Primary Biliary Cirrhosis - PBC

Diagnosis

Indications for Testing

  • Chronic pruritus
  • Jaundice without evidence of other causes

Criteria for Diagnosis

  • Established when two of three criteria are met (Lindor, 2009)
    • Cholestasis with elevation of alkaline phosphatase for at least six months
    • Presence of antimitochondrial antibodies (AMA)
    • Histopathology demonstrating nonsuppurative cholangitis and destruction of small- or medium-size bile ducts

Laboratory Testing

  • Alkaline phosphatase, bilirubin – persistently elevated
    • Mild elevation of transaminase levels is common
  • AMA M2 antibody
    • 5-10% of patients with PBC are AMA-negative
      • Diagnosis based on liver histology and clinical presentation
    • AMA M2 levels do not appear to correlate with clinical consequences or disease progression
  • Serological testing should include other autoimmune liver antibodies to rule out autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), or overlap syndromes
    • Antinuclear antibodies (ANA) – found in nearly 50%
    • Smooth muscle antibody (SMA)
      • Titer >1:80 in conjunction with positive AMA M2 – consider overlap syndrome
    • Liver-kidney microsome-1 antibody
    • Antineutrophil cytoplasmic antibody (ANCA)

Histology

  • Liver biopsy
    • Unnecessary for diagnosis if patient has positive AMA and evidence of cholestasis
    • Allows for classification of disease severity (stages I-IV)
    • Required for AMA-negative disease 
    • Pathological lesion is chronic nonsuppurative destructive cholangitis
    • At least 10-15 portal tracts must be present in liver biopsy specimen for confirmation of PBC
      • Patchy distribution of lesions

Imaging Studies

  • Ultrasound imaging of liver and biliary tree is 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 risk of more severe disease

Differential Diagnosis

  • Autoimmune hepatitis
  • Primary sclerosing cholangitis
  • Biliary carcinoma
  • Cholelithiasis
  • Chronic hepatitis (viral hepatitis B or C)
  • Nonalcoholic steatohepatitis

Screening

Clinical Background

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

Epidemiology

  • Prevalence – 19-402/million (Bowlus, 2014)
  • Age – peak onset in 40s-50s
    • Uncommon <25 years
  • Sex – M<F, 1:10 (Bowlus, 2014)
  • Ethnicity – most common in Caucasians from northern regions (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 patients with PBC, compared to the general population
  • Past or present smoking
  • Frequent use of nail polish or hair dyes
  • Female sex
  • Previous pregnancies

Pathophysiology

  • Disease entity thought to be the result of genetic predisposition and environmental triggers
  • Characterized by T-cell-mediated destruction of bile duct epithelial cells, resulting in loss of ducts and persistent cholestasis
    • Eventual liver failure without treatment
  • Pathogenesis
    • 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
      • Anti-mitochondrial antibody (AMA) forms – present in 95% of patients; highly specific for PBC
    • Involvement of the small intrahepatic ducts

Clinical Presentation

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
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

Initial test in conjunction with ANCA-associated vasculitis profile for evaluation of autoimmune liver disease (ALD)

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

Reflex pattern – if F-actin, IgG result ≥20 units, then SMA, IgG titer will be added

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

 
ANCA-Associated Vasculitis Profile (ANCA/MPO/PR-3) with Reflex to ANCA Titer 2006480
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Initial test in conjunction with autoimmune liver disease panel for evaluation of ALD

Panel detects ANCA, MPO, and PR-3 antibodies

Reflex pattern – if screen is positive, titer will be added

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

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

Aids in the diagnosis of PBC; differentiate AIH from PBC

Negative mitochondrial M2 antibody test result does not rule out PBC; about 5-10% of patients with PBC are seronegative

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

 
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

Aids in initial diagnosis of connective tissue disease

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

Reflex pattern – all ELISA results reported as “detected” are further tested by IFA

ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and speckled ANA-IFA patterns

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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

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

F-actin antibodies have greater sensitivity and specificity for autoimmune liver disease than anti-smooth muscle antibodies

Negative result does not rule out autoimmune liver disease or chronic active hepatitis; not all patients are F-actin antibody positive

Reflex pattern – if F-actin ≥20 units, then SMA, IgG IFA titer will be added

Liver-Kidney Microsome - 1 Antibody, IgG 0055241
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Differential evaluation of ALD of unknown etiology, especially autoimmune hepatitis (AIH) of childhood onset

Use in combination with Liver Cytosolic Antigen Type 1 (LC-1) Antibody, IgG when evaluating for AIH-2

More likely to be positive than LC-1

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be done in conjunction with clinical presentation – overlap may occur between diseases and antibodies

Neither LKM-1 nor LC-1 has absolute diagnostic sensitivity for AIH type 2

Liver Cytosolic Antigen Type 1 (LC-1) Antibody, IgG 2010711
Method: Semi-Quantitative Immunoblot

Differential evaluation of ALD of unknown etiology, especially AIH of childhood onset

Use in combination with LKM-1, IgG when evaluating for AIH-2

Consider if other serological tests in autoimmune liver disease panel are negative, or in combination with specific tests (anti-LKM-1, ANA, F-actin, SMA)

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