What are the recommended tests and treatment for a patient suspected of having primary biliary cholangitis (PBC)?

Diagnostic Tests for Primary Biliary Cholangitis

The diagnosis of PBC requires two key tests: serum antimitochondrial antibodies (AMA) and alkaline phosphatase (ALP) measurement, with AMA positivity at titre ≥1:40 combined with elevated ALP being sufficient for diagnosis in most cases. 1

Essential Diagnostic Laboratory Tests

First-Line Serological Testing

• AMA testing is mandatory in all adults presenting with chronic intrahepatic cholestasis, as it represents the diagnostic hallmark of PBC with >90% sensitivity and >95% specificity 1
• AMA positivity is defined as titre ≥1:40 by immunofluorescence, or alternatively, anti-AMA-M2 (anti-PDC-E2) immunoenzymatic assays can be used with even higher sensitivity and specificity 1
• The combination of elevated ALP and positive AMA (≥1:40) establishes the diagnosis confidently without requiring liver biopsy in most cases 1

Biochemical Markers

• Measure serum ALP and gamma-glutamyl transpeptidase (GGT) to confirm cholestasis, with ALP elevation of liver origin for at least 6 months being a key diagnostic criterion 1
• Perform GGT measurement or ALP fractionation to confirm the ALP elevation originates from liver rather than bone, particularly important in post-menopausal women who may have bone-derived ALP from osteoporosis 1
• Serum aminotransferases (ALT, AST) and conjugated bilirubin should be measured but are not diagnostic; in early-stage PBC, 50% have normal ALT and 37.5% have normal AST 2
• Total bilirubin measurement is essential as elevations indicate more advanced disease and poorer prognosis 1

AMA-Negative PBC Testing

• In AMA-negative patients with cholestasis, test for specific antinuclear antibodies (ANA) including anti-Sp100 and anti-gp210, which show >95% specificity for PBC though sensitivity is lower (found in at least 30% of PBC sera) 1
• When AMA and AMA-M2 are negative, ANA positivity—particularly ANA centromere pattern (38.5% in early disease)—strongly suggests PBC 2
• Liver biopsy should be performed in patients with unexplained intrahepatic cholestasis and negative AMA test 1

Additional Diagnostic Tests

Immunological and Metabolic Markers

• Immunoglobulin M (IgM) levels are typically elevated in PBC patients 1
• Serum cholesterol is commonly elevated as in other cholestatic conditions 1
• Prothrombin time and serum albumin alterations occur only in advanced disease and serve as markers of hepatic synthetic function 1

Genetic Testing

• When available, consider genetic testing for ABCB4 (encoding the canalicular phospholipid export pump) in AMA-negative patients with biopsy findings compatible with PBC 1

Role of Liver Biopsy

Liver biopsy is NOT routinely required when typical serological and biochemical findings are present (elevated ALP + positive AMA) 1. However, biopsy is indicated in specific scenarios:

• AMA-negative patients with otherwise unexplained cholestasis 1
• Patients with disproportionately elevated aminotransferases to exclude PBC-autoimmune hepatitis overlap syndrome 3
• When diagnosis remains uncertain despite serological testing 1

Non-Invasive Assessment of Disease Severity

Baseline Risk Stratification

• Perform transient elastography (liver stiffness measurement by TE) at baseline to discriminate early from advanced disease, using a cut-off of 10 kPa to identify advanced fibrosis 3
• Baseline assessment should include serum bilirubin and albumin levels (both normal vs. at least one abnormal) combined with LSM to stratify disease stage 3

Monitoring During Treatment

• Risk stratification during ursodeoxycholic acid (UDCA) treatment should use continuous risk scores (GLOBE and UK-PBC scores) and/or qualitative response criteria (Paris II, Toronto, Rotterdam, Barcelona, Paris I) combined with repeat LSM by TE 3
• The GLOBE score (including age, total bilirubin, ALP, albumin, and platelet count) accurately predicts liver transplant-free survival at 5 and 10 years with c-statistics of 0.81-0.82 3
• The UK-PBC score (including baseline albumin and platelet count, plus bilirubin, AST or ALT, and ALP at 12 months after starting UDCA) predicts risk of major outcomes at 5,10, and 15 years 3

Special Considerations and Monitoring

Patients with Normal Biochemistry

• Patients with normal ALP and GGT but positive serological markers (AMA or PBC-specific ANA) should be reassessed clinically and biochemically at annual intervals 1

Early-Stage Disease Recognition

• In early-stage PBC, 29.2% may have normal ALP levels, but GGT is more robustly elevated with 29.2% having levels >10 times the upper limit of normal 2
• Significantly elevated GGT with normal or mildly elevated ALP, combined with ANA positivity (especially centromere pattern) when AMA is negative, should raise suspicion for early PBC 2

Common Pitfalls to Avoid

• Do not attribute all elevated ALP to PBC without confirming hepatobiliary origin through GGT or ALP fractionation, especially in post-menopausal women 1
• Do not perform routine liver biopsy when typical cholangiographic or serological findings confirm the diagnosis 1
• Do not overlook AMA-negative PBC—approximately 10% of PBC patients are AMA-negative, requiring ANA testing (anti-Sp100, anti-gp210) and potentially liver biopsy 1
• Do not delay assessment for overlap syndromes when aminotransferases are disproportionately elevated relative to ALP 3