Troxis necrosis, a novel mechanism for drug-induced hepatitis secondary to immunomodulatory therapy

Abstract

OBJECTIVES A case of drug-induced hepatitis mediated by troxis necrosis, a form of autoimmune hepatitis, is described. METHODS Clinical data, light and electron microscopy of an ultrasound-guided core needle liver biopsy specimen, were examined to investigate the cause of transaminitis in a 26 year old male patient on Cellcept and Plaquenil for the treatment of lupus erythematosus. A systematic PUBMED review of troxis necrosis as the underlying mechanism for drug-induced hepatitis was performed. RESULTS Liver function tests (LFT) were significant for elevated AST (305) and ALT (174); autoimmune workup was significant for anti-ANA positivity and α-SMA negativity. On light microscopy, the liver biopsy shows focal areas of lymphocytic infiltrate surrounding and forming immunologic synapses with lobular hepatocytes, indicating lobular hepatitis of autoimmune nature. Electron microscopy confirmed the presence of immunologic synapses. Upon cessation of the offending medications, the LFT returned to baseline with no further intervention. Literature search yielded 7 previously reported cases of drug-induced hepatitis mediated by troxis necrosis. CONCLUSION Troxis necrosis is a novel mechanism for drug-induced hepatitis, including immunomodulatory medications including monoclonal anti-TWEAK antibody, Cellcept and Plaquenil, two widely used immunosuppression/anti-rejection medications.

Case Report: Hepatotoxicity Associated with the Use of Hydroxychloroquine in a Patient with COVID-19

“…[22][23][24][25] Severe liver dysfunction during the use of HCQ is rare, although it has been documented. [26][27][28][29] Makin et al reported two cases of patients with rheumatological disease, who, after 2 weeks of using 400 mg of HCQ daily, were admitted with fulminant hepatitis; one required liver transplant, and both patients died. 27 A rapid normalization of liver enzymes has been described after the withdrawal of HCQ.…”

“…10,30 The mechanisms of hepatic injury related to HCQ are poorly established, and toxicity may be due to reactive metabolites and oxidative stress induced by this drug or an idiosyncratic toxic or synergistic effect associated with inflammatory processes. 26,31,32 Referring to an experimental rat model, Nikanahad et al have suggested that concomitant inflammatory processes, including those induced by infections such as malaria, may increase liver damage caused by antimalarial drugs. 32 Therefore, the potential deleterious synergistic effect of COVID-19 infection and antimalarial drugs needs to be assessed.…”

Mechanisms and consequences of COVID-19 associated liver injury: What can we affirm?

“…The mechanisms of hepatic injury related to HCQ are poorly established, and toxicity may be due to reactive metabolites and oxidative stress induced by this drug or an idiosyncratic toxic or synergistic effect associated with inflammatory processes induced by the infection itself[ 41 - 43 ].…”

Cytolytic syndrome in patients with COVID-19

“…Известно, что применение гидроксихлорохина, рекомендовавшегося в первых клинических руководствах, также может вызвать отклонение от нормы функциональных печеночных проб [13]. Механизмы повреждения печени, связанные с гидроксихлорохином, изучены недостаточно, предполагается, что гепатотоксичность может быть обусловлена воздействием метаболитов, окислительным стрессом, токсическими или синергетическими эффектами [14]. Согласно клиническим рекомендациям по профилактике, диагностике и лечению новой коронавирусной инфекции (COVID-19), версия 13 от 14.10.2021 в качестве этиотропной терапии рекомендуется противовирусный препарат фавипиравир, который часто вызывает повышение активности АЛТ, АСТ [15] и обладает повреждающим действием на печень [16].…”