Primary Biliary Cirrhosis(PBC)

Thomas W. Faust, M.D., M.B.E.Associate Prof. of Clinical Medicine

The University of PennsylvaniaMay 19, 2010

PBCOverview

Introduction Epidemiology Genetics Pathogenesis Clinical presentation Extrahepatic

manifestations Differential diagnosis Diagnosis

Management– Medical– Surgical

Complications– Portal hypertension– Cholestasis

Natural history and prognosis

Summary

PBCIntroduction

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

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

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

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):500Selmi et al. Gastroenterology 2004;127(2):485

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):1194Selmi et al. Gastroenterology 2004;127(2):493Kaplan et al. NEJM 2005;353:1261

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

PBCSymptomatic Disease

Fatigue (common) Pruritus Jaundice Hepatosplenomegaly RUQ pain Hyperpigmentation

Xanthomas and xanthelasmas

Dyslipidemia Extrahepatic

autoimmune diseases Complications

– Portal hypertension– Chronic cholestasis

Koulentaki et al. Am J Gastroenterol 2006;101(3):541

PBCComplications

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

PBCPortal Hypertension

HCC

Varices

Ascites

PBCMetabolic Bone Disease

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

Compression fractures

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

PBCDyslipidemia

Xanthelasmas

Xanthomas

Xanthomas

Xanthomas

PBCAssociated Diseases

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)

PBCCrest Syndrome

Calcinosis Raynauds

Sclerodactyly Telangiectasia

PBCDifferential Diagnosis

Biliary stones or strictures

Pancreaticobiliary malignancies

PSC Autoimmune

hepatitis Alcoholic hepatitis

Viral hepatitis Sarcoidosis Autoimmune

cholangiopathy Medications Granulomatous

hepatitis

PBCNon-Invasive Tests

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

Dickson et al. Hepatology 1989;10(1):1Muratori et al. Clin Liver Dis 2008;12(2):261Kaplan et al. N Engl J Med 2005;353(12):1261

PBCHistology

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

Scheuer et al. Mayo Clin Proc 1998;73(2):179

PBCPathology

NRH

Cirrhosis

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

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

PBCMedical Management

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

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):1342Heathcote et al. Hepatology 1994;19(5):1149

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):759Poupon et al. J Hepatolol 2003;39(1):12

PBCMethotrexate

Dose: 7.5-15 mg/week orally Improvement

– Symptoms– LFTs– Histology?– Survival?

Side effects limit long-term use

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

PBCNovel Agents

Malotilate– Improvement in LFTs– No improvement in survival

Bezafibrate– Improvement in LFTs

Thalidomide– No improvement in LFTs– No improvement in histology

PBCLiver Transplantation

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

Lee et al. Clin Gastroenterol Hepatol 2007;5(11):1313Dickson et al. Hepatology 1989;10(1):1

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

PBCComplications of Portal Hypertension

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

PBC Metabolic Bone Disease

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

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

PBCPruritus

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

PBCVitamin Deficiency

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

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

PBCSteatorrhea

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

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

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

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):1Murtaugh et al. Hepatology 1994;20(1 Pt 1):126

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

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