Pathogenesis of diseases of the gallbladder and

biliary tract

John J O’Leary

Biliary tract disorders

Disease of intra-hepatic ducts

LARGE DUCT BILIARY OBSTRUCTION,

PRIMARY BILIARY CIRRHOSIS,

PRIMARY SCLEROSING CHOLANGITIS

LARGE DUCT BILIARY OBSTRUCTION

• Usually extrahepatic, rarely intrahepatic at porta hepatis• Causes - gallstones, tumours, strictures, biliary atresia• Effects on the liver:

Acini - perivenular (zone 3) cholestasis Portal tracts - bile duct proliferation at margins of tracts - neutrophil polymorph infiltrate - oedema of connective tissue Sometimes bile “infarcts” and bile lakes (duct rupture)

• Complications: - acute suppurative cholangitis (ascendingcholangitis).

- liver abscesses if untreated - secondary biliary cirrhosis if unrelieved

• Clinical features of cholestatic jaundice

PRIMARY BILIARY CIRRHOSIS

• A chronic cholestatic disease due to a non-suppurative destructive cholangitis of intrahepatic bile ducts, immune mediated

• F:M as 10:1. Age range 20-80years, peak at 40-50• May be associated with other autoimmune diseases• Very insidious onset, may be asymptomatic for decades, pruritis,

fatigue, xanthelasmas, leading to frank cholestatic jaundice, cirrhosis• 90-95% positive anti-mitochondrial antibodies (AMA) against E2 subunit

of pyruvate dehydrogenase complex inner mitochondrial membrane• Characteristically a granulomatous destruction of bile ducts. Leads to

ductopenia. Copper accumulates in periportal hepatocytes due to chronic cholestasis. Chronic inflammation in portal tracts with interface hepatitis. Portal fibrosis progresses to cirrhosis

• Liver biopsy used to confirm diagnosis and to stage the disease

PRIMARY SCLEROSING CHOLANGITIS

• A chronic cholestatic disease due to a non-specific inflammatory fibrosis of bile ducts, intrahepatic and extrahepatic

• M:F as 2:1. Affects mostly young men

• 70% have ulcerative colitis. Linkage with HLAB8, DR2, DR3. pANCA+

• May be associated with other rare fibrosing conditions

• May be asymptomatic, pruritis and cholestatic jaundice and then cirrhosis develop over many years

• Concentric fibrosis of bile ducts; may result in a scar at site of duct. Leads to ductopenia. Copper accumulates in periportal hepatocytes. Usually scanty lymphocytic infiltrate. Portal fibrosis progresses to cirrhosis. Liver biopsy used to confirm diagnosis and stage

• 10% at risk of developing cholangiocarcinoma

MISCELLANEOUS BILE DUCT DISEASES

• Acquired sclerosing cholangitis can occur in a number of conditions including AIDS.

• Bile duct injury can also occur with liver allografts, graft-versus-host-disease (GVHD), viral hepatitis, drugs, toxins, pyogenic infections, parasitic infestations and other rare conditions.

Disease of extra-hepatic bile ducts

• Biliary atresia is among several neonatal and childhood disorders such as the fibropolycystic disorders which include congenital hepatic fibrosis and various cystic conditions.

• Cholangitis – acute inflammation of the wall of bile ducts. Can result from obstruction of the biliary tree.

• Choledocholithiasis – presence of gallstones in the biliary tree

Cholangitis

Biliary atresia

• Neonatal cholestasis• Occurs in 1:10,000 live births• Complete obstruction of bile flow caused by destruction or

absence of all or part of the extra-hepatic bile ducts• Most likely an acquired inflammatory disorder on unknown cause• Most frequent cause of death from liver disease in early childhood• Features:

– Inflammation and fibrosing stricture of the hepatic or common bile duct

– Inflammation of the major intra-hepatic ducts with destruction– Features of biliary obstruction on biopsy– Peri-portal fibrosis within 3-6 months of birth

Biliary atresia

Gall bladder disorders

Cholelithiasis: gallstones

• Gallstones afflict 10% of the population• 80% of stones are cholesterol stones• Remainder: bilirubin calcium salts [pigment stones]• Risk factors:

– Demography [Europe, N & S America, Mexico]– Advancing age– Female sex– Obesity– Rapid weight reduction– Gallbladder stasis– Hyerlipidaemia– Chronic haemolytic syndromes– Biliary infection– Gastrointestinal disorders: [CD, CF, pancreatic insufficiency]

Gallstones

Cholecystitis

• Inflammation of the gallbladder• Acute and chronic• Almost always occurs in association with stones• May get empyema [pus] in the acute phase• Approx. 5-10% of gallbladders removed for acute

cholecystitis do not contain stones• Chronic: results from acute bouts and is commonly

associated with gallstones

Acute cholecystitis

Chronic cholecystitis

Carcinoma of the gallbladder

• Fifth most common cancer of the digestive tract• Most frequently occurs in the 7th decade of life• 5 year survival: 1%• Rarely resectable when found• Gallstones are present in 50-70% of cases• In Asia: parasitic and pyogenic disease associated• Symptoms:

– Abdominal pain, anorexia, jaundice, nausea and vomiting

Carcinoma of the gallbladder

Molecular progression of carcinoma of the gallbladder

2 molecular pathways fordevelopment of gallbladder carcinoma

Carcinoma of the extra-hepatic bile ducts [including the Ampulla of Vater]

• Cholangiocarcinomas• Extremely insidious onset, painless with progressive

jaundice• Hepatomegaly present in 50% of patients• Distended gallbladder in approx. 25% of patients• Features of extra-hepatic bile duct obstruction

Carcinoma of extra-hepatic bile ducts