Can Letrozole (Femara) cause liver injury?

Letrozole and Liver Injury

Yes, letrozole can cause liver injury, though it is a rare adverse effect. Patients taking letrozole should be monitored for signs of hepatotoxicity, particularly those with pre-existing liver disease or cirrhosis, as letrozole blood concentrations can be significantly increased in these populations, requiring dose adjustment. 1

Evidence of Letrozole-Induced Liver Injury

The FDA drug label for letrozole specifically addresses hepatic impairment:

• In patients with cirrhosis and severe hepatic dysfunction (Child-Pugh classification C), letrozole exposure (AUC) increases two-fold with a 47% reduction in systemic clearance 1
• The recommended dose for patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% (2.5 mg administered every other day) 1
• For patients with mild to moderate hepatic impairment, no dosage adjustment is recommended, although letrozole blood concentrations are modestly increased 1

Case Reports of Letrozole-Induced Liver Injury

There are documented cases of letrozole causing hepatotoxicity:

• A case report described letrozole-induced hepatitis with autoimmune features in a 70-year-old female with breast cancer who developed jaundice 3 months after starting letrozole 2
• The patient had markedly elevated hepatic transaminases, positive ANA and anti-smooth muscle antibody, and liver biopsy features consistent with drug-induced hepatitis 2
• Liver tests returned to normal within 3 weeks after discontinuing letrozole 2

Risk Factors and Monitoring

Patients at higher risk for letrozole-induced liver injury include:

• Those with pre-existing liver disease or cirrhosis 1
• Patients concurrently taking other medications associated with liver injury 3
• Patients who drink excessive amounts of alcohol 3

Monitoring Recommendations

For patients on letrozole with risk factors for hepatotoxicity:

• Baseline liver function tests before starting therapy
• Regular monitoring of liver enzymes during treatment
• Immediate discontinuation if signs of liver injury develop (jaundice, right upper quadrant pain, fatigue, nausea)

Potential Protective Effects

Interestingly, a recent study suggests that letrozole might actually have protective effects against liver fibrosis:

• A 2024 study showed that letrozole treatment was associated with a significant decrease in liver fibrosis markers (FIB-4 index and APRI) at 18 and 24 months compared to baseline in patients with elevated fibrosis markers 4
• This effect was not observed with anastrozole, another aromatase inhibitor 4

Management of Letrozole-Induced Liver Injury

If liver injury is suspected:

1. Discontinue letrozole immediately
2. Monitor liver enzymes closely
3. Consider alternative hormonal therapies after liver function normalizes
4. Avoid rechallenge in cases of severe hepatotoxicity

Conclusion

While letrozole-induced liver injury is rare, healthcare providers should be aware of this potential complication, particularly in patients with pre-existing liver disease. The FDA drug label provides clear guidance on dose adjustments for patients with hepatic impairment, emphasizing the importance of individualized dosing in these populations.