02.03.12: Cholestatic Liver Diseases

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  • 1.Author(s): Rebecca W. Van Dyke, M.D., 2012License: Unless otherwise noted, this material is made available under the termsof the Creative Commons Attribution Share Alike 3.0 License:http://creativecommons.org/licenses/by-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.

2. Attribution Key for more information see: http://open.umich.edu/wiki/AttributionPolicyUse + Share + Adapt{ Content the copyright holder, author, or law permits you to use, share and adapt. }Public Domain Government: Works that are produced by the U.S. Government. (17 USC 105)Public Domain Expired: Works that are no longer protected due to an expired copyright term.Public Domain Self Dedicated: Works that a copyright holder has dedicated to the public domain.Creative Commons Zero WaiverCreative Commons Attribution LicenseCreative Commons Attribution Share Alike LicenseCreative Commons Attribution Noncommercial LicenseCreative Commons Attribution Noncommercial Share Alike LicenseGNU Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. }Public Domain Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC 102(b)) *laws inyour jurisdiction may differ{ Content Open.Michigan has used under a Fair Use determination. }Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC 107) *laws inyour jurisdiction may differOur determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guaranteethat your use of the content is Fair.To use this content you should do your own independent analysis to determine whether or not your use will be Fair. 3. M2 GI Sequence Cholestatic Liver DiseasesRebecca W. Van Dyke, MDWinter 2012 4. Learning ObjectivesAt the end of this lecture the student should be able to: 1. Define cholestatic and hepatocellular liver disease, provide examples of bothand be able to interpret panels of liver tests. 2. Define the difference between intrahepatic and extrahepatic cholestasis andoutline approaches to distinguishing them. 3. Define the pathophysiology of representative cholestatic diseases, includingdrug-induced cholestasis, primary biliary cirrhosis, primary sclerosingcholangitis and bile duct obstruction. 4. Outline an approach to the evaluation of the jaundiced patient. 5. Define acute and chronic hepatocellular liver disease and providerepresentative examples. 5. Industry Relationship Disclosures Industry Supported Research and Outside Relationships None 6. Common Types of Liver DiseaseHepatocellular: Injury to hepatocytes (necrosis/apoptosis)Consequences: decreased synthetic/metabolic activity release of intracellular contents (AST/ALT)Cholestasis: Impaired bile formation (hepatocytes) Impaired bile flow (bile ducts/ductules) Consequences: build up in blood of substances normally excreted in bile (bilirubin, bile acids) synthesis/release of apical membrane proteins (AP) 7. Cholestasis =impaired bileflowStructuresinvolved insecretion andpassage ofbile 8. Cholestatic Liver DiseaseClassification of cholestatic diseases:1. A functional impairment in bile formation at the level of the hepatocyte.2. A structural interference with normal bile secretion andflow at the level of small intrahepatic bile ducts.3. A structural interference with normal bile flow at thelevel of large and extrahepatic bile ducts. 9. Cholestatic Liver DiseaseBiochemical cholestasis:increased serum bilirubinincreased serum alkaline phosphataseClinical cholestasis: jaundicedark urine/clay-colored fecespruritusPathological cholestasis: bile plugs in dilated canaliculiincreased bile pigment in hepatocytesbile lakes/bile infarctsbiliary infection (acute cholangitis) 10. Tests for Evaluating Cholestasis Screening tests that suggest cholestasis Color change in skin/sclerae/stool/urine Laboratory biochemical tests (Alk Phos, Bilirubin) Diagnostic tests to establish proof of disease Liver biopsy Indirect visualization of dilated bile ducts and/or massescompressing bile ducts/stones (CT, U/S) Direct visualization of lumen of bile ducts allowingidentification of plumbing problems ERCP - endoscopic retrograde cholangiopancreatography MRCP - magnetic resonance cholangiopancreatography 11. Jaundice: Consequence of Cholestasis 12. Hypercarotenemia (hand on the right) the only other potential disease in the differential diagnosis of yellow skin 13. Clinical Consequences of SevereCholestasis: 1. Clay-colored stools 2. Bilirubin in urine 14. Cholestasis: Specific Examples1. Intrahepatic cholestasis due to decreased bile formation:SepsisEstrogens2. Intrahepatic cholestasis due to diseases that alterintrahepatic bile ducts: Primary biliary cirrhosis Infiltration of liver with tumor/granulomas3. Intrahepatic cholestasis due to any severe liver disease:Viral hepatitis4. Extrahepatic bile duct obstruction: Tumor, gallstones, duct strictures Primary sclerosing cholangitis 15. Cholestasis:Specific Abnormalities in Bile FormationTransporters involved in uptake and biliary secretionof bilirubin and/or bile acids may be inhibited byvarious agents, leading to cholestasis and jaundice.Examples: EstrogensEndotoxin/tumor necrosis factor 16. Intrahepatic Cholestasis: Retained bilepigments/bilirubin in hepatocytesRetained bile 17. Transporters Inhibited by Estrogens HepatocyteSinusoidalBlood N+aBileCanaliculusBileAcid ADPBile acids ATPBilirubin conjugatesG lutathione S-conjugatesother organic anionsPADPAT 18. Intrahepatic CholestasisIntrahepatic cholestasis due to diseases thatcompress and/or destroy intrahepatic bile ducts:Primary Biliary CirrhosisInfiltration of liver with tumor/granulomas 19. Primary Biliary Cirrhosis Chronic, slowly evolving cholestaticdisorder Primarily affects middle-aged women Primary lesion: T cell mediated destruction of intrahepaticbile ducts Slow progression to cirrhosis Relative sparing of hepatocytes withrelative preservation of liver function 20. Primary Biliary Cirrhosis (PBC)Typical laboratory abnormalities:Alk Phos1050 IU/l (nl 50-110)Bilirubin 1.0-2.0 mg/dl (nl 0.4-1.0)AST/ALT 75-150 IU/l (nl 25-60)Albumin 3.7 gm/dl (nl 3.5-4.5)Prothrombin time11 seconds(nl 8-12)Cholesterol 420 mg/dl (nl 110-200)Antimitochondrial antibody:positive in 95%Liver copper: may be elevated due to chronic cholestasis 21. Early lesion of Primary Biliary Cirrhosis 22. Bile duct 23. Primary Biliary Cirrhosis (PBC)Clinical Findings: Jaundice Pruritus (related to retention of bile acids and other substances) Xanthomas/xanthalasmas (cholesterol deposits in skin) 24. Jaundice 25. Skin lesions onthe back fromscratching dueto pruritus inPrimary BiliaryCirrhosis 26. PBC: xanthalasmas 27. PBC: xanthomas 28. Infiltrative/Granulomatous DiseasesOften present with cholestasis: elevated alkaline phosphatase with or without jaundiceIncreased alk phos due to compression of small intrahepatic bile ducts by expanding granulomasExamples: tuberculosissarcoidosis 29. Hepatic Granulomas/Sarcoidosis 30. Hepatic Sarcoidosis: granulomas and giant cells 31. Extrahepatic BiliaryObstruction 32. LiverExtra- Commonhepatic ductHepatic GallbladderBileIntrahepaticDucts PerihilarObstruction ofDistalthe bile ducts extrahepaticat any pointoutside theCommon bile ductliver cancauseAmpulla Of VatercholestasisDuodenumby blockingbile flow.Adapted from Gordon Flynn, Wikimedia Commons 33. ERCP (normal)Endoscopic Retrograde CholangioPancreatography 34. Common Liverhepatic ductGallbladderDoes Intrahepaticobstructionof the cysticPerihilarductor gallbladder Distalcause jaundice? extrahepaticCommonbile ductAmpullaOf Vater Duodenum Adapted from Gordon Flynn, Wikimedia Commons 35. Subsets of Extrahepatic Biliary ObstructionIntrinsic ObstructionExtrinsic ObstructionGallstones Tumor:Biliary Strictures pancreatic postsurgicalcholangiocarcinomaPrimary sclerosing cholangitis periampullary lymphomaWorms/parasitesor metastatic tumorBlood clot/hemobilia Acute/chronic pancreatitis (edema/fibrosis in headof pancreas) Congenital disease: biliary atresia choledochal cyst 36. Primary Sclerosing Cholangitis Slowly evolving disease with fibrosis, stricturing andinflammation around extrahepatic bile ducts. May also affect intrahepatic ducts Primarily affects middle-aged men Associated with ulcerative colitis. Complications include complete duct obstruction, jaundice, biliaryinfection (cholangitis), pruritus. Relative preservation of hepatocytes. 37. Primary Sclerosing CholangitisTypical laboratory abnormalities:Alk Phos875 IU/l(nl 50-110)Bilirubin 2.0-5.0 mg/dl (nl 0.4-1.0)AST/ALT 75-150 IU/l (nl 25-60)Albumin 3.5 gm/dl (nl 3.5-4.5)Prothrombin time11 seconds(nl 8-12) 38. Primary Sclerosing CholangitisTypical Clinical Findings: Bile duct obstruction: best seen on direct imaging Jaundice and dilated bile ducts if complete obstruction of major duct occurs. Bile plugs/bile lakes/bile infarcts on liver biopsy Biliary infection (cholangitis) - acute bacterial infection of stagnant bile. Cirrhosis 39. Sclerosing Cholangitis:onion-skinning fibrosi