What is Gilbert syndrome?

Gilbert Syndrome: Definition and Clinical Overview

Gilbert syndrome is a benign hereditary condition affecting 5–10% of the general population, characterized by intermittent unconjugated hyperbilirubinemia that requires no treatment beyond patient reassurance. 1, 2

Pathophysiology

• Gilbert syndrome results from reduced activity of the hepatic enzyme uridine diphosphate-glucuronosyltransferase (UGT1A1) to approximately 20–30% of normal levels, impairing the conjugation of bilirubin with glucuronic acid. 1
• The condition is inherited in an autosomal dominant pattern and is commonly associated with the UGT1A1*28 promoter polymorphism (homozygous TA insertion). 3

Laboratory Characteristics

The hallmark laboratory finding is mild unconjugated hyperbilirubinemia with total bilirubin typically ranging from 1.5–3 mg/dL, rarely exceeding 4–5 mg/dL. 2

• Unconjugated bilirubin comprises more than 70–80% of total bilirubin, meaning conjugated bilirubin is less than 20–30% of the total. 1, 2
• All other liver function tests remain completely normal, including ALT, AST, alkaline phosphatase, GGT, albumin, and prothrombin time. 1, 2
• Complete blood count and peripheral smear are normal, excluding hemolysis as a cause of hyperbilirubinemia. 2

Clinical Significance and Common Pitfalls

• The most important clinical pitfall is mistaking Gilbert syndrome for drug-induced liver injury (DILI), which can lead to unnecessary drug interruption or discontinuation. 1
• In DILI, the direct bilirubin fraction is typically greater than 35%, whereas in Gilbert syndrome it remains less than 20–30%. 1
• Males are affected approximately 5 times more frequently than females. 2
• The condition is entirely benign and does not affect life expectancy or require any pharmacologic therapy. 1

Diagnostic Approach

• Calculate the percentage of conjugated bilirubin; if less than 20–30% of total bilirubin with absent hemolysis, Gilbert syndrome can be presumed. 1
• Systematically exclude hemolysis using complete blood count, reticulocyte count, peripheral smear, haptoglobin, and LDH measurements. 1
• Verify normal hepatocellular function by confirming ALT, AST, and alkaline phosphatase are within reference ranges. 1
• Routine abdominal ultrasound is not indicated because imaging adds no diagnostic value when unconjugated hyperbilirubinemia is present with normal liver enzymes. 1

Drug Metabolism Considerations

• Gilbert syndrome decreases the ability to conjugate certain medications, particularly affecting the metabolism of some antineoplastic agents. 4
• In oncology clinical trials, eligibility and monitoring should focus on elevations of direct (conjugated) bilirubin rather than total bilirubin when participants have Gilbert syndrome. 1
• The UGT1A1*28 polymorphism may reduce glucuronidation by 30%, potentially causing severe toxicities with certain chemotherapy agents like irinotecan. 4, 3

Management

Management consists solely of patient education and reassurance that the condition is benign, with no specific pharmacologic therapy required. 1