Primary Biliary Cirrhosis - PBC

Diagnostic Algorithm

  Liver Disease or Hepatitis of Unknown Etiology Testing Algorithm

Clinical Background

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

Epidemiology

• Incidence – 25-27/1,000,000 in U.S.
• Age – peak onset in 40s
• Sex – M<F, 1:9

Risk Factors

• Presence of another autoimmune disorder
• Family history of PBC
  • The risk for a first-degree relative of a PBC patient is 50- to 100-fold higher than the general population

Pathophysiology

• Etiology is unknown
• Pathogenesis of PBC is believed to be caused by:
  • 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
• PBC is characterized by T-cell mediated destruction of bile duct epithelial cells resulting in loss of ducts and persistent cholestasis, which may lead to end-stage liver failure without treatment

Clinical Presentation

• Large majority of patients initially diagnosed are asymptomatic or only mildly fatigued
• Fatigue, pruritus, jaundice
• Complications
  • Osteoporosis
  • Esophageal varices
  • Hepatocellular carcinoma
• 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 (SLE)
  • Autoimmune thrombocytopenia or hemolytic anemia
  • Rheumatoid arthritis
  • Scleroderma

Treatment

• Medical therapy
  • Ursodeoxycholic acid does not reduce the risk for mortality or liver transplantation
  • Cholestyramine for pruritis
• Liver transplantation for endstage cirrhosis

Diagnosis

• Indications for testing – chronic pruritis, jaundice; elevated liver enzymes with predominant cholestatic picture
• Laboratory testing
  • Initial testing – aminotransferases, alkaline phosphatase, bilirubin
  • Serologic testing should include other autoimmune liver antibodies to rule out AIH
    • Anti-nuclear antibodies (ANA)
    • Smooth muscle antibody (SMA)
    • Liver-kidney microsome-1 antibody (LKM1)
    • Perinuclear staining anti-neutrophil cytoplasmic antibody (pANCA)
  • 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
  • Pathological lesion is chronic non-suppurative destructive cholangitis
• Imagining studies
  • If AMA negative and PBC is suspected, endoscopic retrograde cholangiopancreatography (ERCP), 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
• Biliary carcinoma
• Cholelithiasis
• Chronic hepatitis
• Nonalcoholic fatty liver disease
• Primary sclerosing cholangitis (PSC)

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Anti-Nuclear Antibodies (ANA), IgG Screen with Reflex to IFA Titer 0050080 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody
F-Actin (Smooth Muscle) Antibody, IgG by ELISA with Reflex to Smooth Muscle Antibody, IgG Titer 0051174 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody
Liver-Kidney Microsome - 1 Antibody, IgG 0055241 Method: Enzyme-Linked Immunosorbent Assay
Anti-Neutrophil Cytoplasmic Antibody, IgG 0050811 Method: Indirect Fluorescent Antibody
Centromere Antibody, IgG 0050714 Method: Multi-Analyte Fluorescent Detection

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®