What laboratory tests are used for the diagnosis and management of Primary Biliary Cholangitis (PBC)?

Laboratory Testing for Primary Biliary Cholangitis (PBC)

The diagnosis of PBC requires testing for antimitochondrial antibodies (AMA) combined with alkaline phosphatase (ALP) measurement, with AMA being mandatory in all adults with chronic intrahepatic cholestasis. 1

Essential Diagnostic Laboratory Tests

Immunological Markers (Highest Priority)

• Antimitochondrial antibodies (AMA) are the diagnostic hallmark of PBC, detected in more than 90% of affected individuals with specificity greater than 95% 1
• AMA testing is considered positive at a titre ≥1:40 by immunofluorescence 1
• Anti-AMA-M2 (anti-PDC-E2) immunoenzymatic assays with recombinant proteins may be used as an alternative, offering higher sensitivity and specificity 1
• In AMA-negative patients, specific antinuclear antibodies (ANA) including anti-Sp100 and anti-gp210 show high specificity for PBC (>95%) and can serve as diagnostic markers, though sensitivity is low (found in at least 30% of PBC sera) 1

Biochemical Markers for Diagnosis

• Serum ALP and gamma-glutamyl transpeptidase (GGT) are raised in PBC, with elevation of ALP of liver origin for at least 6 months being a key diagnostic criterion 1
• The diagnosis of PBC is made confidently on the combination of abnormal serum liver tests (elevated ALP) and presence of AMA (≥1:40) 1
• Serum aminotransferases (ALT, AST) and conjugated bilirubin can be elevated but are not diagnostic 1
• GGT and/or ALP fractionation should be performed to confirm the ALP elevation is of hepatobiliary origin, particularly important in post-menopausal women who may have bone-derived ALP from osteoporosis 1

Additional Biochemical Tests for Disease Assessment

• Patients with PBC typically present with elevated immunoglobulin M (IgM) levels 1
• Serum cholesterol is commonly elevated as in other cholestatic conditions 1
• Alterations in prothrombin time, serum albumin, and conjugated bilirubin are observed only in advanced disease and serve as markers of hepatic synthetic function 1
• Total bilirubin should be measured, with elevations indicating more advanced disease and poorer prognosis 1, 2

Laboratory Tests for Disease Monitoring and Management

Response to Treatment Assessment

• For patients on ursodeoxycholic acid (UDCA), ALP <1.67× upper limit of normal (ULN), total bilirubin ≤ULN, and ALP decrease of at least 15% define adequate response 2
• In clinical trial settings for PBC without advanced cirrhosis, inclusion criteria typically require ALP >1.5× ULN (lower limit) and <10× ULN (upper limit), with aminotransferases <5× ULN 1
• Normal ALP levels in UDCA-treated patients are associated with better long-term outcomes, particularly in patients with liver stiffness ≥10 kPa and/or age ≤62 years 3

Monitoring for Disease Progression

• Baseline antinuclear antibody, anti-smooth muscle antibody titres, and immunoglobulin G levels should be established to rule out overlap syndromes 1
• If ANA or anti-smooth muscle antibody titres are >1:80 or IgG >2× ULN in combination with ALT <5× ULN, liver biopsy should be performed to exclude overlap disease 1
• Routine monitoring should include assessment for hepatic decompensation markers: total bilirubin, direct bilirubin, prothrombin time, albumin, and platelet count 2

Special Considerations and Caveats

AMA-Negative PBC

• Liver biopsy should be considered in patients with otherwise unexplained intrahepatic cholestasis and negative AMA test 1
• When available, genetic testing for ABCB4 (encoding the canalicular phospholipid export pump) should be considered in AMA-negative patients with biopsy findings compatible with PBC 1

Early-Stage Disease Detection

• In early-stage PBC, 29.2% of patients may have normal ALP levels, though GGT is typically more robustly elevated 4
• For treatment-naive patients with positive AMA but normal ALP, baseline serum IgM >0.773× ULN and age >42 years strongly suggest PBC diagnosis and indicate need for liver biopsy 5
• When AMA and AMA-M2 are negative in early disease, ANA positivity (particularly ANA centromere pattern at 38.5%) is the highest autoantibody finding 4

Pitfalls to Avoid

• Patients with normal ALP and GGT but serological stigmata of PBC should be reassessed clinically and biochemically at annual intervals 1
• Do not rely solely on aminotransferase levels for diagnosis, as 50% of early-stage patients have normal ALT and 37.5% have normal AST 4
• ALP may originate from bone rather than liver, necessitating GGT measurement or ALP isoenzyme fractionation for accurate interpretation 1