Immune-mediated hepatitis. A literature review

Abstract

Aim. Immune checkpoint inhibitors (ICIs) have transformed the standards of systemic therapy across a broad range of malignancies; however, the expansion of their indications has inevitably been accompanied by a rise in immunerelated adverse events. The aim of this review is to summarise current understanding of the pathogenesis, clinical presentation, incidence, differential diagnosis and management of immune-mediated hepatitis associated with immune checkpoint inhibitor therapy, comparing the approaches adopted by international and Russian professional societies.Methods. Publications were searched in PubMed/MEDLINE and eLIBRARY, as well as on the official websites of the professional societies ASCO (American Society of Clinical Oncology), ESMO (European Society for Medical Oncology), RUSSCO (Russian Society of Clinical Oncology) and NCCN (National Comprehensive Cancer Network), and of regulatory agencies (FDA Food and Drug Administration). Current clinical guidelines, official prescribing information, systematic reviews, meta-analyses, randomised trials and real-world data were included. Results. The liver ranks third among the organs affected, after the skin and the gastrointestinal tract. According to the integrated safety databases of regulatory agencies, the incidence of immune-mediated hepatitis was 0.7% for pembrolizumab, 1.8% for nivolumab and atezolizumab, 2.8% for durvalumab, and 7.0 to 15.0% for nivolumab combined with ipilimumab, depending on the dose ratio. PD-1 inhibitors were associated with more frequent transaminase elevations than PD-L1 inhibitors. Management is based on stepwise immunosuppression; mycophenolate mofetil is the second-line agent, whereas infliximab is not used in hepatic involvement.Conclusion. Immune-mediated hepatitis requires differential diagnosis, since a substantial proportion of liver test elevations is due to alternative causes. The extent of immunosuppression should be matched to the clinical severity of the condition rather than to the formal CTCAE grade alone.