Indications for Testing

• Chronic pruritus, jaundice; elevated liver enzymes with predominant cholestatic picture

Criteria for Diagnosis

• Established when 2 of 3 criteria are met (Lindor 2009)
  • Cholestasis with elevation of alkaline phosphatase for at least 6 months
  • Presence of AMA
  • Histopathology – nonsuppurative cholangitis and destruction of small or medium size bile ducts

Laboratory Testing

• Nonspecific – aminotransferases, alkaline phosphatase, bilirubin; expect persistent elevation >6 months
• Serologic testing should include other autoimmune liver antibodies to rule out AIH
  • Anti-nuclear antibodies
  • Smooth muscle antibody
  • Liver-kidney microsome-1 antibody
  • Perinuclear staining anti-neutrophil cytoplasmic antibody
• PBC is strongly associated with antimitochondrial antibody (AMA), M2 type
  • However, M2 levels in PBC do not appear correlated with clinical activity or disease progression
  • Approximately 5-10% of PBC patients are AMA negative

Histology

• Biopsy is not always indicated and not necessary for diagnosis if patient has positive AMA and evidence of cholestasis on liver testing, but it does allow classification of disease severity (stages I-IV)
• Pathological lesion is chronic non-suppurative destructive cholangitis
  • Staging also uses presence/absence of cirrhosis
  • Most advanced features in histology are used in staging
  • At least 10-15 portal tracts need to be present

Imaging Studies

• Ultrasound – imaging of liver and biliary tree obligatory to rule out extrahepatic cholestasis
• If all studies are negative and PBC is suspected, endoscopic retrograde cholangiopancreatography, cholangiography or magnetic resonance cholangiopancreatography should be performed

Prognosis

• AMA with IgG3 subclass may identify patients with more severe disease risk

Differential Diagnosis

• Autoimmune hepatitis
• Primary sclerosing cholangitis
• Biliary carcinoma
• Cholelithiasis
• Chronic hepatitis (hepatitis B or C)
• Nonalcoholic fatty liver disease

• TSH – due to high incidence of autoimmune thyroid disease, screening should be considered when PBC is diagnosed
• Hepatocellular carcinoma – imaging and alpha fetoprotein (αFP) every 6-12 months

Primary biliary cirrhosis (PBC) is an autoimmune liver disorder characterized by chronic, progressive cholestatic disease.

Epidemiology

• Incidence – 0.7-49/1,000,000
• Age – peak onset in 40s
  • Uncommon in persons <25 years
• Sex – M<F, 1:9
• Ethnicity – highest in northern Caucasians (Scandinavia, Canada, U.S.)

Risk Factors

• Presence of another autoimmune disorder
• Family history of PBC
  • 50- to 100-fold higher risk for first-generation relatives of PBC patients as compared to the general population

Pathophysiology

• Etiology is unknown
• Characterized by T-cell mediated destruction of bile duct epithelial cells resulting in loss of ducts and persistent cholestasis
  • Eventual liver failure if no treatment initiated
• Pathogenesis of PBC is believed to be caused by the following
  • Defect in immune tolerance resulting in the expansion of self-mitochondrial antigen specific for T and B lymphocytes
  • Inappropriate immune response following environmental or infectious agent causes modification of mitochondrial proteins or molecular mimicry

Clinical Presentation

• Large majority of patients initially diagnosed are asymptomatic or only mildly fatigued
• Fatigue, pruritus, jaundice
• Complications
  • Osteoporosis
  • Esophageal varices
  • Hepatocellular carcinoma – more frequent in males
• Association with other autoimmune disorders
  • CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia)
  • Sicca syndrome
  • Autoimmune thyroid disease
  • IgA deficiency
  • Chronic autoimmune hepatitis (AIH)
    • PBC and AIH have many overlapping immunologic features
    • Some patients may have serologic tests and histologic findings suggestive of AIH in addition to PBC (may be continuum of a single disease entity)
  • Addison disease
  • Systemic lupus erythematosus
  • Autoimmune thrombocytopenia or hemolytic anemia
  • Rheumatoid arthritis

Treatment

• Medical therapy
  • Ursodeoxycholic acid
    • 13-15 mg/kg as first-line therapy
    • May not reduce risk for mortality or liver transplantation
  • Cholestyramine for pruritis
• Liver transplantation for endstage cirrhosis
  • ~20% recurrence at 5 years post-transplant

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51 (2) :660-678.PubMed
• Morisco F, Pagliaro L, Caporaso N, Bianco E, Sagliocca L, Fargion S, Smedile A, Salvagnini M, Mele A. Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis. 2008; 40 (7) :585-598.PubMed
• Primary biliary cirrhosis. American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2000 April (Revised 2009 July). NGC:007372

General

• Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008; 14 (21) :3374-3387.PubMed
• Crosignani A, Battezzati PM, Invernizzi P, Selmi C, Prina E, Podda M. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008; 14 (21) :3313-3327.PubMed
• Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin Immunopathol. 2009; 31 (3) :283-307.PubMed
• Kumagi T, Heathcote EJ. Primary biliary cirrhosis. Orphanet J Rare Dis. 2008; 3 :1-.PubMed
• Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology. 2009; 50 (1) :291-308.PubMed
• Nguyen DL, Juran BD, Lazaridis KN. Primary biliary cirrhosis. Best Pract Res Clin Gastroenterol. 2010; 24 (5) :647-654.PubMed
• Selmi C, Lleo A, Pasini S, Zuin M, Gershwin ME. Innate immunity and primary biliary cirrhosis. Curr Mol Med. 2009; 9 (1) :45-51.PubMed
• Siegel SM, Selmi C, Dottorini L, Antelmi M, Zuin M, Lanfredini M, Gershwin ME. Late-onset autoimmunity: the paradigm of primary biliary cirrhosis--a mini-review. Gerontology. 2008; 54 (4) :193-201.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Layfield LJ, Cramer H. Primary sclerosing cholangitis as a cause of false positive bile duct brushing cytology: report of two cases. Diagn Cytopathol. 2005; 32 (2) :119-124.PubMed

Cirrhosis
Hepatitis, Autoimmune
Hepatitis B Virus
Hepatitis C Virus
Hepatocellular Carcinoma
Liver Disease Evaluation
Scleroderma