How is Gilbert's syndrome diagnosed and treated?

Diagnosis of Gilbert's Syndrome

Gilbert's syndrome is diagnosed by demonstrating mild unconjugated hyperbilirubinemia (total bilirubin typically <4-5 mg/dL with >70-80% unconjugated) in the presence of completely normal liver enzymes (ALT, AST, alkaline phosphatase) and no evidence of hemolysis. 1

Essential Laboratory Tests

Primary Diagnostic Panel

• Measure total and direct bilirubin to calculate the unconjugated fraction, which must be >70-80% of total bilirubin (or conversely, conjugated bilirubin <20-30% of total) 1
• Check ALT, AST, and alkaline phosphatase – all must be completely normal; any elevation excludes Gilbert's syndrome and indicates alternative hepatobiliary pathology 1
• Obtain complete blood count to assess for hemolysis as a competing cause of unconjugated hyperbilirubinemia 1

Hemolysis Exclusion Tests

• Reticulocyte count should be normal (elevation indicates hemolysis rather than Gilbert's syndrome) 1
• Haptoglobin should be normal (low levels suggest hemolysis) 1
• Hemoglobin/hematocrit should be normal 1

Critical Diagnostic Thresholds

The bilirubin pattern is the cornerstone of diagnosis:

• Total bilirubin rarely exceeds 4-5 mg/dL (68-85 μmol/L), though rare cases with levels >6 mg/dL have been reported and require exclusion of hemolytic disorders 1, 2
• Unconjugated fraction must represent >70-80% of total bilirubin 1
• If conjugated bilirubin exceeds 30% of total, Gilbert's syndrome is excluded and hepatobiliary disease must be investigated 1

Important Diagnostic Pitfall

Be aware that direct bilirubin measurements include both conjugated bilirubin AND delta bilirubin. If hyperbilirubinemia persists unexpectedly or the pattern seems inconsistent, request fractionation of direct bilirubin into conjugated and delta components to avoid misdiagnosis 1.

Confirmatory Testing

DNA testing for UGT1A1 gene mutations (most commonly the homozygous A(TA)7TAA polymorphism, designated UGT1A1*28) provides definitive confirmation, particularly useful when bilirubin elevations occur with atypical features or diagnostic uncertainty 1, 3

Provocative Tests (Optional, Not Routinely Necessary)

While historically used, provocative tests are not required for diagnosis when the laboratory pattern is classic:

• Rifampicin test: 600 mg rifampicin causes increased unconjugated bilirubin at 4 hours in Gilbert's syndrome, but lacks specificity as it also elevates bilirubin in approximately 50% of patients with chronic liver disease 4, 5
• Fasting/caloric restriction test: 400 calorie/day diet for 24 hours increases unconjugated bilirubin in Gilbert's syndrome, but similarly lacks specificity in differentiating from acute hepatitis 4, 6

These tests are gaining less favor because they add little diagnostic value beyond the basic laboratory pattern and have poor specificity 4, 6.

Clinical Context Requirements

Before finalizing the diagnosis, verify:

• No evidence of hemolysis (normal reticulocyte count, haptoglobin, CBC) 1
• No medications causing hyperbilirubinemia 1
• No alcohol consumption or viral hepatitis risk factors 1
• Intermittent jaundice pattern, often first noticed in adolescence 3

When Liver Biopsy Is NOT Needed

Liver biopsy is not mandatory when patients demonstrate mild hyperbilirubinemia with high unconjugated fraction, completely normal liver enzymes, and no signs of hemolysis 6. The diagnosis is primarily one of exclusion based on the characteristic laboratory pattern.

Common Clinical Pitfalls to Avoid

• Do not diagnose Gilbert's syndrome if ANY liver enzyme is elevated – this indicates alternative pathology 1
• Do not rely solely on provocative tests – they lack sufficient specificity and can be positive in other liver diseases 4, 6
• Gilbert's syndrome may coexist with and potentiate other conditions (G6PD deficiency, thalassemia, spherocytosis, cystic fibrosis), leading to more severe hyperbilirubinemia than expected 3