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Primary Biliary Cirrhosis (PBC). Thomas W. Faust, M.D., M.B.E. Associate Prof. of Clinical Medicine The University of Pennsylvania May 19, 2010. Introduction Epidemiology Genetics Pathogenesis Clinical presentation Extrahepatic manifestations Differential diagnosis Diagnosis.

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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

pbc overview
Introduction

Epidemiology

Genetics

Pathogenesis

Clinical presentation

Extrahepatic manifestations

Differential diagnosis

Diagnosis

Management

Medical

Surgical

Complications

Portal hypertension

Cholestasis

Natural history and prognosis

Summary

PBCOverview
pbc introduction
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
pbc epidemiology
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

pbc genetics
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
pbc pathogenesis
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

pbc pathogenesis7
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

pbc asymptomatic disease
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

pbc symptomatic disease
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

pbc complications
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
pbc portal hypertension
PBCPortal Hypertension

HCC

Ascites

Varices

pbc metabolic 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
pbc metabolic bone disease13
PBCMetabolic Bone Disease

Compression fractures

pbc dyslipidemia
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
pbc dyslipidemia15
PBCDyslipidemia

Xanthomas

Xanthelasmas

Xanthomas

Xanthomas

pbc associated 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)

PBCAssociated Diseases
pbc crest syndrome
PBCCrest Syndrome

Calcinosis

Raynauds

Sclerodactyly

Telangiectasia

pbc differential diagnosis
Biliary stones or strictures

Pancreaticobiliary malignancies

PSC

Autoimmune hepatitis

Alcoholic hepatitis

Viral hepatitis

Sarcoidosis

Autoimmune cholangiopathy

Medications

Granulomatous hepatitis

PBCDifferential Diagnosis
pbc non 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

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

pbc histology
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

pbc pathology
PBCPathology

Cirrhosis

NRH

pbc overall management
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
pbc medical management
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
pbc medical management24
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
pbc udca
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

pbc incomplete responders to udca
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

pbc methotrexate
PBCMethotrexate
  • Dose: 7.5-15 mg/week orally
  • Improvement
    • Symptoms
    • LFTs
    • Histology?
    • Survival?
  • Side effects limit long-term use
pbc combination therapies
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
pbc novel agents
PBCNovel Agents
  • Malotilate
    • Improvement in LFTs
    • No improvement in survival
  • Bezafibrate
    • Improvement in LFTs
  • Thalidomide
    • No improvement in LFTs
    • No improvement in histology
pbc liver 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

PBCLiver Transplantation

Lee et al. Clin Gastroenterol Hepatol 2007;5(11):1313

Dickson et al. Hepatology 1989;10(1):1

pbc liver transplantation31
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

pbc complications 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

PBCComplications of Portal Hypertension
pbc metabolic bone disease33
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
pbc treatment of metabolic bone 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
pbc pruritus
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
pbc vitamin 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

PBCVitamin Deficiency
pbc hypercholesterolemia
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
pbc steatorrhea
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
pbc preventive care
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

pbc natural history and prognosis
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
pbc prognostic models
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

pbc summary
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
pbc summary43
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