What medications can cause elevated bilirubin levels?

Medications That Can Cause Elevated Bilirubin Levels

Several medications can cause elevated bilirubin levels through various mechanisms, with protease inhibitors like atazanavir, indinavir, and simeprevir being among the most common culprits.

Protease Inhibitors

HIV Protease Inhibitors

• Atazanavir: Causes unconjugated (indirect) hyperbilirubinemia by inhibiting the UGT1A1 enzyme responsible for bilirubin conjugation 1. In clinical studies, 30-62% of patients experienced hyperbilirubinemia, with higher rates at higher doses 1.
• Indinavir: Associated with indirect hyperbilirubinemia through inhibition of UGT1A1 2. The combination of indinavir with ritonavir can lead to severe symptomatic hyperbilirubinemia due to metabolic inhibition and increased indinavir concentrations 3.

HCV Protease Inhibitors

• Simeprevir: Causes mild to moderate indirect hyperbilirubinemia in approximately 10% of patients due to inhibition of the hepatic transporters OATP1B1 and MRP2 4. The elevation is typically not associated with ALT changes.
• Paritaprevir: Inhibits OATP1B1 transporter, leading to increased indirect bilirubin levels 4.

Genetic Susceptibility Factors

Patients with Gilbert syndrome (UGT1A1*28 variant allele) have a significantly higher risk of developing severe hyperbilirubinemia when taking certain medications:

• Homozygous UGT1A1*28 increases baseline bilirubin levels by 5.2 μmol/L (0.3 mg/dL) 5.
• 67% of individuals homozygous for UGT1A1*28 receiving atazanavir or indinavir had multiple episodes of hyperbilirubinemia in the jaundice range (>43 μmol/L or >2.5 mg/dL) 5.

Antimycobacterial Drugs

• Rifampin: Can cause transient asymptomatic hyperbilirubinemia in up to 0.6% of patients. More severe clinical hepatitis with a cholestatic pattern may also occur, especially when combined with isoniazid 4.

Monitoring Recommendations

For patients on medications known to cause hyperbilirubinemia:

1. Monitor bilirubin levels regularly, especially during the first few weeks of treatment.
2. For patients receiving simeprevir, monitor for rashes, indirect bilirubin elevations without ALT elevations 4.
3. For patients receiving ritonavir-boosted paritaprevir, ombitasvir and dasabuvir, monitor for indirect bilirubin increases 4.
4. Consider UGT1A1*28 genotyping before initiating therapy with atazanavir or indinavir to identify individuals at higher risk for hyperbilirubinemia 5.

Clinical Significance and Management

• Isolated indirect hyperbilirubinemia without liver enzyme elevations is generally benign and often does not require discontinuation of therapy 6.
• In patients with HIV/HCV coinfection, who have a 2-10 fold higher risk of developing elevated liver enzymes during HAART, monthly liver function tests are recommended 7.
• For severe hyperbilirubinemia with clinical jaundice, consider:
  • Dose reduction if possible
  • Switching to an alternative agent
  • Continuing therapy with close monitoring if the benefit outweighs the risk

Important Considerations

• Differentiate between isolated hyperbilirubinemia (often benign) and hyperbilirubinemia with liver enzyme elevations (may indicate liver injury).
• In HIV patients, consider the possibility of concurrent viral hepatitis reactivation or alcohol use as contributors to liver abnormalities 7.
• Efavirenz may decrease bilirubin levels through induction of UGT1A1 enzyme 5.

When evaluating elevated bilirubin in patients on medication, determine whether it's predominantly conjugated (>35% direct) or unconjugated (<20-30% direct) to help identify the mechanism and appropriate management strategy 8.