Primary Biliary Cirrhosis - PBC

Diagnosis

Indications for Testing

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

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
Test Name and Number Recommended Use Limitations Follow Up
Alanine Aminotransferase, Serum or Plasma 0020008
Method: Quantitative Enzymatic

Initial testing to evaluate liver dysfunction

   
Bilirubin, Direct and Total, Serum or Plasma 0020426
Method: Quantitative Spectrophotometry

Initial testing to evaluate liver dysfunction, particularly biliary involvement

   
Alkaline Phosphatase Isoenzymes, Serum or Plasma 0021020
Method: Quantitative Heat Inactivation/Enzymatic

Initial testing to evaluate cholestasis

   
Autoimmune Liver Disease Evaluation with Reflex to Smooth Muscle Antibody (SMA), IgG by IFA 2007210
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Rule out autoimmune hepatitis

Components include mitochondrial M2 antibody, IgG; liver-kidney microsome-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG; smooth muscle antibody, IgG titer

   
Mitochondrial M2 Antibody, IgG (ELISA) 0050065
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Aid in the diagnosis of PBC

Negative M2 antibody result does not rule out PBC; about 5-10% of these patients are seronegative  
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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