Liver and Biliary Tract

Question 1

Hepatic Failure

Answer 1

• when 80-90% of hepatic function is lost.
• mortality is 80%.
• presentation: jaundice, hypoalbuminemia with systemic edema, hyperammonemia, fetor hepaticus (odor from mercaptan formation), hyperestrogenemia from impaired estrogen metabolism (have palmar erythema, spider angiomata, hypogonadism, gynecomastia).
• complications: coagulopathy, multiple organ failure, hepatic encephalopathy (from porto-systemic shunting and loss of hepatocellular function. excess ammonia ⇒ brain edema, disturbances in consciousness, limb rigidity, hyperreflexia, asterixis), hepatorenal syndrome (↓ renal perfusion pressure, renal vasoconstriction, sodium retention, impaired free-water excretion), hepatopulmonary syndrome (from intrapulmonary vascular dilation and functional shunting from pulmonary arteries to veins, have hypoxia, V/Q mismatch).

Question 2

Acute Liver Failure

Answer 2

• liver illness associated with encephalopathy within 6 months of initial diagnosis.
• from hepatic necrosis from drug/toxin injury, viral hepatitis, autoimmune damage.

Question 3

Chronic Liver Disease

Answer 3

• most common cause of failure.
• ends in cirrhosis

Question 4

Hepatic Dysfunction without Overt Necrosis

Answer 4

• viable hepatocytes can’t perform normal metabolic functions.

Question 5

Liver Cirrhosis

Answer 5

• from alcohol abuse, viral hepatitis, non-alcoholic steatohepatitis. biliary disease and hemochromatosis less common.
• 20% are cryptogenic cirrhosis = unknown cause.
• characteristics = bridging fibrosis (links portal tracts with central veins), parenchymal nodules (hepatocyte regeneration when encircled by fibrosis), disrupted hepatic parenchymal architecture.
• pathogenesis: hepatocyte death, ECM deposition, vascular reorganization.
  
  • types I and III collagen deposited in space of Disse. sinusoidal endothelium loses fenestration. new vascular channels link portal triads to central veins.
  • fibrosis from proliferation and activation of stellate cells, promoted by PDGFreceptor beta. causes ↑ collagen synthesis and ↑ intrahepatic vascular resistance.
  • stellate cells and fibroblasts activated by: TNFalpha and IL-1beta, TFG-beta, direct toxin stimulation, disruption of ECM.
• presentation: silent until advanced. anorexia, weight loss, weakness, debilitation. precipitated by infection or GI hemorrhage.
  
  • death from progressive liver failure, complication of portal HTN, hepatocellular carcinoma.

Question 6

Portal Hypertension

Answer 6

• from ↑ flow into portal circulation and/or ↑ resistance to portal blood flow.
• prehepatic = from thrombosis, portal vein narrowing, ↑ splanchnic arterial circulation, massive splenomegal with ↑ splenic vein blood flow.
• intrahepatic = cirrhosis, schistosomiasis, massive fatty change, granulomatous disease, or nodular regenerative hyperplasia.
• posthepatic = right-sided heart failure, constrictive pericarditis, hepatic vein obstruction.
• consequences: ascites, portosystemic shunts, splenomegaly
  
  • ascites = have hypeatic sinusoidal hypertension from hypoalbuminemia, hepatic lymph in peritoneum, splanchnic vasodilation causes hypotension so retain sodium and water, have intestinal capillary transudation.
  • portosystemic shunts = from ↑ portal pressure. flow reversed from portal into systemic circulation. usually at esophagogastric varices, can rupture and have massive hematemesis. also at rectum (hemorrhoids), and falciform ligament/umbilicus (caput medusa).
  • splenomegaly = from long-standing congestion. can get thrombocytopenia from hypersplenism.

Question 7

Bilirubin and Bile Formation

Answer 7

• heme degraded to biliverdin to bilirubin, then bound to albumin, delivered to liver, conjugated to glucuronic acid by **UGT1A1 **⇒ water soluble bilirubin glucuronides excreted in bile, deconjugated in gut, degraded to urobilinogen and fecally eliminated.
• 20% urobilinogen reabsorbed and go to liver.

Question 8

Icterus

Answer 8

• yellow sclera discoloration.

Question 9

Jaundice

Answer 9

• yellow skin discoloration.
• bilirubin production exceeds hepatic uptake, conjugation, and/or excretion.
• unconjugated hyperbilirubinemia = excess production or diminished uptake and/or conjugation.
• conjugated hyperbilirubinemia = defective excretion

Question 10

Unconjugated Bilirubin

Answer 10

• water insoluble. usually bound to albumin.
• small amount circulates free and can diffuse into tissues (neonatal brain).
• unbound fraction increases with severe hemolysis or when drugs displace from albumin.

Question 11

Conjugated Bilirubin

Answer 11

• water-soluble, non-toxic, loosely bound to albumin.
• excess is renally excreted.

Question 12

Neonatal Jaundice

Answer 12

• transient, mild unconjugated hyperbilirubinemia until 2 weeks of age.
• hepatic metabolic machinery doesn’t develop until about 2 weeks.
• exacerbated by breast-feeding from bilirubin-deconjugating enzymes in breast milk.

Question 13

Crigler-Najjar Syndrome Type 1

Answer 13

• autosomal recessive.
• total absence of UGT1A1 causes jaundice with high serum levels of unconjugated bilirubin, normal liver histology.
• need liver transplantation or will get kernicterus (fatal neurologic damage).

Question 14

Crigler-Najjar Syndrome Type 2

Answer 14

• autosomal dominant.
• less severe UGT1A1 deficiency.
• not usually lethal but can get kernicterus.

Question 15

Gilbert Syndrome

Answer 15

• autosomal recessive. 6-10% population.
• mild, fluctuating unconjugated hyperbilirubinemia, 30% ↓ UGT1A1 activity.
• exacerbated by infection, strenuous exercise, fasting.

Question 16

Dubin-Johnson Syndrome

Answer 16

• autosomal recessive.
• defective hepatocyte secretion of conjugated bilirubin from absent MDR2 (does bilirubin glucuronide transport).
• liver is brown, accumulated pigment granules.
• jaundiced but have normal life expenctancy.

Question 17

Rotor Syndrome

Answer 17

• autosomal recessive.
• defective hepatocellular bilirubin uptake or excretion.
• jaundiced with normal life expectancy.

Question 18

Cholestasis

Answer 18

• impaired bile formation or flow ⇒ accumulation of intrahepatic bile pigments.
• extrahepatic = duct obstruction
• intrahepatic = hepatocellular dysfunction or canalicular obstruction.
• consequences: jaundice, pruritus, xanthomas (skin accumulations of cholesterol), intestinal malabsorption, ↑ serum levels alkaline phosphatase and GGT.
• morphology: bile pigment accumulates in hepatic parenchyma ⇒ dilated bile canaliculi and hepatocye degeneration.
  
  • obstruction ⇒ distended proliferating bile ducts in portal tracts, edema, periductular neutrophils.
    
    • prolonged ⇒ bile lakes, portal tract fibrosis, and cirrhosis.

Question 19

Progressive Familial Intrahepatic Cholestasis (PFIC)

Answer 19

• autosomal recessive disorders from mutated ATP-dependent transporter proteins.
• PFIC-1 = Bylder disease or Benign recurrent intrahepatic cholestasis.
• PFIC-2 = mutated ABCB11 gene for bile salt export pump in canaliculi.
  
  • have cholestasis, extreme pruritus, growth failure, progession to cirrhosis in 1st decade.
  • GGT levels normal.
• PFIC-3 = mutated ABCB4 gene for MDR3 protein for biliary phosphatidycholine secretion.
  
  • ↑ GGT levels from biliary epithelium damage by bile salts.

Question 20

Byler Disease

Answer 20

• PFIC-1. mutated ATP8B1 gene impairs bile secretion.
• cholestasis in infancy, progesses to liver failure by aduthood.
• no damage to canaliculi or biliary tree, normal GGT, normal bile ducts.

Question 21

Benign Recurrent Inrahepatic Cholestasis

Answer 21

• mild form of PFIC-1. affects ATP8B1 gene.
• intermittent attacks of cholestasis, doesn not progress to chronic liver disease.

Question 22

Hepatitis A Virus

Answer 22

• aka HAV. related to picornavirus.
• 25% acute hepatitis.
• ssRNA virus causing benign, self-limited disease.
• transmission: fecal-oral
• incubation: 2-4 weeks.
• damage from CD8+ T cell response.
• does not progress to chronic liver disease.
• detection: anti-HAV IgM in acute infection. IgG remains with immunity.

Question 23

Hepatitis B Virus

Answer 23

• aka HBV. hepadnavirus.
• dsDNA virus,causes acute, self-limited hepatitis, non-progressive chronic hepatitis, progressive chronic disease with cirrhosis, fulminant hepatitis with massive liver necrosis, asyptomatic carrier state.
• Dane particle with outer surface protein and lipid envelope encasing electron-dense core.
• 4 reading frames: HBcAg (core antigen), HBeAg (into bloodstream), HBsAg (surface antigen), HBx (for viral replication).
• strong response by CD4+ and CD8+ IFN-gamma for resolution. damage via CD8+ cells.
• related to cancer development (hepatocellular carcinoma).
• transmission: parenteral, sexual contact, perinatal.
  
  • high prevalence = from childbirth.
  • intermediate-prevalence = minor cuts or breaks in mucus membranes.
  • low prevalence = IV drug abuse, unprotected sex.
• incubation: 1-4 months.
• 10% get chronic liver disease.
• morphology: finely granular ‘ground-glass’ cytoplasm with HBsAg.
• detection: HBsAg before symptoms (anorexia, fever, jaundice). HBeAg and HBV DNA after HBsAG and before disease onset, persistence of HBeAg means chronic disease. Anti-HBcAg IgM first, then anti-HBeAg IgM and anti-HBcAg IgG. anti-HBsAg means end of acute disease and immunity.
  
  • chronic carrier = HBsAg in serum for 6 months.
  • detect by HBsAg or Ab to HBcAg.

Question 24

Hepatitis C Virus

Answer 24

• aka HCV. flaviridae.
• ssRNA, enveloped. substantial genomic variability (quasispecies).
• E2 envelope protein targeted by Abs, also most variable.
• antibodies don’t cause immunity.
• 80-85% go on to chronic liver disease. cirrhosis in 20-30%.
• damage is immune mediated.
• transmission: parenteral, intransal cocaine.
• risk groups: IV drug abusers, multiple sexual partners.
• incubation: 7-8 wks.
• morphology: portal lymphoid aggregates, bile duct reactive changes, lobular regions of macrovesicular steatosis.
• detection: HCV RNA in blood for 1-3 wks during active infection with transaminase elevation. anti-HCV Ab in 50-70% in acute, 90% in chronic.
  
  • PCR for HCV RNA.
• tx: for chronic use IFN-gamma and ribovarin.

Question 25

Hepatitis D Virus

Answer 25

• aka HDV.
• circular defective ssRNA, requires host RNA polymerase activity.
• only replicates and infects when encapsulated by HBsAg, so only when with HBV.
• ranges mild to fulminant, chronicity rare (5% for co-infection, <70% with superinfection).
• high prevalence in Africa, Middle East, Italy, and Amazon basin.
• Dane-like particle with HBV envelope. makes delta antigen.
• incubation: 1-4 months.
• detection: HDV RNA in blood and liver during infection, recent exposure has anti-HDV IgM, anti-HBcAg IgM = co-infection, HBsAg = superinfection
• have a vaccine.

Question 26

Hepatitis E Virus

Answer 26

• aka HEV. Calicivirus.
• non-enveloped ssRNA, self-limiting, does not become chronic liver disease.
• transmission: water-borne enteric infection (fecal-oral) via monkeys, cats, pigs, dogs.
• epidemic in Asia, Africa, Mexico.
• endemic in India = 30-60% acute hepatitis.
• high rate of fatal fulminant hepatitis in pregnant women.
• incubation: 4-5 wks.
• detection: HEV antigen in hepatocytes (PCR), RNA and virions in stool and serum before onset.
  
  • IgG anti-HEV = immunity.

Question 27

Hepatitis G Virus

Answer 27

• aka HGV.
• non-pathogenic RNA virus in 1-4% blood donors.
• replicates in marrow and spleen.

Question 28

Acute Asymptomatic Viral Hepatitis with Recovery

Answer 28

• identified by ↑ transaminases or anti-viral Ab titers.
• HAV and HBV frequently subclinical.

Question 29

Acute Symptomatic Viral Hepatitis with Recovery

Answer 29

• asymptomatic pre-icteric phase, symptomatic icteric phase, convalescence.
• peak infectivity during last few days of asymptomatic days and first few symptomatic days.

Question 30

Chronic Hepatitis

Answer 30

• symptomatic disease with biochemical or serologic evidence of ongoing heptaic damage of more than 6 months.
• HCV>>HBV or HDV
• younger patients more likely to develop this, maternal-fetal transmission.
• causes ongoing liver injury, cirrhosis, hepatocellular carcinoma, immune complex disease with vasculitis and glomerulonephritis.
• 35% chronic HCV develop cryoglobulinemia.
• morphology: mild to severe cirrhosis. mild = limited to portal tracts.
  
  • extension of chronic inflammation from portal tracts with interface hepatitis, linking of portal-portal and portal-central regions = bridging necrosis.
  • continued loos of hepatocytes ⇒ fibrous septum formation, associated hepatocyte regeneration causes cirrhosis.
• major cause of morbidity and mortality in HIV pts. second most common cause of death in AIDs.

Question 31

Carrier State (viral hepatitis)

Answer 31

• harbors and tramsits hepatitis without symptoms.
  
  • patients with chronic disease and few/no symptoms, and those with few or no adverse effects (healthy carriers).
• for HBV, healthy carriers lack HBeAg but have anti-HBeAg, normal aminotransferase levels, low serum HBV DNA, no significant necrosis or inflammation.

Question 32

HIV and Chronic Viral Hepatitis

Answer 32

• 10% HIV pts have HBV, 30% have HCV causing aggressive liver disease.

Question 33

Acute Hepatitis Morphology

Answer 33

• injured hepatocytes are eosinophilic and rounded with shrunken or fragmented nuclei (apoptosis).
• ballooning degeneration = swollen hepatocytes.
• when severe = bridging necrosis btw portal and central regions of adjacent lobules. can have cholestasis.
• Kupffer cell hyperplasia, macrophage aggregates mark site of hepatocyte loss.
• portal tracts have mononuclear cell inflammation, spillover into adjacent parenchyma. associated with periportal apoptosis (interface hepatitis).

Question 34

Fulminant Hepatic Failure

Answer 34

• hepatic insufficiency with hepatic encephalopathy occuring within 2-3 wks after symptom onset.
• 12% from virus (HBV>HAV>HCV)
• >50% from drug or chemical toxicity.
• 15% unknown cause.
• in HBV type, have massive hepatocyte apoptosis.
• mortality is 80% without transplant, 35% with transplant.
• morphology: can involve portions or entire liver. can shrink liver. areas are soft and muddy-red or bile-stained.
  
  • destroys lobules ⇒ cellular debris and collapsed reticulin network.
  • regeneration is disorderly when substantial. leaves scar ring that produces lobulated pattern of cirrhosis.

Question 35

Bacterial/Parasitic/Helminthic Infections of Liver

Answer 35

• extrahepatic sepsis ⇒ hepatic inflammation, some degree of cholestasis from kupffer cell and endothelial cell production of cytokines to endotoxin.
• biliary obstruction and intra-biliary proliferation ⇒ severe acute inflammatory response (ascending cholangitis).
• parasitic infection ⇒ hepatic abscesses in developing countries.
• abscesses in developed countries rare. from bacterial or candidal infection.
  
  • associated with fever, RUQ pain, tender hepatomegaly, jaundice.
  • morality 30-90%.
  • rupture of echinoccal cysts ⇒ spread of organisms and severe immune-mediated shock.
• morphology: parasitic fragments or fungal organisms in abscess.
  
  • cystic structures with laminated/calcified walls, hooklets, and intact organisms in echinococcal infections.

Question 36

Autoimmune Hepatitis (AIH)

Answer 36

• chronic, progressive hepatitis from T cell mediated autoimmunity (cytotoxic T cells and production of IFNgamma).
• triggered by viral infections, drugs, or from other autoimmune diseases.
• female predominance with ↑ serum IgG but no markers of viral infection.
• type 1 = autoAb to nuclear, smooth muscle, actin, soluble liver Ag/liver-pancreas Ag. associated with HLA-DR3 haplotype.
• type 2 = autoAb to liver kidney microsome-1 and liver cytosol-1 Ag.
• morphology: hepatitis picture with clusters of periportal plasma cells.
• presentation: acute onset liver failure in 40%. show substantial liver destruction and scarring.
  
  • untreated ⇒ mortality of 40%, 40% survivors get cirrhosis.
• tx: immunosuppression, transplant later on.
• 22-42% recurrence in transplants.

Question 37

Drug and Toxin Induced Liver Disease

Answer 37

• considered in any form of liver disease.
• can be immediate or develop over wks to months.
• mechanisms: direct toxicity, hepatic conversion to toxin, immune-mediated injury.
• acetaminophen = uniformly hepatotoxic, leading cause of drug-induced acute liver failure.

Question 38

Reye Syndrome

Answer 38

• rare, potentially fatal syndrome of mitochondrial dysfunction.
• massive microvesicular steatosis.
• occurs in kids taking aspirin for febrile illness.

Question 39

Alcoholic Liver Disease (ALD)

Answer 39

• leading cause of liver pathology in West.
• morphology: hepatic steatosis (fatty liver) = micovesicular lipid droplets in hepatocyes. chronic alcohol ⇒ droplets displace nucleus. becomes enlarged, soft, greasy, yellow. little to no fibrosis, reversible.
  
  • alcoholic hepatitis = ballooning degeneration and hepatic necrosis. Mallory body formation (intracellular aggregates of intermediate filaments), neutrophilic reaction to degenerating hepatocytes, portal/periportal mononuclear inflammation, fibrosis.
  • alcoholic cirrhosis = irreversible final outcome. brown and shrunken, nonfatty liver. regenerative nodules prominent or obliterated by fibrous scar.
• pathogenesis: in 10-15% alcoholics. F>M; AA>whites.
  
  • polymorphisms in metabolizing enzymes or cytokine promotors.
  • iron overload or viral hepatitis increases severity.
  • steatosis from: impaired lipoprotein assembly and secretion, ↑ peripheral catabolism of fat, shunting of substrates from catabolism to lipid biosynthesis.
  • **acetaldehyde **⇒ lipid peroxidation and acetaldehyde protein adduct formation.
  • induced cytochrome P450 ⇒ ROS and toxic metabolites.
  • impaired methionine metabolism ⇒ ↓ glutathione levels.
  • malnutrition and vitamin deficiency.
  • ↑ inflammatory response from alcohol mediated release of bacterial endotoxins in GI.
  • cirrhosis from collagen deposition by perisinusoidal stellate cells. deranges hepatic blood flow from fibrosis and endothelins.
• presentation: hepatic steatosis ⇒ hepatomegaly with ↑ serum bilirubin and alkaline phosphatase. treat by abstention and diet.
  
  • alcoholic hepatitis ⇒ acute after heavy drinking. malaise, anorexia, tender hepatomegaly. ↑ bilirubin and alkaline phosphatase, with neutrophilic leukocytosis. leads to cirrhosis in 1/3. treat by abstention and diet.
  • alcoholic cirrhosis = irreversible, same symptoms as cirrhosis.
• death from hepatic coma, massive GI hemorrhage, intercurrent infection, hepatorenal syndrome, and hepatocellular carcinoma.

Question 40

Nonalcoholic Fatty Liver Disease (NAFLD)

Answer 40

• hepatic steatosis in absence of heavy alcohol consumption.
• from obesity.
• most pathologic = nonalcoholic steatohepatitis (NASH) = steatosis plus hepatocyte damage and inflammation. goes to cirrhosis in 10-20%.
  
  • associated with metabolic syndrome of dyslipidemia, hyperinsulinemia, and insulin resistance.
• pathogenesis: from hepatocyte fat accumulation and ↑ hepatic oxidative stress ⇒ ↑ lipid peroxidation and ROS.
• morphology: hepatocytes filled with fat vacuoles with or without inflammation. varying degrees of fibrosis.
• presentation: steatosis = asymptomatic. NASH = fatigue, malaise, RUQ discomfort, ↑ transaminase levels.
  
  • morbidity and mortality from cardiovascular disease.
• tx: correct obesity, hyperlipidemia, and insulin resistance.

Question 41

Hemochromatosis

Answer 41

• excessive iron accumulation in parenchymal cells of organs (liver and pancreas).
• hereditary = primary = homozygous recessive heritable disorder from excessive iron absorption.
• hemosiderosis = secondary = associated with parenteral iron administration (transfusions, intake, chronic liver disease).
• pathogenesis: damage from direct iron toxicity via free radicals, stimulation of collagen formation, and/or iron and ROS-DNA interactions.
  
  • hepcidin lowers plasma iron, deficiency causes iron overload.
  • mutation of HFE on chromosome 6. cysteine to tyrosine at C282Y inactivates HFE ⇒ ↓ hepcidin
• morphology: iron accumulates in: liver, pancreas, myocardium, endocrine glands, joints, skin. get cirrhosis and pancreatic fibrosis.
• presentation: micronodular cirrhosis, diabetes mellitus and skin pigmentation in 75-80%. symptoms appear after age 40. usually men.
  
  • death from cirrhosis, hepatocellular carcinoma, cardiac involvement.
• tx: phlebotomy.

Question 42

Wilson Disease

Answer 42

• autosomal recessive by mutated ATP7B gene that codes for canalicular copper-transporting ATPase.
• ↓ copper excretion in bile, copper not incorporated into ceruloplasmin, inhibited ceruloplasmin secretion into blood.
• copper accumulation in liver ⇒ injury via ROS.
  
  • also affects cornea and brain.
• morphology: fatty change, acute and chronic hepatitis (Mallory bodies), cirrhosis, massive necrosis (rare).
  
  • CNS toxicity affects basal ganglia ⇒ atrophy and cavitation.
  • Kayser-Fleischer rings - eye lesion from neurologic involvement, green-brown coper deposits in Descemet’s membrane of corneal limbus.
• presentation: acute or chronic liver disease before age 40. neuropsychiatric disorders: behavioral changes, psychosis, Parkinson-like symptoms.
• diagnosis: ↓ serum ceruloplasmin, ↑ hepatic copper, ↑ urinary copper excretion.
• tx: copper chelation therapy, transplantation.

Question 43

alpha1-Antitrypsin Deficiency

Answer 43

• autosomal recessive marked by very low serum levels of protease inhibitor ⇒ emphysema and hepatic disease.
• pathogenesis: alpha1-AT made by hepatocytes by PiMM. PiZZ homozygotes have <10% normal levels.
  
  • causes misfolding and prevents egress from ER ⇒ ER stress response: autophagy, mitochondrial dysfunction, NF-kB activation ⇒ hepatocyte damage.
  • overt liver disease in 10-15% PiZZ.
• morphology: PAS-positive cytoplasmic globules in periportal hepatocytes. ranges from cholestasis to hepatitis to cirrhosis.
• presentation: neonatal hepatitis with cholestatic jaundice in 10-20% of newborns with alpha1-AT deficiency. later presentation from acute hepatitis or complications of cirrhosis.
  
  • hepatocellular carcinoma in 1-2% of PiZZ.
• tx: liver transplant

Question 44

Neonatal Cholestasis

Answer 44

• prolonged conjugated hyperbilirubinemia.
• caused by cholangiopathies (primarily biliary atresia) and neonatal hepatitis. 50% unknown, 15% alpha1-AT deficiency.
• morphology: hepatocyte death, lobular disarray, hepatocyte giant cell formation, prominent cholestasis, portal tract inflammation, extramedullary hematopoiesis.
• presentation: jaundice, dark urine, light stools, hepatomegaly.

Question 45

Secondary Biliary Cirrhosis

Answer 45

• due to uncorrected obstruction of extrahepatic biliary tree.
• causes: cholelithiasis, malignancies of biliary tree or ancreatic head, strictures, biliary atresia, cystic fibrosis, choledochal cysts.
• prolonged cholestasis ⇒ inflammation ⇒ periportal fibrosis and cirrhosis.
• subtotal obstruction promotes secondary bacterial infection (ascending cholangitis) that aggravates inflammatory injury.

Question 46

Primary Biliary Cirrhosis (PBC)

Answer 46

• autoimmune destructive disorder of intrahepatic biliary tree ⇒ portal inflammation ⇒ cirrhosis.
• usually middle aged women.
• morphology: varying degrees of severity. dense chronic portal tract inflammation with focal non-caseating granulomas along with interlobular bile duct destruction and generalized cholestasis.
  
  • intrahepatic biliary obstruction ⇒ upstream damage with ductular proliferation, inflammation/necrosis of periprotal hepatocytes.
  • end stage = same as all cirrhosis.
• presentation: insidious with pruritus, hepatomegaly, jaundice, and xanthomas. with cirrhosis have variceal bleeding and encephalopathy
  
  • ↑ serum alkaline phosphatase and cholesterol.
  • ↑ antimitochondrial Ab in 90-95%.
  • can have extrahepatic autoimmune manifestations (Sjogren, scleroderma, thyroiditis, Raynaud, membranous glomerulonephritis).
  • cause of mortality: liver failure, variceal bleeding, intercurrent infection.
  • ↑ risk hepatocellular carcinoma.

Question 47

Primary Sclerosing Cholangitis (PSC)

Answer 47

• chronic cholestatic disease having inflammation and obliterative fibrosis of both extrahepatic and intrahepatic biliary tree.
• dilation of preserved segments ⇒ beading of injected radiologic material.
• 70% have ulcerative colitis, circulating autoAb (ANA and anti-smooth muscle Ab, RF, atypical pANCA) = autoimmune.
• morphology: periductal inflammation and concentric fibrosis (onion-skin), progressive atrophy and luminal obliteration. get biliary cirrhosis and hepatic failure.
• presentation: middle aged men. takes 5-15 yrs. severe disease ⇒ weight loss, ascites, variceal bleeding, encephalopathy.
  
  • ↑ incidence chronic pancreatitis and hepatocellular carcinoma.
  • 7% get cholangiocarcinoma.
• tx: liver transplant

Question 48

Von Meyenberg Complexes

Answer 48

• aka bile duct hamartomas.
• associated with polycystic kidney disease from PKD1 mutation.
• small clusters of dilated bile ducts or cysts within a fibrous stroma.
• very common
• can present as hepatosplenomegaly and portal HTN or be silent.

Question 49

Polycystic Liver Disease

Answer 49

• handful to hundreds of biliary epithelium-lined lesions.
• usually associated with PKD1 mutation (polycystic kidney disease).
  
  • if not, the have mutated PRKCSH that encodes hepatocystin (substrate for protein kinase C).
• can be silent or present as hepatosplenomegaly and portal HTN.

Question 50

Congenital Hepatic Fibrosis

Answer 50

• from incomplete involution of embryonic ductal structues with ensuing portal tract fibrosis ⇒ portal HTN.
• strongly associated with PKHD1 mutation of autosomal recessive polycystic kidney disease.
• can be silent or present as hepatosplenomegaly and portal HTN.

Question 51

Caroli Disease

Answer 51

• segmental dilation of larger ducts of intrahepatic biliary tree with bile inspissation.
• complicated by cholelithiasis and hepatic abscesses.
• ↑ risk of cholangiocarcinoma.
• associated with mutated PKD1 of polycystic kidney disease.
• can be silent or present as hepatosplenomegaly and portal HTN.

Question 52

Alagille Syndrome

Answer 52

• aka syndromatic paucity of bile ducts or arteriohepatic dysplasia.
• rare, autosomal dominant. absence of intrahepatic bile ducts.
• mutated Jagged 1 - Notch signaling pathway.
• have chronic cholestasis, extrahepatic anomalies: peculiar facies, vertebral and cardiovascular defects.
• may be silent or present with hepatosplenomegaly and portal HTN.

Question 53

Hepatic Artery Compromise

Answer 53

• infarct is rare but thrombosis or compression of intrahepatic arterial branches can cause localized pale infarct.
• occasionally made hemorrhagic by portal blood suffusion.

Question 54

Portal Vein Obstruction and Thrombosis

Answer 54

• extrahepatic portal vein obstruction can be insidious/well tolerated or catastrophic and lethal from variceal bleeding.
• causes: neonatal umbilical vein infection, intra-abd sepsis causing pylephlebitis, coagulopathies, trauma, pancreatic lesions causing thromboses, cirrhosis.

Question 55

Sinusoidal Occlusion

Answer 55

• caused by DIC, sickle cell disease, metastatic tumors, sarcoidosis.

Question 56

Passive Congestion and Centrilobular Necrosis

Answer 56

• systemic hypoperfusion ⇒ hepatocyte necrosis around central vein (centrilobular necrosis).
• passive congestion = hemorrhage and hepatocyte necrosis around central vein = centrilobular hemorrhagic necrosis. nutmeg liver.
• cardiac sclerosis = chronic passive congestion and pericentral fibrosis from right-sided heart failure ⇒ cirrhosis.

Question 57

Peliosis Hepatitis

Answer 57

• reversible hepatic sinusoid dilation associated with malignancy, AIDS, TB, post-transplant immunosuppression.
• also from anabolic steroids, oral contraceptives, danazol.

Question 58

Hepatic Vein Thrombosis and Inferior Vena Cava Thrombosis

Answer 58

• Budd-Chiari syndrome = two or more major hepatic veins are obstructed.
• in setting of primary myeloproliferative disorders (polycythemia vera), heritable coagulopathies, pregnancy, anti-phopholipid Ab syndrome, paroxysmal nocturnal hemoglobinuria, and intra-abd cancers.
• can get obstruction from membranous inferior vena cava valve.
• need porto-systemic shunting.

Question 59

Veno-Occlusive Disease (VOD)

Answer 59

• aka sinusoidal obstruction syndrome.
• in Jamaican drinkers of pyrrolizidine alkaloid-containing bush tea. now from toxic injury to sinusoidal endothelium by chemo.
• mortality = 30%.
• morphology: patchy obliteration of smaller hepatic vein radicles by endothelial swelling and collagen deposition.
  
  • acute = centrilobular congestion with hepatocellular necrosis
  • progressive = venule lumen obliteration with dense perivenular fibrosis and hemosiderin deposition.
• presentation: tender hepatomegaly, ascites, weight gain, jaundice.

Question 60

Graft-Versus-Host Disease

Answer 60

• from bone marrow or stem cell transplantation.
• have direct lymphocyte attack on liver cells, particularly bile duct epithelium.
• acute = hepatitis (parenchymal inflammation and hepatocyte necrosis), chronic vascular inflammation and intimal proliferation (endothelialitis), and bile duct destruction.
• chronic = portal tract inflammation, bile duct destruction or loss, and fibrosis.

Question 61

Rejection of Liver

Answer 61

• acute = portal tract inflammation with eosinophils, bile duct damage, endothelialitis.
• chronic = months or years later, bile duct loss and arteriopathy with eventual failure.

Question 62

Preeclampsia and Eclampsia

Answer 62

• in 3-5% of pregnancies.
• preeclampsia = HTN, proteinuria, peripheral edema, coagulation abnormalities, varying degrees of DIC.
• eclampsia when have hyperreflexia and convulsions.
• primary manifestation preeclampsia = HELLP syndrome = hemolysis, elevated liver enzymes, low platelets.
• morphology: small red hemorrhagic patches with yellow-white areas of infarct. perportal sinusoidal fibrin deposition, periportal necrosis, hemorrhage.
  
  • coalesced blood forms hepatic hematomas that can rupture.

Question 63

Acute Fatty Liver of Pregnancy (AFLP)

Answer 63

• rare. ranges from subclinical hepatocyte dysfunction to hepatic failure, coma, death.
• usually has mitochondrial dysfunction.
• congenital fetal deficiency in long chain 3-hydroxyacyl coenzyme A dehydrogenase ⇒ toxic levels of fetal metabolites, cause maternal hepatotoxicity.
• have microvesicular steatosis.
• severe cases have portal inflammation, hepatocyte dropout, lobular dysarray.
• tx: terminate pregnancy.

Question 64

Intrahepatic Cholestasis of Pregnancy (ICP)

Answer 64

• from altered hormonal state of pregnancy.
• presentation: pruritus and jaundice in 3rd trimester with mild cholestasis.
• pruritus can be severe, can get maternal gallstones or malabsorption.

Question 65

Nodular Hyperplasia

Answer 65

• solitary or multiple benign hepatocellular nodules in absence of cirrhosis.
• from focal hepatic vascular obliteration with compensatory hypertrophy of adjacent well-vascularized lobules.
• focal nodular hyperplasia = young to middle aged adults. irregular, unencapsulated mass with central stellate fibrous scar.
• nodular regenerative hyperplasia = diffuse nodular transormation without fibrosis. from conditions affecting intrahepatic blood flow (solid-organ transplants, bone marrow transpants, vasculitis).

Question 66

Cavernous Hemangiomas

Answer 66

• most common benign liver tumor.
• identical to blood vessel tumors.

Question 67

Hepatic Adenomas

Answer 67

• benign hepatocyte neoplasms up to 30cm in diameter. in young women, associated with oral contraceptives.
• mutation in beta-catenin and transcription factor HNF1alpha.
• made of sheets of hepatocytes containing arteries and veins. portal tracts with bile ducts are absent.
• rupture is rare but with massive hemorrhage and rarely have hepatocellular carcinoma.

Question 68

Hepatocellular Carcinoma (HCC)

Answer 68

• most common primary liver cancer
• more common in developing countries, high rates HBV.
• 2.4:1 M:F.
• 4 major factors: HBV or HCV, chronic alcoholism, NASH, and food contaminants.
  
  • also hemochromatosis, tyrosinemia, and alpha-1 antitrypsin deficiency.
• HBV-related = key events are integration of HBV DNA into host genome and presence of viral proteins.
• HCV core and NS5A viral proteins may participate in HCC onset.
• in high prevalence areas with vertical transmission of HBV, cirrhosis absent in 50% and carcinoma presents btw ages 20-40.
• morphology: solitary mass, multifocal nodules, or diffusely infiltrative cancer with massive liver enlargement and cirrhosis.
  
  • intrahepatic spread and vascular invasion.
  • range from well differentiated to highly anaplastic.
  • fibrolamellar carcinoma = 5% HCC, single scirrhous, hard tumor occuring btw age 20-40yrs without chronic liver disease. well-differentiated cells in cords or nests and separated by dense lamellar collagen bundles.
• presentation: hepatomegaly, RUQ pain, weight loss, ↑ serum alpha-fetoprotein.
  
  • mortality from cachexia, GI or esophageal variceal bleeding, liver failure with hepatic coma, or tumor rupture and fatal hemorrhage.

Question 69

Angiosarcomas

Answer 69

• associated with exposure to vinyl chloride, arsenic, or Thorotrast (contrast agent).
• malignant and in liver.

Question 70

Hepatoblastoma

Answer 70

• most common liver tumor of early childhood.
• activation of Wnt/beta-catenin pathway.
• associated with familial polyposis syndrome and Beckwith-Wiedemann syndrome.
• epithelial type = recapitulates liver development.
• mixed epithelial and mesenchymal type = foci of mesenchymal differentiation including osteoid, cartilage, or striated muscle.
• fatal if untreated.
• 80% survival with resection and chemo.

Question 71

Cholangiocarcinoma (CCA)

Answer 71

• arises from elements of intra- and extrahepatic biliary tree.
• 50-60% are perihilar (Klatskin tumors), 20-30% distal, 10% intrahepatic.
• pathogenesis: can be associated with primary sclerosing cholangitis, congenital fibropolycystic lesions, HCV infection, and Thorotrast administration.
  
  • in SE Asia, protracted biliary tree parasitic infection by Opisthorchis sinensis.
  • IL-6 overexpression ⇒ AKT activation and ↑ production of anti-apoptotic protein MCL-1.
  • p53 expression is ↓.
• morphology: single large mass or multifocal nodules, can be diffusely infiltrative. pale.
  
  • variably differentiated bile duct elements that resemble adenocarcinomas. markedly desmoplastic with dense collagenous stroma.
  • mixed variants of hepatocellular-cholangiocarcinoma are rare.
• outlook dismal. rarely resectable.

Question 72

Metastatic Tumors

Answer 72

• most common: colon, breast, lung, and pancreas.
• multiple implants with massive hepatic enlargment.
• large implants have central necrosis.
• massive involvement before hepatic failure develops.

Question 73

Congenital Anomalies of Biliary Tract

Answer 73

• gallbladder can be absent or in different locations (within liver).
• phrygian cap = folded fundus.
• duplicated or bilobed gallbladder.
• agenesis of common or hepatic bile ducts
• hypoplastic narrowing of biliary channels.

Question 74

Cholelithiasis

Answer 74

• afflict 10-20% of adults.
• 90% of calculi are cholesterol stones (>50% cholesterol monohydrate), rest are bilirubin calcium salts.
• risk factors: ↑ hepatic cholesterol uptake or synthesis or to ↑ biliary cholesterol secretion.
  
  • Native Americans, industrialized countries, ↑ age, female, oral contraception, pregnancy, obesity, metabolic syndromes, hypercholesterolemia, rapid weight loss, gallbladder stasis (spinal cord injury).
  • D19H variant of ATP-binding cassette transporter using ABCG5 and ABG2 genes.
• pathogenesis: cholesterol stones = cholesterol supersaturated. nucleates into cholesterol monohydrate crystals.
  
  • 4 conditions: supersaturated cholesterol, gallbladder hypomotility, accelerated cholesterol nucleation in bile (promoted by calcium salts), and mucus hypersecretion in gallbladder traps crystals.
  • pigment stones = in setting of unconjugated bilirubin (chronic hemolytic conditions) and precipitate calcium bilirubin salts.
    
    • underdeveloped areas = infection (E.coli, Ascaris lumbricoides, Opisthorchis sinesis) promotes bilirubin glucuronide deconjugation.
• morphology: cholesterol stones in gallbladder, hard and pale yellow. bilirubin salts are black. having 10-20% calcium carbonate makes radiopaque, if mostly cholesterol then radiolucent. single stones are ovoid, multiple stones are faceted.
  
  • pigmented stones can be black (sterile) or brown (infected). soft and multiple. 50-75% stones radiopaque.
• presentation: 70-80% asymptomatic. 1-4% get symptomatic per year. spasmodic colicky pain from passage, RUQ pain. potential empyema, perforation, fistulas, biliary tree inflammation, obstructive cholestasis or pancreatitis, erosion into bowel.
  
  • mucocele when clear mucinous secretions obstructed in gallbladder and it distends.
  • ↑ risk gallbladder carcinoma.

Question 75

Acute Cholecystitis

Answer 75

• acute inflammation of gallbladder precipitated by gallstone obstruction. 10% without gallstones
• pathogenesis: with gallstones (calculous) = chemical irritation by retained bile acids, release lysolecithin and prostaglandins, develop dysmotility.
  
  • severe cases = distention, luminal pressures compromise mucosal blood flow ⇒ ischemia
  • acalculous = without stones. from ischemia due to diminished flow in end arterial cystic artery circulation. in setting of sepsis with hypotension and multiorgan failure, immunosuppression, major trauma/burns, diabetes mellitus, or infections.
• morphology: enlarged, tense, bright-red to blotchy green-black gallbladder with serosal fibrinous exudate. contents can be turbid to purulent.
  
  • severe = gangrenous cholecystitis with multiple perforations.
  • mild = edema and hyperemia.
• presentation: RUQ or epigastric pain, fever, anorexia, tachycardia, diaphoresis, and nausea and vomiting. Jaundice = common bile duct obstruction.
  
  • self-limited ones resolve over a few days.

Question 76

Chronic Cholecystitis

Answer 76

• repeated bouts of acute cholecystitis but often without.
• 90% have gallstones.
• chronic bile supersaturation with cholesterol permits cholesterol suffusion and inflammation and gallbladder dysmotility.
• morphology: can be small, normal, or large. wall variably thick, mucosa preserved but atrophied. cholesterol-laden macrophages in lamina propria (cholesterolosis) and gallstones. Rokitansky-Aschoff sinuses = inflammation with mucosal outpouchings.
  
  • mural dystrophic calcification (porcelain gallbladder) rare.
  • xanthogranulomatous cholecystitis = rare. fibrosed, nodular gallbladder with marked histiocytic inflammation.
• presentation: recurrent attacks of steady or colicky epigastric or RUQ pain.
  
  • complications = superinfection, perforation, abscess formation or peritonitis, formation of biliary enteric fistulas.

Question 77

Choledocholithiasis

Answer 77

• stones within biliary tree. in 10% of pts with cholelithiasis.
• in West, almost all stones are cholesterol.
• in Asia, usually in biliary tree and are pigmented.
• symptoms due to obstruction, pancreatitis, cholangitis, hepatic abscess, secondary biliary cirrhosis, acute calculous cholecystitis.

Question 78

Cholangitis

Answer 78

• bile duct bacterial infection.
• in setting of choledocholithiasis.
• due to enteric bacteria entering biliary tract through sphincter of Oddi.
• presentation: fever, abd pain, jaundice.
  
  • sepsis can be fatal.

Question 79

Biliary Atresia

Answer 79

• causes 1/3 neonatal cholestasis.
• extrahepatic biliary tree obstruction within first 3 months of life.
• most frequent cause of death from liver disease in early childhood and most liver transplantation in kids.
• pathogenesis: severe early fetal form (20%) due to aberrant intrauterine development of biliary tree, associated with other anomalies.
  
  • perinatal form = secondary to viral infections and/or autoimmunity, from destruction of normal biliary tree.
• morphology: inflammation and fibrosing stricture of extrahepatic biliary tree, goes into intrahepatic biliary system. liver shows: bile duct proliferation, portal tract edema, fibrosis going to cirrhosis within 6 months.
  
  • early severe form = aberrant intrahepatic biliary morphology, paucity of bile ducts.
  • 90% that extends above porta hepatis not amenable to surgery.
• presentation: infant of normal birth weight and postnatal weight gain. untreated ⇒ death by age 2yrs.

Question 80

Choledochal Cysts

Answer 80

• congenital dilations of common bile duct.
• in kids <10yrs, nonspecific symptoms of jaundice, recurrent colicky abd pain.
• F>M
• predispose to stones, stenosis and stricture, pancreatitis, obstructive biliary complications, and bile duct carcinoma in adult.

Question 81

Gallbladder Tumors

Answer 81

• primary = epithelial.
• adenomas = benign.
• inflammatory polyps = sessile mucosal projections containing chronic inflammation and lipid-laden macrophages.
• adenomyosis characterized by muscle hyperplasia.

Question 82

Carcinoma of Gallbladder

Answer 82

• more common in women, usually >70yrs.
• risk factor: chronic gallbladder infection.
• less common in Asians.
• morphology: infiltrating = diffuse thickening and induration.
  
  • exophytic = grow into lumen as irregular, cauliflower mass.
  • most common = adenocarcinomas.
  • can be papillary to infiltrating, moderately to undifferentiated.
  • rare: squamous, adenosquamous, carcinoid, or mesenchymal.
  • spread by local invasion, extension to cystic duct and portohepatic lymph nodes, metastatic seeding of peritoneum, viscera, and lungs.
• presentation: insidious, indistinguishable from cholelithiasis.
  
  • usually unresectable.