Is Hydroxychloroquine Hepatotoxic?
Yes, hydroxychloroquine can cause hepatotoxicity, but it is rare—classified as a "possible rare cause of clinically apparent liver injury" with less than 5% of patients experiencing ALT elevations, though severe cases including fulminant hepatic failure have been documented. 1, 2, 3
Hepatotoxicity Classification and Frequency
The NIH LiverTox resource assigns hydroxychloroquine a likelihood score of "D" (possible rare cause of clinically apparent liver injury), indicating that while hepatotoxicity occurs, it is uncommon. 1, 2 The FDA label confirms that hepatotoxicity has been reported but notes the frequency is not yet fully characterized. 1, 3
In clinical practice, ALT elevation occurs in less than 5% of patients taking hydroxychloroquine. 2 However, the severity spectrum ranges from mild transaminase elevations to life-threatening acute liver failure. 2, 4, 5
High-Risk Populations Requiring Caution
Patients with Porphyria Cutanea Tarda
The most critical hepatotoxicity risk occurs in patients with porphyria cutanea tarda (PCT), where hydroxychloroquine can trigger hypersensitivity attacks with marked serum aminotransferase elevations (>20 times upper limit of normal) within days to one month of initiation. 2, 3 The FDA specifically warns that some PCT cases were only diagnosed after treatment-induced liver injury occurred. 3
Pre-existing Liver Disease
Patients with hepatitis or other chronic liver diseases face increased risk because hydroxychloroquine concentrates in the liver. 2 While less than 1% of patients without liver disease show enzyme elevations, this percentage can reach 50% in those with chronic liver disease. 4
Additional Risk Factors
- Concomitant use of other hepatotoxic medications 2
- Alcohol misuse 2
- High-dose regimens (particularly in PCT treatment where 250 mg three times daily caused transient hepatotoxic reactions in the majority of patients) 6
Clinical Presentation and Severity
Mild to Moderate Cases
Most hepatotoxicity presents as asymptomatic transaminase elevations that resolve with drug discontinuation. 2, 4 In COVID-19 treatment studies, 23% of patients experienced elevated hepatic enzymes, with 8% discontinuing treatment prematurely—half due to elevated aminotransferases. 2
Severe Cases
Three documented cases of fulminant hepatic failure have occurred in patients without pre-existing liver disease, developing within two weeks of starting hydroxychloroquine. 4, 5 These cases appear to represent a dose-dependent, idiosyncratic, molecule-specific toxic effect. 4 One patient required emergency liver transplantation, while another died before a donor became available. 5
A case report from COVID-19 treatment documented a 10-fold increase in transaminases that rapidly decreased after hydroxychloroquine withdrawal. 7
Monitoring Recommendations
The American Gastroenterological Association recommends checking baseline liver function tests on admission and monitoring throughout hospitalization, particularly in patients receiving potentially hepatotoxic drug therapy including hydroxychloroquine. 2
Specific Monitoring Protocol
- Measure liver tests promptly in patients reporting symptoms suggesting liver injury: fatigue, rash, nausea, dark urine, or jaundice 3
- If ALT exceeds 3 times the upper limit of normal or total bilirubin exceeds 2 times the upper limit, interrupt hydroxychloroquine and investigate further 3
- Monitor blood cell counts periodically in patients on prolonged therapy due to potential myelosuppression 3
Management of Hepatotoxicity
Discontinue hydroxychloroquine immediately if hepatotoxicity is suspected or demonstrated. 3 Recovery typically takes 1-2 months after discontinuation. 1 Re-challenging may lead to recurrence and should be avoided if possible. 1
Important Caveat
Abnormal liver function tests are not an absolute contraindication to hydroxychloroquine use, but regular monitoring is necessary. 2 In COVID-19 patients, liver function abnormalities may result from multiple factors including the virus itself, complications, or other therapeutic drugs, making causality assessment challenging. 2
Cross-Reactivity Considerations
Most hepatotoxicity reactions appear to be hypersensitivity-mediated with no known cross-reactivity between chloroquine and hydroxychloroquine. 1 If hepatotoxicity occurs, it may be reasonable to switch between chloroquine therapies, though this should be done cautiously. 1