What medications can cause hyperbilirubinemia?

Medications That Can Cause Hyperbilirubinemia

Multiple medications can cause hyperbilirubinemia through various mechanisms, with the most common being rifampin, indinavir, atazanavir, phenytoin, and certain anticonvulsants. Understanding the specific mechanisms and patterns of drug-induced hyperbilirubinemia is essential for proper management and prevention of adverse outcomes.

Common Medications Causing Hyperbilirubinemia

Antimicrobials

• Rifampin: Causes transient asymptomatic hyperbilirubinemia in up to 0.6% of patients, typically with a cholestatic pattern 1
• Antiviral medications:
  • Protease inhibitors: Indinavir and atazanavir commonly cause indirect hyperbilirubinemia through inhibition of bilirubin transporters OATP1B1 and OATP1B3 1
  • Ritonavir-boosted paritaprevir: Causes transient increases in indirect bilirubin 1

Anticonvulsants

• Phenytoin: Can cause hyperbilirubinemia, particularly in patients with impaired liver function 2
• Valproic acid, lamotrigine, phenobarbital, carbamazepine: Can impair liver function to varying degrees, potentially leading to hyperbilirubinemia 3

Other Medications

• Chlorpromazine (Thorazine): Can result in abnormal liver function tests with hyperbilirubinemia 1
• Oral contraceptives: May cause cholestatic liver injury with elevated bilirubin 1
• Anabolic/estrogenic steroids: Can lead to cholestasis with elevated bilirubin 1
• Acetaminophen: Particularly in overdose situations, can cause hepatocellular injury with hyperbilirubinemia 1
• Penicillin: May cause drug-induced liver injury with hyperbilirubinemia 1

Mechanisms of Drug-Induced Hyperbilirubinemia

1. Direct Hepatotoxicity

• Medications like acetaminophen can cause direct injury to hepatocytes, leading to impaired bilirubin metabolism and conjugated hyperbilirubinemia

2. Inhibition of Bilirubin Transport

• Protease inhibitors (atazanavir, indinavir) inhibit OATP1B1 and OATP1B3 transporters, causing indirect hyperbilirubinemia 1

3. Cholestatic Injury

• Drugs like rifampin, oral contraceptives, and anabolic steroids can cause cholestatic patterns of liver injury 1

4. Hemolysis

• Some medications can cause hemolytic anemia, leading to increased bilirubin production and indirect hyperbilirubinemia
• Rifampin can rarely cause hemolytic anemia, especially with intermittent therapy 1

Patterns of Drug-Induced Hyperbilirubinemia

Indirect (Unconjugated) Hyperbilirubinemia

• Typically seen with:
  • Protease inhibitors (atazanavir, indinavir)
  • Hemolysis-inducing drugs
  • Drugs that impair bilirubin conjugation

Direct (Conjugated) Hyperbilirubinemia

• Associated with:
  • Hepatocellular injury
  • Cholestatic drug reactions
  • Biliary obstruction

Risk Factors for Drug-Induced Hyperbilirubinemia

• Pre-existing liver disease: Patients with impaired liver function are at higher risk 2
• Genetic factors: Gilbert syndrome (affecting 5% of the population) can predispose to drug-induced hyperbilirubinemia 1
• Advanced age: Elderly patients may show early signs of toxicity with certain medications 2
• Polypharmacy: Drug interactions can potentiate hyperbilirubinemia

Monitoring Recommendations

• For patients on rifampin: Monitor for transient hyperbilirubinemia, particularly in those with pre-existing liver disease 1
• For patients on antiretrovirals: Monitor for indirect bilirubin increases, especially with atazanavir 1
• For patients on anticonvulsants: Regular liver function tests are recommended 3
• For patients on hepatitis C treatment: ALT levels should be assessed at weeks 4,8, and 12 of therapy 1

Clinical Pearls

• Isolated increases in indirect bilirubin without ALT elevations are typically benign and may not require discontinuation of the medication
• Hyperbilirubinemia accompanied by elevated transaminases suggests more significant liver injury and warrants closer monitoring or medication adjustment
• Genetic testing for Gilbert syndrome should be considered in patients with recurrent episodes of mild indirect hyperbilirubinemia during drug therapy
• When evaluating drug-induced hyperbilirubinemia, always distinguish between direct and indirect fractions to guide management

Remember that drug-induced hyperbilirubinemia can range from benign, self-limited elevations to severe liver injury requiring immediate intervention. The pattern of bilirubin elevation (direct vs. indirect) and presence of other liver function abnormalities are key to determining the clinical significance and appropriate management.