Pathogenesis of diseases of the gallbladder and biliary tract

1. Pathogenesis of diseases of the gallbladder and biliary tract John J O’Leary

2. Biliary tract disorders

3. Disease of intra-hepatic ducts LARGE DUCT BILIARY OBSTRUCTION, PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING CHOLANGITIS

4. 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 (ascending cholangitis). - liver abscesses if untreated - secondary biliary cirrhosis if unrelieved • Clinical features of cholestatic jaundice

5. 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

7. 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

10. 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.

11. Disease of extra-hepatic bile ducts

12. 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

13. Cholangitis

14. 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

15. Biliary atresia

17. Gall bladder disorders

18. 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]

19. Gallstones

20. 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

21. Acute cholecystitis

22. Chronic cholecystitis

23. 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

24. Carcinoma of the gallbladder

25. Molecular progression of carcinoma of the gallbladder

26. 2 molecular pathways for development of gallbladder carcinoma

27. 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

28. Carcinoma of extra-hepatic bile ducts