What is the workup for Gilbert syndrome?

Workup for Gilbert Syndrome

The workup for Gilbert syndrome should include liver function tests with fractionated bilirubin, genetic testing for UGT1A1 mutations, and exclusion of other causes of unconjugated hyperbilirubinemia. 1, 2

Initial Laboratory Evaluation

• Complete liver function panel including total bilirubin, direct (conjugated) and indirect (unconjugated) bilirubin fractionation 1
• Calculate the proportion of conjugated bilirubin, which should be less than 20-30% of total bilirubin in Gilbert syndrome 1
• Complete blood count to rule out hemolysis 1
• Liver enzymes (AST, ALT, ALP, GGT) which should be normal in Gilbert syndrome 2
• Serum electrolytes, kidney function tests 1

Confirmatory Testing

• Genetic testing for UGT1A1 gene mutations, particularly the TA insertion in the promoter region (UGT1A1*28) which is the most common genotype in Gilbert syndrome 2, 3
• For Asian patients, testing for G71R mutation in exon 1 of the UGT1A1 gene may be necessary as this is more common in this population 3
• If genetic testing is unavailable, provocative tests can be considered:
  • Caloric restriction test: 24-48 hour fast which typically increases unconjugated bilirubin levels in Gilbert syndrome 4
  • Rifampin test: administration of rifampin can help confirm diagnosis by competing for bilirubin excretion 4

Differential Diagnosis Evaluation

• Rule out hemolytic disorders through reticulocyte count, haptoglobin, LDH, and peripheral blood smear 1
• Rule out other liver diseases that may cause hyperbilirubinemia 1
• Consider testing for other hereditary hyperbilirubinemia syndromes (Crigler-Najjar syndrome) in cases with higher levels of unconjugated bilirubin 5

Imaging

• Abdominal ultrasound may be performed to rule out structural liver or biliary tract abnormalities, though this is not mandatory if other tests are normal 1

Important Clinical Considerations

• Gilbert syndrome typically presents with mild unconjugated hyperbilirubinemia (usually <3 mg/dL), though rare cases may present with levels >6 mg/dL 5
• Symptoms typically first appear during adolescence with intermittent mild jaundice 2
• No liver biopsy is required for diagnosis; this is a clinical and laboratory diagnosis 6
• Gilbert syndrome may be unmasked during periods of fasting, stress, mild illness, or physical exertion 2

Special Considerations

• In patients with persistent isolated elevations of direct bilirubin, close monitoring is recommended as this may indicate drug-induced liver injury rather than Gilbert syndrome 1
• Gilbert syndrome in combination with other conditions such as G6PD deficiency, thalassemia, or spherocytosis may lead to more severe hyperbilirubinemia 2
• If the etiology of prolonged hyperbilirubinemia remains unclear, a breakdown of the direct bilirubin fraction into conjugated and delta bilirubin should be considered 1

Gilbert syndrome is a benign condition with excellent prognosis, requiring no specific treatment. However, proper diagnosis is important to differentiate it from more serious liver conditions and to prevent unnecessary investigations or treatments.