if death secondary to


bleeding will not stop!
severe hemorrhage

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

histology: hyperkeratosis

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

Disease

Clinical
Variants
Low grade
papillary
urothelial
carcinoma

High grade
papillary
urothelial
carcinoma

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

malignant

Treatment

Complications

histology: finger like projections w/


cohesive epithelial cell lining;
fibrovascular core w/ blood
vessels, few mitotic figures

non-invasive usually
orderly arrangement w/ minimal
variation in polarity; minimal
atypia (scattered enlarged
hyperchromatic nuclei), few
mitotic figures
malignant

histology: scattered single cells


(discohesion), apoptotic bodies,
increased # mitotic figures, nuclear
polymorphism, hyperchromatic (Dark
appearing), increased vasculature

usually invasive
overall disorderly arrangement w/
irregular clusters of cells & fused
papillae; marked atypia (similar
to CIS), numerous mitotic figures;
discohesive single cells

Squamous cell malignant


carcinoma

Lab/Imaging

does tumor invade


muscularis propria? NO local chemotherapeutic
agents; YES - cystectomy
or cystoprostectomy

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

5% of
bladder
tumors in
US; 75% of
bladder
tumors in
Egypt, Sudan

smoking,
Schisto
infection,
chronic
catheter
placement

smoking

Renal
obstruction

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

glands + mucin

Small cell
carcinoma

malignant

histology: high N/C ratio but small


cells; necrosis (pink), rapid
proliferation

Unilateral

acute - painful renal colic +


CVA tenderness

bilateral

UPJ

chronic - silent
fluid overload, weight gain,
less pain than unilateral
obstruction
occasionally, acute symptoms
hydronephrosis
renal distention increases
susceptibility to trauma

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

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

may spontaneously
resolve in infants

urinary stasis,
decreased renal
function (reversibility
related inversely to
amount of time
obstructed), HTN,
postobst diuresis,
electrolyte abnl

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

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

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

Screening /
Education

Disease
Kidney
infections

Clinical
Variants
Pyelonephritis

Defining Characteristics

Pathogenesis

Etiologies

Epi

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

Risk factors

Lab/Imaging

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

Treatment

Complications

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)

Chronic - loss of renal


parenchyma
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

Others
Urinary
retention

Urinary
incontinence

(general)

Intrarenal - comp of ascending


PN or hematogenous seeding of
kidneys; S. aureus
TB infection, fungal infection of
kidney
unable to void urine

involuntary loss of urine


through urethral meatus

problem w/ bladder not being able to


squeeze (detrusor muscle) or obstruction of
bladder outflow pathway

diabetes

CT shows gas formation within the


kidney

urgent nephrectomy

70% mortality even


w/ app Abs

perinephric renal calculi,


DM, prior
GU sx

neurologic issues;
certain drugs;
prostate
enlargement;
urethral stricture;
trauma (urethral
disruption)

leakage of urine despite higher brain function

treatment dependent on type of


incontinence & cause
Stress

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)

Urge

Overflow

Total

coughing, laughing,
sneezing, valsalva
bladder infection

diabetes

Total incontinence - complete inability to hold complicated


urine; fistula or ectopic ureter
childbirth

developing
countries
FEMALES

Vesicoureteral
reflux

bidirectional urine flow

congenital bladder anomaly

stasis --> infection, scarring,


chronic pyelonephritis

(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

Urethral
stricture

Urethral cancer

Squamous cell carcinoma is most


common type
obstructive symptoms

genetics

only urologic
cancer more
common in
females; very
rare!

obstruction

Screening /
Education

Disease

Clinical
Variants

Benign
prostatic
hypertrophy/
hyperplasia
(BPH)

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

Etiologies

enlargement of prostate gland from


upregulation of androgen-R (inc prod of DHT)
= overgrowth of stromal tissue, inhibition of
glandular cell apoptosis = hyperplasia

presence of
androgens (DHT testosterone
converted to DHT by
stromal cells via 5a
reductase)

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)

Epi

Risk factors
age

Lab/Imaging
prostate exam
cystoscopy for bladder diverticulum

if metastasize to bone, usually osteoblastic


so a/w elevated serum alkaline phosphatase

reduce symptoms & limit stasis of urine =


progression
infxn, stone, renal
dysfxn, urinary
watching waiting
retention, bleeding

surgery (TURP transurethral resection of


prostate)

BPH

highest
incidence of
all US male
cancers
(outside of
skin Ca)

age, FH,
race (African
Americans),
diet
(lycopene
maybe
protective)

2nd leading
cause of
cancer
deaths in
men

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

spermatocele / spermatocele occurs outside


epididymal cyst the testis so almost feels like
extra testicle
varicocele
blood filled, enlarged veins

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)

if torsioned, untwist the


spermatic cord

testicular torsion
(dead testis from
lack of bloodflow)

blocked cysts or ducts from the epididymis

dilation of veins of spermatic cord


(pampiniform plexus)

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

outside the testis


within the testis parenchyma
usually discovered by abnl self
exam

involves most commonly the germ cells


(seminiferous tubules)

Screening /
Education

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)

2 main pathophys mechanisms: blockage of


outflow tract (= obstruction) & bladder
hypertrophy/ diverticula

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)

Complications

gross: nodular hyperplasia, medial


lobe hypertrophy, hypertrophied
detrusor muscle

irritative sx due to hypersensitivity of bladder

Prostate cancer

Treatment

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

Clinical
Variants

Male infertility

Defining Characteristics

Pathogenesis

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

Epididymitis

Erectile
dysfunction

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

Screening /
Education

varicoceles most
common factor
any age

Flouroquinolones (Cipro)

sometimes send for


cardio referral

exercise in earlier
ages prevents
ED

tx patient, partner, &


couple
PDE5 inhibitors
(sildenafil, vardenafil,
tadalafil, avanafil) contraind if pt is on
nitrates
Peyronie's
disease

curvature of penis - usually on


dorsal side

Penile cancer

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

10% of men
by age of 5060

almost always occur in


uncircumcised males

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)

spread by local extension rather than


lymphatics

usually squamous cell


carcinoma (bc skin cancers)
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

Symptomatic
bacteriuria/
uncomplicated
UTI

kids: non-spec sx; fever,


incontinence, FTT, vomiting
adults: urgency, frequency,
dysuria
elderly: worsening incontinence,
abd pain, AMS, FTT

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

mostly
Caucasians
but other
races too

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)

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

Etiologies

Epi

Risk factors

Lab/Imaging

urinary stasis and obstruction are primary


mechanisms for complicated UTIs

Treatment
remove underlying
mechanism (catheter,
obstruction)

biofilm formation by uropathogens can cause


chronic bacterial presence on devices
(catheters) --> resistance

Complications

Screening /
Education

indwelling devices
can become havens
for biofilms;
encrusted

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

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

GU
tuberculosis

Asymptomatic
bacteriuria

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)

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

15% of
homeless
extrapulm TB
disease

imaging: renal/ GU mass,


calcifications, or stricture
Urine AFB culture or biopsy

changes in GU tract prevalence


(occur w/ age)
inc w/ age

catheters

may respond to TB
therapy but usually
requires surgery bc very
extensive dz by time dx

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

catheters --> asympt


Candiduria

otherwise, remove
catheters if source (and
no longer needed)

Cystitis

lower tract infection

if local TMP-SMX
resistance <20%: TMPSMX DS BID x3d

frequency, urgency,
suprapubic pain, dysuria,
gross hematuria

Vaginitis,
urethritis

Prostatitis

If local resistance >20%:


Cipro 250 PO BID;
Levofloxacin 250 daily
x3d; Nitrofurantoin x7d

gradual onset of milder dysuria,


+/- freq and/or urgency; dysuria
w/o pyuria

Acute bacterial very severe clinical onset prostatitis


fevers, chills, perineal pain,
(Type I)
back pain, UTI sx, possible
obstruction

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)

PE: VERY tender prostate

very small
proportion of
prostate
cases

urine cx: increased WBCs and


positive culture

treat based on culture


results

would NOT want prostate


specimen (tenderness of prostate;
inc risk for bacteremia)

initial therapy: IV Ab
(fluoroquinolones)
later therapy: oral Ab

PSA - mod to marked elevation


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

Prostate abscess

Disease

Clinical
Variants
Chronic pelvic
pain, no
detectable
inflamm
(Type III)

Asymptomatic
inflamm
(Type IV)
Autosomal
dominant
polycystic
kidney disease
(ADPKD)

Defining Characteristics

Etiologies

Epi

most frequently seen conditions


(>90%)

large, fluid filled cysts and


enlarged kidneys BUT nl renal
fxn (differentiates from acquired
PKD)

autosomal dominant mutation in PKD1 gene


(which lies very close to TSC2 gene so
patients can have tuberous sclerosis too!) +
second acquired mutation =phenotype

a/w tuberous sclerosis

10-15% spont PKD1 mutations

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

phenotype: renal cysts, liver cysts, asymp


intracranial aneurysms, HTN, proteinuria

PKD2 patients have 12.5 million


better prognosis than peeps
PKD1
worldwide

Treatment

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

Complications

loss of primary cilia fxn: altered


mechanosensation of Ca+2 currents

cystic epith cells: dedifferentiated, no


polarization, abnl cell matrix proteins, hi rate
of div & apop, form cysts instead of tubules,
secrete fluid

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)

ESRD

HTN, gross
hematuria, pain,
nephrolithiasis, UTI long before dec
GFR!

altered mitotic orient & cell polarity

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

hemorrhage of cysts
- acute onset of pain
localized to kidney

comp of polycystic
liver dz (ascites,
portal hypertension,
varices, hepatic
venous obst, liver
cyst infection)

ARPKD (PKD2) appears same

nonoliguric: urine vol >400 mL/d


oliguric: urine vol 100-400
anuric: urine vol <100
Prerenal
azotemia

Lab/Imaging

culture negative, less likely to see


inflamm cells

M=F

(general)

Risk factors

usually negative culture but some


inflamm cells present after prostate
massage

sometimes evidence of WBCs &


inflamm cells in expressed
prostatic secretions; no active
bacterial process
incidental finding related to
elevated PSA

extral-renal: liver cystic dz


(massive polycystic liver dz females, mild renal involvement,
more hospitalizations),
intracranial aneurysms, HTN,
proteinuria
Acute renal
failure/ acute
kidney injury

Pathogenesis

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

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]
increased BUN/Cr ratio, Uosm >500,
Una <20, FENA <1%; FEurea <35%

CT for complications

Screening /
Education

Disease

Clinical
Variants
Intrinsic Renal
Failure

Defining Characteristics

Pathogenesis

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

Etiologies
ATN - ischemic
causes,
nephrotoxins (Abs,
contrast dyes, heavy
metals, chemo
agents; myoglobin,
Hg, calcium
phosphate stones,
uric acid)

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

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

U/S for obstruction

Treatment

Complications

Screening /
Education

Disease
Diabetes
mellitus

Clinical
Variants
(general)

Type 1 DM

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

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)

hyperglycemia & glycosuria due


to inability to oxidize/utilize
carbs + disturbance in insulin
function + imperfect fat
combustion (hi ketones)

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)

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)

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%)

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

CD4, CD8, & MOs infiltrate &


accumulate in islet cells -->
insulitis; unk triggering event
occurs promoting autoimmune
destruction of islet cells

Lab/Imaging

Treatment

Diabetic ketoacidosis,
hypoglycemia, see
chronic complications
below

subcutaneous insulin
DKA
therapy that mimics
physiologic insulin
(continuous insulin - pump
or basal injection w/ bolus
injection at meals)

Whites
colder climate

clinical manifestations when 8090% B-cells destroyed


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)

24 million
diabetics in
U.S. in 2012

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)

Complications

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

Defining Characteristics

Chronic
complications
of DM

Etiologies

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)

Diabetic
Ketoacidosis
(DKA)

Pathogenesis

severe insulin deficiency


nth degree of diabetes sx:
massive polyuria, massive
dehydration, life threatening
electrolyte shifts and
metabolic acidosis

Retinopathy microvascular

Nephromicrovascular
pathy
Neuropathy microvascular
CAD,
macrovascular
ischemic
heart dz

7% of all
pregnancies
complicated
by GD
1/3 of GDM
patients will
have DM
postpartum

insulin resistance increases as


pregnancy progresses (higher
the maternal glucose levels =
worse fetal outcomes)

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

Epi

Risk factors

Lab/Imaging

FH of DM
h/o macrosomia
obesity
AMA (>35y.o.)
h/o poor
obstetric
outcome
h/o GD
ethnicity (AA,
hispanic, NA, PI)

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)

50% of GDM
patients will
develop DM
within 10y of
affected
pregnancy

medical illness,
stress, or
omission of
insulin

T1DM

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 -

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

metabolic acidosis
hyperglycemia (usually >
300)
ketosis
pseudo-hyponatremia
(dilutional), hyperkalemia
pre-renal azotemia

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)

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

Substratelimited
Hormone
deficiencies
GSDs
D/Os of gluconeogenesis
Drugs alcohol,
salicylates,
quinine,
valproic acid,
insulin

Alcohol? metab by alcohol


dehydrogenase in liver, requires
NAD+; results in NADPH
accumulation, inhibiting
gluconeogenesis by inh malate -> OAA
Non-ketotic
hypoglycemia

Medium Chain
Acyl
Dehydrogenas
e Deficiency
(MCADD)
HyperCongenital
insulinism

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)

presents at 3-24 months


(peak at 15 months),
during periods of fasting
or sickness

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

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
PHHI = persistent
hyperinsulinemic
hypoglycemia of infancy

1/15,000

K-ATP channel 1/40,000


mutation
(SUR1/Kir6.2) K-ATP >>
GDH >
glutamate
glucokinase
dehydrogenas
e mutation
(AD)

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

avoid periods of reduced


carb intake (problematic
when sleeping)

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

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

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

Treatment

Complications

glucose tablets, IV
glucose, or glucagon (if
seizing or unconscious)

reactive hypoglycemia
can be a precursor to
T2DM

Levothyroxine
(Synthroid, 1.6ug/kg
body weight)- pure T4;
DOC for replacement/
suppression, keep TSH
WNL, watch free T4 w/
sec/ tert hypothyroidism

diabetes,
atherosclerosis,

reactive hypoglycemia =
ingestion of simple sugars w/o
fats or carbs = insulin spike that
easily takes up simple sugars
Hypothyroidism (general)

Congenital

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

Failure to thrive!

reduced production of T3 &


T4

thyroid gland dysgenesis or


agenesis - most common
cause

iodine def =
elderly
most common
cause globally
of hypothyroidism
F>M,
increased
prevalence w/
age

goiter.

Subclinical

Painful thyroid following


URI or viral infection

postpartum

Painless thyroid

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

hi TSH/TRH could possibly


cause prolactinemia
secondary: low T3, T4; low
TSH

10% of elderly

slow titration of
Levothyroxin in elderly
to avoid complications
w/ coronary heart
disease

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

thyroid gland
dysgenesis or
agenesis

newborn screen - confirm


w/ TSH (extremely hi if no
thyroid hormone present) &
serum free T4

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

Hashimoto's most common cause of


thyroiditis
hypothyroidism in
FEMALES

primary: low T3, T4;


extremely hi TSH
(compensation to increase
TH)

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

2nd most
common
cause of
hypoT AFTER
iatrogenic!

CRETINISM = mental
retardation if not
treated early!!!
Signs?? Impaired
skeletal/CNS
development)
risk of bleeding if
removal of lingual
thyroid

low T3, T4; hi TSH; positive


thyroid antibodies (TPO)

NO uptake on I-123 scan

transient - supportive care rarely progresses to


& treatment of underlying overt hypothyroidism
dz

Disease
Hyperthyroidism

Clinical
Variants
(general)

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

Etiologies

Epi

Risk factors

exaggerated T3 and T4
production causes suppressed
TSH (negative feedback)

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

Lab/Imaging

Treatment

hi T4, T3; undetectable TSH Thioureylenes


(compensation to decrease (Propylthiouracil or
Methimazole/Tapazole)
TH)

Complications
osteoporosis, bone fx

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)

amiodarone
Graves
disease

Toxic
adenoma

Thyroid storm
(Thyrotoxicosis)

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

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

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

2% of
hyperthyroid
cases

low iodine intake I-123: hot nodule w/


complete to partial
supression of paranodular
thyroid tissue

tachycardia, fibrillation,
shock, heart failure

usually metastasis from


papillary thyroid carcinoma

Propanolol +
thioureylenes + large
doses of Lugol's

histology: variable
epithelium cyst lining (nondescript cuboidal,
sometimes squamous)
histology: lymphoid tissue
+ thyroid glands

blindness and
decreased ocular
vision if exophthalmos
not treated!
Radioactive iodine -->
hypothyroidism

Disease
Goiter

Clinical
Variants
(general)

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

Etiologies

Epi

endemic
(iodine
deficiency,
goitrogens!),
sporadic,
familial

Risk factors

Lab/Imaging

endemic areas
(Alps, Andes,
Himalayas;
iodine def = TSH
= hyperplasia)

histology: large colloid


lakes w/ involuted areas of
variable appearance,
surrounded by smaller
thyroid follicles

FH of Graves

euthyroid - nontoxic

Treatment

Complications

Iodine if related to iodine


def

causes in developed countries:


diffuse simple goiter, Graves,
Hashimotos, subacute
thyroiditis, multinodular
goiter, malignancy, genetic
Diffuse

diffuse, symmetrical
enlargement
Toxic (Graves disease)
Non-toxic (simple)

F>M

diffuse non-toxic: diffuse


hyperplasia w/o nodularity;
usually related to goitrogens
(Ca, Fl, veggies), may develop
in multinodular

hyperthyroid - Graves

diffuse toxic (Graves dz): a/w


autoimmune dz

Multinodular

nodular, lumpy
enlargement

autonomous function of nodular


thyroid tissue -->
hyperthyroidism (toxic)

older age

Toxic (Plummer's dz)


non-toxic (simple)
toxic sx: unexplained
weight loss, depression,
Afib
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!!!

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

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)

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

Disease

Thyroiditis

Clinical
Variants
Thyroid
carcinoma

Defining Characteristics
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

Acute
Chronic

Subacute

Fibrous

Hashimoto's 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!!)

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

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)

Riedel's thyroiditis
woody/ stone hard
thyroid gland

long-term inflammation -->


fibrosis --> destruction of thyroid
gland and adjacent neck
structures
clinically resembles malignancy

Etiologies

Epi

Risk factors

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%)

very rare

immunocomp

<1%

familial

F>M

F>M

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)

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)

VERY rare

gross: woody hard area


around periphery of thyroid
gland

Treatment

Complications

thyroidectomy,
radioactive iodine

papillary carcinoma lymphogenic spread

Thyroid replacement
therapy if
hypothyroidism results

follicular carcinoma angio-invasion/


vascular spread to
bone & lungs

whole body scan post


surgery
serum thyroglobulin tumor marker after total
thyroidectomy

total thyroidectomy required exogenous


hormone replacement

inc risk for thyroid


carcinoma &
malignant lymphoma

Disease

Clinical
Variants
Postpartum

Defining Characteristics

Pathogenesis

Etiologies

Epi
very
common!!

painless thyroiditis
appearing 1-2m postdelivery, lasts 2-5m

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!

goiter increases 1-2m


postpartum, fatigue/
moodiness (hard to dx!!)
hyperthyroidism state -->
hypothyroidism state
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)

germline mutation in menin


(tumor suppressor gene) chromosome 11
other early signs of menin
mutation? Facial
angiofibromas &
collagenomas

Autosomal
dominant

0.25%
population

dx: 2 or more of "3Ps" +


relative w/ 1P

all ages, no
sex pref

4 gland hyperplasia
(sporadic dz only has single
parathyroid adenoma)

80% manifest
tumor by 5th
decade

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

first
manifestation
s occur earlier
than in
sporadic dz

adrenal hyperplasia

Osteitis fibrosa
cystica

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

MEN2B

Pheochromocytoma +
thyroid medullary
carcinoma (or C- cell
hyperplasia) + mucosal
neuromas (neural tissue
nodules in GI tract or
mouth) + marfanoid
habitus

germline mutation in RET


oncogene

calcitonin secretion

prophylactic
thyroidectomy

hypercalcemia,
pathological fractures,
bone pain

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

hyperparathyroid bone
disease

path: dissecting osteitis

some variants of
MEN2A have
Hirschsprungs dz
(megacolon from
lower intestinal
obstruction) or
cutaneous lichen
amyloidosis (upper
back)

Disease
Hypocalcemia

Clinical
Variants
(general)

Defining Characteristics

Pathogenesis

Etiologies

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

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

low Mg+2, low


albumin (binds
calcium so can
cause
unadjusted low
total calcium)

low total calcium, high


phosphorus
PTH deficiency - low Ca, low
PTH
PTH resistance or renal
failure - low Ca, high PTH

meds (Lasix,
calcitonin, antineoplastic
agents, anticonvulsants,
citrated blood
products)

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...)

hi PTH?
Hyperparathyroidism,
familial hypocalcuric
hypercalcemia

Familial
hypercalcuric
hypocalcemia

Epi

Risk factors

Lab/Imaging

Treatment
acute - IV calcium
gluconate
chronic - calcium
carbonate
vitamin D - if PTH
problem, give calcitriol; if
vitD deficient, give
cholecalciferol (precursor)

inherited activating mutation of


calcium-sensing receptor on
parathyroid chief cells; results in
constitutive supression of PTH
release and low serum calcium
levels

Hypercalcemia (general)

Hypercalcemia
from
malignancy

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

most common cause of


symptomatic
hypercalcemia

humoral hypercalcemia of
malignancy (HHM) - major
cause of severe hypercalcemia,
usually due to ectopic PTHrP

SCC - lung
cancer, RCC,
lymphomas.
Local bone
metastasis
from breast Ca
or myeloma

PTH independent
hypercalcemia
FATIGUE, polyuria

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)

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

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

Complications

Disease

Clinical
Variants
hypercalcemia
from
granuloma
dz

Familial
hypocalcuric
hypercalcemia

Defining Characteristics

Pathogenesis

Etiologies

PTH independent
hypercalcemia

Granulomas make 1aTB, sarcoid,


hydroxyase = increased 1alymphomas,
hydroxylase activity = increased fungal infection
production of vitamin D =
increased calcium absorption

PTH dependent
hypercalcemia

inherited inactivating mutation


of the calcium-sensing receptor
on parathyroid chief cells;
results in constitutive release of
PTH and high serum calcium
levels

Epi

Hispanic
origin

Risk factors

FH

Lab/Imaging

Treatment

low 24h urine excretion of


calcium

benign condition that


usually doesnt require tx

hi PTH, hi Ca, hi 24h urine


excretion of Ca

parathyroid adenomas are


treated by surgical
excision IF criteria met
(Ca > 11.5, reduced
kidney fxn, T-score on
BMD <-2.5, age <50)

Complications

CaR senses low calcium when


the Ca levels are actually
normal --> causes hi PTH, hi
calcium

HyperPrimary
parathyroidism

PTH dependent
hypercalcemia

lesions directly to the


parathyroid gland cause
excessive PTH release

most often asymptomatic


hypercalcemia

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)

parathyroid
adenoma

25/100,000
cases in U.S.

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

osteitis fibrosa
cystica (see above)

path of parathyroid
carcinoma: much larger
than adenoma; bland
cytology (may have fibrosis,
scarring within tumor nests,
subtle infiltrative growth);
local invasion & metastasis

Secondary

Tertiary

dialysis patients!

possibly associated w/
duration of dialysis; can
occur in post-kidney
transplant 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

brown tumors of
hyperparathyroidism
(reactive mass formed
secondarily to
microfractures and
hemorrhages as a
result of
multinucleated giant
cells and fibrous
tissue influx)

parathyroidectomy if PTH
cannot be controlled w/
meds

Disease
Hypoparathyroidism

Clinical
Variants
primary

Defining Characteristics

Pathogenesis

Etiologies

Epi

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)
insuff activity of
parathyroid gland = low
PTH and hypocalcemia

Iatrogenic

history of neck surgery,


thyroidectomy, cervical
lymph node dissection

removal of parathyroids from


surgery (thyroidectomy), TPN,
thyroid ablation w/ radiation

Congenital

DiGeorge syndrome
(pharyngeal pouch
maldevelopment) posteriorly rotated ear,
flat nasal bridge,
hypertelorism (lots of
space btwn eyes), small
chin

absence of 3rd & 4th


pharyngeal pouches, the
embryological origin of
parathyroids
DiGeorge syndrome - defect in
chromosome 22; 95% de novo
mutation

Velocardiofacial syndrome
Familial
(APS-I)

candidiasis,
hypoparathyroidism,
Addison disease

recessive autoimmune regulator


gene (AIRE) mutations cause
autoimmune polyendocrine
syndrome 1

Pseudo

increased serum PTH

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)

Type 1a = Pseudohypoparathyroidism (abnl


biochem findings) +
Albright's hereditary
osteodystrophy (AHO)
(short stature, obesity,
brachymetaphalangia,
calcifications, mental
retadation)

Risk factors

Lab/Imaging
low (or nl) PTH, low
calcium, hi phosphate

Treatment

Complications

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)

most common
cause of
hypocalcemia

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

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

DiGeorge syndrome abdominal aortic


arches, VSDs life
threatening after birth;
immune dysfxn (abnl
thymus development)

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

Hypophosphatemia

Pathogenesis
normal bone development
involves mixture of osteoid (nonmineralized component of
collagen, chondroitin sulfate, &
osteocalcin) with mineralized
component (calcium phosphate)

Epi

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

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)

Hyperphosphatemia

Etiologies

increased intake (TPN,


phosphate enemas)
decreased excretion (usually
chronic kidney disease,
hypoparathyroidism)
excess bone resorption
transcellular shift (tumor lysis,
rhabdo)

hi PTH
hi FGF-23 (low
P, low vitD3)
low vitD3
PHEX mutation

Risk factors

Lab/Imaging

Treatment

decreased 1,25(OH)2 vit D


OR total 25(OH) vitD2/D3 better indicator bc longer
half life

bone disease/ inc fx


(osteoporosis - bone
resorption > bone
formation), rickets/
osteomalacia
(osteoid does not
mineralize --> "soft
bone"), cancer, CVD,
T2DM, autoimmunity

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

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)

Complications

give VitD (increases


phosphate & calcium
absorption, preventing
PTH action)

Disease
Pituitary
adenoma

Clinical
Variants
(general)

Defining Characteristics

Pathogenesis

microadenomas (usually
secrete hormones) - <1cm;
prolactinomas, corticotroph
adenomas, somatotroph
adenomas

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)

macroadenomas (usually
present w/ mass effect
without syndromic effect)
>1cm - bitemporal
heminopsia, diplopia
(CN3, 4, 6 palsy),
headache

Etiologies

Epi

MENI (menin
most common
mutation),
in adults (40other mutations 50 y.o.; M=F)
(CREB, Gs
protein, loss of
Rb, excessive
growth factor
production)

evasion of apoptosis ->


unlimited replicative potential > growth signal independence
-> anti-growth insensitivity ->
sustained survival ->
adenoma formation

order of hormone
disruption: GH--> LH/FSH -> TSH --> ACTH
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

Risk factors

Lab/Imaging

pituitary apoplexy pituitary adenoma


infarction from
expansion --> severe
headache & loss of
vision (MED
EMERGENCY!!
Interferes w/ ACTH
secretion)

MRI: homogenously
contrast enhancing (no
cystic components or
calcifications)

pressure/mass effects,
hypersecretion of
hormones

increased serum prolactin


(usually > 200 ng/mL) &
positive immunohistochemistry for prolactin
(brown = positive)

Treatment IF macroadenoma, mass effect,


fxnal compromise
(infertility, galactorrhea);
o/w monitor

possible decrease in FSH,


LH; possible
hypopituitarism depending
on size of prolactinoma

dopamine agonists
(Bromocripitine,
Cabergoline) for tx of
microadenomas

MRI of pituitary for mass

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

Complications

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!

R/O secondary causes


(kidney, liver tests; TSH;
pregnancy test, med eval)

Nonfunctional

Treatment

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)

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

Gonadotroph

Pathogenesis
adenoma that secretes excess
GH

Epi
15% of
pituitary
adenomas

GH over production leads to


gigantism or acromegaly;
most likely due to pituitary
adenoma

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)

can also have mixed GH &


prolactin secreting adenomas
(better prognosis than GH
adenoma alone)

impaired glucose
intolerance
insidious onset - check
pictures of pt from years
before

excess secreted by
adenoma could cause
precocious puberty

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

overgrowth of cells of one


type, leading to hormone
hypersecretion without
presence of obvious tumor
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
located within sellar
space or extends into
suprasellar space

hyperplasia of cystic structures


of intermediate lobe of pituitary

histology: lined by single


layer of columnar ciliated
epithelium, everything else
is cyst fluid

single cell layer (simple)


cyst
Pituitary
carcinoma

Complications

1% of pituitary
adenomas

Pituitary
hyperplasia

Rathke's cleft
cysts

Treatment

5% of pituitary
adenomas

Thyrotroph

Craniopharyngioma

Etiologies

aggressive lesions that


invade soft tissue structure,
vasculature, & bony
structures

<5% of
masses

Disease

Clinical
Variants

Germinoma

Defining Characteristics

Pathogenesis

Etiologies

suprasellar tumor

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

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)

Granular cell
tumor

suprasellar tumor

arises from posterior pituitary


gland

ADH deficiency Diabetes


Insipidus

excessive urinary loss of


solute-free water

central causes: loss of


posterior pituitary function -->
deficiency of ADH

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)

excessive thirst/ H2O


intake (polydipsia),
polyuria (>2.5L/d),
hypernatremia,
hyperosmolarity

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)

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

Disease
ADH excess

Clinical
Variants
Syndrome of
Inapprop
ADH
(SIADH)

Defining Characteristics

Pathogenesis

Etiologies

gradual onset of dilutional


hyponatremia (mild sx:
headaches, muscle
cramps, nausea, lethargy;
severe sx: AMS, seizures,
coma, death!)

inappropriate (nl/hi)
concentration of ADH for low
plasma osmolality --> water
retention & hypo-osmolality
despite euvolemic status

malignancy
(small cell lung para-neoplastic
synd; non-pulm
cancers), CNS
d/o (mass
lesions, inflam
dz - SLE,
meningitis,
degenerative
dz, subarach
hemorrhage,
trauma)

Epi

(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)

Lab/Imaging

Treatment

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

drugs, pulm dz
(TB, pneumo,
mech
ventilation),
other (AIDS)

Short stature

Risk factors

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)

Complications

Disease

Clinical
Variants
hypothalamic
defect

Pituitary
defect

Defining Characteristics

Pathogenesis

GHRH deficiency

GH deficiency

Etiologies

Epi

Risk factors

Lab/Imaging

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)

GHRH def = low basal GH,


IGF-1, & IGF-BP3

possible craniopharyngioma

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 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

no GH released with direct


admin of GHRH
End organ
defect

Hypopituitarism

(general)

GH receptor mutations
(deletion, non-functional)
prevents end organs from
responding to GH

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

Treatment

GH receptor
mutations?
(Laron
Syndrome)

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

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

Complications

Disease

Precocious
puberty

Clinical
Variants
MPHD

(general)

Defining Characteristics

Pathogenesis

Epi

Risk factors

Lab/Imaging

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)

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
Multiple pituitary
hormone deficiency

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

Central

Etiologies

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)

caloric intake
(excess
adipose)

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

Disease

McCuneAlbright
Syndrome

Clinical
Variants
Non-central

Defining Characteristics

Pathogenesis

Epi

Risk factors

Lab/Imaging

Treatment

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)
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

Van WykGrumbach
Syndrome

Etiologies

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

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

Complications

Disease
Turner
Syndrome

Polycystic
ovary
syndrome
(PCOS)

Clinical
Variants

Defining Characteristics

Pathogenesis

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)

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

secondary amenorrhea,
hirsutism/acne, infertility,
obesity, hyperlipidemia,
insulin resistance

androgens cause early


follicular arrest & atresia -->
oliganovulation, infertility, &
cysts on ovaries

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)

androgens provoke
accelerated GnRH pulsatility,
causing enhanced release of
LH and subsequent production
of more ovarian androgens

acanthosis nigricans

lymphatics drainage prob -->


cystic hygroma, non-pitting
edema

Etiologies

Epi

Risk factors

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.

hi arched palate --> feeding/


speech problems, dental
crowding
gene dosage effect - SHOX
(pseudoautosomal region)
deficiency --> skeletal abnl &
short stature

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

Lab/Imaging

Treatment

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

short stature - GH
replacement

DX OF EXCLUSION:
supportive data?
Hyperandrogenism,
oligoanovulation, polycystic
ovaries on U/S, obesity,
IR/DM, hi LH/FSH ratio

weight loss & exercise


for insulin resistance &
hirsutism (can also use
OCPs)

Complications

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!!

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

Disease
Abnormal
uterine
bleeding (AUB)

Clinical
Variants
(general)

Defining Characteristics
any disruption from
normal cycle (24-35d x 46d, 30 ml blood loss)

Pathogenesis
structural or functional
abnormality??

Etiologies

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

Epi
2nd most
common
reason for
OB/GYN
visits

Risk factors
perimenopause

most
common
cause of
adolescent
hospital
admissions

Lab/Imaging

Treatment

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)

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

Menstrual diaries

Polyps

intermenstrual spotting

Adenomyosis

painful periods

Leiomyomas
(fibroids)

primarily benign but can


convert to tumor (rare)

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

submucosal fibroids (in


uterus) have severe
bleeding
Malignancy

Coagulopathy

most common
lesion
causing AUB
in
reproductive
aged women

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)

Ovulatory
dysfunction

nl H/P/O axis, nl steroid


hormones

local abnl prostaglandin


synthesis, increased tissue
plasminogen activator (TPA)
activity, increased local
fibrinolytic activity

Endocrinopathy

usually PCOS

bleeding due to unopposed


estrogen

Endometrial

diagnosed with pathology


only!

endometritis, hyperplasia

obese, elderly,
postmenopausal,
PCOS

20% w/ heavy
menstrual
bleeding have
underlying
bleeding d/o

CBC/platelets
prothrombin time
partial thromboplastin time

PCOS

Complications

Disease

Clinical
Defining Characteristics
Pathogenesis
Variants
Inflammatory bleeding without relation vulvitis, vaginitis, cervicitis,
endometritis, salpingitis, PID
to menses

Iatrogenic
Pregnancy
bleeding

bleeding + PAIN - think


ECTOPIC!!

Etiologies

Epi

Risk factors

a/w signs of infections


foreign bodies (children), coital
lacerations, trauma
implantation bleeding 1-2d
following missed menses (often
mistaken as menses)

Lab/Imaging

Treatment

Complications

snowstorm pattern on U/S molar pregnancy

Uterus S>D, quant b-hCG


> 100,000 - think MOLAR ectopic pregnancy, molar
pregnancy
pregnancy!

gestational sac seen


outside of the uterus ectopic pregnancy

20-25% of women spot/ bleed


during 1st trimester
Hypertension
during
pregnancy

Chronic
HTN

hi BP before pregnancy, or
<20 weeks gestational age

mosy
common med
comp of
pregnancy

systolic > 140, diastolic >


90 predating pregnancy
or identified before 20
weeks gestation

6-8% of all
live births
17.6% of
maternal
deaths in U.S.

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

Preeclampsia

hi BP > 20 weeks AND


PROTEINURIA

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

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)

hx of HTN in
pregnancy
minority groups

vasoconstriction/ vasospasm
[circul vasoconstrictors + endog
vasoconstrictors -> endothelial
damage (dec prostacyclin, inc
TbxA2) --> primary DIC]

HELLP syndrome
(>24wks): hemolysis,
elevated liver enzymes, low
platelets
improper trophoblast
implantation --> immunologic
response
Eclampsia

mild or severe preeclampsia PLUS


SEIZURES!!!

cause of
maternal
mortality

DELIVERY!!

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

Disease

Clinical
Defining Characteristics
Variants
Atypical pre- vague RUQ or epigastric
eclampsia
discomfort, small
headache, incidental
thrombocytopenia

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

new swelling of legs,


general sick appearance
Spontaneous
abortion

1st trimester bleeding

aneuploidy - monosomy X0 or
trisomy 16

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
Ectopic
pregnancy

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

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

10% mortality w/
rupture
INFERTILITY
chronic pain

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

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

Clinical
Variants

Placenta previa

Defining Characteristics
3rd trimester bleeding

Pathogenesis

Etiologies

placenta covers the internal


cervical os

Epi

Risk factors

Lab/Imaging

10% of 3rd
trim bleeding

multiparity, prior NO CERVICAL EXAM!!!


C/S, prior D&C,
smoking, prior
U/S
0.5% of births previa, AMA

PAINLESS bleeding

Treatment

fetalComplications
hypoxia (cerebral
palsy, seizures),

immediate hospitalization,
maternal hemorrhage
IV access/ fluids/ type &
shock,
cross
C/S delivery if unstable
or term

DIC (abruption)

Stable & pre-term?


expectantly manage,
eventual C/S
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)

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

5% of
deliveries

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

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

primarily affecting
peri/postmenopausal
women

estrogen sensitive neoplasm unopposed estrogenic


stimulation of endometrium

Leading
cause of
death for gyn
malig
1/70 women

protective factors? Multiparity,


OCP use, breast feeding
[increased risk of ovarian
cancer a/w increased
ovulatory cycles, so events
that decrease # cycles
protective]

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

increased
estrogen
synthesis
(obesity,
granulosa cell
tumors)
decreased
estrogen
metabolism
(hepatic dz)
inapprop HRT
(estrogen only)

IV access/fluids/ type &


cross immediately

Inspect for lacerations if


uterus is firm feeling

atony? Pitocin-like
oxytocin, prostaglandins

evaluate the placenta &


explore uterus

retained
placental frags:
prior C/S, uterine
curretage,
accreta

coagulation
disorders

Ovarian cancer Germ cell &


stromal cell
(more
common in
younger
women)

evaluate uterine fundus bogginess?

most
common gyn
malignancy
in U.S.

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)

If mass on PE, increased


CA-125, and suspicious
U/S --> SURGERY
(exploratory surgery,
maximal tumor reduction,
biopsies)

palpable mass on pelvic


exam

+ postoperative
treatment w/ IV
chemotherapy or clinical
trials

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

no screening test so
patients present at
later stage (Stage III) -> higher mortality

Disease

Clinical
Variants
Cervical cancer Squamous
(80-90%)

Defining Characteristics

Pathogenesis

abnl bleeding, discharge

HPV 16 & 18

POST-COITAL BLEEDING
adenocarcinoma
(10-20%)

back/ flank pain,


hematuria, dysuria advanced stages

Epi
globally, most
common gyn
malignancy
(lower in U.S.
bc screening)
3rd most
common gyn
malignancy

small cell &


sarcomas
(worst
prognosis)

Germ cell
Ovarian Dys- dysplastic germ cells
tumors of ovary germinoma (similar to testicular
seminoma)

Etiologies

unilateral germ cell tumor

Risk factors

Lab/Imaging

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

young women,
often a/w
pregnancy

usually NO hormone
production

gross: solid, yellow,


lobulated/ septated tumor;
no necrosis

Treatment
Stage I-II A: radical
surgery/ hysterectomy +
additional cervical tissue

stage I - cervix
Stage II - upper vag
Stage III - lower vag

Stage IIB - IV:


chemo+radiation

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

radiosensitive, treated
malignant but good
conservatively (R/O mixed prognosis
germ cell tumor!!)

histology: large nucleus &


nucleoli; lobular
appearance

Endodermal
sinus (yolk
sac) tumor

young women

gross: solid tumor w/


multiple areas of necrosis

combo of chemo,
radiation, & surgery
improve 5y survival

histology: Schiller Duval


body (central vessel
surrounded by tumor cells),
globules with alpha-feto
protein
AFP - hi but decrease postsurgery (unless some
tumor remaining)
embryonal
carcinoma
polyembryoma
Choriocarcinoma

histology: embryoid body

markedly hemorrhagic

arise from trophoblasts

produces hCG!!

gestational: arise from


placenta & products of
conception

+pregnancy test in men!

Complications

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

malignant tumor

Disease
Ovarian
Teratoma

Clinical
Variants
(general)

Defining Characteristics
benign teratomas? Brain
& choroid plexus (nonfunctioning)

Pathogenesis
germ cell tumors that make
somatic tissue

sacrococcygeal teratoma sacral growth in newborns

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

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)

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

Mature

carcinoid (serotonin-like
substances)

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

Ovarian Theca
cell tumor

MOSTLY benign!
Usually produces
estrogens

Ovarian
fibroma

usually benign but can


produce Meigs syndrome
(ascites, pleural effusion,
benign ovarian fibroma)

gross: solid - hemorrhagic


& necrotic
histology: neuroepithelial
rosettes (immature brain
glial tissue, resembles brain
tissue in newborns)
postmenopausal teratoma SCC

solid or cystic (dermoid cyst


or dermoid cyst w/
malignant transformation postmenopausal women)

monodermal struma ovarii

Ovarian
Granulosa cell
tumor (GCT)

immature teratomas are


arrested in embryonic
development - BAD!!

struma ovarii: benign but


functioning thyroid in a
teratoma

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)

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

check opposite ovary if similar appearance,


check intestines for
metastasis

malignancy shown by
recurrence > 15 years
later
a/w uterine
endometrioid
carcinoma
(unopposed
estrogen)

Disease

Clinical
Variants

Sertoli- Leydig
cell tumor of
ovary

Germ cell
tumors of
testes

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

benign masculinizing
tumor --> clitormegaly,
hirsutism

(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)

90% of
testicular
neoplasms

adult germ cell tumors =


MALIGNANT!

Lab/Imaging

15-34 year old


males

histology large columnar


cells (Sertoli cells, Leydig
cells); Leydig cells have
Reinke crystals (androgen
producing)
CXR: check for mediastinal
masses in Klinefelters pts

Caucasians
cryptorchidism
familial
clustering

hCG & alpha-feto protein


are markers for spread of
germ cell or recurrence
following orchidectomy

Treatment

radical orchidectomy +
chemo/radiation

Complications

MALIGNANT in
adults

testicular
dysgenesis
(Klinefelters)
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

Seminoma

asymptomatic,
sometimes pain/
discomfort

5% of
contralateral
testes of men
who had
orchiectomy
for germ cell
neoplasm

most common pure type,


resembles spermatogonium

embryonal
carcinoma

composed of primitive
undifferentiated epithelia

Teratoma

composed of tissue components


resembling normal or immature
organ tissue

cryptorchidism, histology: enlarged nuclei


prior germ cell
neoplasm
(contralaterally)

50% of men who


develop ITGCN will
develop invasive
germ cell tumors w/I
5y

DO NOT BIOPSY!!! Risk


spreading germ cell tumor

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

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

Defining Characteristics

Pathogenesis

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

Carcinoma of
scrotum
Periductal
mastitis

Duct ectasia

Etiologies

topical exposure to coal


tars/ soot
inflammatory, benign
lesion in large ducts of
breast

development of inflammatory
cells in the periductal area of
breast

Epi
<1% of male
cancers in
U.S.
More
common in
Asia, Africa,
S. America

Risk factors

Lab/Imaging

Treatment

Complications

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

middle aged older women

sagging of the breast


dilation of duct due to dried out
non-bloody, gritty
bilateral nipple discharge secretions

histology: inflammatory cell


infiltration, weakened duct
tissue

histology: dilation / stretch


of duct w/ dried out
secretions

No predisposition to
carcinoma!

gross: pale, moist


papilloma from collecting
duct

small risk of
carcinoma
development

NO PAIN
Papilloma

unilateral, non-milky
nipple discharge from 1
duct orifice, +/- blood

proliferative lesion

histology: nodule that


projects into the duct w/
proteinaceous secretions
(pink lines), blood supply
present (fibrovascular
core), epithelial +
myoepithelial layers present

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

Defining Characteristics

Pathogenesis

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

Etiologies

Epi
VERY
common!

Risk factors
reproductive
aged women

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

teenagers
African
Americans

more cellular lesion in


women after age 40

non-proliferative lesions arising


from terminal ductule units

> age 40

Adenosis

lumpy breasts due to


cyclical hormone
changes

proliferative lesions arising in


TDLUs

women age 3040

Usual
hyperplasia

aspiration if extremely
painful

recurrence

MUST BE TOTALLY
EXCISED

absolutely recurrent
so excision required!

histology: sometimes large


calcifications (sclerosis w/
age - benign!)

histology: very cellular


stroma that grows in leaflike pattern
usually picked up on
mammogram due to
calcification formation

adenosis = increase in lobular


units
proliferative lesions arising in
TDLUs
proliferative lesions arising in
TDLUs; increased number of
cells WITHOUT MUTATION!!

Complications

needle core biopsy: sharp


demarcation of lesion w/
characteristic feature of
enlarged duct, ductules, &
stroma

Phyllodes
tumor

Sclerosing
adenosis

gross: dark orange


structures (cysts) that are
firm & tender, swell during
luteal phase of cycle;
bumpy stroma from
collagen response to
hormones

Treatment

histology: pink secretions


seen in TDLUs, expansion
and interconnection of
TDLUs; apocrine cells +
calcifications - benign
findings

arise in TDLUs in response to


hormones --> hypertrophy of
lobules (stroma, ductules,
ducts) --> fibroadenoma
formation

Benign
sclerotic collagenous
material causes FIRM
breasts

Lab/Imaging

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

usually does not require


routine f/u - no RR of
malignancy
development
very low probability
of becoming
malignant!
Benign lesion w/
minimal risk of
malignancy

Disease
Atypical
hyperplasia
(ADH)

Ductal
Carcinoma In
Situ (DCIS)

Clinical
Variants
(general)
ductal,
lobular

Low grade

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

deletions in
chromosomes
16 &17 -->
"Roman
bridge"
structure

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

increased risk for


DCIS or invasive
carcinoma

non-motile mass on
breast exam

deletions in
chromosomes
16 &17 -->
"Roman
bridge"
structure

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!

very hi risk for


development into
invasive ductal
carcinoma (if not
excised adequately w/
clean margins)

atypical hyperplasia +
persistent mutations --> low
grade DCIS

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)

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

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

mammogram: calcifications
that form mold/cast in duct
(linear calcifications)
gross: linear pattern;
necrotic material in the duct
(yellow)

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

Etiologies

Epi

low grade DCIS--> infiltrating


ductal carcinoma, grade 1
over time due to digestion of
basement membrane and
acquisition of vascular supply

Risk factors

Lab/Imaging

Treatment

gross: firm, immobile mass suppressed by antiw/ irregular spiculations


estrogen drugs
(tamoxifen)
mammogram: spiculations
(stars) @ periphery

Complications
potential to invade
lymphatic spaces!

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

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

non-motile mass
histology: poor gland
formation, necrotic cells,
mitotic figures
Atypical lobular
hyperplasia
(ALH)

precursor lesion to LCIS!

Lobular
carcinoma in
situ (LCIS)

non-calcifying lesion so
hard to find!!

histology: ductule spaces


full of round cells

progresses from ALH


precursor!!
ALL LACK E-CADHERIN =
poorly cohesive!!

Infiltrating
lobular
carcinoma

deletion of
gene for Ecadherin
adhesion
molecules

mammogram: no
calcifications
histology: proliferation of
round cells within the
lobule (bag of marbles)

10% of
invasive
breast
carcinomas

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)

mammogram: no
calcifications - difficult to
detect!
Gross: looks like fatty
fibrous breast but can't see
lesion

responds to tamoxifen!!

bilateral risk!!! (if


lesion in one breast,
check same spot on
the other brest w/
biopsy!)

histology: tumor cells


arranged in linear fashion
or concentric circles (bull's
eye)

low grade bc ER/PR


positive and HER2/neu
negative!!
Induration might be felt
on breast exam

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

Clinical
Variants

Mucinous
(colloid)
carcinoma

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

(general) see above


for deets

BRCA1/2 mutations - FH
breast cancer < age 50,
FH of papillary ovarian
cancer; triple negative
(ER/PR, HER2)

painful menstrual period,


cramping lower abd pain
(radiates to the back &
legs), plus GI, neurological
symptoms, & malaise

related to the number of


uninterrupted menstrual periods
(hence more estrogen
exposure)

estrogen
exposure
(endogenous
or exogenous)

pregnancy is protective in the


long-run

hi risk
mutations
(BRCA1,2;
PTEN, TP53)

primary / idiopathic - without


pelvic pathology
secondary - underlying pelvic
pathology (endometriosis,
ovarian cysts)

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

good prognosis if
properly diagnosed!!

histology: islands of DCIS


lesions floating in mucin
(clear); vasular supply

A/w cyclical periods!!


Primary

Complications

gross: infiltrating mucinous


(wet, sticky appearing) w/
hemorrhage

#1 cancer
among U.S.
women; #2
cause of
cancer
mortality in
women

increased age

tamoxifen & raloxifene reduces breast cancer


risk by 50%; increase
bone density; however,
a/w increased risk for
thromboembolic events

Caucasians
(after age 45;
before age 45,
AA have higher
risk) > AA> NA,
Hispanic, Asian

increased uterine tone + hi


amplitude contractions =
reduced blood flow = ischemic
pain

staged based on
tumor grade, ER/PR
stattus, HER2 status,
lymph node status
(axillary lymph nodes
first!!)

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

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

Dysmenorrhea (general)

Treatment

women ages 55- mammogram: round


60 years old
calcifications (looks like
fibroadenoma)

rounded periphery
lesions that also
resemble fibroadenomas
(BUT fibroadenomas
appear at younger age
usually & would have been
noticed in earlier
mammograms)
ER/PR positive

Breast cancer

Lab/Imaging

sentinel LN studies

50% of
menstruating
women

OCPs
NSAIDs for moderate pain

5-10% dysmen
affects QoL
PE: nl except some
tenderness

prostaglandin
synthetase inhibitors

confirm cyclical nature of


pain, R/O underlying pelvic
pathology

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

Disease

Chronic Pelvic
Pain

Clinical
Variants
Secondary

(general)

Endometriosis

Defining Characteristics

Etiologies

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

Epi

Risk factors

occurs many years after


onset of menarche

pain worsens w/ age

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

Pelvic
adhesions
(asherman's
syndrome)
Pelvic
venous
congestion
syndrome

Pathogenesis

infection, pelvic
bands of scar tissue form
between two pelvic organs --> surgery,
trauma
infertility & chronic pain

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

Lab/Imaging
PE: abd & vaginal exam
may reveal underlying
lesion

Treatment

Complications

analgesics
treatment of underlying
cause

U/S of vaginal/abd,
laparoscopy, hysteroscopy

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)

cause of
chronic pelvic
pain in young
women
3-15% of
general
population; 2050% of
infertile
population

FH, increased
exposure to
menstruation
(early menarche,
nulliparity), flow
obstruction,
obesity

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

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

exclude other pathology,


laparoscopy, consistent
history

women aged 20- CT or U/S diagnosis


45 w/ multiparity

hi fiber diet (avoid stool


buildup)
surgical lysis (dense
adhesions)
surery, laparoscopy,
pelvic vein embolization

Disease

Sexually
transmitted
infections

Clinical
Variants
Pelvic floor
dysfunction

(general)

Defining Characteristics

Pathogenesis

Etiologies

Epi

pelvic floor muscles myofascial pain usually


involving levator ani

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

Risk factors
Interstitial
cystitis (80%)

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+

Lab/Imaging
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)

Treatment

Complications

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)

Urethricitis

dysuria, urinary
frequency, intermittent
penile discharge

gonorrhea, chlamydia,
Mycoplasma genitalium

painful meatus? HSV

GC (5-20%),
CT (15-40%),
NGU (non
gonoccocal
urethritis - all
other agents)

Gram stain: increased polys


(>5 per HPF), GN
intracellular diplococci
(Gonorrhea - suff for dx in
men only!)

frequently asymptomatic

chlamydia, gonorrhea,
trichomonas, herpes, BV

chlamydia

Writer's syndrome Keratoderma


blenorrhagica
(autoimmune
syndrome w/ rash
after CT infection)

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
GC/CT NAAT

Cervicitis

Azithromycin - 1g PO
once if NGU infection OR
doxycycline 100mg/ PO
bid x7d

NAAT for GC/CT &


trichomonas or wet mount
culture for trich/ BV

Disease

Clinical
Variants
Genital
ulcers

Vaginal
discharge

Defining Characteristics

Pathogenesis

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

Trichomonas, bacterial
vaginosis

Candidiasis: cottage
cheese d/c
BV: fishy odor

vaginitis: vaginal D/C, vulvar


itching, irritation, odor

Etiologies

Epi

majority due
to HSV or
syphilis

Granuloma mostly in
Caribbean

noninfectious
sources?
Yeast, fixed
drug eruption,
psoriasis

HSV - 1/4
young people

Risk factors

Lab/Imaging

underlying dz
syphilis serology, herpes
(immunocomp, culture/ PCR serology
Crohns),
residence, travel
hx
# partners

Treatment

Complications

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

Trich (15-20%),
BV (40-45%;
a/w sex), vulvovaginal
candidiasis (2025%)

Trich: pH>4.5; wet mount:


motile flagellated protozoa
w/ many WBCs

Trich: metronidazole, HIV increased HIV risk w/


screening
trich
BV: metronidazole

Candidiasis: pH<4.5; wet


mount: few WBCs; KOH:
pseudohyphae
BV: positive KOH whiff test;
wet mount: Clue cells

Genital
warts
Proctitis

PID

DGI

HPV

HPV low risk


types 6&11

inflamed rectum w/ blood gonorrhea, chlamydia, syphilis,


herpes
& pus
mucoid anal discharge,
rectal bleeding
lower abdominal pain
AND uterine/ adnexal/
cervical motion
tenderness, dysuria,
purulent vaginal d/c

monoarticular septic
arthritis of large joints;
tenosynovitis/ dermatitis
(rash); 1-3% w/ mucosal
infection; fever/ chills
septic vasculitis - pustula
(pus filled vesicle)

MSM, women w/
rectal
intercourse

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)

PE: severe PID can have


swollen uterus/ tubes w/
extruded pus

tubal inflammation -->


scarring & loss of
function = tubal
factor infertility,
ectopic pregnancy,
chronic pelvic pain
NO USE OF IUD!!!
IUD + PID = TUBAL
ABSCESS
FORMATION

complement
deficiency
patients
younger,
sexually active
women

Disease

Clinical
Variants

Tubo-ovarian
abscess

Defining Characteristics

Pathogenesis

Etiologies

Epi

sepsis symptoms (fever,


shaking chills, tachycardia,
elevated WBC), lower abd
pain, mild rebound, large
tender adnexal mass

Risk factors
PID + IUD

Lab/Imaging

Treatment

vaginorectal exam: pus


palpated btwn rectum &
uterus

IV antibiotics first followed


by draining/ removal of
abscess

gross: ovary, multiple


thickened luteal cysts &
abscess

usually requires removal


of uterus and ovaries bc
fibroids present!

Complications

path: actinomyces if a/w IUD


Pyosalpinx
Hydrosalpinx

Adrenal
insufficiency

Fallopian tube filled with pus


Fallopian tube dilated with
watery fluid

(general)

hyponatremia,
hypercalcemia,
weakness/ fatigue/
anorexia, weight loss,
postural hypotension,
nausea, diarrhea,
myalgia/ arthalgia

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+)

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

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

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

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

0.3% of TB
patients
Addisons;
85% of pts
who die from
TB have
adrenal involv

HI ACTH (pit trying to


stimulate adrenals but
adrenals unresp)
short cosyntropin test - IV
ACTH will cause no change
in cortisol secretion

chronic replacement of
GC & MC

hyperpigmentation
does NOT resolve
even post-tx

Disease

Clinical
Variants
Secondary

Defining Characteristics
NORMAL POTASSIUM
LEVELS!!!! + symptoms
above in general category

Pathogenesis
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

Etiologies

Epi

Risk factors

HIV,
iatrogenic
(most
common!!) prolonged GC
treatment

Lab/Imaging
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)

HP axis dz
(tumors of pit,
hypothalamus,
infiltrative dz,
trauma)

Long Cosyntropin test repeated ACTH infusion


awakens the atrophic
adrenals and shows
cortisol secretion - reversal
of atrophy proves
secondary adr insuff

Adrenal
tuberculosis

adrenal insuff (see above)

gross: caseous necrosis


histology: Acid fast stain for
Mycobacterium tuberculosis
bacilli (red fish)

Autoimmune
adrenal
disease
WaterhouseFriderichsen
syndrome

adrenal insuff (see above) polyendocrinopathies; isolated


autoimmune adrenalitis

usually not biopsied but would


see lymphocytic infiltration

acute hemorrhagic
necrosis /infarct of
adrenal glands as a
complication of DIC
child presents w/ adrenal
insufficiency + infection +
pic of hemorrhagic
adrenals

Polyglandular Type I
Autoimmune
Disease (PGA)

adrenal insuff (see above) antibodies form to 17a & 21hydroxylase


+ mucocutaneous
candidiasis (thrush) +
hypoparathyroid disease AIRE gene mutation

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

autosomal
recessive

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

Treatment
Chronic replacement of
GC

Complications

Disease

Clinical
Variants

Adrenal Leukodystrophy

Congenital
Adrenal
Hyperplasia
(CAH)

Defining Characteristics

Pathogenesis

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

(general)

most common cause of


ambiguous genitalia

Etiologies

Epi

Risk factors

Lab/Imaging

X-linked
recessive
mutation of
ABCD1 gene
(MALES only)

25-35% of
"idiopathic"
Addisons now
known as mild
ALD

neuropsychiatric testing

most
common of
CAH!!

Cortrosyn stimulation
testing = gold standard for
dx - measures 17-OH
progesterone & cortisol levels
pre& post stimulation

Treatment

MRI for prognosis

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)
11B
adrenal insuff, severe
hydroxylase HTN + ambiguous
deficiency
genitalia

loss of 11B-hydroxylase
prevents formation of
corticosterone & aldosterone =
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

1:15,000

surgery for females


replace cortisol
(hydrocortisone), replace
aldosterone if needed
(fludrocortisone)

Complications

Disease

Clinical
Defining Characteristics
Variants
17aadrenal insuff, ambiguous
hydroxylase genitalia, sexual
deficiency
infantilism, primary
amenorrhea, HTN
NO CORTISOL OR SEX
ANDROGENS; EXCESS
ALDOSTERONE

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

Cushing
syndrome/
disease

(general)

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
adrenocortical hyperadrenal androgen production - constitutive
-> androstenedione production -- activation of
function
> 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

much less
common

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

adrenal disease:
adrenalectomy (last
resort) + radiation

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)

Disease

Clinical
Variants
Pituitary
ACTH
production

Defining Characteristics

Pathogenesis

Etiologies

Cushing disease caused by


ACTH producing
microadenoma (maj),
corticotroph cell hyperplasia,
hypothalamic corticotrophin
releasing hormone tumor

Epi
70-80% of
endogenous
Cushings
Females 5:1

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
Ectopic
ACTH

Carney
complex

Cushing syndrome

Adreno-cortical (general)
adenoma

Conn
syndrome

HTN, hypokalemia,
alkalosis, hi urinary
potassium

aldosterone-producing
adrenocortical adenoma

Lab/Imaging
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

Treatment
pituitary disease: transsphenoidal resection +
radiation

Complications
complications of transsphenoidal resection?
Transient DI
(disruption of post pit),
CSF leak, meningitis

post-surgery cortisol
supplementation until HPA
axis recovers
panhypopituitarism
from radiation
therapy (90%
patients over 10y
time frame)

CRH stimulation test:


elevated ACTH prod (if give
CRH, still stimulates ACTH
prod from ant pituitary - just at
a new set point)

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

hypercortisolism +
lentiginosis (spotty
pigmentation) + cardiac
myxoma, endocrine
autonomous cAMP pathway
tumors (adrenal cortical,
GH, or thyroid adenomas/ stimulation downstream
carcinomas, melanocytic
schwanomas, testicular or
breast ductal carcinomas
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

Risk factors

plasma ACTH > 200

treat underlying cancer

Imaging of other organ


systems for masses

very rare

plasma ACTH < 10 (ACTH


independent cause for
hypercortisolism)
need CT scan of adrenals for
masses

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

adrenalectomy (last
resort) + radiation

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)

Disease

Clinical
Variants

Adreno-cortical
carcinoma

Defining Characteristics

Pathogenesis

Etiologies

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

Epi
kids: ~4y.o.
adults: ~45yo
F>M
very rare
compared to
adenomas

Risk factors

Lab/Imaging
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

Treatment

Complications

adrenalectomy + radiation very poor prognosis


(med survival ~2y)

plasma ACTH < 10 (ACTH


independent cause for
hypercortisolism)

Adrenal
metastasis

need CT scan of adrenals for


masses
CXR: check for lung mass

adrenal mets from primary


lung, breast, or kidney
cancer
Bilateral, nonfunctional
adrenal masses in older
individuals - THINK METS!

Secondary
hypertension

(general)

hyperaldosteronism,
MC excess,
pheochromocytoma,
renal artery
stenosis, renal
disease,
endocrine
causes
(Cushings,
hypo/hyperthyroidism,
OSA)
Pheochromo onset of HTN at young age, adrenal medullary
syndromes:
cytoma
episodic HTN,
(neuroendocrine) tumor arising MEN2, neuropalpitations, tachycardia, from chromaffin cells =
fibromatosis,
tremor, weakness, pallor, production of catecholamines von HippelLindau, Sturgeanxiety (adrenergic stim),
= stimulation of alpha & beta
Weber
retinopathy, hyperglycemia, receptors = inc BP,
polyuria/ polydypsia, chest contractility, & HR =
pain, nausea, hypercerebrovascular &
reninemia (orthostatic
cardiovascular consequences
hypotension), ileus
resistant HTN (BP>140/90
w/ full doses of >3 meds +
suddent onset +
younger/older age at onset)

Classic triad??
Palpitations w/ tachycardia,
headache, perspiration
(drenching sweats)

Rule of 10s: 10% a/w


syndrome, 10% bilateral,
10% kids, 10% malignant

most common
causes?
Hyperaldosterone,
renal dz

rare
usually adults
(50y.o.)

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

preoperative alpha-adrenergic
blockers (lowers
BP&catech surges;
Phenoxy-benzamine,
terazosin)
B-adrenergic blockers
(only start AFTER ablockers; used for
tachycardia)
SURGERY required!!

50% 5y survival in
malignant tumors
certain drugs can
interfere w/
catecholamine assay
so might need to
change meds around

Disease

Clinical
Defining Characteristics
Pathogenesis
Variants
Hyperaldost adrenocortical
Conn's syndrome - HTN,
eronism
hyperfunction
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

Glucocorticoid
remedial
hyperaldoste
ronism

Etiologies
aldosterone
producing
adrenal
adenoma,
bilateral
adrenal
hyperplasia,
hypertensive
forms of CAH
(11B &17a
hydroxlase
def), adrenal
cancers

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

Deoxycortic
osterone
HTN

Epi
2-15%
prevalence

Risk factors

Lab/Imaging
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)

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

Treatment
adenoma? Surgery
(curative)
medical mgmt?
aldactone, epleronone,
amilioride (K+ sparing)

lowest dose of longacting steroid


(dexamethasone,
prednisone) to control BP

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

Liddle
syndrome

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

Syndrome of
Apparent
MC Excess
(AME)

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

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

low renin & aldosterone


(RAAS system not part of the
etiology of this syndrome)

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

Complications

Disease

Clinical
Variants
Licorice

Virilizing
syndromes

Sexual pain
disorders

Dyspareunia

Defining Characteristics

Pathogenesis

recurrent or persistent
involuntary genital pain
associated w/ sexual
intercourse

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

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;

Hypoactive
sexual
desire
disorder
(HSDD)

a/w menopause - reduced


androgen production =
reduced testosterone =
decreased libido

persistent or recurrent
deficiency or absence of
sexual fantasies and
desire for sexual activity

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
Sexual
aversion
disorder

Epi

Risk factors

persistent or recurrent
extreme aversion to, and
avoidance of, all genital
sexual contact w/
appropriate sexual
partner

Lab/Imaging

Treatment
stop offending agent & BP
reverts to normal

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

vulvodynia hypersensitivity to touch,


erythema, pain w/
penetration

Sexual desire
disorders

Etiologies

vulvo/
vestibulodynia
=
hypersensitivity
to yeast,
allergic
response,
HPV, genital
rash, autoimm,
estrogen def

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

inf = HSV,
HPV, GC, CT,
PID, UTI, BV,
trich,
candidiasis

menopause
(natural or
surgical)
meds (OCPs,
SSRIs - inhibit
pleasure
pathways)

tx infections

childhood
trauma

vaginal dilators,
psychogenic therapy,
muscle relaxatants

menopause,
OCP side
effect??

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

Disease

Clinical
Variants

Sexual arousal
disorder

Defining Characteristics
persistent or recurrent
inability to attain or
maintain an adequate
lubrication - swelling
response of sexual
excitement

Pathogenesis

Etiologies

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

Epi

Risk factors

Lab/Imaging

Treatment
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

directed masturbation
program (if lifelong d/o),
relationship therapy (if
situational d/o),

orgasmic capacity <


reasonable for age, sex
experience, and
adequacy of stimulation

education about sexual


fxn & response,
anxiety reduction
techniques,
testosterone/ DHEA/ local
estrogen/ oxytocin

Paratesticular
disorders

Hydrocele

painless enlargement of
scrotum that
transilluminates
lymphatic obstruction

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

congenital or
acquired

most common
cause of
scrotal
enlargement
usually 1st
year of life congenital
more
common

prior surgery,
neoplasm/ inf of
testis/
epididymis,
trauma

gross: distended testis full of


fluid; thin membrane so able
to see veins & tunica
vaginalis

Complications

Disease

Clinical
Variants
Varicocele

Defining Characteristics
painless dilation &
tortousity of veins

Pathogenesis

Etiologies

dilation of vein plexus in


spermatic cord

Epi

Risk factors

10% of young
adults

Lab/Imaging

Treatment

PE: veins engorge w/ blood


when standing

a/w infertility (inc


termpature in scrotum optimal
spermatogenesis is
more efficient at lower
temps)

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)
Spermatocele

cyst formation in
epididymis
hard, pea-sized nodules
above the testis
inflammation of
epididymis

Epididymitis

enlarged & TENDER


epididymis

Testicular
torsion

EXTREME PAIN that may


occur spontaneously during
sleep or be related to minor
injury
urologic surgical
EMERGENCY!!

Cryptorchidism

condition where one or


more testis has not
descended to its nl
position in the scrotal sac

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

NOT a/w infertility!!


BENIGN!

young men gonococcal &


chlamydial
infections

gross: purulent exodate in the


epididymis (above the testis)
if gonococcal

most
common
intrascrotal
inflamm d/o

untreated gonococcal
epididymitis -->
epididymis abscess
spread to testicles

older men E.coli, M.


tuberculosis

infertility if chronic
scarring &
obstruction

2nd decade of
life

twisting of spermatic cord =


compression of venous
drainage = vascular
engorgement & congestion =
infarction of testis

gross: necrotic testis,


edematous spermatic cord

surgery to manually
untwist spermatic cord

minor injury?

testicular infarction /
necrosis if not
surgically managed in
time!
Bilateral risk so
gubernaculum is
fixed on both testes

anomaly of testicular
suspension - gubernaculum
attached horizontally instead of
at the bottom of the testis
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

Complications

3% of male
infants at birth

histology: atrophy of
orchiopexy
cryptorchid testis after 2y w.o
treatment; fibrosis of
seminiferous tubules

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

Orchitis

Bacterial

inflammation of testis

Syphilitic

inflammation of testis

extension of bacterial infection


from epididymis
infiltration of lymphocytes
causes obliteration of small
blood vessels --> tubular
atrophy & fibrosis

Disease

Infertility

Male infertility

Clinical
Variants
Mumps
orchitis

Defining Characteristics

enlarged & PAINFUL testis viral mumps infection -->


lymphocytic infiltration -->
edema & pain --> focal atrophy
in 50% of involved testis

Primary - no one year of unprotected


prior preg
intercourse w/o
conception
Secondary preg in the
past

Supratesticular

Pathogenesis

above the testis


results from
abnormalities in organs
that regulate hormonal &
metabolic aspects of
spermatogenesis

Etiologies

Risk factors

Lab/Imaging

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)

histology: anatomic
seminiferous tubules but no
active spermatogenesis;
Leydig cells are
indistinguishable from
stromal cells

no gonadotropins

disorders or lesions of testis


itself
varicoceles --> increased
temperature = low
spermatogenesis

varicocele
cryptorchid
testis w/
scarring
Klinefelters

Cryptorchid testis can develop


atrophy & peritubular fibrosis

idiopathic

Klinefelters syndrome - atrophy


of gonads --> fibrotic testis
Posttesticular

obstruction of excretory
ducts, particularly the
epididymis

untreated
epididymitis
trauma

results in no spermatozoa in
the ejaculate, despite being
made properly in the testis

vasectomy

most common
cause

Complications
fertility usually
preserved in
unilateral infections

result in immature
seminiferous tubules - no
signs of spermatocyte
differentation (resemble those
of prepubertal testes), or
decreased spermatogenesis
Testicular

Treatment

mumps
30% of postchildhood virus pubertal
males w/
mumps

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)

Epi

histology: IDIOPATHIC?
Germ cell maturation arrest,
germ cell aplasia (Sertoli
cells only, no germ cells)

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)

Disease

Clinical
Variants
Hypogonadism (general)

Defining Characteristics

Pathogenesis

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

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

pre-pubertal = small
testes, eunuchoidal
skeletal proportions, hi
pitched voice, dec muscle
mass, delayed bone age,
dec body hair

Etiologies

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

hypogonado decreased FSH & LH,


testicle is functioning but
congenital or
trophic hypo- decreased testosterone = insufficient signal from
acquired
gonadism
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

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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!

Disease
Gonadal
dysgenesis

Clinical
Variants

Defining Characteristics
congenital
hypergonadotropic
hypogonadism

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

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

47XXY --> impaired


seminiferous tubules

1:10,000

prisoners

increased limb length,


decreased verbal IQ, "odd" impulsive behavior
Leydig cell
hyperplasia

Sertoli Cell
Only Syndrome

congenital
hypergonadotropic
hypogonadism

46XY but inactivating


mutations of LH receptor -->
female phenotype

male
pseudohermaphroditism
congenital
hypergonadotropic
hypogonadism

LH required for Leydig cells to


produce testosterone
Germ cell aplasia/ DelCastillo
syndrome

Male sterility without


sexual abnormality & nl
secondary sex
characterisitics

Vanishing
Testes
Syndrome

Septo-optic
dysplasia

congenital
hypergonadotropic
hypogonadism

congenital
hypogonadotrophic
hypogonadism

autosomal
recessive
mutations of
LH receptor

nl testosterone & LH; HI


FSH

sertoli cells are not


functioning --> impaired
sperm production

NO seminiferous tubules or
sperm!

normal secondary sexual


characteristics bc nl
testosterone & LH levels
nl 46XY karyotype but absent
testes (anorchia), due to
prenatal testicular torsion or
INSUL3 transcription factor
defect

low testosterone, hi FSH &


LH

regression of testes during 814w gestation


de Morsier's syndrome -->
absent septum pellucidum

optic nerve hypoplasia,


potential hypopituitarism
Kallman's
Syndrome

congenital
hypogonadotrophic
hypogonadism
HYPOSMIA OR ANOSMIA
(loss of smell) a/w
hypogonadism bc same
anatomic location as
olfactory bulb

problem w/ KAL gene (codes for


adhesion molecule) = loss of
migration of cells required to
make GnRH

1:10,000
M>F 5:1

Treatment

Complications

Disease
Hypergonadism

Clinical
Variants
(general)

Defining Characteristics
androgen excess, acne,
virilization, anger, small
testes

Pathogenesis
early pubertal development
from excessive androgen
secretion

Etiologies

Epi

Risk factors

Lab/Imaging

anabolic
steroids

Treatment
treat cause

Complications
often also have low
HDL so at risk for CVD

inhibit testosterone w/
GC (if adrenal cause),
surgery (if tumor), or
discontinuation of meds
(if exogenous anabolic
steroids)

endogenous (central
precocious puberty, adrenal
gland abnormality, androgen
secreting tumor)
exogenous (anabolic steroids)
Menopause

natural

occurs
around age
50

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

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

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

Premature

Primary ovarian
insufficiency

idiopathic
(maj), Turners
syndrome,
chemotherapy,
familial, pelvic
surgery,
gonadal
dysgenesis
(46XY),
galactosemia,
pelvic
irradiation

premature or
primary
ovarian insuff
occurs <40
1% of women

endometrial
hyperplasia & cancer if
continuous estrogen
exposure w/o enough
progesterone in
perimenopausal
women

osteoporosis tx: estrogen,


bisphosphonates,
SERMs, calcitonin,
calcium & vit D
supplements, exercise

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

Disease

Clinical
Variants

Defining Characteristics

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

Screening /
Education

Screening /
Education

every patient
over age 60
should have
TSH checked!
Increase
levothyroxine
dose by 30% in
pregnant
patients!!

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

recurrent
parathyroid dz
possible

Screening /
Education

Screening /
Education

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

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

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

Screening /
Education

Screening /
Education

Screening /
Education

expectant
management &
reassurance

Screening /
Education

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

Screening /
Education

Screening /
Education

continue to
monitor other
testicle if prior
germ cell tumor!

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

yearly
mammograms
for women >
age 40
breast exams q
3y for women
20-40; yearly
age > 40
hi risk women yearly MRI of
breasts

Screening /
Education

Screening /
Education

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!

Screening /
Education
PROTECTIVE
SEX!!

Gardisal
quadrivalent
vaccine

Chlamydia =
leading
preventable
cause of tubal
factor infertility

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

check testes
regularly to
screen for
development of
neoplasms,
even after
orchiopexy!

Screening /
Education

Pre-implantation
genetic
diagnosis
(PGD) aneuploidy
screen, single
gene defect,
HLA matching,
sex selection

Screening /
Education

Screening /
Education

Screening /
Education

CVD &
osteoporosis
screening

Screening /
Education

Screening /
Education

Disease

Clinical
Variants

Aplastic anemia

Defining Characteristics

all cell lines are down!!

Pathogenesis

Etiologies

premalignant condition w/ loss of Paroxysmal


self renewal (affects the stem cell) nocturnal
hemoglobinuria
(PNH),
Fanconi's
anemia

Epi

Risk factors

Lab/Imaging

BM: hypocellular (empty


marrow), fat vacuoles only; hi
power reveals lymphs only
(suggest that whole myeloid line
is gone)

Treatment

sometimes
immunosuppression helps
restore cell lines

Complications

infections - unable to
generate new
lymphocytes

allogeneic stem cell


transplant

CBC: loss of all cell lines


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

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)

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

elevated platelet count


(>450K)

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

pegylated interferon suppresses abnl


hematopoiesis

MUST R/O iron deficiency (iron


studies), other MPDs (CML,
PRV)
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 transform


to polycythemia vera
some patients, over
time, can develop
myelofibrosis

some patients, over


time, can develop
myelofibrosis

Disease

Clinical
Variants

Defining Characteristics

Primary
anemia, splenomegaly,
myelofibrosis elevated or decreased WBC
& platelets
portal hypertension

Pathogenesis

Etiologies

Epi

Risk factors

fibroblasts prompted to make extra JAK2 mutation


fibrous tissue --> filling of bone
marrow w/ fibrotic tissue -->
hematopoiesis then occurs at
other sites (extramedullary
hematopoiesis)

Lab/Imaging

tear drop RBCs (dacrocytes),


immature granulocytes,
nucleated RBCs

Treatment

Complications

JAK2 inhibitors - useful for


reducing spleen size and
improving symptoms; not
helpful for clone reduction

"dry tap" on marrow aspiration


(scarring of marrow)
hypercellular marrow + fibrous
tissue

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

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

apoptosis is shifted to bone


marrow = inappropriate cell
death before delivery to
peripheral blood

5q syndrome

Acute
myelogenous
leukemia (AML)

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

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

Acute
lymphocytic
leukemia (ALL)

Chronic
lymphocytic
leukemia (CLL)

Clinical
Variants

Defining Characteristics

malignant d/o of lymphoid


progenitor cells that
completely replace the
marrow --> pancytopenia

Etiologies

lymphadenopathy +
elevated WBC/ ALC

autoimmune disorders AIHA, ITP, Evan's syndrome

precursor to CLL

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

Epi

Risk factors

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)

infections - decreased
polyclonal immunoglobulins

Monoclonal Bcell
Lymphocytosis

Pathogenesis

most
common
childhood
malignancy

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

3/100,000
per yr

neoplastic B cells do not


differentiate into functioning
plasma cells =
hypogammaglobulinemia

most
common
overall
leukemia &
most
common
cause of
general
lymphadenopathy
in adult >
60

MBL
(monoclonal B
cell
Caucasian> lymphocytosis
AA>Asian
)
patients >
age 60

6-15% of
age
relatives of (increased
CLL patients CLL clones)

Lab/Imaging

Treatment

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

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!!

detectable clonal CLL cells at


less than 5000

use of maintenance tx
(administer low dose drugs
1.5-2.5y) - hallmark of ALL

Complications

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

CNS prophylaxis

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

1.2-1.4% of MBL
becomes CLL

Disease

Clinical
Variants

Plasma Cell
Myeloma

Defining Characteristics

fatigue, bone pain, renal


dysfunction, hypercalcemia,
recurrent infections w/
encapsulated organisms
(H.influenzae, Strep pneumo)

Pathogenesis

plasma cell dyscrasia (B cell


malignancies) common because
germinal centers have such
high error rates!

Etiologies

MGUS

precursor to myeloma!!!

Evan's syndrome

autoimmune hemolytic
anemia + ITP

Lymphomas

median age
66y.o.

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

Risk factors

Lab/Imaging

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)

Treatment

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

should always order HIV test if


suspect lymphoma!!

Complications

autologous transplant

incurable!

Thalidomide,
lenalidomide, bortezomib
most impt for remission
rates & improved
outcomes

Staged by Beta-2
microglobulin (total body
burden of plasma cells)
& albumin; cytogenetics
for high risk mutations

<10% plasma cells in marrow, observation


<3g monoclonal protein,
absent CRAB!

Fight infections fine bc normal


polyclonal Ig's not decreased;
no lytic lesions,
hypercalcemia, or organ
damage (CRAB); < 10%
plasma cells in marrow

(general)

4.3/100,000
AA>
Caucasians

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

Monoclonal
Gammopathy of
Undetermined
Significance
(MGUS)

Epi

1/3 of MGUS patients


progres to myeloma obligated to observe and
follow these patients!!

Disease

Clinical
Variants
Hodgkin's
lymphoma

Defining Characteristics

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

Pathogenesis

Etiologies

contiguous LN involvement
suggests spread via lymphatic
system

Epi

Risk factors

bimodal
age
distribution
(15-34; >50)

later exposure
to EBV, HIV,
iatrogenic
immunosupp
, higher SES

Reed Sternberg cell - releases


cytokines that cause severe
inflammation, fever, deranged
immune system

Lab/Imaging

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

Treatment

Complications

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)

NonHodgkin's
lymphoma

Fever
neutropenia

Low risk

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

see risk factors

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
indolent / low grade - dec
apoptosis; aggressive /
intermediate grade - dec
apoptosis, slightly inc mitosis; very
aggressive / high grade - dec
apoptosis, VERY inc mitosis

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

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
BM bx: not std of care, but if
abnl lymphocytes automatically
stage IV disease

Ceftazadime (3rd gen


cephalosporin)

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

Fever
neutropenia

Disease

Clinical
Variants
High risk

Defining Characteristics

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!!

Pathogenesis

GN bacteremia (Pseudomonas),
GP bacteremia (Staph, Strep)
abdominal symptoms present?
GN bacteremia (Pseudomonas),
GP bacteremia (Staph, Strep), or
Anaerobes
unstable? Tachycardia,
hypotension, respiratory
distress

Etiologies

Epi

Risk factors

Lab/Imaging

GN enterics,
Staph/ Strep,
Anaerobes

GN bacteremia: ceftazadime

other sources?
HSV, varicella,
dysphagia
(fungal, CMV,
HSV), yeasts/
molds

abdominal symptoms:
meropenum (anaerobes,
Pseudo), vancomycin, +/tobramycin

Tumor lysis
syndrome

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

Normally, potassium load is


excreted by the kidneys; however,
the administration of
chemotherapy causes the release
of DNA, phosphorus, and
potassium

Complications

GP bacteremia: vancomycin

unstable: meropenum,
vancomycin, amikacin
(double coverage against
pseudo)

perirectal abscess, port pocket


infection

Typhlitis

Treatment

CT: thickened bowel wall from


fluid/ air/ bacteria within the
lumen

BSA
management of
constipation/ diarrhea

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

DNA gets further metabolized to


uric acid via xanthine oxidase

hypocalcemia -->
muscle spasm, heart
failure, seizures
hyperuricemia &
hyperphosphatemia -> renal failure
hyperkalemia -->
arrhythmias (sine wave,
Torsaud's)

Calcium and phosphorus can


complex & precipitate --> kidney
stones & renal failure
inability to excrete potassium -->
cardiac manifestations
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

Mediastinal
mass

Clinical
Variants

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

CXR!!

tripod position, accessory


muscle usage - suggests
airway compression (presents
w/ cough, dysphagia,
orthopnea, hoarseness,
wheezing)

Treatment

sedation is
contraindicated!!

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)

Spinal cord
compression

back pain, decreased


strength, increased
reflexes, sensory changes,
rectal tone

Thrombocytopenia

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

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

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

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

Complications

Disease

Clinical
Variants

Heparin-induced
thrombocytopenia (HIT)

Defining Characteristics

Pathogenesis

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

Drug induced
thrombocytopenia

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)

Platelet
sequestration

Etiologies

Epi

Risk factors

Lab/Imaging

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

Treatment

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

thrombocytopenia

infiltrative diseases (MPD,


Guacher's dz)
Inflammatory dz (Sarcoid, TB)
Hyperplastic responses (chronic
hemolysis)
blood & fluid resuscitation results
in fall in platelet count

Dilutional
thrombocytopenia

Thalassemias

(general)

Alpha

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

replete 1 unit of platelets per


every 5-6 units of blood

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

Complications

Disease

Clinical
Variants
Beta

Defining Characteristics

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

Hypoproliferative
anemias

(general)

decreased absolute retic


count (<75,000) or
corrected reticulocyte %
(<2%)

Pathogenesis

Etiologies

multiple mutations (promotor


mutations, frame shift, splicing) -->
abnl translation --> decreased
production of beta globin chain
(B+) or no production of beta
globin chain (B0)

Epi

Risk factors

Lab/Imaging

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

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

decreased production of
hemoglobin/ RBCs

Microcytic, normocytic, or
macrocytic (see below)

Microcytic
anemias

(general)

corrected retic % < 2%


MCV <80

Iron
deficiency
anemia

weakness, fatigue, dyspnea loss of iron > absorption of iron


PE findings: pallor, angular
stomatitis, glossitis,
koilonychia (spoon nails),
pica

anemia resulting from


problematic hemoglobin
synthesis

sx of underlying disease process

Treatment

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

Complications

hemochromatosis (iron
overload following blood
transfusions) - require
iron chelating agents
cardiac dz, GI dz, & DM
(from iron deposition on
other organs)

Disease

Clinical
Variants

Defining Characteristics

Anemia of
chronic
disease
(ACD)

Pathogenesis

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

Normocytic
anemias

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

(general)

anemia resulting from inadequate


stem cells that become RBCs or
decreased demand for RBCs

Metabolic

corrected retic % < 2%


MCV 80-94

Etiologies

Epi

chronic
infections (TB,
abscess,
syphilis),
neoplasms,
chronic
inflammation
(arthritis, RA,
gout)

2nd most
common
cause of
anemia,
hospitalize
d patients!

Lab/Imaging

Iron studies: low serum iron, low


transferrin, low % saturation,
high ferritin
BM bx: increased RES iron
storage

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

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

Risk factors

Treatment

Complications

Disease

Clinical
Variants

Defining Characteristics

Endocrine

Pathogenesis

androgen deficiency testosterone stimulates EPO


release from kidney; when
androgen deficient, no
testosterone to stimulate EPO

Etiologies

Epi

Risk factors

Lab/Imaging

androgen
deficiency
hypothyroidism
adrenal failure

Hypothyroidism = reduced
thyroid hormone causes reduced
metabolic rate & decreased need
for O2 (thus Hb)
adrenal failure = corticosteroid
deficiency causes anemia

Macrocytic
anemias

Marrow
replacement

damage to bone marrow -->


fibrosis

infections,
tumors, scar
tissue

Marrow
failure

stem cells can't differentiate so


they accumulate in primitive
forms

aplastic anemia
leukemia

Anemia of
chronic
disease
(ACD)

initially presents as
normocytic anemia (as
disease progresses, it
becomes microcytic anemia)

(general)

corrected retic % < 2%


MCV >94

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 resulting from problematic


RBC division, most likely due to
abnormal DNA synthesis

high
reticulocyte
count

retics are not recognized by CBC


as different RBCs so can cause
increased MCV; must correct
retic count with anemia!!!

Target cells

large RBCs from increased red cell liver disease,


membrane (target cells)
obstructive
jaundice, post
splenectomy

Severe hypothyroidism

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

Treatment

Complications

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

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

Etiologies

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

Epi

Risk factors

FH of
autoimmune
dz (B12d)

Lab/Imaging

Treatment

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

Complications

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

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

Other
acquired extrinsic RBC
abnormalities defect resulting in noncausing
immune mediated hemolysis
acquired, nonimmune
mediated

Etiologies

valvular/
vascular
prosthesis,
severe AS, DIC,
vasculitis, RA,
SLE, TTP, HUS,
hemangiomas,
eclampsia,
malignant
hypertension,
pulm HTN

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)

Epi

Risk factors

systemic
illness

Lab/Imaging

Treatment

Complications

Smear: schistocytes

Smear: marble appearing RBCs


(physical or chemical agents),
acanthocytes (abnl lipid
deposition w/ severe liver dz,
low phosphate), infectious
agents (malaria)

Infectious agents - malaria,


babesiosis

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)

acute transfusion rxn activation of coagulation


system, renal failure, &
death

delayed transfusion reaction Hb increases but then begins to


fall 7-10d later (hemolysis); pt
made new antibodies that attacked
the transfused RBCs
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

Inherited
hemolytic
anemias

Clinical
Variants

Defining Characteristics

Pathogenesis

Etiologies

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

(general)

corrected retic >2% or


75,000

intrinsic defect in RBC leads to


hemolysis

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

gallstones? Increased Hb
breakdown = inc indirect bili = inc
bile salts = inc pigmented
gallstones --> cholecystectomy

Epi

Risk factors

Lab/Imaging

Treatment

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

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)

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)

Hereditary
elliptocytosis

Hereditary
pyropoikilocytosis

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)

major deletions in portions of


spectrin molecule = abnormal
fragments of RBCs

autosomal
recessive

Smear: fragments of RBCs,


worse w/ heat

Complications

Disease

Clinical
Variants
Sickle cell
disease

G6PD
deficiency

Transfusion
associated
GvHD

Transfusion
reactions

Defining Characteristics

Pathogenesis

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)

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

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

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

can present w/ drug-induced


hemolytic anemia (antimalarials, sulfonamides),
Mediterranean favism,
congenital nonspherocytic
hemolytic anemia, neonatal
jaundice, hemolysis w/ infxns
or DKA

Mature RBCs depend on


anaerobic glycosis for ATP
generation, reducing capacity
(requires NADPH & NADH)

nearly uniformly fatal

occurs if immunocompromised
patients receive blood that is not
irradiated!!

involves marrow, liver, skin,


gut

Acute
hemolytic
transfusion
rxn

skin sloughing
often due to ABO
incompatability, most likely
due to clerical error (misidentification of patient)

Etiologies

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)

intravascular hemolysis,
complement mediated, IgM

3-10d after transfusion of


blood that appeared
compatible
often asymptomatic w/
fever, mild jaundice, anemia

Risk factors

8-10% of
African
Americans

Lab/Imaging

Hb electrophoresis: HbS only


(Sickle cell disease), HbS + HbA
(sickle cell trait), HbS + HbC (Hb
SC disease)

pain is the
most
severe
complicatio
n
(disability,
healthcare
$)

Treatment

hydroxyurea - increases
production of HbF to
interfere w/ sickle cell
polymerization & reduce
frequency of sickle events

Complications

stroke, sepsis, sickle


nephropathy
#1 cause of death?
Acute Chest Syndrome

pain mgmt - nonopiods


(absolute dose ceiling),
opiods (no abs dose ceiling)

7-8% of
African
Americans,
10-15% of
Mediterrane
an heritage

Smear: bitocytes, staining of


Heinz body inclusions

severely
immunocompromise
d; neonates

STOP transfusion!!

DIC, renal failure

Flush w/ IVF
Check CBC to monitor
platelets & Hb, check renal
fxn labs and coagulation
studies

Sx: fevers, chills, back pain,


hypotension, n/v
Delayed
hemolytic
transfusion
rxn

Epi

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

Defining Characteristics

One degree Celsius rise in


temperature to the febrile
range

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

occurs from cytokine release from


WBCs in the unit being transfused,
antibodies to donor WBCs, or
bacterial contamination

Treatment

STOP transfusion!!

cannot be distinguished
from fever in acute
hemolytic rxn so
transfusion must be
stopped!!
Septic
reaction

Urticarial
reactions

rash and/or itching

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

ONLY reaction where blood


can be restarted & work up
is not mandatory
Anaphylactic
reactions

Tranfusion
fluid overload --> breathing
associated
problems
circulatory
overload
(TACO)
Iron overload liver/ cardiac/ endocrine
problems

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

Benadryl, then start


transfusion again

consider IgA
deficiency!

hypotension, chills, fever,


dyspnea, n/v, diarrhea,
urticaria

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

Aspergillosis

3% of
transfusions
(second
most
common
reaction)

#1 leading
cause of
death from
transfusion

antihistamine, epinephrine,
steroids, supportive care

CXR: bilateral chest infiltrates does not improve w/


diuretics

occurs in patients w/ pre-existing


cardiopulmonary compromise,
perhaps a/w hypertension

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

chelation therapy (Exjade)

transmission of Aspergillus mold


from environmental source

CT of head to check for


dissemination to brain
CT: characterisitc halo
description of nodular
infiltrate

Complications

Disease

Clinical
Variants

Mucormycosis

Defining Characteristics

mold w/ high mortality rate


Rhinocerebral nasocongestion, pain behind
eye, proptosis, AMS

Pathogenesis

spores are inhaled and deposit on


mucosa, then germinate and
invade tissue; angioinvasion -->
tissue necrosis

Pulmonary - dyspnea, fever,


non-productive cough,
pleuritic chest pain

Candidiasis

most common fungal


infection in hospitalized
patients
variety of presentations - UTI,
pneumonia,
mucocutaneous (thrush,
esophagitis, diaper rash),
tissue, bloodstream

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

Etiologies

Epi

low
incidence
(1.7/100K)

Risk factors

Lab/Imaging

Treatment

neutropenia,
immunocomp
(HSCT, organ
transplant,
cancer,
autoimmune
dz), poorly
controlled DM

MRI shows opacification of


sinuses, brain edema & invasion

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)

CXR shows dense infiltrates; CT


does NOT have halo infiltrates
like Aspergillus
Cx: grows very quickly,
branching hyphae

dx? Blood/ mucus/ bx culture,

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)

irreversible inhibitor of ADP


receptor, blocks platelet activation

Uremia (renal
dysfxn)

accumulated metabolites impair


fxn of circulating platelets

dialysis corrects platelet


dysfxn

Complications

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

Glanzmann
thrombasthenia

normal platelet count w/


mucocutaneous bleeding

absence or dysfunction of
integrin aIIbB3, preventing
platelet aggregation

BernardSoulier
syndrome

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

Absence of
platelet
granules

Etiologies

mutation within
the binding site
of aIIbB3 or talin
deficiency (talin
nl exposes
binding site)

Epi

Risk factors

Lab/Imaging

Treatment

PFA - no aggregation but will


agglutinate w/ ristocetin

PFA - aggregation but no


agglutination w/ ristocetin

PFA - loss of 2nd wave (no


aggregation because deficiency
of granules or dysfunctional
granule release)

alpha granule def - gray platelet


syndrome

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

Type 1 (7580%)

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

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

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

Complications

Disease

Inherited
hemophilia

Clinical
Variants

Defining Characteristics

Hemophilia A = factor 8
deficiency
Hemophilia B = factor 9
deficiency

Pathogenesis

defect in platelet surface thrombin


generation (factors 9 & 8 are
required to provide platelet
surface for activation by factor
10)

Etiologies

X-linked
20-30% =
spontaneous
mutations

Epi

Risk factors

Lab/Imaging

Treatment

A = 1/10K
male births

replace missing clotting


factor - recombinant

B = 1/30K
male births

release of stored factor 8


w/ DDAVP

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

Complications

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

Lupus
anticoagulant

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

thrombosis

looks like DVT

Vitamin K
deficiency

muscle bleeding, deep


bleeds

Liver failure

a/w autoimmune 1.4/1million


conditions,
pregnancy,
mortality 6malignancy
20%
(highest in
elderly)

antibodies that inhibit phospholipid


dependent coagulation; neutralized
by presence of excess
phospholipids

blocks conversion of vit K


dependent factors (2, 7, 9, 10,
protein C, protein S) to activated
forms --> bleeding

prolonged PTT, elevated


mixing study (suggests
inhibitor to intrinsic pathway
factor)

control bleeding
eradicate inhibitor w/
steroids, IVIG, rituximab

symptoms + factor 8 >10%


that "titers up" with dilution
titered up PTT post mixing!!!

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

autosomal
recessive

abnl PTT

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

NO TREATMENT!!

Disease

Fibrinogen
abnormalities

Clinical
Variants

Defining Characteristics

Pathogenesis

Etiologies

increased fibrinogen? Acute prevents stable formation of crossphase reactant, inflammation, linked fibrin clot OR
overproduction of fibrin clots
pregnancy

Epi

Risk factors

Lab/Imaging

Treatment

deficiency? Abnl PT & PTT,


prolonged thrombin time, abnl
fibrinogen assay

decreased fibrinogen? DIC,


liver dz, ascites, alcohol
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)

Disseminated
Intravascular
Coagulation
(DIC)

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

bleeding + subclinical or
clinical thrombosis

uncontrolled activation of primary


& secondary hemostasis,
activation of fibrinolysis,
consumption of factors &
inhibitors, and evidence of end
organ damage

sepsis,
malignancy,
trauma/ head
injury/ burns,
obstetric
causes
(eclampsia,
retained fetus,
abruptio
placenta)

sepsis patients!

Cytokines, TF, LPS, hemolysis,


acidosis, turbulence all contribute
to factor activation, endothelial
damage, & platelet activation

plasma exchange & vWF


inhibitors

congenital - def
ADAMTS13

others? AA,
toxins,
transfusion,
immunologic

elevated clotting times &


decreased platelet count

FFP transfusions but watch


for volume

ELEVATED D-DIMER

cryoprecipitate to keep
fibrinogen elevated
platelet transfusions (keep
platelets > 50K)
??heparin

Complications

Disease

Venous
Thrombosis

Clinical
Variants

Defining Characteristics

(general)

Pathogenesis

Etiologies

Epi

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)

Risk factors

Lab/Imaging

Treatment

Complications

age, comorbid Wells score


conditions
(OCP use,
lower extremity U/S, CT of chest
HRT,
to R/O PE
hospitalizati
on, cancer,
surgery)

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

immobilizati
on, burns,
HIT, DIC,
pregnancy

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)

persistent
risk factors?
Inherited
thrombophilia,
acquired
thrombophilia
s, obesity,
CHF,
nephrotic
syndrome,
Superficial
vein
thrombosis
(SVT)

generally benign & self


limiting

thrombosis in superficial vein

low dose heparin for at least


4 weeks

becomes more serious if


extends into deep vein
tender, palpable cord w/
surrounding erythema &
heat

Deep vein
thrombosis
(DVT)

Postthrombotic
syndrome
(PTS)

occlusion of deep veins in leg -->


lack of venous return of blood -->
congestion & pain

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

damage to venous valves


(mechanical damage from clot &
inflammation provoked by acute
thrombosis)

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

regular use of
compression stockings!
(must be replaced every 6
months, worn daily for 2y
after DVT)

hi BMI
prior
ipsilateral
venous
thrombosis

worse sx w/ activity; better


w/ rest

female
older age

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

Protein C
deficiency

Defining Characteristics

variable presentation but


overall risk of thrombosis
increased 15-20x

Protein S
deficiency

Pathogenesis

Protein C (along with Protein S)


normally inhibit factors 5&8 of
coagulation cascade

cofactor to activated protein C,


enhances anticoagulant effect of
protein C

Factor V Leiden

Heterozygotes - VTE risk


increased by 5-7x

Antiphospholipid
syndrome
(APS)

Epi

Risk factors

Lab/Imaging

2-9% of
patients w/
VTE

make sure patient has d/c


warfarin for 2 weeks prior to
testing Protein C

3% of pts w/
VTE

prolonged PTT in protein C


deficient plasma
Prolonged PTT w/ protein S
deficient plasma

deficiency a/w increased


thronbosis risk

make sure patient has d/c


warfarin and not on hormonal
therapy or pregnancy

mutation in factor 5 gene -->


resistance to factor 5
inactivation by protein C

APC sensitivity ratio = PTT in


presence of protein C/ PTT in
absence of protein C

Homozygotes - VTE risk


increasd by 50x

Acquired
thrombophilia

Etiologies

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

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

Treatment

Complications

Screening /
Education

Screening /
Education

remission =
residual leukemia
burder below
level of detection
cure = remission
beyond 5 years

Screening /
Education
better prognosis
than AML
COG - children's
oncology group guarantees
clinical research
trial for every kid
w/ leukemia

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education
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!!

Screening /
Education

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

Screening /
Education

Screening /
Education

Screening /
Education

give VitK to all


newborns as
prophylaxis
against
hemorrhagic
disease of
newborn

Screening /
Education

Screening /
Education

Compression
stockings
IVC filters if
contraind for
anticoagulation

Screening /
Education

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Subdural
hematoma

usually in shaken brains

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)

CT: best for acute bleeds


MRI: best for subacute bleeds;
shows blood spread out across
the surface of the brain

Epidural
hematoma

blood accumulates rapidly,


forming a bulge between
regions of dural attachment
to bone --> increased
intracranial pressure

PE: lucid interval (delayed


neurological signs)

tearing of the middle meningeal


artery (high pressure rapid
bleed that separates dura from
skull)

blow to skull
(baseball)

Treatment

CT: best for acute bleeds


MRI: best for subacute bleeds

epidural space = potential space


btwn dura & skull; fills w/ blood or
fluid w/ trauma

Subarachnoid
hemorrhage,
intracranial
hemorrhage
Coup contra
coup injury

Brain herniation

sudden onset, "worse


headache of life"

Falx cerebri

Tentorium
cerebelli
(uncal
herniation)

Left (dominant)
hemisphere
lesion

ABCs, Neurosurgical
consult

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!)

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

Foramen
magnum

Hydrocephalus

CT: blood in ventricles or other


brain areas

brain herniates from left to


right side
brain undergoes tonsillar/
cerebellar herniation

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

decompressive surgery

surgical placement of shunt


to divert CSF from brain

Complications

Disease

Clinical
Variants

Defining Characteristics

Right
(nondominant)
hemisphere
lesion

left visual field deficit, left


hemiparesis, left
hemisensory loss, left
hemineglect, right gaze
deviation/ preference

Medial midbrain
syndrome

ptosis, diplopia, anisocoria


(uneven pupils), contralateral
hemiparesis, contralateral
UMN facial weakness

Lateral
medullary
syndrome

Pathogenesis

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)

Etiologies

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 above
T1 (Pancoast
tumor, BrownSequard
syndrome, late
stage
syringomyelia)

Medial medullary
syndrome

contralateral weakness,
contralateral loss of fine
touch, ipsilateral tongue
weakness

lesion affecting the corticospinal


tract (CL weakness), dorsal
column-medial lemniscus (CL
loss of fine touch, vibration), and
hypoglossal nucleus (IL tongue
weakness)

infarct of
vertebral artery
or anterior
spinal artery
(posterior
circulation)

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

LMN lesion of facial nerve or


nucleus --> peripheral ipsilateral
facial paralysis with inability to
close eye on involved side

reactivation of
viral
inflammation of
facial nerve by
stress,
emotional
triggers??

unilateral hearing loss,


peripheral facial weakness,
possible development of
horizontal diplopia

tumor impinges on pontomedullary


junction, where CN 6,7,8 all exit

Cerebellar
pontine angle
tumor

Epi

Complication of
AIDS, lyme dz,
HSV,
sarcoidosis,
tumors, DM

most
common
mononeuropathy

Risk factors

Lab/Imaging

Treatment

Complications

Disease

Basilar pontine
infarction

Clinical
Variants
Locked in
syndrome

Defining Characteristics

bilateral facial weakness,


inability to abduct both eyes,
bilateral quadraplegia,
extensor plantar responses

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

1-2% of
population

2+ unprovoked seizures,
generalized or focal

PMH of
complex
febrile
seizures as a
kid, head
trauma,
alcoholism,
recreational
drug use,
encephalitis,
develop
delay, stroke,
focal brain
lesions

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)

FH of
epilepsy
Idiopathic
(primary)

relatively self-limited,
medication responsive

no underlying pathology; normal


development

considered
genetic

generalized > focal


Childhood
Absence
Epilepsy

absence seizures ("spacing idiopathic generalized epilepsy


syndrome; genetic
out")

EEG: 3Hz spike wave

good prognosis,
resolves by teenage
years

onset age: 3-8 y.o.


frequent daily seizures

Juvenile
Myoclonic
Epilepsy

normal development
myoclonic (muscle
twitching), GTC seizures

idiopathic generalized epilepsy


syndrome; genetic

onset age: 13-20 y.o.


rare GTC, myoclonic
seizures in AM

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

requires lifelong
treatment, medication
responsive

exacerbated by AEDs like


carbamazepine &
phenytoin

normal development

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

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

Symptomatic frequent seizures, difficult to structural or metabolic neurologic


abnormalities
control

LennoxGastaut
Syndrome

focal > generalized


any type of seizures can
occur (GTC, atonic, tonic)

symptomatic (structural or
metabolic) generalized epilepsy
syndrome

EEG: 1-2Hz slow spike wave

symptomatic localization related


epilepsy syndrome; structural
(abnl MRI) or unknown (nl MRI)

EEG: temporal spikes


MRI: mesial temporal
sclerosis (scarred
hippocampus)

poor prognosis, very


difficult to control

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

Nocturnal
Frontal Lobe
Epilepsy
(NFLE)

+/- cognitive dysfunction


seizures occur most often
during sleep! (most
common in stage2 sleep so
early in night)

mean age
of onset
14y (mostly
kids)

Carbamazepine or other
AED
Safe environment

70% men

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)

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)

more
common in
adults
(acquire risk
factors;
complex
partial
seizures)

aura of any kind indicates


focal onset of seizure

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)

often refractory to meds, but poor prognosis for


surgery can be curative (80- remission; often
85%)
refractory to meds

MRI of brain with and without


gadolinium
EEG, asleep & awake

Disease

Clinical
Variants
Complex
partial

Defining Characteristics

loss of consciousness;
lasts 1-2m

Pathogenesis

focal seizure

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)

Etiologies

Epi

Risk factors

focal brain
lesion (tumor,
AVM, abscess,
old stroke, posttrauma, mesial
temporal
sclerosis, HIV
dementia,
Alzheimer's)

Lab/Imaging

require brain MRI to look for


causative agent

Treatment

Complications

AEDs or if refractory to
multiple meds, surgical
resection

EEG: focal spikes over


epileptogenic focus

amnesia

Secondarily
generalized
tonic-clonic
Generalized
seizures

post-ictal confusion or
weakness
convulsive seizure

(general)

Tonic-clonic

evolves from focal seizure to


bilateral, convulsive 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)

Todd's paralysis
(transient, post-ictal
hemiparesis CL to
seizure focus)
more
common in
kids
most
common
type of
seizure

lateral tongue bite common;


bladder/bowel incontinence;
postictal confusion

Absence

brief loss of awareness;


lasts 5-20s

2nd most
common
seizure

kids

EEG: 3Hz generalized spike &


waves

AEDs: ethosuximide &


valproic acid

often misdiagnosed as
ADHD

staring spells; subtle


movements/ automaticisms
(eye blinks, head nod),
no aura
no postictal period
ALWAYS start in childhood
& resolve before adulthood

Myoclonic

brief shocklke muscle


contractions in head,
shoulders, & upper
extremities
consciousness preserved,
precipitated by waking

Clonic
Tonic

may progress to
generalized tonic-clonic
seizure

Disease

Clinical
Variants
Atonic

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

kids

loss of consciousness,
sudden onset & lasts few
seconds (but very frequent
in number!!)

Complications

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

conversion
disorders

EEG: normal brain activity


throughout

last up to 45 minutes
(normally seizures last 1-2m
at most)
Stroke

(general)

4th leading
cause of
death

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)

leading
cause of
long-term
disability
blacks are
at higher
mortality
risk than
other
races;
stroke at
earlier age
in blacks

Act F.A.S.T. (face, arm,


speech, time)

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

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

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

Hemorrhagic In addition to SUDDENS, can bleeding into the brain tissues


also have vomiting &
(intracerebral hemorrhage) -->
headache more than
mass effect
ischemic

Stroke
syndromes

Etiologies

aneurysms,
arteriovenous
malformations,
uncont HTN,
tumors,
hemorrhagic
conversion of
infarct, amyloid
angiopathy

Epi

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

Left MCA
stroke

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

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

Left ACA
stroke

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

Basilar artery
stroke
(locked in
syndrome) see above for
basilar
pontine
infarction

basilar artery infarct produces


lesions in the perforators that feed
the brainstem; the amount of
perforators affected correlates w/
symptoms

Treatment

Complications

more fatalities than


ischemic strokes

CT scan -

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

Quadriplegia or hemiplegia,
nystagmus, crossed signs,
vertigo, diplopia, n/v,
ipsilateral ataxia

Lab/Imaging

10% of
strokes

Subarachnoid
hemorrhage

Right ACA
stroke

Risk factors

MRI: hyperintensity in inferior


cerebellar territory

PICA supplies the inferior portion


of the cerebellum & lateral portion
of medulla

MRI: hyperintensity in brainstem

Disease

Clinical
Variants
Lacunar
syndromes

Defining Characteristics

pure motor hemiparesis (if


affects internal capsule),
pure sensory stroke (if
affects thalamus), or
sensorimotor stroke (if
between internal capsule &
thalamus)

Pathogenesis

small (<1.5 cm diameter), deep


infarcts in territory of the deep
penetrating arteries

Etiologies

Epi

long standing
HTN -->
lipohyalinosis -->
ischemia

Risk factors

Lab/Imaging

CT: small round hypodensity


(darker) in deep white matter or
subcortex from infarct of
penetrating arteries

pure motor hemiparesis affects


internal capsule & corticospinal
tracts

ataxic hemiparesis, clumsy


hand dysarthria (weak hand
+ slurred speech)

Tremor

(general)

involuntary rhythmic
oscillating movements

Rest tremors occur during rest


Postural
tremors
Kinetic
(action,
intention)
tremors

Rigidity

occurs while body part is


maintaining posture against
gravity
occurs during goal-directed
movements

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

alternating or synchronous
contraction of reciprocally
innervated antagonist muscles

Parkinsons,
Essential
tremor, drugs
(lithium, valproic
acid,
neuroleptics,
stroke), rubral
(stroke, MS)
Parkinsonism

essential
tremor,
physiologic
(caffeine, stress,
meds, drugs)
MS, stroke

Parkinsonism

stiffness but not major


disability
"lead-pipe"
"cog-wheeling"
Akinesia/
bradykinesia

slowness / fatigue or arrest


in ongoing movements
interferes w/ all activities
and very disabling

Parkinsonism

most
common
movement
disorder

check meds!!

Treatment

Complications

Disease

Dystonia

Clinical
Variants

Defining Characteristics

Pathogenesis

involuntary sustained
muscle contractions that
produce twisting/ squeezing
movements & abnl
postures; may be
stereotyped or repetitive;
usually action induced &
worsen w/ stress/ fatigue

co-contraction of muscle agonists


& antagonists

can be a/w tremor (jerky)


blepharospasm (invol
closing of eyes), use of
"tricks", generalized
dystonia usually begins in
legs

Etiologies

generalized genetic origin


(DYT1), kids

excessive, spontaneous
movements that are
irregularly timed, nonrepetitive, & randomly
distributed
involves multiple body parts

Tic

repetitive, brief, rapid,


involuntary, purposeless, &
stereotyped movements

Doparesponsive
dystonia

Huntington's
chorea
tardive
dyskinesia
(iatrogenic Levodopa in PD
pts)
Tourette's
syndrome,
OCD, excessive
blinking

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

kids generalize
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

contractions stop during


sleep
Chorea

Epi

Alzheimer's
disease, prion
disease, drugs

Risk factors

Ashkenazi
jews (DYT1)

Lab/Imaging

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!)

Treatment

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

Complications

Disease

Parkinson's
disease

Clinical
Variants
(Parkinsonis
m)

Defining Characteristics

Pathogenesis

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

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

PD, strokeinduced (rapid,


stepwise prog),
PSP (abnl eye
movements),
drug induced
(symmetric),
toxins (MPTP),
drugs
(neuroleptics),
Wilson's dz,
neurodegen d/o

Complications

high risk of falls!


Dyskinesia/ dystonia
from Levodopa tx

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

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

Essential tremor

Defining Characteristics

Pathogenesis

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

Etiologies

Epi

1-6% of
population
(most
common
movement
d/o)

Risk factors

Lab/Imaging

often asymmetric

Complications

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

FH

bimodal age
of onset
(peaks in
early adult &
later
adulthood)

location: upper extremities


> head > voice > leg/ chin

Treatment

side effects of primidone


- cognitive effects (fuzzy
memory)

M=F

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"

Parkinsonism disorder that


presents with cardinal features +
eye movement abnormalities
(gaze palsy)

fall very early in dz


course!

intact Doll's eye maneuver


suggests intact brainstem
Wilson's disease

Cerebellar
syndromes

facial dystonia w/ retraction


of mouth, Keyser-Fleischer
rings in eyes (sunflower
cataracts), fixed dystonia
(does not improve w/ tricks)

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

Defining Characteristics

Toxic
syndromes

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

MachadoJoseph
Disease
(MJD) =
SCA3

ataxia, dysarthria, mild


ophthalmoplegia,
periocular or perioral
fasics, dystonia

autosomal dominant disease w/


large degree of phenotypic
variability & hi genetic anticipation

Friedreich's
ataxia
(FRDA)

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

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

Pathogenesis

autosomal recessive ataxia with


strong founder effect
(IndoEuropean races)
mutation in frataxin
(trinucleotide repeat GAA); inc
repeats = inc clinical severity

Etiologies

sx onset in late
childhood/
adolescence

Epi

Risk factors

most
Indocommon
European
inherited
races
ataxia (1/3050K)

Lab/Imaging

Treatment

Complications

supportive (balance,
orthotics)
anti-oxidants? HDAC
inhibitors?

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)

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

Huntington's
disease

Clinical
Variants
slowly
progressive,
degenerative
neuropsychiatric
d/o

Defining Characteristics

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

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

Pathogenesis

Autosomal dominant mutation in


the huntingtin gene, leading to
unstable expansion of CAG
repeats (nl < 26) in the polyQ
area

Etiologies

Epi

AD inheritance 5-10/100K
w/ hi penetrance

Risk factors

FH

huntingtin
gene mutation

Htt role unknown? Protein folds


incorrectly --> aggregation -->
dysreg transcription & abnl RNA
prod, mitoc dysfxn, & oxid
damage; protein is cleaved &
forms polyglutamine fragments
(toxic!)

Lab/Imaging

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

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

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

leading
cause of
nontraumatic
disability in
young
adults
70%
women,
8500-10K
new cases
per yr

Treatment

Complications

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

females,
geography
(inc risk if far
from equator),
vitD def,
smoking,
EBV+, FH,
HLA-DRB 1
gene

age of
genetically
onset: 15-50 protected?
Eskimos,
Native
Americans,
Hungarians

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

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

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

Disease

Dementia

Clinical
Variants
(general)

Defining Characteristics

acquired, persistent, severe


impairment of multiple areas
of higher brain functions (>2
deficits in memory,
language, praxis,
visuospatial skills,
executive fxn, emotions,
personality)

Pathogenesis

characterized by acquired
memory impairment +
performance impairment in
functional domains (language,
visuospatial skills, identification
skills, executive skills)

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

Alzheimer's
disease

memory loss

Etiologies

Epi

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

history, neuro exam, blood tests


(B12, thyroid, syphilis, HIV),
imaging, clinical features
(genetics, CSF), neuropsy
testing

50% of
people >85
have
dementia

Montreal cognitive assessment


or MMSE

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

Lab/Imaging

Treatment

logical memory (read a


paragraph then talk about what
was read), word recall
(immediate & delayed), naming
test (line drawings)

visuospatial (intersecting
pentagons)

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

most
common
type of
dementia
F>M

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

age, Down
syndrome,
head trauma,
depression,
HTN, hypercholesteremia
, hi
homocysteine
, low B12/
folate

CT: mesial temporal atrophy


PIB: increased amyloid
burden
CSF: measure biomarkers like
beta-amyloid & tau protein
(predicts MCI conversion to AD)

symptomatic? AChE
inhibitors (donepezil,
galanthamine, rivastigmine),
memantine
Neuroprotective? VitE

pathology: brain atrophy,


neurofibrillary tangles, senile
amyloid plaques

protective?
Education,
exercise, Med
diet, NSAIDs,
statins, red
wine

10-20% of
dementia
M>F
age of
onset? 5080

FH

cannot be distinguished
neuropathologically from
Parkinson's dementia

Complications

very vulnerable to
delirium

executive fxn (connect the dots,


clock drawing)

10% of AD has familial form: early


onset (<65y.o.), autosomal
dominant w/ 100% penetrance
(mutations in APP, presenilin-1,
presenilin 2, or ApoE4)
Lewy Body
dementia

Risk factors

d/c anticholinergics, lower


doses of dopaminergics
AChE inhibitors,
antidepressants, atypical
antipsychotics

Disease

Clinical
Variants
Frontotemporal
dementia

Defining Characteristics

Consciousness

Etiologies

Epi

Risk factors

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

Delirium

Pathogenesis

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

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)

autosomal dominant mutations


in MAPT and progranulin
TDP a/w ALS
Tau a/w PSP

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

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)

Lab/Imaging

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

Treatment

Complications

Disease

Clinical
Variants
Comatose

Defining Characteristics

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

Persistent
vegetative state
(PVS)

Pathogenesis

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

wakefulness without
awareness

brainstem functions without


cortical function

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

glucose in cerebral cortex is


greatly reduced, to a degree
incompatible w/ consciousness

Etiologies

Epi

Risk factors

Lab/Imaging

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)

hypoxic
ischemic
encephalopathy
(most common
cause of PVS)

pathology: diffuse laminar


necrosis of cerebral cortex w/
extensive hippocampal
involvement

Treatment

Complications

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)

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)

>3m of PVS, functional


recovery is rare

actions have no cognitive


content
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

Brain death

Defining Characteristics

Pathogenesis

Etiologies

Epi

documented loss of
irreversible loss of all brain &
consciousness (coma) + no brain stem function
brain stem reflexes + apnea

Risk factors

Lab/Imaging

Treatment

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

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

Complications

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!

REPEAT CLINICAL EXAM!

Axonal
polyneuropathy

(general)

Metabolic,
majority of
endocrine (DM), polymeds/ toxins,
neuropathy
nutritional (B12
def), connective
tissue (SLE,
Sjogren's)

usually affects both


sensory AND motor fibers
symmetric & distal:
Stocking-glove distribution
(Legs>arms), absent ankle
jerks

HbA1C or 2h GTT, TSH, B12,


serum protein electrophoresis
(multiple myeloma), ESR/CRP

chronic (if acute, think about


vasculitis)

Diabetic
peripheral
neuropathy

burning pain, reduced pin


prick & temp sensation

involves small C fibers (pain), as


well as sensory large fibers
(vibration, mechanical sensation)

absent ankle jerks


symmetric distal pain/
burning, mild weakness, +/autonomic involvement
(postural hypotension,
arrhythmias, bowel/bladder
probs)

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

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

NCS: conduction block (20%


drop in amplitude btwn proximal
& distal sites)

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)

Disease

Clinical
Variants
GuillainBarre
Syndrome
(GBS)

Defining Characteristics

Pathogenesis

ACUTE ascending
weakness, absent reflexes,
can involve CN7 (facial
paralysis) & autonomic
dysfxn (cardiac irregularities,
HTN, hypotension)

immune mediated process (T


cells)--> inflammation &
demyelination of peripheral nerves
& motor fibers of ventral roots

Etiologies

Epi

most
common
cause of
acute
generalized
paralysis
0.61.9/100K

PRECEDING ILLNESS (often


GI - Campylobacter jejuni;
CMV, EBV, HSV, influenza,
mycoplasma), immunization,
recent surgery or renal
transplantation

Risk factors

Lab/Imaging

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)

all age
groups

MRI if suspect spinal cord


involvement

Treatment

IV Ig, plasma exchange


NO CORTICOSTEROIDS!
Admission to ICU if
autonimic dysfxn

Complications

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

may be a/w Hodgkin's dz,


SLE, HIV?

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

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

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

increased strength following


administration of AChE
inhibitor

AChR antibodies lead to


destruction of the AChR by
activating complement fixation
OR inducing endocytosis of
receptors (similar to botulinum
toxin)
Motor neuron
(general)
diseases
(anterior horn
cell dz, motor
neuronopathies)

PAINLESS weakness &


atrophy

cramps, fasciculations
NO sensory loss, NO ptosis
or eye movement probs

progressive course!

cell dz, motor


neuronopathies)

Disease

Clinical
Variants
Poliomyelitis

Defining Characteristics

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

Pathogenesis

neurotropic enterovirus w/
predisposition for ventral horn
in spinal cord & motor cranial
nerve nuclei --> LMN
destruction

Etiologies

fecal oral route


poliovirus,
Coxsackie virus,
echovirus,
enterovirus,
Japanese
encephalitis
virus, rabies
virus, West Nile
virus

Epi

new cases
eradicated
in U.S. but
cases of
post-polio
syndrome

LMN signs: muscle


weakness & atrophy,
fascics, hyporeflexia

Kennedy's
disease

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

progressive hereditary diseases of


anterior horn cells & select motor
cranial nerve nuclei

X-linked bulbospinal
muscular atrophy

mutation of androgen receptor


gene on X chromosome

adult onset, bulbar &


proximal weakness,
lower extremity weakness
very disabling - wheelchair
dependency
ANDROGEN INSENSITIVITY
- gynecomastia, impotence,
testicular atrophy, infertility
increased incidence of DM

SMN (survival motor neuron) 1


on chrom 5 is deleted; severity
of SMA depends on #SMN2
copies available (more SMN2 =
less severe dz)

Lab/Imaging

4-10/100K
SMA1 =
most
common
motor
neuron dz

mostly
males
median age
44

Treatment

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

post-polio syndrome slowly progressive weakness,


occurs ~35y after initial
illness;

Spinal
Muscular
Atrophy
(SMA)

Risk factors

Complications

Disease

Clinical
Variants
Amyotrophic
Lateral
Sclerosis
(ALS)

Defining Characteristics

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)!!

Pathogenesis

progressive disorder of voluntary


motor system - upper & lower
motor neuron dysfxn

Etiologies

90-95%
sporadic;
5-10% AD

Epi

Risk factors

1/100K

Lab/Imaging

Pathology: degeneration &


death of motor neurons; UMN death of Betz cells (cortical
spinal tract); LMN - death of
anterior horn cells

avg age =
mid 50s

cause unknown?

Treatment

Riluzole - prolongs
survival (2-3m); must
monitor LFTs during tx
Nuedexta helps bulbar sx

M:F 3:2
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)

El Escorial criteria (should not spasticity managed by


be used to preclude clinical dx) baclofen

U.S. prev =
30K

SSRIs, benzos for


depression/ anxiety

10%
prevalence
by age 3540

AGE, obesity

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

PT/OT/Speech therapy
bipap for breathing
nutrition

FTD in 5-20%

C-PAP

Cardiovascular
disease (HTN) and
stroke risk!!

non-motor sx: involuntary,


unprovoked laughing &
crying; depression & anxiety

Sleep apnea

Complications

lifestyle modifications

MOST COMMON
CAUSE OF DEATH?
Respiratory dysfxn
(restrictive pattern; sx?
Inability to lay flat,
frequent nighttime
arousal, EDS, exertional
dyspnea)

Increased rates of
mortality
Insomnia

Narcolepsy

(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

most
prevalent
sleep sx

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

F>M

molecular
mimicry &
certain
infections?

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

Restless leg
syndrome (RLS)

Defining Characteristics

urge to move legs,


uncomfortable leg
sensations,
onset/worsening of
symptoms at rest or
inactivity, relief with
movement, worsening at
night

Pathogenesis

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)

Etiologies

most often
familial (AD)
pregnancy,
iron & B12
deficiencies,
anemia

Epi

10% of U.S. FH, women,


population pregnancy,
iron def
12 million
anemia,
Americans Northern
have
European
moderate- descent
severe RLS

Multiple SNPs in 2 of 4 genes are


related in a dose dependent
fashion to # PLMs (not severity)

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

Risk factors

mostly men
> 50y.o.
(unless antidep
related)

Lab/Imaging

R/O secondary causes (iron


deficiency, diabetes, uremia)

Treatment

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

Complications

higher rates of mood


disorders (depression,
anxiety, panic
disorder)
increased rate of CVD
(autonomic arousals
occur w/ PLMs)

Physical measures to
ensure safety: remove
dangerous nearby objects,
bedrails, soothing alarm

RBD is dangerous!!!

Change anti-depressants
to wellbutrin
Pharm tx: Clonazepam,
Melatonin

Occurs during 2nd half of


sleep (REM sleep), nightly,
speech & dream recall?
behavior changes
depending on dream
content, a/w neurodegen dz
or narcolepsy

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

Non-REM
arousal
disorders

Clinical
Variants

Defining Characteristics

Confusional
arousals

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

Pathogenesis

Etiologies

incomplete arousal from slowwave sleep (N3) resulting in


dissociation between behavioral
state (wake) and EEG (sleep)

(general)

Risk factors

Lab/Imaging

disorders
of
childhood

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)

avoid triggers (sleep


deprivation)
Clonazepam (reduces
behaviors)

28 million
Americans

Consider Echo to R/O PFO,


polysomnogram, imaging if
headache persists/worsens

18%
women, 6%
men
peak age:
25-55 y
<10% able
to fxn during
HA

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

Hemiplegic
migraine

Basilar
migraine

Cyclical
vomiting
migraine

common migraine +
"AURA" - visual, dysphasia,
hemisensory deficits
(neurological deficits
reversible >5m but <60m)

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)

inciting event in visual cortex -->


lack of blood flow at that point --?
Neurologic change --> positive or
negative visual phenomena

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

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

cannot attribute to another


d/o
Classic
migraine

Treatment

safe environment

if occur in
adulthood,
consider
occult cause
of arousal
(OSA)

sleep (N3 stage), infrequent


(1-3x/m), no recall

Migraine

Epi

regular lifestyle/ sleep,


exercise, stress mgmt,
avoid triggers (chocolate,
etc)

FH

if symptoms persist, imaging


at ER!

Complications

Disease

Clinical
Variants

Defining Characteristics

Benign
Paroxysmal
Vertigo of
Childhood

multiple episodes of severe


vertigo, occurring wihtout
warning & resolving
spontaneously after minutes
to hours

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Complications

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

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!!

resolves within 7d after


remission or tx of
rhinosinusitis
Medication
overuse
headache

also called
rebound or
drug-induced
headache

Tension
headache

Trigeminal
Autonomic
Cephalgias

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

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

Ibuprofen,
Goody's
powder, tylenol

reduce offending agents


consider IV abortive
therapy if difficult for pt to
endure pain

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

Disease

Clinical
Variants
Hemicrania
continua

Defining Characteristics

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

Indomethacin

non-remitting, remitting
pain 24/7 w/ +/- autonomic
sx, exacerbations w/
coexisting migraines or
cluster HA, "foreign body"
sensation in eye, ice pick
HA

Conjunctivitis

(general)

affects both palpebral &


epibulbar conjunctiva!!

Bacterial

purulent; pain but NO


blurry vision; bilateral

microbes,
viruses, toxins,
allergens, tear
deficiency
S. aureus, Strep
pneumo, H.flu,
Pseudomonas,
N. gonorrhea

Lids stuck in the AM

usually resolves w/I 4-5d or


sooner if use warm
compresses
topical antibiotic

hyperpurulent?? N.
gonorrhea

Viral

watery exudates, starts


monocular, URI +/- sore
throat, fever

Adenovirus pink eye


HSV

pre-auricular
lymphadenopathy - pink
eye

Allergic

HSV keratitis

Herpes Zoster
Ophthalmicus

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

IgE mediated ocular surface


disease affecting mucus
membranes (eyes & nose)

HSV destroys corneal epithelium


and periodically bifurcates -->
dendritic corneal ulcers -->
recruitment of antibodies -->
scarring of corneal --> blindness &
recurrence even in corneal grafts

feel "pain behind the eye"

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

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

OTC lubricants &


decongestants, cool
compresses, topical
antihistamines
fluorescein dye or Rose
bengal stain shows
DENDRITIC ulcers

Acyclovir, steroids

Acyclovir

Complications

Disease

Stye

Chalazion

Clinical
Variants

Defining Characteristics

acute infection of the


eyelid; small, tender &
painful, warm
granulomatous
inflammation involving the
Meibomian gland of eyelid

Pathogenesis

Etiologies

Epi

Risk factors

Lab/Imaging

Treatment

S.aureus

NOT infectious - lipogranuloma

usually self-limiting
Dacrycystitis

purulent material through the infection of lacrimal sac region,


punctum

Dacryoadenitis

prominent eye lids

Orbital cellulitis

usually spread from infection in the


periorbital redness &
swelling often secondary to ethmoid air cells or maxillary
sinusitis, impaired/painful sinuses
EOM, proptosis

inflammation of lacrimal gland

previous facial
trauma
obstructing the
nasolacrimal
passage
infxn, inflamm,
granulomatous
hospitalization

fever, proptosis, periorbital


swelling, ophthalmoplegia
(impaired eye movements)

Subconjunctival
hemorrhage

Scleritis

Hyphema

SELF-LIMITING

inadvertent rubbing or Valsalva


maneuvers -->small vessel
hemorrhage in the substantia
propria of conjunctiva

red eye but able to see


sclera vessels

inflammatory condition in the front Wegener's, RA,


of the eye
infections

hemorrhage/ blood in the


conjunctiva, PAINLESS

deep, throbbing pain worse w/


touch
bleeding INSIDE the eye =
OPHTHALMIC
EMERGENCY! (increased
IOP)

Hypopyon

White blood cells layering


out INSIDE the eye =
OPHTHALMIC
EMERGENCY!

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

bleeding of iris or ciliary body


vessels usually due to blunt
ocular trauma --> blockage of
aqueous outflow w/ RBCs -->
increased IOP

trauma, blood
thinners

if associated w/ trauma emergency! Otherwise,


get better on own

tear of iris or
sphincter
muscle

corneal
abrasions
(contact lenses),
previous
surgeries, septic
emboli
denuded epithelium from abrasion -> irregular fibers/ scarring in
stroma --> vision loss

topical antibiotic

Complications

Disease

Optic neuritis

Clinical
Variants

Defining Characteristics

Pathogenesis

inflammation of the optic nerve


blurry vision or loss of
vision, PAIN on eye
movement, central scotoma

Etiologies

MS

Epi

Risk factors

F>M

Lab/Imaging

ages 15-45
(younger
population)

MRI: acute inflammation of optic


nerve; white matter lesions &
plaques if MS

PAINLESS, permanent
visual loss

ischemia to optic nerve head

DM, HTN, giant M=F


cell arteritis
older
population
(age>50)

fundo exam: swollen disc

Papilledema

painless, BILATERAL

disc edema from raised ICP

intracranial
ANY age
mass lesions,
hydrocephalus,
meningeal
processes,
idiopathic,
venous
thrombosis

fundo exam: bilateral swelling


of optic nerve heads

peripheral vision lost early

Central retinal
artery occlusion

sudden, PAINLESS loss of


vision in ONE eye, RAPD

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

Glaucoma

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

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

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)

"curtain coming down" transient

Complications

fundo exam: normal or swollen corticosteroids


disc (nl if retrobulbar optic
neuritis); 3m later, optic pallor

Anterior
Ischemic Optic
Neuropathy

usually spares central vision


until late

Treatment

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

DM & Chronic
HTN

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

Defining Characteristics

Pathogenesis

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

Macular
degeneration

most common cause of


permanent vision loss in
ELDERLY

congenital
(rubella)
adult (agerelated)

cotton wool exudates +


retinal hemorrhages
#1 cause of worldwide
blindness

degeneration of maculr retinal


pigment epithelium

opacity of the lens

epithelial cells of lens capsule


constantly divide --> thickening/
hardening of lens over time -->
cataract formation

Epi

Risk factors

Lab/Imaging

FH,
Caucasians,
females, light
eyes,
smoking,
heart dz,
HTN, UV light
exposure,
poor nutrition,
AGE

advanced age,
DM, infection,
corticosteroid
use

Treatment

check CXR for hilar adenopathy


if suspect sarcoid!

sarcoidosis,
ulcerative colitis,
ankylosing
spondylitis

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

CMV retinitis

Cataracts

Etiologies

vitamin therapy to prevent


progression from dry-->
wet?? (at least eat healthy!!)

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

Myopia

Enucleation

Retinoblastoma - kids,
white eye reflex
malignant melanoma adults
"near sightedness" =
unable to see far

focal point falls short of the retina


so the focus of light is now in the
vitreous cavity --> blurry vision

concave lens - causes


parallel light rays to diverge,
moving the focal point back
to the retina

all uncontrolled diabetics have


blurry vision bc glucose enters
the lens --> osmotic change in
the lens --> myopia

Hyperopia

Astigmatism

"far sightedness" = unable


to see close

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

Complications

Disease

Clinical
Variants

Presbyopia

Defining Characteristics

"wise old owl has


presbyopia"

Pathogenesis

Etiologies

loss of ability to accommodate,


which normally occurs when you
look at something close

Epi

Risk factors

Lab/Imaging

Treatment

ages 40-50

reading glasses

>70% of pts HbA1c > 7.0


w/ uncont
DM
uncontrolled
HTN, renal
dz,
pregnancy,
anemia

tight glycemic control +


control of HTN + laser
therapy

Complications

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

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

Ectropion

red eye + abnl conjunctiva


epithelium

eye lid turns outward exposing the


tear film and causing red eye

Extropion

red eye + eye infection


usually

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

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

Nonproliferative

lipid exudates +
microaneurysms

longer
duration of
DM
lack of retinal capillary endothelial
integrity --> microaneurysms +
fluid/ protein/ lipid exudates

macular edema --> dec


visual acuity
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

neovascular
glaucoma, DM
(proliferative
diabetic
retinopathy),
central retinal
vein occlusion

trypsin digest microaneurysms, capillary


drop out

macular edema (If


exudates accumulate in
central retina)

Disease

Clinical
Variants

Defining Characteristics

Pathogenesis

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

Retinal
detachment

painless, FLASHING lights/


falling stars/ FLOATERS
followed by shadow in
periphery

Temporal (giant
cell) arteritis

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)

Etiologies

Epi

age >50
(usually
70s,80s)

Risk factors

Lab/Imaging

abnl ESR/ CRP (suggests


systemic process)

Treatment

start IV steroids STAT if


suspect this dx

temporal artery bx to confirm Corticosteroids for 2y can


save the other eye!
dx

Complications

follow pt for
corticosteroid side
effects (BMD, etc)

Screening /
Education

Screening /
Education

Screening /
Education

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

Screening /
Education

Screening /
Education

Screening /
Education

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

Screening /
Education

Screening /
Education

Screening /
Education

Screening /
Education
PD progresses
within 15-20y
timeframe

Screening /
Education

Screening /
Education

Screening /
Education
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

Screening /
Education

Screening /
Education

Screening /
Education
patient
autonomy

Screening /
Education
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

Screening /
Education

Screening /
Education
inactivated polio
vaccine!

progression & life


expectancy ~ age
of onset

Screening /
Education
nutritional &
caregiver
education
end of life
decisions
hospice

Screening /
Education

Screening /
Education

Concerned about
use of OCP,
stroke/ HTN/
OSA risk in
migraine
patients

Screening /
Education

Screening /
Education

VERY
CONTAGIOUS!!!
Avoid social
contacts!

Screening /
Education

Screening /
Education

comprehensive
eye exam for
everyone after
age 40
early eye exams
if FH

Screening /
Education

smoking
cessation
wear sunglasses,
get eye exams,
eat healthy,
control vascular
dz

prevention
involves
controlling
comorbidities

Screening /
Education

T1DM: dilated
eye exam q 3-5y
within dx & yearly
afterwards
T2DM: dilated
eye exam @ time
of dx, yearly
afterwards

Screening /
Education

Bacteria

Streptococcus
pyogenes

Staphylococcus aureus

N. gonorrhea

Classification

GAS

Gram +/-

Morphology

Characteristics

Catalase neg
Facultative anaerobe
hyaluronic capsule
Cocci in pair/chains
(mucoid appearance)
strongly B-hemolytic
Bacitracin susceptible

Cocci in grape-like
clusters

Catalase +
Coagulase + (good test
to distinguish S. aureus
from other Staph)
Facultative anaerobe
Beta-hemolytic
Mannitol +
Yellow colonies
(CoPS)

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

Transplant patients

Skin break

Disease

Risk factors

Age
UV exposure
Type 1- 3 skin
Duration of immunosuppressants
Skin cancers
Intensity of immunosuppressants
HPV
Hx of skin cancer
CD4 lymphopenia

Pathogen

Human bite
(mouth pathogens)

Eikenella corrodens

Cat bite/puncture

Pasteruela multocida

Dog bite/puncture

C. canimorsus

Fresh water
Salt water/fish

Aeromonas hydrophilia
Erysipelothrix rhusiopathiae
Mycobacterium marinum

Aquarium
Spa/ hot tub

Psuedomonas aeruginosa
Gas gangrene

Trauma
Cirrhosis & salt water

Vibrio vulnificus
Streptococci

Edema

S
P
A
C
E
K

Nosocomial Infections
Serratia
Pseudomonas
Acinetobacter
Citrobacter
Enterobacter
Klebsiella