Liver, Gallbladder, and Exocrine Pancreas

Question 1

Jaundice

Answer 1

• Yellow discoloration of skin, and tissues caused by hyperbilirubinemia
• Earliest sign is scleral icterus
• Arises with disturbances in bilirubin metabolism

Question 2

Gilbert syndrome

Answer 2

• Congenital hyperbilirubinemia
• Extremely common
• Characterized by modest elevation of serum unconjugated bilirubin; the liver is otherwise unimpaired.
• Caused by combination of decreased bilirubin uptake by liver cells and reduce activity of glucuronyl transferase

Question 3

Crigler-Najjar syndrome

Answer 3

• Congenital hyperbilirubinemia
• Severe familial disorder characterized by unconjugated hyperbilirubinemia
• Caused by deficiency of glucuronyl transferase

Question 4

Dubin-Johnson syndrome

Answer 4

• Congenital hyperbilirubinemia
• Autosomal recessive form of conjugated hyperbilirubinemia
• Characterized by defective bilirubin transport
• Striking brown-to-black discoloration of the liver

Question 5

Acute viral hepatitis

Answer 5

• Inflammation of liver parenchyma
• Characterized by jaundice with dark urine, fever, malaise, and nausea
• Elevated serum aspartate and alanine aminotransferases
• Usually due to hepatitis virus, but may also be caused by EBV or CMV
• HAV: spread by fecal-oral transmission; parenteral infection does not occur. Does not cause a chronic carrier state
• HBV: transmitted via parenteral, sexual, and vertical routs; associated with a “ground-glass” appearance of hepatocytes; can result in a carrier state or in chronic liver disease; HBsAg, HBeAg, Anti-HBcAg, HBV DNA. Hepatocyte damage results from CD8+ T cells
• HCV: transmittes parenteral, frequent cause of transfusion-mediated hepatitis. 85% progresses to chronic hepatitis
• HDV: replicatively defective, requiring simultaneous infection with HBV (HBsAg is necessary for development of HDV visions); sexual or parenteral transmission; high in IV drug users

Question 6

Chronic hepatitis

Answer 6

• Inflammation of liver parenchyma that persist for more than 6 months
• May result from any of the viral hepatitides except HAV or HEV and also from liver damage induced by nonviral agents
• Risk of progression to cirrhosis
• Inflammation predominantly in portal tract

Question 7

Reye syndrome

Answer 7

• Acute disorder of young children characterized by encephalopathy, coma, and microvesicular fatty liver
• Associated with aspirin administration to children with acute viral infections
• Likely related to mitochondrial damage of hepatocytes
• Characterized by extensive accumulation of fat droplets within hepatocytes
• Present with hypoglycemia, elevated liver enzymes, and nausea with vomiting

Question 8

Alcoholic liver disease

Answer 8

• The most common form of liver disease in US
  (1) Fatty change (steatosis) - most frequent morphological abnormality caused by alcohol and is reversible
  (2) Alcohol hepatitis - characterized by fatty change, focal liver cell necrosis, infiltrates of neutrophils, and presence of Mallory bodies (eosinophilic cytoplasmic clumps in hepatocytes). Often associated with irreversible fibrosis that characteristically surrounds central veins and has been referred to as perivenular fibrosis
  (3) Alcoholic cirrhosis

Question 9

Cirrhosis

Answer 9

• End-stage liver damage
• Characterized by generalized disorganization of hepatic architecture with scarring and nodule formation.
• Liver cell damage, regenerative activity, and generalized fibrosis resulting in a nodular pattern
• In all forms, there is an increased incidence of hepatocellular carcinoma
• Stellate cell: fibrosis is mediated by TGF-beta from stellate cells
• Etiology: prolonged alcohol intake (60-70%), drugs, and chemical agents, viral hepatitis (10%), biliary obstruction, hemochromatosis, Wilson disease and other inborn errors of metabolism, heart failure with long-standing chronic passive congestion of the liver

Question 10

Alcoholic cirrhosis

Answer 10

• Prototype for all forms of cirrhosis
• Present with jaundice, hypoalbuminemia, coagulation factor deficiencies, hyperestrinism,
• Consequences of intrahepatic scarring with increased portal venous pressure: esophageal varicose, rectal hemorrhoids, periumbilical venous collaterals, splenomegaly
• Changes: peripheral edema, ascites, hydrothorax, encephalopathy

Question 11

Postnecrotic cirrhosis

Answer 11

• Characterized by broad fibrous bands dividing the liver into large, irregular nodules
• Often a sequel of chronic active hepatitis; HBV and HCV are the most common viral causes
• Leads to hepatocellular carcinoma more often than other forms of cirrhosis

Question 12

Bilary cirrhosis

Answer 12

• Occur as primary, probably autoimmune, disorder and much more frequently as a secondary from due to biliary obstruction
  (1) Primary biliary cirrhosis - most likely of autoimmune origin, antimitochondrial antibodies are characteristic. Present with severe obstructive jaundice, itching, and hypercholesterolemia
  (2) Secondary biliary cirrhosis - caused by extrahepatic biliary obstruction

Question 13

Primary sclerosing cholangitis

Answer 13

• Associated with inflammatory bowel disease, especially ulcerative colitis
• Characteristically include inflammation, fibrosis (“onion skin fibrosis”), and stenosis of intrahepatic and extra hepatic bile ducts

Question 14

Hemochromatosis

Answer 14

• Excess body iron leading to deposition in tissues and organ damage
• Damage is mediated by generation of free radicals
  (1) Primary - due to mutations in HFE gene on chromosome 6, most commonly C282Y, or mutation in transferrin receptor 2 (TfR2)
• Presents in late adulthood - cirrhosis, secondary DM, increased skin pigmentation, bronze skin, cardiac arrhythmia and gonadal dysfunction
• Increased ferritin, serum iron and precent saturation, and decreased TIBC
  (2) Secondary - most often associated with a combination of ineffective erythropoiesis and multiple transfusions

Question 15

Wilson disease

Answer 15

• Autosomal recessive disorder of copper metabolism - defect in ATP-mediated hepatocyte copper transport
• AR (mutation in ATP7B gene, chr.13)
• Impaired copper excretion into bile + failure to incorporate Cu into ceruloplasmin
• Characterized by decreased serum ceruloplasmin (copper-binding protein)
• Kayser-Fleischer ring - green ton brown deposits of Cu in the cornea
• Result in accumulation of copper in parenchymal cells of the liver and kidney and in the brain and cornea

Question 16

Portal hypertension

Answer 16

• Characterized by the development of venous collaterals with varices in the submucosal veins of the esophagus, the hemorrhoidal plexus, and other sites
• Classified by the site of portal venous obstruction
  (1) Prehepatic - portal and splenic vein obstruction, most often by thrombosis
  (2) Intrahepatic - intrahepatic vascular obstruction, most often by metastatic tumor or cirrhosis
  (3) Posthepatic - venous congestion in the distal hepatic venous circulation

Question 17

Budd-Chiari syndrome

Answer 17

• Abdominal pain, jaundice, hepatomegaly, ascites, and eventual liver failure
• Cuased by thrombotic occlusion of the major hepatic veins
• Most often associated with polycythemia vera, hepatocellular carcinoma, and other abdominal neoplasms

Question 18

Benign hepatic tumors

Answer 18

(1) Hemangioma - most common benign tumor of the liver
(2) Adenoma - related to use of oral contraceptives. When located subcapsular it may rupture, resulting in sever intraperitoneal hemorrhage.

Question 19

Hepatocellular carcinoma

Answer 19

• Most common primary malignancy of the liver
• Almost always develops in association with preexisting cirrhosis of any kind, esp. when HBV infection cirrhosis
• Associated with aflatoxin B1 contamination of nuts and grains - cause point mutations in p53
• Marked by increased serum alpha-fetoprotein
• Propensity for invasion of vascular channels with hematogenous dissemination

Question 20

Cholangiocarcinoma

Answer 20

• Bile duct carcinoma
• Less common than hepatocellular carcinoma
• Associated with Clonorchis sinensis (liver fluke) infestation
• Originates from intrahepatic biliary epithelium
• Propensity for early invasion of vascular channels
• Occurs sometimes as a late complication of thorium dioxide administration

Question 21

Angiosarcoma

Answer 21

• Rare malignant vascular tumor from of hepatic cancer

- Associated with toxic exposure to polyvinyl chloride, thorium dioxide, and arsenic

Question 22

Acute cholecystitis

Answer 22

• Acute inflammation of gallbladder
• Most often pyogenic
• Impact stone in cystic duct results in dilatation with pressure ischemia, bacterial overgrowth, and inflammation
• Present with nausea, vomiting, fever, and leukocytosis associated with right upper quadrant and epigastric pain

Question 23

Chronic cholecystitis

Answer 23

• Chronic inflammation of gallbladder
• Due to chemical irritation from long-standing cholelithiasis
• Thickening of the gallbladder wall occurs as a result of extensive fibrosis
• Frequently complicated by gallstones
• Rokitansky-Aschoff sinus formation

Question 24

Cholelithiasis

Answer 24

• Solid, rund stones in gallbladder
• Due to precipitation of cholesterol or bilirubin in bile
• Associated with obesity and multiple pregnancies
• Higher incidence in women
  (1) Cholesterol stones - usually radiolucent, risk factors: age, estrogen, clofibrate, Native American ethnicity, Crohn disease, cirrhosis
  (2) Pigment stone - excess insoluble unconjugated bilirubin. Associated with hemolytic anemia and bacterial infection. Usually radiopaque
  (3) Mixed stone - account for most stones (75-80%), mixture of cholesterol and calcium salts
• Complications: biliary colic, common bile duct obstruction, ascending cholangitis, cholecystitis, pancreatitis, gallstone ileum, mucocele, malignancy

Question 25

Ascending cholangitis

Answer 25

• Bacterial infection of bile ducts
• Usually due to ascending infection with enteric gram-negative bacteria
• Presents as sepsis, jaundice, and abdominal pain
• Increased incidence with choledocholithiasis

Question 26

Tumors of the gallbladder

Answer 26

• Benign tumors of gallbladder are rare
• Most common primary tumor of the gallbladder is adenocarcinoma, which is often associated with gallstones
• Classically presents as cholecystitis in elderly women
• Poor prognosis

Question 27

Acute pancreatitis

Answer 27

• Inflammation and hemorrhage of pancreas
• Caused by activation of pancreatic enzymes, resulting in autodigestion of the organ
• Premature activation of trypsin leads to activation of other enzymes
• Hemorrhagic fat necrosis and deposition of calcium soaps, and sometimes formation of pseudocysts
• Most common due to alcohol and gallstones
• Other causes: trauma, hypercalcemia and hyperlipidemia, drugs, scorpion stings, mumps, and rupture of posterior duodenal ulcer
• Present with epigastric abdominal pain that radiates to the back, nausea and vomiting, periumbilical and flank hemorrhage, elevation of serum lipase and amylase, hypocalcemia

Question 28

Chronic pancreatitis

Answer 28

• Fibrosis of pancreatic parenchyma; secondary to recurrent acute pancreatitis
• Most common due to alcohol and cystic fibrosis; many cases are idiopathic
• Present with epigastric abdominal pain radiating to back, pancreatic sufficiency, dystrophic calcification of pancreas, secondary DM, increased risk for pancreatic carcinoma

Question 29

Pancreatic adenocarcinoma

Answer 29

• Common tumor
• Incidence is increasing; more common in smokers
• More often, the carcinoma arises in the head of the pancreas, causing obstructive jaundice
• 85% have extension beyond pancreas at diagnosis
• May present with abdominal pain radiating to the back, weight loss and anorexia, sometimes migratory thrombophlebitis, and frequently common bile duct obstruction resulting in obstructive jaundice
• Trousseau sign
• Often silent before widespread dissemination occurs
• Pancreatin intraducatl neoplasia (PanIN) - KRAS oncogene activation is present in most cases
• Also mutations in p53, p16, and DPC4/SMAD4
• Some arises in association with intraductal papillary mucinous neoplasms

Question 30

Cholestasis

Answer 30

• Impaired bile formation and/or bile flow with accumulation of bile pigment (blb) and other bile elements in the hepatic parenchyma
• Bile pigment in hepatocytes
• “Feathery degeneration” of hepatocytes - is a form of liver parenchymal cell (hepatocyte) death associated with cholestasis
• Bile pigment in bile canaliculi
• Bile pigment in Kupffer cells
• Proliferation of the duct epithelial cells (because of bile stasis and increased bile pressure)
• May present with jaundice, pruritus, skin xanthomas (focal accumulation of cholesterol), nutritional deficiencies (because of intestinal malabsorption), high serum lever of AP and GGT, late change: portal tract fibrosis (cirrhosis)

Question 31

α1-antitrypsin deficiency

Answer 31

• AR (gen on chr. 14)
• Polymorphism
• Some allelic variants: moderate reduction in serum level of alpha1-antitrypsin
• Normal protein synthesis
• Secretion from hepatocytes is blocked - alpha1AT accumulates in endoplasmic reticulum of hepatocytes
• Present with pulmonary emphysema + accumulation of this protein in hepatocytes (liver damage) + cutaneous changes
• Only 10% develop clinical liver disease