What medications can cause elevated bilirubin levels?

Medications That Cause Elevated Bilirubin

Several medications can cause elevated bilirubin levels through various mechanisms including inhibition of bilirubin transporters, direct hepatotoxicity, or hemolysis. Understanding these medications is crucial for proper patient management and preventing adverse outcomes.

Antiviral Medications

• Atazanavir causes indirect hyperbilirubinemia by inhibiting bilirubin transporters OATP1B1 and OATP1B3, with 30-62% of patients experiencing elevated bilirubin levels during treatment 1
• Simeprevir commonly causes indirect bilirubin elevations without ALT elevations, requiring monitoring during treatment 2
• Paritaprevir (especially when ritonavir-boosted) causes transient increases in indirect serum bilirubin through inhibition of bilirubin transporters OATP1B1 and OATP1B3 2
• Indinavir increases bilirubin levels by approximately 8 μmol/L (0.46 mg/dL), with higher risk in patients with Gilbert syndrome 3

Anti-tuberculosis Medications

• Rifampicin can cause:
  • Transient elevation of bilirubin through inhibition of hepatic transport of bile acids 4
  • Biphasic effect on bilirubin with initial increase in indirect bilirubin followed by normalization 5
  • Severe hepatitis with hyperbilirubinemia in rare cases 5
• Multiple anti-TB drugs (isoniazid, rifampicin, pyrazinamide) can cause drug-induced liver injury with elevated bilirubin, especially in patients with decreased activities of daily living or chronic cardiac disease 6

Hepatitis C Direct-Acting Antivirals

• Ribavirin causes hemolysis which contributes to indirect hyperbilirubinemia 2
• Combination therapy with ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir can cause indirect bilirubin increases, particularly in patients with cirrhosis 2

Other Medications

• Statins (atorvastatin, fluvastatin, rosuvastatin) can alter hepatobiliary transport of bilirubin by:
  • Inhibiting bilirubin uptake
  • Stimulating sinusoidal and canalicular elimination
  • Affecting Mrp2/3 protein levels and function 7
• Estrogen-containing medications are associated with greater risk of ALT elevations when used with certain antivirals, potentially affecting bilirubin metabolism 2
• Experimental drugs for COVID-19 (remdesivir, chloroquine, hydroxychloroquine, tocilizumab) may induce liver toxicity potentially affecting bilirubin levels 2

Risk Factors for Medication-Induced Hyperbilirubinemia

• Gilbert syndrome (UGT1A1*28 homozygosity) increases baseline bilirubin by approximately 5.2 μmol/L (0.3 mg/dL) and significantly increases risk of hyperbilirubinemia when combined with medications like atazanavir or indinavir 3
• Cirrhosis increases the risk of medication-induced bilirubin elevations, with greater frequency of total bilirubin increases observed in patients with cirrhosis taking certain antivirals 2
• Decreased activities of daily living is the strongest predictor for drug-induced liver injury with elevated bilirubin (≥2.0 mg/dL) from antituberculous drugs 6

Monitoring Recommendations

• For patients receiving medications known to affect bilirubin:
  • Monitor liver function tests regularly, particularly when starting therapy 2
  • Check renal function regularly in patients receiving medications like sofosbuvir 2
  • Be aware that some medications (e.g., simeprevir) may cause bilirubin elevations without corresponding ALT elevations 2
• For patients with elevated bilirubin:
  • Determine whether hyperbilirubinemia is predominantly unconjugated or conjugated to help narrow the differential diagnosis 8
  • Consider medication review and potential adjustment or discontinuation of offending agents 2

Clinical Approach to Medication-Induced Hyperbilirubinemia

• Distinguish between harmless drug-induced hyperbilirubinemia (like atazanavir-induced indirect hyperbilirubinemia) and serious drug-induced liver injury 8
• Recognize that some medications (like efavirenz) may actually decrease bilirubin levels through induction of UDP-glucuronosyltransferase 1A1 3
• Consider genetic testing for UGT1A1*28 before initiating medications known to cause hyperbilirubinemia in susceptible individuals 3