What medications can cause hyperbilirubinemia?

Medications That Cause Hyperbilirubinemia

Several medications can cause hyperbilirubinemia through various mechanisms, with the most common being protease inhibitors, rifamycins, and certain antibiotics. Understanding these medications and their mechanisms is essential for clinical management.

Direct (Conjugated) Hyperbilirubinemia

Protease Inhibitors

• Atazanavir is strongly associated with direct hyperbilirubinemia through inhibition of bilirubin conjugation 1
• Indinavir also commonly causes expected indirect hyperbilirubinemia (not considered a toxicity) 1

Antibiotics

• Ceftriaxone can cause marked direct hyperbilirubinemia, particularly in patients with underlying conditions like sickle cell disease 2
• Ceftriaxone is contraindicated in hyperbilirubinemic neonates as it can displace bilirubin from serum albumin, leading to risk of bilirubin encephalopathy 3
• High-level bilirubin-displacing antibiotics include sulfisoxazole, sulfamethoxazole, dicloxacillin, cefoperazone, and ceftriaxone 4

Indirect (Unconjugated) Hyperbilirubinemia

Rifamycins

• Rifampin can cause transient asymptomatic hyperbilirubinemia in up to 0.6% of patients 1
• Rifampin may have a biphasic effect on bilirubin - initial increase in indirect bilirubin followed by normalization 5
• Rifampin-induced cholestatic hepatitis is more common when given in combination with isoniazid (2.7%) than when given alone (nearly 0%) 1

HIV Medications

• Nevirapine, efavirenz, etravirine, and rilpivirine can cause indirect hyperbilirubinemia 1
• Any protease inhibitor (especially those containing sulfonamide moiety like darunavir) may cause hyperbilirubinemia 1

Medications Causing Hyperbilirubinemia Through Hepatotoxicity

• Isoniazid, pyrazinamide, and ethionamide can cause lactic acidosis with hepatic steatosis, potentially leading to hyperbilirubinemia 1
• Fluoroquinolones may contribute to hepatotoxicity and subsequent hyperbilirubinemia 1
• Grazoprevir (used for hepatitis C) may cause hyperbilirubinemia, especially when coadministered with drugs that inhibit OATP1B1/3 (enalapril, statins, digoxin, and some angiotensin-receptor blockers) 1

Risk Factors for Drug-Induced Hyperbilirubinemia

• Genetic variations in UDP-glucuronosyltransferases, organic anion-transporting polypeptides, and multidrug resistance proteins predispose to drug-induced hyperbilirubinemia 6
• Underlying liver disease increases risk of drug-induced hyperbilirubinemia 7
• HIV infection may increase susceptibility to drug-induced liver injury and hyperbilirubinemia 1
• Patients with Gilbert syndrome (affecting 5% of the American population) are at increased risk for drug-induced unconjugated hyperbilirubinemia 8

Clinical Management Considerations

• When hyperbilirubinemia occurs during antiviral therapy, determine whether it's direct or indirect to guide management 7
• Mild indirect hyperbilirubinemia associated with impairment in conjugation tends to be well tolerated and may not require intervention 7
• For significant direct hyperbilirubinemia or evidence of liver injury, consider medication discontinuation or substitution 7
• Antibiotics with high bilirubin-displacing potential should be avoided in jaundiced newborns when alternatives are available 4
• Monitor liver function tests at baseline and periodically in patients receiving medications known to cause hyperbilirubinemia 1

Special Population Considerations

• Protease inhibitors like grazoprevir are contraindicated in patients with Child-Turcotte-Pugh class B and C cirrhosis due to risk of hepatotoxicity 1
• Rifampin requires careful monitoring in patients with liver disease, though it generally should be included in TB treatment regimens due to its critical importance 1
• Ceftriaxone is contraindicated in neonates (≤28 days) requiring calcium-containing IV solutions due to risk of precipitation 3
• Hyperbilirubinemic neonates should not be treated with ceftriaxone as it can displace bilirubin from serum albumin 3

Understanding the mechanisms and patterns of drug-induced hyperbilirubinemia allows for appropriate monitoring, early detection, and management of this common medication side effect.