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
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Introduction
Epidemiology
Genetics
Pathogenesis
Clinical presentation
Extrahepatic
manifestations
 Differential diagnosis
 Diagnosis
 Management
– Medical
– Surgical
 Complications
– Portal hypertension
– Cholestasis
 Natural history and
prognosis
 Summary
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
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
PBC
Genetics
 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
 A model autoimmune disease
 Genetic susceptibility plus triggering event
 AMA titer
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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
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 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
 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
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Fatigue (common)
Pruritus
Jaundice
Hepatosplenomegaly
RUQ pain
Hyperpigmentation
Koulentaki et al. Am J Gastroenterol 2006;101(3):541
 Xanthomas and
xanthelasmas
 Dyslipidemia
 Extrahepatic
autoimmune diseases
 Complications
– Portal hypertension
– Chronic cholestasis
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
PBC
Portal 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
PBC
Metabolic Bone Disease
Compression fractures
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
PBC
Dyslipidemia
Xanthelasmas
Xanthomas
Xanthomas
Xanthomas
PBC
Associated Diseases
 Thyroid disease
– Hashimoto’s thyroiditis
– Grave’s disease
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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)
PBC
Crest Syndrome
Calcinosis
Sclerodactyly
Raynauds
Telangiectasia
PBC
Differential Diagnosis
 Biliary stones or
strictures
 Pancreaticobiliary
malignancies
 PSC
 Autoimmune
hepatitis
 Alcoholic hepatitis
 Viral hepatitis
 Sarcoidosis
 Autoimmune
cholangiopathy
 Medications
 Granulomatous
hepatitis
PBC
Non-Invasive Tests
 Biochemical tests
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Alkaline phosphatase
GGT
5’ nucleotidase
AST and ALT
Bilirubin
Total cholesterol
Serum IgM
Prothrombin time
Albumin
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
 Serology
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AMA (95%)
ANA (50%)
ASMA (50%)
Anti-centromere
Anti-thyroid
 Medical imaging
– Ultrasound
– CT
– MR or MRCP
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
Scheuer et al. Mayo Clin Proc 1998;73(2):179
 Stage III (septal)
– Inflammation of
interlobular and septal
bile ducts
– Fibrosis
– Bile duct loss
– Cholestasis
 Stage IV (cirrhotic)
– Established cirrhosis
PBC
Pathology
Cirrhosis
NRH
PBC
Overall 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
 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 Management
 Ineffective
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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
PBC
UDCA
 Effective dose: 13-15 mg/kg/day indefinitely
 Mechanism of action
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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 transplantfree 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
 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
 Dose: 7.5-15 mg/week orally
 Improvement
– Symptoms
– LFTs
– Histology?
– Survival?
 Side effects limit long-term use
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
PBC
Novel 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
Lee et al. Clin Gastroenterol Hepatol 2007;5(11):1313
Dickson et al. Hepatology 1989;10(1):1
 Chronic cholestasis
– Intractable pruritus
– Metabolic bone
disease and fractures
– Malabsorption
– Vitamin deficiency
 Hepatocellular
Cancer
 Transplant options
– Cadaveric donation
– Live donation
PBC
Liver Transplantation
 Patient and graft survival
– 1 yr : 83-92%
– 5 yr : 75-85%
 Higher risk of rejection
 PBC recurrence
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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
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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
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 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
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
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
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
PBC
Preventive Care
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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
 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
 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
 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
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