What is the workup for Gilbert's syndrome?

Workup for Gilbert's Syndrome

The workup for Gilbert's syndrome should include liver function tests with focus on unconjugated hyperbilirubinemia in the absence of hepatocellular disease or hemolysis, with genetic testing for UGT1A1*28 polymorphism available when diagnosis is uncertain. 1

Initial Laboratory Evaluation

• Complete liver function panel including total and direct (conjugated) bilirubin levels, with Gilbert's syndrome typically showing mild unconjugated (indirect) hyperbilirubinemia 1
• Complete blood count to rule out hemolysis as a cause of unconjugated hyperbilirubinemia 1
• Basic metabolic panel to assess kidney function 2
• Liver enzymes (AST, ALT, alkaline phosphatase, GGT) which are typically normal in Gilbert's syndrome 1, 3

Diagnostic Criteria

• Mild unconjugated hyperbilirubinemia (typically <5 mg/dL) 1
• Normal liver enzymes and liver function 1, 3
• Absence of hemolysis or other liver diseases 1
• Intermittent jaundice that may worsen with fasting, stress, illness, or physical exertion 1, 3

Confirmatory Testing

• Genetic testing for UGT1A1*28 polymorphism (homozygous TA7/TA7 genotype) when diagnosis is uncertain 1
• Rifampicin test: measurement of unconjugated bilirubin levels before and 4 hours after administration of 600 mg rifampicin (significant increase suggests Gilbert's syndrome) 4
• Fasting test: 400 calorie/day diet for 24 hours with bilirubin measurement (significant increase in unconjugated bilirubin supports diagnosis) 4

Important Considerations

• Clinical trials have shown that both rifampicin and fasting tests have comparable sensitivity for Gilbert's syndrome diagnosis, but specificity is limited as they may also cause increased unconjugated bilirubin in some patients with chronic liver disease 4
• Gilbert's syndrome exceptions are commonly made in clinical trial eligibility criteria, allowing for total bilirubin up to 3-5x upper limit of normal with normal direct bilirubin levels 2
• The condition is benign and does not lead to hepatic inflammation, fibrosis, chronic liver disease, or liver failure 1, 5

Differential Diagnosis

• Hemolytic anemias (rule out with normal hemoglobin, reticulocyte count, and haptoglobin) 1
• Crigler-Najjar syndrome (more severe unconjugated hyperbilirubinemia) 3
• Drug-induced hyperbilirubinemia 5
• Early viral hepatitis or other liver diseases (ruled out by normal liver enzymes) 3

Clinical Relevance

• Gilbert's syndrome may affect drug metabolism, particularly medications metabolized by UGT1A1 enzyme, such as irinotecan and atazanavir 5
• The condition may be associated with essential tremor in homozygous carriers 6
• No specific management is necessary as Gilbert's syndrome is a benign condition 1

Common Pitfalls

• Overdiagnosis of liver disease in patients with isolated unconjugated hyperbilirubinemia 3
• Unnecessary additional testing in patients with established Gilbert's syndrome 1
• Failure to consider Gilbert's syndrome as a contributor to drug toxicity, particularly with medications metabolized by UGT1A1 5