N-Acetylcysteine for the Management of Non-Acetaminophen Drug-Induced Liver Injury in Adults : A Systematic Review

Funding Information: The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional–FEDER (contract numbers: PI19/00883, P18‐RT‐3364‐2020), from the Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain) (UMA18‐FEDERJA‐194, PI18‐RT‐3364) and by the Agencia Española del Medicamento. JS-C holds a “Juan Rodés” research contract from the National System of Health, ISCIII (JR21/00066). IA-A holds a Sara Borrell contract (CD20/00083). HN holds a postdoctoral contract from the Junta de Andalucia (POSTDOC_21_00780). CIBERehd and Plataforma ISCIII Ensayos Clínicos (PT20/000127) are funded by ISCIII. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology) ( www.cost.eu ). All authors of this manuscript are members of COST Action CA17112. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication. Funding Information: The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional–FEDER (contract numbers: PI19/00883, P18‐RT‐3364‐2020), from the Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain) (UMA18‐FEDERJA‐194, PI18‐RT‐3364) and by the Agencia Española del Medicamento. JS-C holds a “Juan Rodés” research contract from the National System of Health, ISCIII (JR21/00066). IA-A holds a Sara Borrell contract (CD20/00083). HN holds a postdoctoral contract from the Junta de Andalucia (POSTDOC_21_00780). CIBERehd and Plataforma ISCIII Ensayos Clínicos (PT20/000127) are funded by ISCIII. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology) (www.cost.eu). All authors of this manuscript are members of COST Action CA17112. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication. Publisher Copyright: Copyright © 2022 Sanabria-Cabrera, Tabbai, Niu, Alvarez-Alvarez, Licata, Björnsson, Andrade and Lucena. Copyright © 2022 Sanabria-Cabrera, Tabbai, Niu, Alvarez-Alvarez, Licata, Björnsson, Andrade and Lucena.Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse reaction to drugs and other xenobiotics. DILI has different grades of severity and may lead to acute liver failure (ALF), for which there is no effective therapy. N-acetylcysteine (NAC) has been occasionally tested for the treatment of non-acetaminophen drug-induced ALF. However, limited evidence for its efficacy and safety is currently available. Our aim was to elucidate the benefit and safety of NAC in DILI and evaluate its hepatoprotective effect. Methods: We conducted a systematic review to evaluate the management and prevention focused on NAC in idiosyncratic DILI. The main outcomes included mortality due to DILI, time to normalization of liver biochemistry, transplant-free survival, and adverse events. We included clinical trials and observational studies, either prospective or retrospective. Results: A total of 11 studies were included after literature screening. All studies had different methodologies, and some of them had important risk of bias that may lead to interpreting their findings with caution. The majority of the studies proved NAC efficacy in a cohort of patients with ALF due to different etiologies, where DILI represented a subgroup. NAC seemed to improve transplant-free survival; however, its benefit was inconclusive in terms of overall survival. With regard to safety, NAC showed an adequate safety profile. In prevention studies, NAC showed a possible hepatoprotective effect; however, this finding is limited by the lack of studies and presence of bias. Conclusion: NAC treatment seems to have some benefit in non-acetaminophen drug-induced liver failure patients with acceptable safety; however, due to the lack of evidence and limitations detected across studies, its benefit must be corroborated in clinical trials with adequate methodology.Peer reviewe