Diagnosis of Gilbert Syndrome
Gilbert syndrome is diagnosed by demonstrating mild unconjugated hyperbilirubinemia (typically <4-5 mg/dL) where conjugated bilirubin comprises less than 20-30% of total bilirubin, in the absence of hemolysis or hepatocellular disease. 1
Initial Laboratory Assessment
Obtain a complete bilirubin fractionation panel to calculate the proportion of conjugated versus unconjugated bilirubin—this is the cornerstone of diagnosis. 2
- Total bilirubin is typically mildly elevated (1.5-5 mg/dL), though it can fluctuate and may occasionally be normal. 1, 3
- Conjugated (direct) bilirubin must be less than 20-30% of total bilirubin to confirm Gilbert syndrome. 1
- Complete blood count with reticulocyte count, haptoglobin, LDH, and peripheral smear to exclude hemolysis. 1, 2
- Liver enzymes (ALT, AST, alkaline phosphatase) should be normal. 1, 4
- Serum electrolytes and kidney function to exclude metabolic causes. 2
Critical Diagnostic Pitfall
Do not confuse "direct" and "conjugated" bilirubin—they are not interchangeable. Direct bilirubin includes both conjugated bilirubin and delta bilirubin (albumin-bound), which has a 21-day half-life and can cause persistent hyperbilirubinemia. 1 If prolonged hyperbilirubinemia is unexplained, request fractionation of direct bilirubin into conjugated and delta components. 1, 2
Clinical Context
Gilbert syndrome affects 5-10% of the population, with males predominating 5:1, and typically presents in the 15-30 year age group. 1, 3
- Intermittent jaundice or scleral icterus, often triggered by fasting, illness, stress, or exertion. 3, 5
- Nonspecific symptoms like fatigue or abdominal discomfort are common but not diagnostic. 3
- Bilirubin fluctuates—levels may be normal at times, so repeated measurements during symptomatic periods are necessary. 3
Excluding Alternative Diagnoses
Rule out hemolytic disorders through:
- Reticulocyte count, haptoglobin, and LDH (should be normal in Gilbert syndrome). 2
- Osmotic fragility and erythrocyte survival may show mild abnormalities in some Gilbert patients, but overt hemolysis should be absent. 3, 4
Rule out hepatocellular disease:
- Normal liver enzymes (ALT, AST) are essential for diagnosis. 1, 4
- If aminotransferases are elevated, consider acute hepatitis or other liver pathology instead. 4
Imaging Considerations
Abdominal ultrasound may be performed to exclude structural liver or biliary abnormalities, but is not mandatory if laboratory findings are characteristic and liver enzymes are normal. 1, 2
Genetic Testing
UGT1A1 genetic testing for the A(TA)7TAA promoter polymorphism (UGT1A1*28) can confirm the diagnosis when clinical presentation is atypical or when diagnostic certainty is needed. 1, 5 This is particularly useful when bilirubin levels exceed 6 mg/dL, which is rare but can occur. 6
Provocative Testing (Rarely Needed)
While historically used, provocative tests have limited clinical utility in modern practice:
- Fasting test: Bilirubin rises during caloric restriction, but this lacks specificity when differentiating from acute hepatitis. 4, 7
- Nicotinic acid test: Causes bilirubin elevation with retention >70% at 5 hours, but is rarely performed today. 3
- Rifampicin test: Can confirm diagnosis but is not routinely necessary. 7
These tests are not recommended for routine diagnosis given their limited specificity and the availability of more definitive laboratory and genetic testing. 4
Monitoring for Drug-Induced Liver Injury
In patients with known Gilbert syndrome who develop persistent isolated elevations of direct bilirubin (>35% of total), consider drug-induced liver injury rather than Gilbert syndrome alone. 1, 2 This is a critical distinction that requires close monitoring and potential medication review.