What is the typical workup for Gilbert's syndrome?

Diagnostic Workup for Gilbert's Syndrome

The diagnostic workup for Gilbert's syndrome should focus on confirming mild unconjugated hyperbilirubinemia with normal liver function tests and ruling out other causes of hyperbilirubinemia. The following algorithm provides a structured approach to diagnosing this benign condition.

Initial Laboratory Testing

• Fractionated bilirubin levels - Gilbert's syndrome typically presents with predominantly unconjugated hyperbilirubinemia (<20-30% conjugated bilirubin) 1
• Complete liver function tests including:
  • ALT, AST, alkaline phosphatase, γ-glutamyltransferase
  • Albumin, total protein
  • Prothrombin time/INR 1
• Complete blood count with differential and peripheral smear to rule out hemolysis 1

Diagnostic Criteria

Gilbert's syndrome can be diagnosed with relative certainty if the patient has:

• Mild unconjugated hyperbilirubinemia (typically <3 mg/dL)
• High fraction of unconjugated bilirubin
• Normal values of liver enzymes
• No overt signs of hemolysis 2

Confirmatory Testing

If the diagnosis remains uncertain after initial testing, confirmatory tests may be performed:

1. Rifampicin Test

• Administer 600 mg of rifampicin orally
• Measure unconjugated bilirubin levels before and 4 hours after administration
• A significant increase in unconjugated bilirubin levels suggests Gilbert's syndrome
• This test is simpler and more practical than the fasting test 3, 4

2. Caloric Restriction Test

• Restrict caloric intake to 400 calories/day for 24 hours
• Measure bilirubin levels before and after the fasting period
• A significant increase in unconjugated bilirubin levels supports the diagnosis of Gilbert's syndrome 3, 2, 4

Important Considerations

• Liver biopsy is not necessary for diagnosing Gilbert's syndrome 2
• Genetic testing for UGT1A1 mutations (particularly UGT1A1*28) can provide definitive confirmation but is not routinely required 1, 5
• Both rifampicin and fasting tests have limited specificity as they may also cause increased unconjugated bilirubin in patients with chronic liver disease 3

Differential Diagnosis to Rule Out

• Hemolytic disorders - Check for anemia, reticulocytosis, haptoglobin levels
• Medication-induced hyperbilirubinemia - Review medication history, particularly for drugs like simeprevir or paritaprevir 1
• Chronic liver disease - Ruled out by normal liver enzymes and function tests
• Crigler-Najjar syndrome - More severe unconjugated hyperbilirubinemia 6

Clinical Pearls

• Gilbert's syndrome affects approximately 40% of Caucasian individuals and is characterized by reduced hepatic bilirubin-UDP-glucuronosyltransferase (UGT1A1) activity to around 30% of normal levels 4, 5
• The condition is benign and does not lead to hepatic inflammation, fibrosis, chronic liver disease, or liver failure 5
• Patients with Gilbert's syndrome may experience exacerbations of jaundice during fasting, illness, or stress
• Knowledge of Gilbert's syndrome is important for drug therapy, as it can affect metabolism of certain medications like irinotecan and atazanavir 5

Management

Once diagnosed, management consists of reassurance alone as Gilbert's syndrome is a benign condition that does not require specific treatment 6.