Is hydroxychloroquine (HCQ) hepatotoxic?

Is Hydroxychloroquine Hepatotoxic?

Hydroxychloroquine is rarely hepatotoxic, with ALT elevation occurring in less than 5% of patients and clinically apparent liver injury being uncommon, though severe cases including fulminant hepatic failure have been documented. 1, 2

Hepatotoxicity Profile

• Hydroxychloroquine is classified by the NIH LiverTox resource with a likelihood score of "D" (possible rare cause of clinically apparent liver injury). 3
• Aminotransferase elevations occur infrequently, with ALT elevation documented in less than 5% of patients during standard therapeutic use. 1
• The FDA label notes that hepatotoxicity can occur, particularly in patients with porphyria cutanea tarda (PCT), where marked transaminase elevations (>20 times upper limit of normal) have been reported within days to a month of initiation. 2

Severe Hepatotoxicity Cases

• Fulminant hepatic failure has been reported in patients without pre-existing liver disease, developing within two weeks of starting hydroxychloroquine. 4
• One case series documented two patients who developed fulminant hepatic failure requiring emergency liver transplantation or resulting in death. 4
• A case of severe acute hepatitis with reversible liver injury occurred in a patient with mixed connective tissue disease shortly after low-dose hydroxychloroquine initiation. 5
• During COVID-19 treatment, a case report documented a 10-fold increase in transaminases that rapidly decreased after hydroxychloroquine withdrawal. 6

High-Risk Populations

Pre-existing liver disease significantly increases hepatotoxicity risk:

• Patients with hepatitis or other hepatic diseases should exercise caution, as hydroxychloroquine concentrates in the liver. 3
• Patients with chronic liver disease may experience liver enzyme increases in up to 50% of cases (compared to <1% in those without liver disease). 5
• Concomitant use with other hepatotoxic medications increases the risk of liver enzyme elevations. 1
• Alcohol misuse is an identified risk factor for hydroxychloroquine-induced liver injury. 1

Porphyria cutanea tarda represents a special high-risk scenario:

• Hydroxychloroquine can trigger hypersensitivity attacks with fever and marked serum aminotransferase elevations in patients with acute intermittent porphyria or PCT. 3
• Some PCT cases were diagnosed only after treatment-induced liver injury occurred. 2
• Risk factors in PCT-related hepatotoxicity include alcohol use and concomitant hepatotoxic medications. 2

Monitoring Recommendations

Baseline and ongoing liver function monitoring is essential:

• The FDA label recommends measuring liver tests promptly in patients reporting symptoms of liver injury (fatigue, rash, nausea, dark urine, jaundice). 2
• If ALT exceeds three times the upper limit of normal or total bilirubin exceeds two times the upper limit, interrupt hydroxychloroquine treatment and investigate further. 2
• For COVID-19 patients, the AGA Institute recommends checking baseline liver function tests on admission and monitoring throughout hospitalization, particularly in those receiving potentially hepatotoxic drug therapy. 3
• Abnormal liver function tests are not an absolute contraindication to hydroxychloroquine use, but regular monitoring is necessary. 1

Clinical Context

• The hepatotoxicity appears to be dose-dependent, idiosyncratic, and molecule-specific. 5
• In COVID-19 treatment studies, 23% of patients experienced elevated hepatic enzymes, with 8% discontinuing treatment prematurely (half due to elevated aminotransferases). 3
• Steatosis may be a risk factor for altered drug metabolism and possibly enhanced toxicity of hydroxychloroquine, particularly relevant in obese patients with metabolic-associated fatty liver disease. 7