Background Hydroxychloroquine is a medication that is used as an antimalarial or a disease-modifying anti-rheumatic drug. It has rare side effects like cardiomyopathy, hematological abnormalities, and dermatological manifestations. Hydroxychloroquine-induced hepatotoxicity is a rare yet serious adverse effect, requiring further investigation and should be considered a differential diagnosis in patients with connective tissue diseases and acute liver issues.

Case Presentation This is a 31-year-old female with a history of uveitis and systemic lupus erythematous (SLE), which was diagnosed two months prior to presentation with a positive anti-dsDNA and anti-Smith antibodies after having initial findings of uveitis, joint pain, and hair loss. She was started on Hydroxychloroquine 200 mg twice daily a month after being diagnosed. A month after Hydroxychloroquine initiation, she developed abdominal pain and vomiting. Subsequently, she took two doses of acetaminophen, dextromethorphan, and phenylephrine, one in the morning and one in the evening for one day at the recommended dosage. The following day, at urgent care, she was diagnosed with viral gastritis and received one gram of acetaminophen. Three days later, in the emergency room, she had acute liver failure with peak aspartate aminotransferase – 4731 U/L and alanine aminotransferase – 5109 U/L. She endorsed minimal social alcohol use, and tested negative for Human Immunodeficiency Virus, Cytomegalovirus, Hepatitis A, B, and C. Liver biopsy showed portal tracts with mild-moderate expansion by mixed inflammatory infiltrates including scattered eosinophils with mild interface activity focally close to bridging inflammation – findings consistent with drug-induced liver injury. Hydroxychloroquine was held, and she was admitted for conservative management. Repeat liver function tests showed down trending during the patient’s hospitalization – normalizing two months post-discharge.

Discussion Hepatotoxicity due to hydroxychloroquine use is rare but has been reported in eight other cases. The mean age of onset was 31.6 years old, mean cumulative dose used was 342 mg daily, and mean duration of hydroxychloroquine use was 53.8 days. Two patients expired, while the others recovered after discontinuing hydroxychloroquine. The mechanism of hydroxychloroquine-induced hepatotoxicity is unclear but may be related to its metabolism by cytochrome P450 in the liver. Hydroxychloroquine may share a similar pathophysiologic mechanism of toxicity as chloroquine due to their similar molecular structure. A study showed that rats treated with both bacterial lipopolysaccharide and chloroquine developed signs of liver injury, suggesting that the quinolone class of drugs can induce liver injury in those with concurrent inflammatory conditions. Early detection and termination of hydroxychloroquine is crucial in preventing progression to fulminant hepatic failure.