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 7 th 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