Gilbert syndrome

Gilbert syndrome results from a genetic polymorphism (commonly a TA repeat insertion in the promoter region of the UGT1A1 gene, UGT1A1*28) that reduces enzyme expression to about 30% of normal, impairing hepatic conjugation of bilirubin. This causes a mild, fluctuating unconjugated hyperbilirubinemia (usually <3 mg/dL), often noticed as scleral icterus during physiologic stress such as fasting, dehydration, febrile illness, exercise, or menstruation. Liver function tests (AST, ALT, ALP), hemolysis markers (reticulocyte count, haptoglobin, LDH), and liver histology are normal, distinguishing it from hemolytic anemia or hepatobiliary disease. It is inherited in an autosomal recessive-like pattern with variable penetrance and affects roughly 3–7% of the population, more common in males. Diagnosis is clinical, based on isolated unconjugated hyperbilirubinemia with otherwise normal labs and no evidence of hemolysis or liver disease; genetic testing is rarely necessary. Gilbert syndrome is important clinically because it can predispose patients to increased toxicity from drugs metabolized by UGT1A1, notably irinotecan (increased risk of severe diarrhea and myelosuppression) and it may complicate interpretation of bilirubin levels in other clinical contexts. It should be differentiated from Crigler-Najjar syndrome (type I and II), which involves more severe UGT1A1 deficiency and more significant hyperbilirubinemia with risk of kernicterus, and from Dubin-Johnson and Rotor syndromes, which cause conjugated hyperbilirubinemia due to defects in bilirubin excretion rather than conjugation. No treatment is required for Gilbert syndrome, though phenobarbital can be used to induce UGT1A1 activity if needed for cosmetic reasons. The condition carries an excellent prognosis with no increased risk of liver damage.