How is Gilbert syndrome diagnosed?

Diagnosis of Gilbert Syndrome

Gilbert syndrome is diagnosed through clinical evaluation, laboratory findings showing mild unconjugated hyperbilirubinemia, normal liver enzymes, and absence of hemolysis, with genetic testing for UGT1A1*28 polymorphism available for confirmation in uncertain cases. 1

Clinical Presentation and Initial Evaluation

• Gilbert syndrome is characterized by:
  • Intermittent mild jaundice, often first noticed in adolescence
  • Unconjugated (indirect) hyperbilirubinemia
  • Normal liver enzymes (AST, ALT)
  • Absence of hepatocellular disease or hemolysis
  • Often exacerbated by fasting, stress, illness, or physical exertion

Diagnostic Approach

Step 1: Laboratory Testing

• Complete blood count to rule out hemolysis
• Liver function tests (must be normal in Gilbert syndrome):
  • AST, ALT
  • Alkaline phosphatase
  • Gamma-glutamyl transferase
• Bilirubin levels:
  • Total bilirubin (typically 1-3 mg/dL)
  • Direct and indirect bilirubin fractions (predominantly indirect/unconjugated)

Step 2: Exclusion of Other Causes

• Rule out hemolytic disorders (normal hemoglobin, reticulocyte count, haptoglobin)
• Rule out viral hepatitis and other liver diseases
• Rule out medication-induced hyperbilirubinemia

Step 3: Confirmatory Tests

When diagnosis remains uncertain, consider:

1. Fasting Test (Caloric Restriction Test):

   • 24-48 hour caloric restriction (400-500 calories/day)
   • Bilirubin levels typically increase by >50% in Gilbert syndrome 2

2. Rifampin Test:

   • Measure bilirubin before and 2-3 hours after administering rifampin (900 mg orally)
   • In Gilbert syndrome, bilirubin increases significantly (>2-fold) 2

3. Genetic Testing:

   • Test for UGT1A1*28 polymorphism (homozygous TA7 repeats in the promoter region)
   • Most common genotype in Gilbert syndrome is homozygous A(TA)7TAA in the UGT1A1 gene promoter 1, 3
   • Particularly useful when diagnosis is uncertain or when there are implications for drug metabolism

Diagnostic Criteria

A diagnosis of Gilbert syndrome can be established when:

• Mild unconjugated hyperbilirubinemia (typically <3 mg/dL)
• Normal liver enzymes
• Absence of hemolysis
• No evidence of other liver disease
• Positive response to provocative testing (if performed)
• Consistent genetic testing results (if performed)

Special Considerations

• Gilbert syndrome may be more pronounced when combined with other conditions:

  • G6PD deficiency
  • Thalassemia
  • Spherocytosis
  • Cystic fibrosis
  • Breastfeeding (in neonates) 1

• Gilbert syndrome affects drug metabolism for certain medications (e.g., irinotecan, atazanavir) due to reduced UGT1A1 activity 4

• The condition is benign and requires no specific treatment, but awareness is important for:

  • Avoiding unnecessary diagnostic procedures
  • Preventing misdiagnosis of more serious liver conditions
  • Guiding medication dosing for drugs metabolized by UGT1A1

Pitfalls to Avoid

• Don't mistake Gilbert syndrome for more serious liver disease
• Don't perform invasive procedures like liver biopsy when clinical and laboratory findings are consistent with Gilbert syndrome
• Don't overlook Gilbert syndrome as a contributor to drug toxicity with medications metabolized by UGT1A1
• Remember that normal bilirubin levels don't exclude Gilbert syndrome, as levels fluctuate

Gilbert syndrome is a benign condition with reduced UGT1A1 activity (approximately 30% of normal), resulting in intermittent unconjugated hyperbilirubinemia 1. While no specific management is necessary, recognizing this condition helps avoid unnecessary testing and guides medication management in affected individuals.