Diagnosis of Gilbert Syndrome
Gilbert syndrome is diagnosed by finding mild unconjugated hyperbilirubinemia with unconjugated bilirubin comprising more than 70-80% of total bilirubin, normal liver enzymes, and absence of hemolysis or other liver disease. 1, 2
Diagnostic Criteria
- Total bilirubin levels are typically mildly elevated, usually less than 4-5 mg/dL 1
- Unconjugated (indirect) bilirubin should comprise more than 70-80% of total bilirubin (or conjugated bilirubin less than 20-30% of total) 1, 2
- Normal liver enzymes and absence of hepatocellular disease 3
- No evidence of hemolysis on complete blood count and other hemolytic markers 2, 4
- Intermittent pattern of hyperbilirubinemia, often triggered by fasting, stress, or illness 3
Laboratory Evaluation Algorithm
Initial Testing
- Complete liver function panel including:
- Complete blood count to rule out hemolysis 2
- Calculate the proportion of conjugated bilirubin (should be <20-30% of total bilirubin) 1, 2
Rule Out Hemolysis
Rule Out Other Liver Diseases
Additional Diagnostic Tests
When Diagnosis Is Unclear
- Breakdown of direct bilirubin fraction into conjugated and delta bilirubin 1, 2
- Genetic testing for mutations in the uridine 5'-diphospho-glucuronyl-transferase (UGT1A1) gene, particularly the UGT1A1*28 polymorphism 1, 3
- Abdominal ultrasound to rule out structural liver or biliary tract abnormalities 1, 2
Specialized Tests (Rarely Needed)
- Caloric restriction test (fasting for 24-48 hours) - causes increased unconjugated bilirubin in Gilbert syndrome, but has low specificity 4, 5
- Rifampin test - can help differentiate Gilbert syndrome from other causes of hyperbilirubinemia 5
Important Clinical Considerations
- Gilbert syndrome affects 5-10% of the population 1
- The condition is caused by reduced activity (20-30% of normal) of the enzyme uridine 5'-diphospho-glucuronyl-transferase 1
- Liver biopsy is not necessary or recommended for diagnosis 4, 3
- While bilirubin levels typically remain below 5 mg/dL, rare cases may present with levels above 6 mg/dL 6
- The diagnosis is primarily one of exclusion, but the pattern of predominantly unconjugated hyperbilirubinemia (>90% of total bilirubin) is highly specific for Gilbert syndrome 7
Common Pitfalls to Avoid
- Misdiagnosing Gilbert syndrome as drug-induced liver injury, particularly in clinical trials 1
- Failing to recognize that Gilbert syndrome can coexist with and exacerbate other conditions like G6PD deficiency, thalassemia, or spherocytosis 3
- Performing unnecessary invasive testing when laboratory findings are characteristic 4, 7
- Overlooking that fasting and illness can temporarily increase bilirubin levels in affected individuals 3