02.03.12: Cholestatic Liver Diseases


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02.03.12: Cholestatic Liver Diseases

  1. 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.
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  3. 3. M2 GI Sequence Cholestatic Liver Diseases Rebecca W. Van Dyke, MDWinter 2012
  4. 4. Learning Objectives• At the end of this lecture the student should be able to:•• 1. Define cholestatic and hepatocellular liver disease, provide examples of both and be able to interpret panels of liver tests.•• 2. Define the difference between intrahepatic and extrahepatic cholestasis and outline approaches to distinguishing them.•• 3. Define the pathophysiology of representative cholestatic diseases, including drug-induced cholestasis, primary biliary cirrhosis, primary sclerosing cholangitis and bile duct obstruction.•• 4. Outline an approach to the evaluation of the jaundiced patient.•• 5. Define acute and chronic hepatocellular liver disease and provide representative examples.
  5. 5. Industry Relationship Disclosures Industry Supported Research and Outside Relationships• None
  6. 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. 7. Cholestasis =impaired bileflowStructuresinvolved insecretion andpassage ofbile
  8. 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 and flow at the level of small intrahepatic bile ducts.3. A structural interference with normal bile flow at the level of large and extrahepatic bile ducts.
  9. 9. Cholestatic Liver DiseaseBiochemical cholestasis: increased serum bilirubin increased serum alkaline phosphataseClinical cholestasis: jaundice dark urine/clay-colored feces pruritusPathological cholestasis: bile plugs in dilated canaliculi increased bile pigment in hepatocytes bile lakes/bile infarcts biliary infection (acute cholangitis)
  10. 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 masses compressing bile ducts/stones (CT, U/S) – Direct visualization of lumen of bile ducts allowing identification of plumbing problems • ERCP - endoscopic retrograde cholangiopancreatography • MRCP - magnetic resonance cholangiopancreatography
  11. 11. Jaundice: Consequence of Cholestasis
  12. 12. Hypercarotenemia (hand on the right) – the only other potential disease in the differential diagnosis of yellow skin
  13. 13. Clinical Consequences of SevereCholestasis: 1. Clay-colored stools 2. Bilirubin in urine
  14. 14. Cholestasis: Specific Examples1. Intrahepatic cholestasis due to decreased bile formation: Sepsis Estrogens2. 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. 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: Estrogens Endotoxin/tumor necrosis factor
  16. 16. Intrahepatic Cholestasis: Retained bile pigments/bilirubin in hepatocytes Retained bile
  17. 17. Transporters Inhibited by Estrogens HepatocyteSinusoidalBlood N+ a Bile Canaliculus Bile Acid ADP Bile acids ATP Bilirubin conjugates G lutathione S-conjugates other organic anions P AD P AT
  18. 18. Intrahepatic CholestasisIntrahepatic cholestasis due to diseases thatcompress and/or destroy intrahepatic bile ducts: Primary Biliary Cirrhosis Infiltration of liver with tumor/granulomas
  19. 19. Primary Biliary Cirrhosis• Chronic, slowly evolving cholestatic disorder• Primarily affects middle-aged women• Primary lesion: – T cell mediated destruction of intrahepatic bile ducts – Slow progression to cirrhosis• Relative sparing of hepatocytes with relative preservation of liver function
  20. 20. Primary Biliary Cirrhosis (PBC)Typical laboratory abnormalities:Alk Phos 1050 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 time 11 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. 21. Early lesion of Primary Biliary Cirrhosis
  22. 22. Bile duct
  23. 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. 24. Jaundice
  25. 25. Skin lesions onthe back fromscratching dueto pruritus inPrimary BiliaryCirrhosis
  26. 26. PBC: xanthalasmas
  27. 27. PBC: xanthomas
  28. 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: tuberculosis sarcoidosis
  29. 29. Hepatic Granulomas/Sarcoidosis
  30. 30. Hepatic Sarcoidosis: granulomas and giant cells
  31. 31. Extrahepatic Biliary Obstruction
  32. 32. LiverExtra- Common hepatic ductHepatic GallbladderBile IntrahepaticDucts PerihilarObstruction of Distalthe bile ducts extrahepaticat any pointoutside the Common bile ductliver cancause Ampulla Of Vatercholestasis Duodenumby blockingbile flow. Adapted from Gordon Flynn, Wikimedia Commons
  33. 33. ERCP (normal)Endoscopic Retrograde CholangioPancreatography
  34. 34. Common Liver hepatic duct GallbladderDoes Intrahepaticobstructionof the cystic Perihilarductor gallbladder Distalcause jaundice? extrahepatic Common bile duct Ampulla Of Vater Duodenum Adapted from Gordon Flynn, Wikimedia Commons
  35. 35. Subsets of Extrahepatic Biliary ObstructionIntrinsic Obstruction Extrinsic ObstructionGallstones Tumor:Biliary Strictures pancreatic postsurgical cholangiocarcinomaPrimary sclerosing cholangitis periampullary lymphomaWorms/parasites or metastatic tumorBlood clot/hemobilia Acute/chronic pancreatitis (edema/fibrosis in headof pancreas) Congenital disease: biliary atresia choledochal cyst
  36. 36. Primary Sclerosing Cholangitis• Slowly evolving disease with fibrosis, stricturing and inflammation around extrahepatic bile ducts. – May also affect intrahepatic ducts• Primarily affects middle-aged men – Associated with ulcerative colitis.• Complications include complete duct obstruction, jaundice, biliary infection (cholangitis), pruritus.• Relative preservation of hepatocytes.
  37. 37. Primary Sclerosing CholangitisTypical laboratory abnormalities:Alk Phos 875 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 time 11 seconds (nl 8-12)
  38. 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. 39. Sclerosing Cholangitis:“onion-skinning fibrosis” around bile ducts very thickened bile duct wall decreases luminal diameter
  40. 40. Biliary obstruction• When bile ducts are obstructed, what happens to the bile?• What happens to the bile duct upstream of the obstruction?
  41. 41. Evidence of Bile Duct Obstruction: Dilated ducts upstream of the obstructionBile-filled dilated bileducts are large darkgray tubularstructures that runparallel to the portalveins (white arrows).Portal veins are whitedue to IV contrast.liver parenchyma islight gray due to IVcontrast.
  42. 42. Dilated bile ducts and gallbladder GallbladderDilated bile ducts Mass in head of the pancreas
  43. 43. Bile Duct Obstruction: Bile Plugs in Bile Ducts Portal vein HA
  44. 44. More canalicular cholestasis
  45. 45. Acute Cholangitis: PMNs in Bile Duct HA
  46. 46. Other Causes of Extra-hepatic Biliary Obstruction
  47. 47. High grade cholangiocarcinoma at the hilum
  48. 48. High grade bilateral obstructionfrom metastatic rectal carcinoma
  49. 49. Biliary stricture due to cholangiocarcinomaAlk phos = 669 IUBili = 17.5 mg/dlAST = 68 IUALT = 38 IU
  50. 50. A plastic stent bridges More permanent metal the stenosis mesh stent placed
  51. 51. Bile ductobstructionfrom chronicpancreatitis
  52. 52. Biliary Obstruction:Multiple stonesin biliary tree
  53. 53. Bile Duct Dilation due to Obstruction Large ducts near Small peripheral hilum massively ducts also enlarged dilated and visible
  54. 54. An unusualcause of biliaryobstructionRadio-opaque dyeinjected through T-tubefills common bile ductand intrahepatic bileducts.Dark linearstructures are ascariasislocated in biliary system(black arrows).
  55. 55. Ascaris emerging from commonbile duct as seen endoscopically
  56. 56. Consequences of Cholestasis• Secondary liver damage – Bile acid-induced hepatocyte injury – Secondary biliary cirrhosis• Failure of substances secreted in bile to reach intestine – Bile acid deficiency in gut – Fat malabsorption/fat-soluble vitamin malabsorption
  57. 57. SUMMARY: EVALUATION OF CHOLESTASIS AND/OR JAUNDICE1. Suspect cholestasis based on history, physical exam, lab tests.2. Look for clues to mechanical obstruction of ducts and/or mass lesions (radiologic studies).3. Visualize, diagnose and treat mechanical obstruction.4. Consider intrahepatic cholestasis, obtain liver biopsy. See algorithms in syllabus and in textbook
  58. 58. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 32 & 34: Adapted from Gordon Flynn, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Digestive_system_with_liver.png, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.5/deed.en