Essential Biliary Cirrhosis PBC

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

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Introduction Epidemiology Genetics Pathogenesis Clinical presentation Extrahepatic signs Differential analysis Diagnosis Management Medical Surgical Complications Portal hypertension Cholestasis Natural history and forecast Summary PBC Overview

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Chronic cholestatic liver ailment Autoimmune premise Middle-matured females Disease of little bile pipes Cirrhosis with gateway hypertension Complications of cholestasis Diagnosis Liver capacity tests Antimitochondrial antibodies (AMA) Histology UDCA for all patients Transplantation Marginal liver hold Poor personal satisfaction Prognostic models PBC Introduction

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PBC Epidemiology Female:male proportion of 9:1 Most basic amid middle age Presentation comparative between sexual orientations, races, and genders Prevalence: 19-150 cases/million Incidence: 4-15 cases/million/yr Incidence/pervasiveness rates expanding? Familial grouping Kaplan et al. NEJM 2005;353(12):1261

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PBC Genetics MHC class II DR8, DQA1 * 0102, and DQ/1 * 0402 MHC class III C4 invalid, and c4B2 Non-MHC qualities Exon 1 of CTLA-4 Increased familial hazard PBC/positive AMA and disabled T-cell direction Extrahepatic immune system maladies

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PBC Pathogenesis A model immune system ailment Genetic vulnerability in addition to activating occasion AMA titer No relationship with sickness seriousness No distinction in AMA (+) and (- ) illness Role in pathogenesis? Responsive against E2 subunit of pyruvate dehydrogenase Antigen expression Inner mitochondrial layer Luminal surface of biliary epithelial cell Interlobular and septal bile pipes Apoptosis Cholangiocyte Fas receptor expression Cholestasis James et al. Ann. Assistant Med 1983;99(4):500 Selmi et al. Gastroenterology 2004;127(2):485

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PBC Pathogenesis Antigens on inward mitochondrial layer Oxoacid dehydrogenase complex Autoreactivity to E2 subunit of this complex Molecular mimicry Bacterial or viral proteins, or halogenated hydrocarbons like E2 subunit? Safe assault of biliary epithelial cells CD4 and CD8 T lymphocytes Aberrantly communicated Antigens like E2 subunit uncovered after contact with exogenous xenobiotics that harm biliary epithelial cells MHC class II and I antigen confinement and T cell collaborations Gershwin et al. Hepatology 2005;42(5):1194 Selmi 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 (prior analysis) 36-89% of asymptomatic patients create side effects inside 4.5-17 years Elevated AMA Liver biopsy C/W PBC Liver science tests Normal Cholestatic 50-70% 10 year survival in asymptomatic patients and middle survival of 5-8 years from onset of manifestations (pre-UDCA period) UDCA connected with better survival when contrasted with pre-UDCA time Balasubramaniam et al. Gastroenterology 1990;98(6):1567

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Fatigue (basic) Pruritus Jaundice Hepatosplenomegaly RUQ torment Hyperpigmentation Xanthomas and xanthelasmas Dyslipidemia Extrahepatic immune system sicknesses Complications Portal hypertension Chronic cholestasis PBC Symptomatic Disease Koulentaki et al. Am J Gastroenterol 2006;101(3):541

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Chronic cholestasis Osteopenia Malabsorption Steatorrhea Bile salt insufficiency Pancreatic sickness Celiac infection Vitamin A, D, E, K inadequacy Portal hypertension Esophageal and gastric varices Ascites Encephalopathy SBP HRS or HPS Hepatocellular carcinoma PBC Complications

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PBC Portal Hypertension HCC Ascites Varices

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Osteoporosis Most regular Duration/seriousness of PBC and jaundice Axial skeleton Reduced osteoblastic action DEXA filtering Calcium, vitamin D, and bisphosphonates? Estrogens? Osteomalacia Less basic Vitamin D lack and fat malabsorption Calcium and phosphate levels 25-hydroxyvitamin D level Calcium and vitamin D supplements PBC Metabolic Bone Disease

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PBC Metabolic Bone Disease Compression breaks

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PBC Dyslipidemia Early illness Increased HDL, LDL, and VLDL Late infection Fall in HDL and ascend in LDL Xanthomas and xanthelasmas Cholesterol > 600 mg/dL Atherosclerosis chance No expanded danger of ischemia coronary illness, stroke or TIA unless there is a different lipid issue

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PBC Dyslipidemia Xanthomas Xanthelasmas Xanthomas

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Thyroid ailment Hashimoto's thyroiditis Grave's sickness Scleroderma CREST disorder Sjogren's disorder Arthritis Raynaud's marvel Celiac ailment Renal tubular acidosis Proximal Distal Gallstones Hematologic disarranges Inflammatory gut ailment (uncommon) Pulmonary interstitial fibrosis (uncommon) PBC Associated Diseases

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PBC Crest Syndrome Calcinosis Raynauds Sclerodactyly Telangiectasia

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

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Biochemical tests Alkaline phosphatase GGT 5' nucleotidase AST and ALT Bilirubin Total cholesterol Serum IgM Prothrombin time Albumin Serology AMA (95%) ANA (half) ASMA (half) Anti-centromere Anti-thyroid Medical imaging Ultrasound CT MR or MRCP PBC Non-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

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Stage I (entrance) Inflammation of interlobular and septal bile conduits Granulomatous (colorful channel) injury Stage II (periportal) Inflammation of interlobular and septal bile pipes Ductular expansion Stage III (septal) Inflammation of interlobular and septal bile pipes Fibrosis Bile pipe misfortune Cholestasis Stage IV (cirrhotic) Established cirrhosis PBC Histology Scheuer et al. Mayo Clin Proc 1998;73(2):179

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PBC Pathology Cirrhosis NRH

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PBC Overall Management Survival of patients with PBC mediocre compared to that of a solid control populace Medical or surgical treatment justified in all patients No medicinal treatment has been appeared to indisputably change the historical backdrop of PBC Goals of treatment Slow malady movement Treat intricacies

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PBC Medical Management PBC: an immune system sickness Improve clinical side effects and indications of infection Improve liver capacity tests Reduce or dispense with bile pipe damage Improve quiet survival free of transplantation

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Ineffective Corticosteroids Azathioprine Cyclosporine Penicillamine Colchicine Chlorambucil Possibly viable Methotrexate Mycophenolate mofetil Effective Ursodeoxycholic corrosive Improvement in manifestations Improvement in LFTs Improvement in histology Improvement in transplant free survival Combination treatment? Extra studies justified PBC Medical Management

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PBC UDCA Effective measurements: 13-15 mg/kg/day uncertainly Mechanism of activity Promotes endogenous bile corrosive discharge Replacement of hepatotoxic (endogenous) bile acids Stabilizes biliary epithelial cell films Alters HLA I-II expression on biliary epithelial cell Inhibits biliary cell apoptosis Improvement in LFTs Delays malady movement and enhances without transplant survival Follow LFTs each 3-6 mo. Poupon et al. N Engl J Med. 1994;330(19):1342 Heathcote et al. Hepatology 1994;19(5):1149

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PBC Incomplete Responders to UDCA 66% of patients Definition Failure to standardize LFTs Development of cirrhosis on treatment Predictors of fragmented reaction High basic phosphatase or GGT Advanced infection preceding UDCA start Assess: quiet consistence, UDCA dosage, cover disorder Combes 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? Reactions restrain long haul utilize

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PBC Combination Therapies UDCA and corticosteroids Improvement in LFTs Variable change in histology UDCA and colchicine No noteworthy advantage UDCA and methotrexate Improvement in LFTs ? Extra studies justified

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PBC Novel Agents Malotilate Improvement in LFTs No change in survival Bezafibrate Improvement in LFTs Thalidomide No change in LFTs No change in histology

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Advanced PBC with minimal save Portal hypertension Refractory variceal draining Intractable ascites Intractable encephalopathy SBP HRS or HPS Chronic cholestasis Intractable pruritus Metabolic bone sickness and breaks Malabsorption Vitamin lack Hepatocellular Cancer Transplant alternatives Cadaveric gift Live gift PBC Liver Transplantation Lee et al. Clin Gastroenterol Hepatol 2007;5(11):1313 Dickson et al. Hepatology 1989;10(1):1

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PBC Liver Transplantation Patient and join survival 1 yr : 83-92% 5 yr : 75-85% Higher danger of dismissal PBC repeat 15 to 25% of patients at 10 years Granulomatous bile conduit harm AMA does not characterize repeat Exclude other post transplant issue Intermediate term patient and unite survival are great Use of UDCA for intermittent infection questionable Liermann et al. Hepatology 2001;33(1):22

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Variceal draining Endoscopic screening Non-particular beta blockers Endoscopic treatment Sclerotherapy Band ligation Surgical shunts TIPS HCC AFP/imaging Ascites Sodium limited weight control plans Diuretics Therapeutic paracentesis TIPS Encephalopathy Lactulose Neomycin Rifaxamin Protein adjustment PBC Complications of Portal Hypertension

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30-half of patients Classification Osteoporosis: normal Osteomalacia: uncommon Bone thickness Below crack edge (33%) Diagnosis and F/U DEXA examine Every 1-2 yrs Management Calcium and vitamin D Adequate practice Estrogen substitution Post menopausal Other meds Alendronate Etidronate Transplantation Progressive malady PBC Metabolic Bone Disease

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PBC Treatment of Metabolic Bone