Which medications can induce or mimic Gilbert's syndrome (hereditary unconjugated hyperbilirubinemia)?

Medications That Can Induce or Unmask Gilbert's Syndrome

Nilotinib is the primary medication documented to induce unconjugated hyperbilirubinemia in patients with Gilbert's syndrome by competing for UDP-glucuronosyltransferase, though this typically has no clinical impact. 1

Direct Drug-Induced Unconjugated Hyperbilirubinemia

Nilotinib (tyrosine kinase inhibitor):

• Directly competes for UDP-glucuronosyltransferase enzyme activity, the same enzyme deficient in Gilbert's syndrome 1
• Results in unconjugated hyperbilirubinemia specifically in patients with underlying Gilbert's disease 1
• This elevation is typically benign and without clinical consequences 1

Atazanavir (protease inhibitor):

• Inhibits hepatic UGT activity, leading to hyperbilirubinemia in treated patients 2
• Increases median bilirubin levels significantly (from 10 to 41 micromol/L in studies) 2
• Hyperbilirubinemia exceeding 43 micromol/L occurred in 37% of treated patients 2
• The effect is strongly associated with UGT1A1*28 polymorphism (the genetic basis of Gilbert's syndrome) and related UGT variants 2
• Patients homozygous for multiple UGT variants had 100% incidence of severe hyperbilirubinemia (>85 micromol/L) 2

Medications Requiring Dose Adjustment in Gilbert's Syndrome

Irinotecan (chemotherapy agent):

• Patients with Gilbert's syndrome have significantly increased risk of severe toxicity from irinotecan 3
• Dose reduction is required in patients with UGT1A1 polymorphisms 3
• The reduced glucuronidation capacity (20-30% of normal in Gilbert's syndrome) severely impacts the ability to metabolize this medication 4, 5

Important Clinical Caveats

Distinguishing drug-induced effects from true Gilbert's syndrome:

• Many drugs can cause hepatotoxicity with elevated bilirubin, but this typically presents with direct bilirubin >35% of total bilirubin and elevated liver enzymes 4
• True Gilbert's syndrome or drug-unmasking of Gilbert's maintains conjugated bilirubin <20-30% of total bilirubin 1, 4
• Drug-induced liver injury usually shows elevated transaminases, which should be absent in pure Gilbert's syndrome 3

Medications causing general hepatotoxicity (not Gilbert's-specific):

• Acetaminophen, penicillin, oral contraceptives, estrogenic/anabolic steroids, and chlorpromazine can cause hyperbilirubinemia through hepatocellular injury 4
• These cause a different pattern than Gilbert's syndrome, with elevated conjugated bilirubin and liver enzymes 4

Key monitoring principle:

• When evaluating hyperbilirubinemia in patients on any medication, calculate the conjugated fraction: if <20-30% of total bilirubin with normal liver enzymes, consider drug-unmasking of underlying Gilbert's syndrome rather than drug-induced liver injury 1, 4