Primary Biliary Cirrhosis (PBC)

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

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PBC Overview  Introduction  Management  Epidemiology – Medical  Genetics – Surgical  Pathogenesis  Complications  – Clinical presentation Portal hypertension – Cholestasis  Extrahepatic  Natural history and manifestations prognosis  Differential diagnosis  Summary  Diagnosis

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PBC Introduction  Chronic cholestatic  Diagnosis liver disease – Liver function tests  Autoimmune basis – Antimitochondrial  Middle-aged females antibodies (AMA) – Histology  Disease of smal bile  ducts UDCA for al patients – Cirrhosis with portal  Transplantation hypertension – Marginal liver reserve – Complications of – Poor quality of life cholestasis – Prognostic models

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PBC Epidemiology  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

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PBC Genetics  MHC class II – DR8, DQA1*0102, and DQ/β1*0402  MHC class III – C4 nul , and c4B2  Non-MHC genes – Exon 1 of CTLA-4  Increased familial risk – PBC/positive AMA and impaired T-cel regulation– Extrahepatic autoimmune diseases

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PBC Pathogenesis  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 Jame s et al. Ann. Intern Med 1983;99(4):500 Selmi et al. Gastroenterology 2004;127(2):485

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PBC Pathogenesis  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 cel s • 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):1194Sel mi et al. Gastroenterology 2004;127(2):493 Kaplan et al. NEJM 2005;353:1261

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PBC Asymptomatic 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

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

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PBC Complications  Chronic  Portal cholestasis hypertension – Osteopenia – Esophageal and – Malabsorption gastric varices – Steatorrhea – Ascites • Bile salt deficiency – Encephalopathy • Pancreatic disease – SBP • Celiac disease – HRS or HPS – Vitamin A, D, E, K – Hepatocel ular deficiency carcinoma

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PBC Portal Hypertension HCC Ascites Varices

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

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PBC Metabolic Bone Disease Compression fractures

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PBC Dyslipidemia  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

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PBC Dyslipidemia Xanthelasmas Xanthomas Xanthomas Xanthomas

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PBC Associated Diseases  Thyroid disease  Renal tubular acidosis – Hashimoto’s thyroiditis – Proximal – Grave’s disease – Distal  Scleroderma  Gal stones  CREST syndrome  Hematologic  Sjogren’s syndrome disorders  Arthritis  Inflammatory bowel  Raynaud’s disease (rare) phenomenon  Pulmonary interstitial  Celiac disease fibrosis (rare)

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PBC Crest Syndrome Calcinosis Raynauds Sclerodactyly Telangiectasia

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PBC Differential Diagnosis  Biliary stones or  Viral hepatitis strictures  Sarcoidosis  Pancreaticobiliary  Autoimmune malignancies cholangiopathy  PSC  Medications  Autoimmune  Granulomatous hepatitis hepatitis  Alcoholic hepatitis

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

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

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PBC Pathology Cirrhosis NRH

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PBC Overal 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

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PBC Medical 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

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PBC Medical Management  Ineffective  Effective – Corticosteroids – Ursodeoxycholic acid – Azathioprine • Improvement in – symptoms Cyclosporine • Improvement in LFTs – Penicil amine • Improvement in – Colchicine histology – Chlorambucil • Improvement in transplant free survival  Possibly effective  Combination therapy? – Methotrexate – Additional studies – Mycophenolate mofetil warranted

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PBC UDCA  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 cel membranes– Alters HLA I-II expression on biliary epithelial cel– Inhibits biliary cel apoptosis  Improvement in LFTs Delays disease progression and improves transplant-free survival  Fol ow LFTs every 3-6 mo. Poupon et al. N Engl J Med. 1994;330(19):1342Heathcote et al. Hepatology 1994;19(5):1149

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PBC Incomplete 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 Com bes et al. Hepatology 1995;22(3):759 Poupon et al. J Hepatolol 2003;39(1):12

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PBC Methotrexate  Dose: 7.5-15 mg/week orally Improvement – Symptoms– LFTs– Histology?– Survival?  Side effects limit long-term use

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PBC Combination 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

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PBC Novel Agents  Malotilate – Improvement in LFTs– No improvement in survival  Bezafibrate – Improvement in LFTs  Thalidomide – No improvement in LFTs– No improvement in histology

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

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PBC Liver 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

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

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

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

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

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

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PBC Hypercholesterolemia  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

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PBC Steatorrhea  Causes  Management – Reduced bile delivery – Reduced bile delivery to intestine • Low fat diet – Coexisting pancreatic • Medium chain insufficiency triglycerides – Coexisting celiac – Pancreatic disease disease • Pancreatic enzymes – Coexisting bacterial – Celiac disease overgrowth • Gluten-free diet – Bacterial overgrowth • Antibiotics

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PBC Preventive 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

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PBC Natural 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

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PBC Prognostic 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 Di ckson et al. Hepatology 1989;10(1):1 Murtaugh et al. Hepatology 1994;20(1 Pt 1):126

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

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PBC Summary  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

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