Primary Biliary Cirrhosis - PBC

Diagnosis

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 antimitochondrial antibodies (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
  • Antinuclear antibodies
  • Smooth muscle antibody
  • Liver-kidney microsome-1 antibody
  • Perinuclear staining antineutrophil cytoplasmic antibody
• PBC is strongly associated with 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
  • Does allow for classification of disease severity (stages I-IV)
• Pathological lesion is chronic nonsuppurative 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, perform endoscopic retrograde cholangiopancreatography, cholangiography, or magnetic resonance cholangiopancreatography

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

Screening

Clinical Background

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 posttransplant

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 by ELISA with Reflex to ANA, IgG by IFA 0050080 Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody	All ELISA results reported as Detected are further tested by IFA ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns
F-Actin (Smooth Muscle) Antibody, IgG by ELISA with Reflex to Smooth Muscle Antibody, IgG Titer 0051174 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Liver-Kidney Microsome - 1 Antibody, IgG 0055241 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Anti-Neutrophil Cytoplasmic Antibody, IgG 0050811 Method: Semi-Quantitative Indirect Fluorescent Antibody	If ANCA screen detects antibodies ≥1:20 dilution, titer to end point will be added
Centromere Antibody, IgG 0050714 Method: Semi-Quantitative Multiplex Bead Assay

Diagnostic Algorithm

  Liver Disease or Hepatitis of Unknown Etiology Testing Algorithm