reduced activity of uridine diphosphate glucuronyl transferase - unconjugated (indirect) bilirubin - benign, asymptomatic hereditary jaundice, hyperbilirubinemia increased by 24-36 hour fast

Gilbert syndrome - no tx required - assoc with reduced mortality from cardiovascular disease

Jaundice DSA - McGowan Flashcards by Elizabeth Mazza

transfusion reactions, sickle cell anemia, thalassemia (inadequate Hg), autoimmune disease

prehaptic

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hepatitis, cancer, cirrhosis, congenital disorders, drugs

intrahepatic

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gallstones, inflammation, scar tissue or tumors that block the flow of bile into the intestines

posthepatic

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primary injury is to the hepatocytes

primarily AST/ALT elevation
ALT more specific for liver injury than AST

hepatocellular injury

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primary injury is to the bile ducts

primarily Alk Phos and bilirubin elevated
failure of bile to reach duodenum
jaundice and pruritis
pure cholestasis (no signs of hepatocellular necrosis)

cholestatic injury

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what are the TRUE liver function tests that McGowan wants us to know?

NOTE: AST/ALT, Alk Phos and bilirubin (LDH, GGT) can come from other sources and are not accurate to determine liver’s function

PT/INR
albumin
cholesterol
ammonia

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what are the 4 main DDx for unconjugated (indirect) jaundice?

hemolytic syndrome (anemia/reaction)
Gilbert syndrome
Criggler-Najjar syndrome
viral hepatitis

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what are the 5 main DDx for conjucated (direct) jaundice?

hepatitis (acute/chronic, infectious/non-infectious)
cirrhosis
obstruction
Dubin-Johnson syndrome
Rotor syndrome

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what are the first steps in evaluating pt with jaundice?

determine conjugated vs unconjugated

2. other biochemical liver tests are normal

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how to diagnose jaundice

order CBC to look for anemia and thrombocytopenia
order chemistry labs: AST/ALT, total bilirubin, Alk phos (will need to request fractionated bilirubin to tell you indirect vs. direct)

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when ALP is elevated, what is your next step?

fractionate by ordering gamma glutamyl transferase (GGT)

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what if ALP and GGT are elevated?

most commonly coming from liver source

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what if ALP elevated, but GGT is normal?

consider bone or other source (placenta) for elevated ALP

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what would you order to look for anemia and thrombocytopenia?

CBC

- can check for hemolysis: haptoglobin (low), reticulocyte count (elevated) and LDH (elevated)

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reduced activity of uridine diphosphate glucuronyl transferase

unconjugated (indirect) bilirubin
benign, asymptomatic hereditary jaundice, hyperbilirubinemia increased by 24-36 hour fast

Gilbert syndrome

no tx required
assoc with reduced mortality from cardiovascular disease

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AR, absent UGT1A1 activity

no liver pathology
fatal in neonatal period

Crigler-Najjar Type 1

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AD with variable penetrance, decreased UGT1A1 activity

no liver pathology
generally mild, occasional kernicterus

Crigler-Najjar Type 2

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AR, decreased UGT1A1 activity

no liver pathology
innocuous (not harmful) clinical course

Crigler-Najjar Type 3

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AR, impaired biliary excretion of bilirubin glucuronides due to mutation in canalicular multidrug resistance protein (MRP2)

pigmented cytoplasmic globules
innocent clinical course

Gilbert Syndrome

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what is the main serum antibody present in acute viral hepatitis?

IgM

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what is the main serum antibody present in chronic?

IgG

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viral, drugs, ischemia, Budd-Chiari

pt has aversion to smoking
stools my be acholic (no bile = pale yellow)
dx: CVC, CMP, PT/INR, acetaminophen level (use rumack-matthew nomogram)

acute hepatitis

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ssRNA virus
aversion to smoking
2-3 week incubation
enlarged tender liver, jaundice, acholic stools
fecal-oral transmission
elevated bilirubin and alk phos = cholestasis
both IgM and IgG are detectable in serum soon after onset

Hep A
- vaccine!

NOTE: detection of IgN anti-HAV is excellent test for dx acute Hep A

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partially dsDNA
acute illnes usually subsides over 2-3 weeks, 5-10% chronic
low-grade fever, enlarged and tender liver, jaundice
assoc with polyarteritis nodosa
parenteral, sexual, perinatal transmission
endemic in sub-saharan Africa and SE Asia
HBsAg-positive mothers may transmit HBV at delivery, risk of chronic infection in infant is 90%
elevated aminotransferases early in course (higher than HAV infection)
substantial risk for cirrhosis -> HCC

Hep B

- vaccine!

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what is the window period of HBV infection?

between HBsAg disappearing and HBaAb appearing, which may take several weeks - pt is still considered to have acute HBV - infection is only detectable with **HBcAb IgM** NOTE: VERY important when screening blood donations

persistence of HBsAg more than 6 months after acute illness signifies what?

chronic Hep B

what appears in most individuals after clearance of HBsAg and after successful vaccination against Hep B?

anti-HBsAb

what does IgM anti-HBc indicate?

acute Hep B | - may also reappear during flares of previously inactive chronic Hep B

what appears during acute Hep B but persists indefinitely?

IgG anti-HBc

what is HBeAg?

Hep B envelope Ag = secretory form of HBcAg - in serum shortly after detection of HBsAg - indicated viral replication and infectivity - persistence of HBeAg beyond 3 months = increased likelihood of chronic Hep B

defective RNA virus that required HBV for replication - endemic among HBV carriers in Mediterranean Basin - spread by non-percutaneous (not skin) means - non-endemic areas (US, Europe) spread percutaneously (skin)

Hep D | - vaccinate against HBV!

ssRNA flavi-like virus (7 genotypes) - coinfection with HCV found in 30% of HIV patients - accounts for 90% of transfusion-assoc hepatitis - IV drug use accounts for >50% of cases - **boxers! bloody fisticuffs can transmit** - most sentitive serum indicator is RNA - cirrhosis, HCC, mixed cryoglobulinemia, MPGN, increased risk non-Hodgkin lymphoma

Hep C - pt with chronic liver dz should be vaccinated against HAV and HBV NOTE: occasional persons found to have anti-HCV in serum, without HCV RNA in serum -> recovery from prior HCV infection (spontaneous clearance)

what are the CDC and USPSTF screening recommendations for HCV?

all persons born between 1945-1965 should be screened - vaccinate against HAV and HBV - check for co-infection with HIV

ssRNA hepevirus - risk factor for immunocompromised hosts - endemic in Asia, middle east, North Africa, Central America, India - fecal-oral transmission, waterborne epidemics, **spread by swine** - chronic infection with progression to cirrhosis reported in transplant patients treated with tacrolimus (immunosupressant) - high mortality in pregnant women

HEV

what is the main cause of drug-induced hepatitis?

acetaminophen

what is the tx of drug-induced hepatitis (DILI)?

supportive - withdraw suspected agent - include use of gastric lavage and oral administration of charcoal or cholestyramine

what is the #1 cause of acute liver failure?

acetaminophen

nausea, vomiting, icterus and jaundice, itching, elevated liver enzymes - life threatening coagulation abnormalities - hepatic encephalophathy - asterixis

acute liver failure NOTE: in acetaminophen toxicity, AST/ALT > 500 u/L

what is the tx of acetaminophen overdose?

N-acetylcysteine (NAC) - provides a reservoir of sulfydryl groups to bind to the toxic metabolites or by stimulating synthesis of hepatic glutathione - **should be given within 8 hours of ingestion**

development of hepatic encephalopathy within 8 weeks after the onset of acute liver disease - coagulopathy (INR 1.5 or higher)

fulminant hepatic failure

development of hepatic encephalopathy between 8 weeks - 6 months

subfulminant hepatic failure

acute deterioration in liver function in pt with preexisting chronic liver disease

acute-on-chronic liver failure

massive hepatic necrosis with impaired consciousness occurring within 8 weeks of onset of illness - **rapidly shrinking liver size + rapidly rising bilirubin level** - marked prolongation of PT - disorientation, somnolence, ascites, edema

fulminant hepatitis

what is the tx/management of fulminant hepatitis?

supportive, maintenance of fluid balance, support of circulation, respiration - oral lactulose and neomycin administered - meticulous intensive care + prophylactic abx coverage can improve survival - consider liver transplant

what is the dx of chronic hepatitis?

biopsy -> histologic classification classified based on: - grade (necrosis and inflammatory activity) - stage (disease progression/degree of fibrosis)

classic, ANA (most common) and/or ASA (anti-smooth muscle antibodies)

Type 1 autoimmune hepatitis

associated with anti-liver/kidney microsomal (anti-LKM antibodies)

Type 2 autoimmune hepatitis

what is the dx of AIH?

* *serologic abnormalities** - type 1: hypergammaglobulinemia, smooth muscle Ab, ANA - type 2: anti-LKM Ab **serum aminotransferase levels may be greater than 1000 units/L, and total bilirubin is usually increased

what is the tx of AIH?

**glucocorticoids** complications: leads to cirrhosis -> increased risk HCC

excessive alcohol use can cause fatty liver - exceeds 80g/day in men and 30-40g/day in women - Hep B and C may be cofactors in dvlpment of liver disease

alcohol liver disease

asymptomatic -> severe liver failure with jaundice, ascites, GI bleeding, encephalopathy - typical anorexia, nausea vomiting, fever, jaundice, tender hepatomegaly and RUQ pain - **2:1 AST:ALT ratio** - Mallory-Denk bodies

alcohol liver disease

what is the main risk of alcoholic cirrhosis?

> 50 grams of alcohol (5 drinks) daily for over 10 years

what is the tx/management of alcohol liver disease?

abstinence from alcohol! - glucose administration increase the thiamine requirement and can precipitate Wernicke-Korsakoff syndrome if thiamine is not coadministered - if severe, can consider Pentoxifylline or liver transplantation (pt's must abstain from alcohol for 6 months to be considered)

what are the complications of alcoholic liver disease?

- Wernicke encephalopathy (confusion/ataxia) - Korsakoff syndrome (severe memory issues) - adverse prognostic factor: critically ill pts with alcoholic hepatitis have 30-day mortality rates >50%

what does the Glasgow Alcoholic hepatitis score predict?

mortality based on: - age - serum bilirubin - BUN - prothrombin time - peripheral WBC count

what is a Model for End-Stage Liver Disease (MELD) score > 21 associated with?

significant mortality in alcoholic hepatitis

triad: (only 10% have all 3) - confusion - ataxia (staggering/stumbling/lack coordination) - treat with thiamine

Wernicke encephalopathy

- permanent - progressive from Wernicke - severe memory issues - confabulate/make up stories to fill in gaps

Korsakoff syndrome

a way to estimate disease severity and mortality risk in patients with alcoholic hepatitis - patients with a DF value > 32: have high short-term mortality and may benefit from treatment with **glucocorticoids** - those with lower scores have low short term-mortality and do not appear to benefit from glucocorticoids

Maddrey discriminant function

what does a GAH score > 9 mean?

survival benefit for those who received glucocorticoids compared with those who did not

what does a GAH score < 9 mean?

no survival benefit with glucocorticoids

what is the threshold used to allow diagnosis of NAFLD?

<20 g of alcohol per day in women and <30g in men

what is steatosis? | what is steatohepatitis?

``` steatosis = fatty liver steatohepatitis = fatty liver than causes liver inflammation ```

what is the most common cause of chronic liver disease in the US?

NAFLD

obesity, DM, hypertriglyceridemia in association with insulin resistance as part of the metabolic syndrome -> increased risk for cardiovascular disease, chronic kidney disease and colorectal cancer

principal causes of NAFLD

asymptomatic, or may have mild RUQ discomfort - hepatomegaly is up to 75% of cases - labs may show mildly elevated aminotransferase and alk phos - macrovascular steatosis may be seen on US or CT - **biopsy: focal infiltration by polymorphonuclear neutrophils and Mallory hyaline** indistinguishable from alcoholic hepatitis and referred to as nonalcoholic steatohepatitis (NASH)

NAFLD

what is the tx of NAFLD?

lifestyle modification - weight loss, dietary fat restriction, exercise, vitamin E - statins are NOT contraindicated

HFE gene mutation on chromosome 6 - men>women - elevated iron saturdation or serum ferratin - increased accumulation of iron as hemosiderin in liver, pancreas, heart, adrenals, testes, pituitary, and kidneys - hepatic and pancreatic insufficiency, heart failure, and hypogonadism may develop

hemochromatosis | - increased iron absorption in the duodenum

what is the classic tetrad of hemochromatosis?

- cirrhosis with hepatomegaly - abnormal skin pigmentation - DM - cardiac dysfunction

what are the later clinical manifestations of hemochromatosis?

- arthropathy (and ultimate need of joint replacement) - hepatomegaly - skin pigmentation - DM - ED in men

- elevated plasma iron with greater than 45% transferrin saturation - elevated serum ferretin - liver biopsy: homozygous for C282Y - HFE mutation

hemochromatosis

what is the tx/management of hemochromatosis?

- avoid foods right in iron - weekly phlembotomies of blood - PPI -> reduces intestinal iron absorption - chelating agent deferoxamine (for pt with hemochromatosis and anemia)

what is the main association/complication that McGowan wants us to know with hemochromatosis?

Yersinia infection

AR, mutation in ATP7B - people under age 40 - results in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin - leads to hemolytic anemia (copper is toxic to RBC) - liver disease in adolescents and neuropsychiatric disease in young adults

Wilson disease

what is the pathognomic sign of Wilson disease?

Kayser-Fleischer rings (brown-green rings around the iris) | - represents fine pigmented granular deposits in Descemet membrane in the cornea

elevated liver enzymes: - AST/ALT - alk phos - bilirubin - **low serum ceruloplasmin** molecular analysis of ATP7B mutations can be diagnostic

Wilson disease | - tx: **oral penicillamine** increases urinary extretion of chelated copper

AR, defective a1AT - most commonly diagnosed inherited hepatic disorder in infants and children - Pi gene chromosome 14 - development of pulmonary (panacinar) emphysema - causes liver disease as a consequence of hepatocellular accumulation of the misfolded protein

alpha-1 antitrypsin deficiency | - tx: smoking abstinence/cessation and liver transplant

``` HBsAg: + HBcAb IgM: + HBcAb IgG: + HBeAg: + HBV DNA: + ``` HBs Ab: -

chronic Hep B infection

- African Americans have higher rate of chronic disease, but lower fibrosis - coffee slows progression - pts have normal AST/ALT - high risk of cirrhosis and HCC (higher risk in genotype 1b)

chronic HCV

passive congestion of the liver **nutmeg liver** - ischemic hepatitis = ischemic hepatopathy, hypoxic hepatitis, shock liver, acute cardiogeneic liver injury - statin therapy prior to admission may protect against ischemic hepatitis - **hepatojugular reflex is present** -> tricuspic regurg may be pulsatile - jaundice associated with worse outcomes

right heart failure

- markedly elevated serum N-terminal-proBNP or BNP - rapid and striking **elevation of serum aminotransferase** (often greater than 5000 units/L) - **early rapid rise in the serum lactate dehydrogenase**

right heart failure

development of liver fibrosis to the point that there is architectural distortion with formation of regenerative nodules -> decreased liver function

cirrhosis mexican and blacks > whites

what are the 3 types of cirrhosis?

1. compensated 2. compensated with varices 3. decompensated

what has been reported to reduce the risk of cirrhosis?

higher coffee and tea consumption

- spider telangiectasias - palmar erythema - dupuytren contractures - glossitis and cheilosis - jaundice - caput medusae - asterixis

signs of cirrhosis

what are the diagnostic studies of cirrhosis?

- CBC: pancytopenia, anemia - prolonger PT/INR - glucose disturbances - hypoalbuminemia

definitive diagnosis of cirrhosis depends on what?

liver biopsy | - histologic classification (grade and stage)

what is the tx/management of cirrhosis?

* *abstinence from alcohol!** - pts should receive HAV, HBV, pneumococcal, and yearly flu vaccines - **transjugular intrahepatic portosystemic shunt (TIPS/TIPSS)** * *NSAIDS ARE CONTRAINDICATED** - Ang-converting enzyme inhibitors and Ang II antagosnists should be avoided

SAAG > 1.1 g/dL

- portal HTN | - myxedema

SAAG < 1.1 g/dL

- hypoalbuminemia | - diseased peritoneum (peritonitis, peritoneal cancer)

increasing abdominal girth - alcohol consumption, transfusions, tattoos, IV drug use, hx of viral hepatitis or jaundice - fevers -> infected peritoneal fluid - PE: elevated JVP, **asterixis, shifting dullness**

ascites

what diagnostic tool reliably establishes the presence of fluid?

abd US + Doppler - abdominal paracentesis: development of fever, adb pain, rapidly declining renal function, or worsened hepatic encephalopathy -> **exclude SPONTANEOUS BACTERIAL PERITONITIS**

what are the routine studies on ascitic fluid?

CBC: - **WBC with diff = most important test** -> increase in ascitic white blood cell count highly suggestive of SBP - albumin: serum-ascites albumin gradient (SAAG) is best single test for ascites classification

how is SAAG calculated?

subtract ascitic fluid albumin from serum albumin | - the gradient correlates directly with portal pressure

alteration in mental status and cognitive function occuring in the presence of liver failure - elevated ammonia levels - confusion, slurred speech, change in personality, asterixis (flapping tremor) - precipitated by GI bleeding, azotemia, constipation

hepatic encephalopathy | - tx: **lactulose, or rifaximin if lactulose not tolerated**

spontaneous bacterial infection - occurs in the absence of apparent intra-abdominal source of infection - caused by monomicrobial infection - NOT assoc with anaerobic bacteria - hx of chronic liver disease and ascites

SBP - **IMPERATIVE THAT ANY PATIENT PRESENTING WITH ASCITES, ESPECIALLY WITH INFECTION SX GET A PARACENTESIS TO RULE OUT SBP**

what is the dx of SBP?

- **WBC count with diff is MOST important test** (NL = less than 500 leukocytes, less than 250 PMNs) - ascitic fluid PMN count GREATER THAN 250

what is the most effective tx of SBP?

liver transplant - empiric abx: third-generation cephalosporin IV (ceftriaxome) NOTE: kidney injury develops in 40% of patients and is a major cause of death

what must spontaneous bacterial peritonitis be distinguished from?

SECONDARY bacterial peritonitis - secondary: ascitic fluid has become secondarily infected by an intra-abdominal infection - tx: broad-spectrum abx

male: female ratio 4:1 - tumor usually develops in cirrhotic liver - high incidence in Asia and Africa - *Aflatoxin* exposure contributes to etiology and leaves molecular signature -> mutation in codon 249 of p53 gene

HCC

* pt with known liver disease develops an abnormality on - US - rising AFP * abnormal liver function tests/liver enzymes

HCC

what is the tx/management of HCC?

- surgical resection or liver transplantation - radiofrequency ablation - transcatheter arterial embolization (TACE)

stones in common bile duct

choledocolithiasis | - tx: **ERCP with sphincterotomy and stone extraction**

charcot triad: RUQ pain, fever, jaundice Raynold pentad: triad + altered mental status, hypotension labs show positive blood culture for E.coli, klebsiella, or enterococcus

ascending cholangitis

chronic liver diease - autoimmune destruction of small intrahepatic bile ducts and cholestasis - asymptomatic isolated elevation in alk phos - PE: pruritis, jaundice, *xanthelasma* - dx: positive AMA in 90-95%, elevated serum alk phos, bilirubin, cholesterol, and IgM - biopsy: **florid duct lesion**

primary biliary cirrhosis/cholangitis (PBC) | - tx: ursodeoxycholic acid, calcium and vit D given for osteoporosis

- associated with IBD (primarily UC) - men (20-50 years old) - **beads on a string** on MRCP or ERCP - **onion skinning** on liver biopsy - smoking and coffee consumption decrease risk of UC and PSC - associated with increased risk of cholangiocarcinoma

primary sclerosing cholangitis (PSC) - no proven therapy exists - symptomatic treatment with steroids, bile salt chelators for pruritis - liver transplant

female - 95% AMA positive - florid duct lesions and loss of small ducts only

primary biliary cirrhosis

male - 70% associated with IBD - 65% ANCA positive - strictures and beading of large bile ducts, pruning of smaller ducts

primary sclerosing cholangitis

occlusion of hepatic veins or IVC - caval webs (on venography), right sided heart failure - hypercoaguable state (75% of patients) - in India, China, South Africa is associated with poor standard of living - tender, painful hepatic enlargement (RUQ pain), jaundice, splenomegaly, ascites, nutmeg liver - imaging: prominent caudate liver lobe - **screening test of choice is contrast-enhanced CEUS** - color or pulsed-Doppler US

Budd-Chiari syndrome | - tx: symptomatic, sometimes anticoag or thrombolytic therapy

painless jaundice, weight loss, steatorrhea - if there is pain, is worse at night laying down - trousseau sign of malignancy - courvoisier sign - **CA19-9 elevated**

pancreatic cancer

conjugated hyperbilirubinemia - reduced excretory function of hepatocytes - benign, asymptomatic hereditary jaundice - gallbladder does not visualize on oral cholecystography - **liver DARKLY PIGMENTED on gross exam**

Dubin-Johnson syndrome

conjugated hyperbilirubinemia - reduced hepatic reuptake of bilirubin conjugates - similar to Dubin-Johnson, but liver is NOT pigmented, and the gallbladder IS visualized on oral cholecystography

Rotor syndrome

predominantly conjugated hyperbilirubinemia - cholestasis - benign cholestatic jaundice, usually occuring in third trimester of pregnancy - itching, GI symptoms, abnormal liver excretory function tests - cholestasis noted on liver biopsy - excellent prognosis, but recurrence with subsequent pregnancies or use of oral contraceptives

intrahepatic cholestasis of pregnancy