GI 1.3 Final

alcoholic liver disease mechanism? features?

• steatosis (reversible fatty liver) → steatohepatitis → cirrhosis (irreversible) → AST>ALT (2:1)

• steatohepatitis → mallory hyaline (eosinophilic inclusion), ballooning neutrophil infiltrate, sinusoidal + periventricular fibrosis

• cirrhosis → hepatic fibrosis, diffuse nodularity (nodules trapped in blue staining fibrous tissue), hepatic stellate cell (inc. myofibroblasts = inc. collagen)

alcoholic liver disease effects?

• neurotoxicity (NMDA/GABA), vitamin deficiencies (thiamine)

• chronic use → inc. MEOS (CYP2E1) → ROS (ox. stress)

• inc. NADH → dec. B-ox., hyperlipidemia (inc. TAG), lactic acidosis, hypoglycemia

non alcoholic fatty liver disease mechanism? risk? histology?

• benign steatosis (NAFL- TG accumulation) → NASH → cirrhosis/HCC

• obesity, T2DM/insulin resistance, met. syndrome, PNPLA3 gene

• mallory hyaline, macrovesicular steatosis (Z3), ballooning neutrophil infiltrate, lobular inflammation, fibrosis, ALT>AST

• Tx w/ metformin/pioglitazone (diabetic), VitE/omega 3 (non diabetic), stats (dyslipidemia)

autoimmune hepatitis mechanism? trigger? labs? findings?

• immune-mediated destruction of hepatocyte ass. w/ HLA-DR3/4

• infection, drugs, autoimmune disease (thyroiditis, sjogren)

• inc. IgG, transaminase, ALT/AST, y-globulin

• interface hepatitis (emperipolesis), lymphoplasmacytic infiltrate

autoimmune hepatitis types? treatment?

• type 1 (adult; ANA+, SMA+), type 2 (child; LKM-1+, ACL-1+), type 3 (anti-SLA/LP)

• Tx w/ corticosteroid (prednisone) ± azathioprine w/in 12 mths, other immunosuppressants, transplant

  • no Tx or relapse = HCC

acetaminophen (direct) induced liver injury?

• acetaminophen → centrilobular necrosis (Z3) via NAPQI; Tx w/ NAC (N-acetylcysteine, glutathione precursor)

  • alcohol → inc. CYP2E1 → acetaminophen biotransformation → inc. NAPQI formation (ROS) → take lower dose of tylenol

  • AST/ALT >500 IU (acute), inc. AP (cholestasis), inc. bilirubin

amanita phalloides (direct) induced liver injury? idiosyncratic? cholestatic?

• yellow-green mushroom → panlobular necrosis via amatoxins blocking RNA polymerase; Tx w/ silibinin (milk thistle)

• amoxicillin-clavulanate → mixed injury, vanishing bile duct syndrome

• steroids/oral contraceptive → inhibit bile transport → cholestasis, inc. ALP + bilirubin

cholestatic liver disease markers? budd chiari syndrome?

• ALP, bilirubin, GGT (bile duct), 5 nucleotidase (canalicular enzyme)

• hepatic vein thrombosis = centrilobular congestion (nutmeg liver) → ischemia → hepatomegaly, ascites, liver failure

  • via hypercoagulable state (PV, pregnancy, OCPs, PNH), HCC, idiopathic

  • SAAG ≥ 1.1 → portal HTN; protein level ≥2.5 = budd chiari, HF (lower= cirrhosis)

primary sclerosing cholangitis (PSC) features? presentation? treatment?

• inflammation + fibrosis of intra/extrahepatic bile duct

• inc. p-ANCA; concentric periductal (onion skin), bile duct stenosis

  • ERCP/MRCP → beads on a string of bile duct

• jaundice, pruritis, fatigue, fever, abdominal pain, steatorrhea; men (30s), ass. w/ IBD (UC)

  • cirrhosis, cholangiocarcinoma

• Tx w/ ursodiol, liver transplant

primary biliary cholangitis (PBC) features? presentation? treatment?

• chronic autoimmune destruction of intralobular bile ducts

• inc. AMA (anti-mit.); non-caseating granuloma, bile duct loss

  • liver biopsy if unclear; inc. ALP, inc. IgM

• jaundice, pruritis, fatigue, hyperlipidemia; women (50s), ass. w/

  • cirrhosis

• Tx w/ ursodiol, liver transplant

liver cirrhosis mechanism? histo/patho? labs?

• diffuse/bridging fibrosis (fibrosis septa), regenerative nodules, loss of fenestration → disrupted architecture/fxn + loss of flow

• periportal (viral hep) vs pericentral (alcohol, toxins); cytokines (TNF-a, TGF-B, PDGF) → act. stellate (Ito) cells → myofibroblasts → fibrosis (ECM deposit)

• PT/INR best marker of liver synthetic fxn

• SAAG ≥ 1.1 → portal HTN; protein level <2.5 = cirrhosis (higher = HF, budd chiari)

compensated liver cirrhosis? decompensated?

• liver extensively scarred but maintain sufficient fxn = prevent clinical symptoms; asymptomatic (some hepatomegaly) w/ 12+ yrs prognosis

• onset of ascites (inc. cap hydrostatic pressure), variceal bleeding, hepatic encephalopathy, jaundice, HCC w/ 2 yrs prognosis

liver cirrhosis direct clinical manifestation?

• fatigue, weight loss, muscle wasting, cytokine-med. malaise

• hepatic encephalopathy (inc. NH3 =asterixis + altered mental status), hepatomegaly, HCC, ascites, varices

• portal HTN → prehepatic (thrombosis), intra (cirrhosis, PBC, sinusoidal obstruction), post (RHF, budd chiari)

• spon. bacterial peritonitis (SBP) → ascitic fluid infection, bacterial translocation = bacteremia (neutrophils in ascites 250+)

  • Tx w/ cephalosporin (ceftriaxone), albumin transfusion, avoid nephrotoxic drugs

liver cirrhosis related clinical manifestation?

• spider angioma (estrogen + VEGF), palmar erythema, jaundice, pruritis, caput medusae, dupuytren contracture

• gynecomastia/testicular atrophy OR menstrual irr./virilization

• inc. splenic venous pressure → congestion → hypersplenism + splenomegaly (anemia, leukopenia, thrombocytopenia)

general hepatitis features?

• acute → lobular inflammation, hepatocellular injury (confluent necrosis, ballooning degeneration, apoptosis, MQ aggregates), cholestasis

• chronic hepatitis → portal inflammation, bridging necrosis/fibrosis (w/ lymphoplasmic infiltrate), ground-glass cells (HBV), steatosis (HCV), ductular rxn

HAV features? transmission? MOA?

• picornavirus, ssRNA, non enveloped

• fecal oral (seafood, travel) → replicate in intestinal mucosa → viremia → liver

• via cytotoxic T cells + NK cells (NO chronicity risk)

HAV symptoms? diagnosis + treatment?

• = fever, anorexia, RUQ pain, jaundice, dark urine (self-limit, low fulminant hepatitis)

• Dx w/ IgM anti-HAV (recent infection), IgG (lifelong immunity)

• formalin-killed vaccine, ISG for post-exposure, precaution while travel

HEV features? transmission? risks? diagnosis?

• non enveloped ssRNA

• fecal oral (contaminated water, undercooked pork)

• self-limiting BUT severe in pregnant women (fulminant hep = liver failure + necrosis)

• Dx w/ anti-HEV IgM (acute), HEV RNA

HBV features? transmission?

• hepadnavirus, partially dsDNA, enveloped

• parenteral (sex, needles, childbirth/breastfeed, transfusion)

  • entry via NTCP receptor → replicate via RT (RNA int.) → form cccDNA in nucleus

• CD8+ T cells = hepatocyte injury (moderate chronicity, esp. neonate)

HBV symptoms? diagnosis? treatment?

• immune complex deposition = extrahepatic manifestation

• HBsAg+, IgM anti-HBc, ground glass hepatocyte (chronic)

• recombinant vaccine → prevent HBV + HDV

  • vert. transmissions w/ HBV + mom prevented via combined HBIG + HBV vaccine w/in 12 hrs of birth

immune complex deposition manifestations?

• serum sickness-like = deposition of HBsAg-anti-HB circulating immune complex in tissue BV walls

• glomerulonephritis = HBsAg, Ig, C3 deposition found in glomerular BM

• polyarteritis nodosa (PAN) = affect small + med. arterioles → contain HBsAg, Ig, complement components

• essential mixed cryoglobulinemia (EMC) = arthritis, cutaneous vasculitis (purpura), glomerulonephritis, circulating cryoprecipitate immune complex

HBV antigen markers?

• acute → sAg (+); eAg (+), cAb (IgM)

• window → cAb (IgM)

• resolved → cAb (IgG), sAb (IgG)

• chronic → sAg (+); eAg (+); cAb (IgG)

• immunized → sAb (IgG)

HCV features? transmission? MOA? symptoms?

• flaviviridae, enveloped, ssRNA

• via blood (IV drug use, transfusion), less common sexually/perinatally

• core proteins → p7, NS2, NS3/4a (protease), NS5A (replication complex), NS5B (RNA polymerase)

• = lymphoid aggregates in portal tracts; associated w/ cryoglobulinemia, glomerulonephritis, Bcell lymphoma

HCV diagnosis? treatment?

• Dx w/ anti-HCV Ab (often seronegative bc LF RNA poly) → confirm w/ HCV RNA PCR

• no vaccine via high genetic variability → mut. prone low fidelity RNA polymerase (high chronicity)

  • Tx = direct acting antiviral (DAAs): sofosbuvir, ledipasvir

HDV features? transmission? MOA? diagnosis?

• defective circ. ssRNA → require host RNA polymerase + HBsAg from HBV to replicate

• via blood, sexual contact, perinatal

• superinfection (HDV w/ chronic HBV = HR fulminant hep + prog. to cirrhosis) OR coinfection (severe acute hep)

• Dx w/ anti-HDV Ab, HDV RNA

yellow fever features? symptoms? diagnosis? treatment?

• flavivirus, ssRNA, aedes mosquito (endemic in africa + south america)

• biphasic= fever, myalgia, nausea → jaundice, hemorrhage (blood = black vomit), multiorgan failure

• Dx w/ serology (IgM), PCR

• live attenuated vaccine (b4 travel to endemic region)

cholesterolosis features? cholelithiasis features?

• foamy MQ in LP (strawberry gallbladder) → may be present in chronic cholecystitis

• US, CT, HIDA (cystic duct), MRCP (biliary tree)

  • cholesterol → yellow, radiolucent, multiple (female, fat, fertile, forty)

  • bile → black/brown, radiopaque (via hemolytic syndrome/SCD, infection, ileal disease, CF)

cholelithiasis symptoms? risk factors? treatment?

• RUQ pain after fatty meals + inc. malignancy risk

• risk= rapid weight loss, western diet, native american, FHx

• Tx w/ ERCP (ductal stone), cholecystectomy, ursodiol (dissolves cholesterol stones)

cholecystitis cause? symptoms? diagnosis + treatment?

• inflammation of gallbladder due to gallstones (calculous)

  • acalculous → via ischemia in critically ill pt. w/ no collateral to cystic artery

• RUQ pain radiating to shoulder/back, nausea, vomiting, fever, +murphy sign

  • complication → empyema, perforation, abscess, peritonitis, fistula, gallstone ileus

• US, HIDA, CT, MCRP; inc. WBC, bilirubin, ALP, GGT, ALT

• Tx w/ cholecystectomy

chronic cholecystitis association? symptoms? features?

• cholelithiasis (stone in cystic duct)

• recurrent RUQ pain, +murphy sign, fatty food intolerance

• lymphoplasmacytic infiltrate, fibrosis, Rokitansky-Aschoff sinus (deep mucosal outpouching), porcelain gallbladder (calcified wall), hydrops (clear sec. in obstructed gallbladder)

ascending cholangitis cause? features? treatment?

• bile duct obstruction (ie stone in common bile duct) + infection (E. coli, Klebsiella)

• charcot triad = RUQ pain, jaundice, fever

• reynold pentad = hypotension, confusion (altered mental status), abdominal pain, jaundice, fever → 50% mortality rate

• antibiotics + ERCP (diagnostic + treatment)

cholestasis cause? choledochal cyst cause?

• dec. bile flow via cholelithiasis, PSC, PBC, sepsis, drugs → jaundice, pruritis

• congenital bile duct dilation via stones or cholangiocarcinoma

  • caroli disease = intrahepatic cyst (+congenital hepatic fibrosis = syndrome)

benign liver tumors?

• cavernous hemangioma → hepatic hemangioma (thin dilated vessel) + asymptomatic; biopsy CI due to hemorrhage; most common BLT

• focal nodular hyperplasia → dystrophic artery/thick wall = hyperplastic rxn = central stellate scarring; 35-50 women

• hepatocellular adenoma → 1-2 cell thick, OCP + anabolic steroids linked; regress or rupture since subcapsular (abdominal pain + thick, hemorrhage)

malignant liver tumors?

• hepatocellular carcinoma (HCC) → inc. AFP, trabeculae 3+ cells thick; via cirrhosis + HBV: lead to decompensation; Tx adv w/ sorafenib

• fibrolamellar HCC → hepatocyte in thick trabeculae w/ dense collagen lamellae (better prognosis)

• cholangiocarcinoma → gland-like malignant epi. cell; @ R/L hepatic duct jxn (extrahepatic); inc. risk w/ gallstones, PSC, liver flukes

unconjugated (indirect) hyperbilirubinemia cause? types?

• def. of UGT-1A (UDP-glucuronosyltransferase) → inability to conjugate bilirubin

• physiologic (24 hrs after birth, peaks 2-5 days) → via insufficient milk intake, breastmilk (interferes w/ bilirubin breakdown), premature (light therapy) = inc. UCB

• pathologic (w/in 24 hrs) → hemolytic, non hemolytic

• Tx w/ feeding/stooling, phototherapy, XC transfusion

hemolytic indirect hyperbilirubinemia types?

• pre-hepatic w/ excess RBC breakdown (inc. UCB)

• intrinsic → G6PD def. (XL; ox. stress via primaquine or infection), hereditary spherocytosis, thalassemia

• extrinsic → drugs, isoimmune (ABO, Rh incompatible via previous IgG)

non hemolytic indirect hyperbilirubinemia types?

• sepsis, hypothyroidism, cephalohematoma

• crigler najjar T1 (AR) = absent UGT-1A → UCB pass BBB → acute bilirubin encephalopathy → kernicterus (fatal)

• crigler najjar T2 (AR) = major dec. UGT-1A (Tx w/ phenobarbital to make more)

• gilbert syndrome (AR) = mild dec. UGT-1A (more benign)

conjugated (direct) hyperbilirubinemia cause? types?

• overactive UGT-1A (UDP-glucuronosyltransferase)

• extrahepatic (bile flow obstruction) → biliary atresia, choledochal cyst, perforated bile duct, tumor, cystic fibrosis, galactosemia (= inc. CB w/ pale stool + dark urine)

• intrahepatic (live cell damage) → infection (ToRCHeS, UTI, hepatitis), genetic (alagille syndrome, a-antitrypsin def., dubin johnson, rotor, galactosemia), drugs (ceftriaxone, sulfonamides)

biliary atresia symptoms? diagnosis + treatment?

• most common liver transplant cause

• jaundice (0-8 wks), dark urine, alcoholic stool, hepatomegaly

• Dx w/ US (absent gallbladder/echogenic), HIDA scan

• Tx w/ kasai procedure (hepatoportoenterostomy)

direct hyperbilirubinemia intraheptic infections?

• toxoplasmosis → hydrocephalus, chorioretinitis, intracerebral calcification

• rubella → PDA, cataracts, hearing loss, blueberry muffin rash

• CMV → sensorineural hearing loss, mental deficit, PV calcification

• HSV → vesicular rash, meningoencephalitis, liver/lung disease

• syphilis → hutchinson teeth, saddle nose, saber shin, CNVIII deafness

• HSM, jaundice, thrombocytopenia, growth restriction, microcephaly

a-antitrypsin deficiency (AATD) cause? treatment?

• codominant; PiMM (normal), PiMZ, PiZZ (2 null alleles) = severe

• cirrhosis from defective AAT accumulation, emphysema via neutrophil elastase

  • jaundice, chronic liver disease

• Tx w/ augmentation therapy

dubin johnson syndrome cause?

• ABCC2 mut. → dec. MRP2 transporter → dec. sec. of CB out of hepatocyte into bile duct (conj. hyperbilirubinemia) = liver pigmentation

  • also via pigmented gallstones (blocked bile duct)

• most benign of all

rotor syndrome cause?

• SLCO1B1+B3 → dec. activity of organic anion transporting polypeptide

• less CB into hepatocyte + more CB in circ. (conj. hyperbilirubinemia) → high mixed bilirubin

• coproporphyrin-1 colors urine red; no liver pigmentation

galactosemia cause? symptoms? diagnosis + treatment?

• AR; GALT deficiency → toxic metabolites (galactose-1-phosphate, galactitol)

• jaundice, vomit, diarrhea, hepatomegaly, cataracts, E. coli, sepsis

• newborn screen, RBC, galactose-1-phosphate

• Tx w/ eliminate dietary galactose (soy formula)

emetic bacillus cereus; diarrheal B. cereus class? toxin? features?

• gram (+)

• heat stable cereulide (survives cooking + germinates in warm food) → via rice; <6hr incubation

• heat labile enterotoxin → via meat+ vegetables; 6+ hrs incubation

staphylococcus aureus; clostridium botulinum class? toxin? features?

• gram (+)

• enterotoxin A/B

• botulinum toxin (ACh) → anaerobic, spore-form (infant ingestion), foodborne (toxin ingestion = flaccid paralysis)

norovirus; rotavirus; adenovirus family? features?

• caliciviridae → naked (+) ssRNA; adult outbreak @ cruise w/ fever, vomit, watery diarrhea; low infectious dose

• reoviridae → naked dsRNA; 3 layer, infant diarrhea w/ NSP4 toxin-like

• adenoviridae → naked dsDNA; infant diarrhea, types 40-42

fat soluble vitamin deficiency cause? symptoms?

• fat malabsorption (CF, chronic pancreatitis, celiac)

• vitA (nigh blindness), vitD (osteomalacia/rickets), vitE (hemolytic anemia/NMD), vitK (easy bruise/bleed, inc. PT/PTT, post-antibiotics)

water soluble vitamin deficiency cause? mineral deficiency cause? symptoms?

• alcoholics, restrictive diets, GI disease, drug-induced deficiency

• linked to diet, absorption, kidney/GI loss, medication (diuretics, PPIs, ACE inhibitors)

  • vitC (corkscrew hair, gum bleed), Fe (microcytic anemia), Zn (poor wound heal, alopecia), I (hypothyroid)

vitamin B deficiency symptoms?

• B1 (thiamin) → wernicke-korsakoff (confusion + ataxia)

• B2 (riboflavin) → cheilosis, glossitis

• B3 (niacin) → dermatitis, diarrhea, dementia

• B9 (folate) → megaloblastic anemia + neuro w/ slower onset

• B12 (cobalamin) → megaloblastic