Pathogenesis of diseases of the gallbladder and biliary tract

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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. - PowerPoint PPT Presentation

Transcript of Pathogenesis of diseases of the gallbladder and biliary tract

  • Pathogenesis of diseases of the gallbladder and biliary tractJohn J OLeary

  • Biliary tract disorders

  • Disease of intra-hepatic ductsLARGE DUCT BILIARY OBSTRUCTION, PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING CHOLANGITIS

  • LARGE DUCT BILIARY OBSTRUCTIONUsually extrahepatic, rarely intrahepatic at porta hepatisCauses - gallstones, tumours, strictures, biliary atresiaEffects on the liver:Acini - perivenular (zone 3) cholestasisPortal tracts - bile duct proliferation at margins of tracts - neutrophil polymorph infiltrate - oedema of connective tissueSometimes bile infarcts and bile lakes (duct rupture)Complications: - acute suppurative cholangitis (ascendingcholangitis). - liver abscesses if untreated - secondary biliary cirrhosis if unrelievedClinical features of cholestatic jaundice

  • PRIMARY BILIARY CIRRHOSISA chronic cholestatic disease due to a non-suppurative destructive cholangitis of intrahepatic bile ducts, immune mediatedF:M as 10:1. Age range 20-80years, peak at 40-50May be associated with other autoimmune diseasesVery insidious onset, may be asymptomatic for decades, pruritis, fatigue, xanthelasmas, leading to frank cholestatic jaundice, cirrhosis90-95% positive anti-mitochondrial antibodies (AMA) against E2 subunit of pyruvate dehydrogenase complex inner mitochondrial membraneCharacteristically 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 cirrhosisLiver biopsy used to confirm diagnosis and to stage the disease

  • PRIMARY SCLEROSING CHOLANGITISA chronic cholestatic disease due to a non-specific inflammatory fibrosis of bile ducts, intrahepatic and extrahepaticM:F as 2:1. Affects mostly young men70% have ulcerative colitis. Linkage with HLAB8, DR2, DR3. pANCA+May be associated with other rare fibrosing conditionsMay be asymptomatic, pruritis and cholestatic jaundice and then cirrhosis develop over many yearsConcentric 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 stage10% at risk of developing cholangiocarcinoma

  • MISCELLANEOUS BILE DUCT DISEASESAcquired 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 atresiaNeonatal cholestasisOccurs in 1:10,000 live birthsComplete obstruction of bile flow caused by destruction or absence of all or part of the extra-hepatic bile ductsMost likely an acquired inflammatory disorder on unknown causeMost frequent cause of death from liver disease in early childhoodFeatures:Inflammation and fibrosing stricture of the hepatic or common bile ductInflammation of the major intra-hepatic ducts with destructionFeatures of biliary obstruction on biopsyPeri-portal fibrosis within 3-6 months of birth

  • Biliary atresia

  • Gall bladder disorders

  • Cholelithiasis: gallstonesGallstones afflict 10% of the population80% of stones are cholesterol stonesRemainder: bilirubin calcium salts [pigment stones]Risk factors:Demography [Europe, N & S America, Mexico]Advancing ageFemale sexObesityRapid weight reductionGallbladder stasisHyerlipidaemiaChronic haemolytic syndromesBiliary infectionGastrointestinal disorders: [CD, CF, pancreatic insufficiency]

  • Gallstones

  • CholecystitisInflammation of the gallbladderAcute and chronicAlmost always occurs in association with stonesMay get empyema [pus] in the acute phaseApprox. 5-10% of gallbladders removed for acute cholecystitis do not contain stonesChronic: results from acute bouts and is commonly associated with gallstones

  • Acute cholecystitis

  • Chronic cholecystitis

  • Carcinoma of the gallbladderFifth most common cancer of the digestive tractMost frequently occurs in the 7th decade of life5 year survival: 1%Rarely resectable when foundGallstones are present in 50-70% of casesIn Asia: parasitic and pyogenic disease associatedSymptoms: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]CholangiocarcinomasExtremely insidious onset, painless with progressive jaundiceHepatomegaly present in 50% of patientsDistended gallbladder in approx. 25% of patientsFeatures of extra-hepatic bile duct obstruction

  • Carcinoma of extra-hepatic bile ducts