Primary Biliary Cirrhosis (PBC)

1. Primary Biliary Cirrhosis(PBC) Thomas W. Faust, M.D., M.B.E. Associate Prof. of Clinical Medicine The University of Pennsylvania May 19, 2010

2. Introduction Epidemiology Genetics Pathogenesis Clinical presentation Extrahepatic manifestations Differential diagnosis Diagnosis Management Medical Surgical Complications Portal hypertension Cholestasis Natural history and prognosis Summary PBCOverview

3. Chronic cholestatic liver disease Autoimmune basis Middle-aged females Disease of small bile ducts Cirrhosis with portal hypertension Complications of cholestasis Diagnosis Liver function tests Antimitochondrial antibodies (AMA) Histology UDCA for all patients Transplantation Marginal liver reserve Poor quality of life Prognostic models PBCIntroduction

4. PBCEpidemiology • Female:male ratio of 9:1 • Most common during middle age • Presentation similar between genders, races, and sexes • Prevalence: 19-150 cases/million • Incidence: 4-15 cases/million/yr • Incidence/prevalence rates increasing? • Familial clustering Kaplan et al. NEJM 2005;353(12):1261

5. PBCGenetics • MHC class II • DR8, DQA1*0102, and DQ/1*0402 • MHC class III • C4 null, and c4B2 • Non-MHC genes • Exon 1 of CTLA-4 • Increased familial risk • PBC/positive AMA and impaired T-cell regulation • Extrahepatic autoimmune diseases

6. PBCPathogenesis • A model autoimmune disease • Genetic susceptibility plus triggering event • AMA titer • No correlation with disease severity • No difference in AMA (+) and (-) disease • Role in pathogenesis? • Reactive against E2 subunit of pyruvate dehydrogenase • Antigen expression • Inner mitochondrial membrane • Luminal surface of biliary epithelial cell • Interlobular and septal bile ducts • Apoptosis • Cholangiocyte Fas receptor expression • Cholestasis James et al. Ann. Intern Med 1983;99(4):500 Selmi et al. Gastroenterology 2004;127(2):485

7. PBCPathogenesis • Antigens on inner mitochondrial membrane • Oxoacid dehydrogenase complex • Autoreactivity to E2 subunit of this complex • Molecular mimicry • Bacterial or viral proteins, or halogenated hydrocarbons similar to E2 subunit? • Immune attack of biliary epithelial cells • CD4 and CD8 T lymphocytes • Aberrantly expressed antigens • Antigens similar to E2 subunit exposed after contact with exogenous xenobiotics that damage biliary epithelial cells • MHC class II and I antigen restriction and T cell interactions Gershwin et al. Hepatology 2005;42(5):1194 Selmi et al. Gastroenterology 2004;127(2):493 Kaplan et al. NEJM 2005;353:1261

8. PBCAsymptomatic Disease • 50-60% of patients (earlier diagnosis) • 36-89% of asymptomatic patients develop symptoms within 4.5-17 years • Elevated AMA • Liver biopsy C/W PBC • Liver chemistry tests • Normal • Cholestatic • 50-70% 10 year survival in asymptomatic patients and median survival of 5-8 years from onset of symptoms (pre-UDCA era) • UDCA associated with better survival when compared to pre-UDCA era Balasubramaniam et al. Gastroenterology 1990;98(6):1567

9. Fatigue (common) Pruritus Jaundice Hepatosplenomegaly RUQ pain Hyperpigmentation Xanthomas and xanthelasmas Dyslipidemia Extrahepatic autoimmune diseases Complications Portal hypertension Chronic cholestasis PBCSymptomatic Disease Koulentaki et al. Am J Gastroenterol 2006;101(3):541

10. Chronic cholestasis Osteopenia Malabsorption Steatorrhea Bile salt deficiency Pancreatic disease Celiac disease Vitamin A, D, E, K deficiency Portal hypertension Esophageal and gastric varices Ascites Encephalopathy SBP HRS or HPS Hepatocellular carcinoma PBCComplications

11. PBCPortal Hypertension HCC Ascites Varices

12. Osteoporosis Most common Duration/severity of PBC and jaundice Axial skeleton Reduced osteoblastic activity DEXA scanning Calcium, vitamin D, and bisphosphonates? Estrogens? Osteomalacia Less common Vitamin D deficiency and fat malabsorption Calcium and phosphate levels 25-hydroxyvitamin D level Calcium and vitamin D supplements PBCMetabolic Bone Disease

13. PBCMetabolic Bone Disease Compression fractures

14. PBCDyslipidemia • Early disease • Increased HDL, LDL, and VLDL • Late disease • Fall in HDL and rise in LDL • Xanthomas and xanthelasmas • Cholesterol > 600 mg/dL • Atherosclerosis risk • No increased risk of ischemia heart disease, stroke or TIA unless there is a separate lipid disorder

15. PBCDyslipidemia Xanthomas Xanthelasmas Xanthomas Xanthomas

16. Thyroid disease Hashimoto’s thyroiditis Grave’s disease Scleroderma CREST syndrome Sjogren’s syndrome Arthritis Raynaud’s phenomenon Celiac disease Renal tubular acidosis Proximal Distal Gallstones Hematologic disorders Inflammatory bowel disease (rare) Pulmonary interstitial fibrosis (rare) PBCAssociated Diseases

17. PBCCrest Syndrome Calcinosis Raynauds Sclerodactyly Telangiectasia

18. Biliary stones or strictures Pancreaticobiliary malignancies PSC Autoimmune hepatitis Alcoholic hepatitis Viral hepatitis Sarcoidosis Autoimmune cholangiopathy Medications Granulomatous hepatitis PBCDifferential Diagnosis

19. Biochemical tests Alkaline phosphatase GGT 5’ nucleotidase AST and ALT Bilirubin Total cholesterol Serum IgM Prothrombin time Albumin Serology AMA (95%) ANA (50%) ASMA (50%) Anti-centromere Anti-thyroid Medical imaging Ultrasound CT MR or MRCP PBCNon-Invasive Tests Dickson et al. Hepatology 1989;10(1):1 Muratori et al. Clin Liver Dis 2008;12(2):261 Kaplan et al. N Engl J Med 2005;353(12):1261

20. Stage I (portal) Inflammation of interlobular and septal bile ducts Granulomatous (florid duct) lesion Stage II (periportal) Inflammation of interlobular and septal bile ducts Ductular proliferation Stage III (septal) Inflammation of interlobular and septal bile ducts Fibrosis Bile duct loss Cholestasis Stage IV (cirrhotic) Established cirrhosis PBCHistology Scheuer et al. Mayo Clin Proc 1998;73(2):179

21. PBCPathology Cirrhosis NRH

22. PBCOverall Management • Survival of patients with PBC inferior to that of a healthy control population • Medical or surgical treatment warranted in all patients • No medical therapy has been shown to conclusively alter the history of PBC • Goals of treatment • Slow disease progression • Treat complications

23. PBCMedical Management • PBC: an autoimmune disease • Improve clinical symptoms and signs of disease • Improve liver function tests • Reduce or eliminate bile duct injury • Improve patient survival free of transplantation

24. Ineffective Corticosteroids Azathioprine Cyclosporine Penicillamine Colchicine Chlorambucil Possibly effective Methotrexate Mycophenolate mofetil Effective Ursodeoxycholic acid Improvement in symptoms Improvement in LFTs Improvement in histology Improvement in transplant free survival Combination therapy? Additional studies warranted PBCMedical Management

25. PBCUDCA • Effective dose: 13-15 mg/kg/day indefinitely • Mechanism of action • Promotes endogenous bile acid secretion • Replacement of hepatotoxic (endogenous) bile acids • Stabilizes biliary epithelial cell membranes • Alters HLA I-II expression on biliary epithelial cell • Inhibits biliary cell apoptosis • Improvement in LFTs • Delays disease progression and improves transplant-free survival • Follow LFTs every 3-6 mo. Poupon et al. N Engl J Med. 1994;330(19):1342 Heathcote et al. Hepatology 1994;19(5):1149

26. PBCIncomplete Responders to UDCA • 66% of patients • Definition • Failure to normalize LFTs • Development of cirrhosis on therapy • Predictors of incomplete response • High alkaline phosphatase or GGT • Advanced disease prior to UDCA initiation • Assess: patient compliance, UDCA dose, overlap syndrome Combes et al. Hepatology 1995;22(3):759 Poupon et al. J Hepatolol 2003;39(1):12

27. PBCMethotrexate • Dose: 7.5-15 mg/week orally • Improvement • Symptoms • LFTs • Histology? • Survival? • Side effects limit long-term use

28. PBCCombination Therapies • UDCA and corticosteroids • Improvement in LFTs • Variable improvement in histology • UDCA and colchicine • No significant benefit • UDCA and methotrexate • Improvement in LFTs ? • Additional studies warranted

29. PBCNovel Agents • Malotilate • Improvement in LFTs • No improvement in survival • Bezafibrate • Improvement in LFTs • Thalidomide • No improvement in LFTs • No improvement in histology

30. Advanced PBC with marginal reserve Portal hypertension Refractory variceal bleeding Intractable ascites Intractable encephalopathy SBP HRS or HPS Chronic cholestasis Intractable pruritus Metabolic bone disease and fractures Malabsorption Vitamin deficiency Hepatocellular Cancer Transplant options Cadaveric donation Live donation PBCLiver Transplantation Lee et al. Clin Gastroenterol Hepatol 2007;5(11):1313 Dickson et al. Hepatology 1989;10(1):1

31. PBCLiver Transplantation • Patient and graft survival • 1 yr : 83-92% • 5 yr : 75-85% • Higher risk of rejection • PBC recurrence • 15 to 25% of patients at 10 years • Granulomatous bile duct injury • AMA does not define recurrence • Exclude other post transplant disorders • Intermediate term patient and graft survival are good • Use of UDCA for recurrent disease uncertain Liermann et al. Hepatology 2001;33(1):22

32. Variceal bleeding Endoscopic screening Non-selective beta blockers Endoscopic therapy Sclerotherapy Band ligation Surgical shunts TIPS HCC AFP/imaging Ascites Sodium restricted diets Diuretics Therapeutic paracentesis TIPS Encephalopathy Lactulose Neomycin Rifaxamin Protein modification PBCComplications of Portal Hypertension

33. 30-50% of patients Classification Osteoporosis: common Osteomalacia: rare Bone density Below fracture threshold (33%) Diagnosis and F/U DEXA scan Every 1-2 yrs Management Calcium and vitamin D Adequate exercise Estrogen replacement Post menopausal Other medications Alendronate Etidronate Transplantation Progressive disease PBC Metabolic Bone Disease

34. PBCTreatment of Metabolic Bone Disease • Calcium • 1000-1500 mg/d • Vitamin D • 800-1000 IU (normal 25-OH vitamin D level) • 50,000 IU vitamin D2, 2-3 times weekly if 25-OH vitamin D level is low) then maintenance • Bisphosphonates • Alendronate 70 mg weekly • Data lacking regarding efficacy • Estrogens • Not first line because of complications

35. Antihistamines 50% response rate Cholestyramine 90% response rate Phenobarbital Somewhat beneficial Sedative side effects UDCA Inconsistent results Rifampin Rapid onset of action Can cause liver injury Other medications Opiate antagonists Sertraline Ondansetron? Other Extracorporeal support OLT PBCPruritus

36. Vitamin A 20% of patients Night blindness Replace as appropriate Can cause liver injury Vitamin D Replace as appropriate Can cause liver injury Supplemental calcium Vitamin E Rarely seen in adults Neurologic sequelae Reduced proprioception Ataxia Replace as appropriate Vitamin K Risk of hemorrhage Replace as appropriate PBCVitamin Deficiency

37. PBCHypercholesterolemia • Elevated cholesterol: 85% of patients • Stage I or II disease: increased HDL predominates • Stage III or IV disease: increased LDL • No increased risk for ischemic heart disease • Lipid-lowering drugs not recommended unless there is a separate lipid disorder • Plasmapheresis for xanthomatous neuropathy and symptomatic planar xanthomas

38. Causes Reduced bile delivery to intestine Coexisting pancreatic insufficiency Coexisting celiac disease Coexisting bacterial overgrowth Management Reduced bile delivery Low fat diet Medium chain triglycerides Pancreatic disease Pancreatic enzymes Celiac disease Gluten-free diet Bacterial overgrowth Antibiotics PBCSteatorrhea

39. PBCPreventive Care • Avoid excess ETOH, obesity, smoking • Monitor thyroid function annually • EGD every 1-3 years • DEXA every 1-4 years • Fat soluble vitamin assessment every 1-3 years depending upon liver function • AFP and cross sectional imaging in patients with cirrhosis Lindor et al. Hepatology 2009;50(1):291

40. PBCNatural History and Prognosis • PBC progresses over 15-20 yrs • Median survival • Asymptomatic disease: 10-16 yrs • Symptomatic disease: 7.5-10 yrs • Bili. (8-10 mg/dL): 2 yrs • 40-100% of asymptomatic patients develop symptoms within 2-4 yrs

41. PBCPrognostic Models • Benefits • Predicting survival without transplantation • Determining need for transplant evaluation • Assessing effectiveness of medical therapies • Mayo model • Age, total bilirubin, albumin, PT, and volume overload • Bilirubin: most important variable • Doesn’t take into account intercurrent events • Variceal hemorrhage, liver cancer, quality of life Dickson et al. Hepatology 1989;10(1):1 Murtaugh et al. Hepatology 1994;20(1 Pt 1):126

42. PBCSummary • Important cause of chronic cholestatic liver disease • Middle-aged females predominate • Immune pathogenesis favored • Other autoimmune diseases frequently coexist • PBC progresses in most patients

43. PBCSummary • Complications of portal hypertension and chronic cholestasis associated with progressive disease • UDCA is standard medical therapy for all patients • Transplantation reserved for patients with marginal liver reserve and complications • Prognostic models predict disease severity and need for transplantation