Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives

Abstract

In recent years, cancer immunotherapy has made remarkable achievements. Immune checkpoint inhibitors (ICIs) have been used successfully in several types of cancer in the past decade. However, expanded indication and increased use of Immune checkpoint inhibitors have resulted in increased reports of toxicity called immune-related adverse events (irAEs). Due to the unique immunological characteristics of the liver, a hepatic immune-related adverse events has also been reported, which is usually termed Immune-mediated hepatitis (IMH). So far, it is generally considered that the mechanism of IMH induced by Immune checkpoint inhibitors is mainly the overactivation of T cells. It has been reported that the incidence of IMH ranges from 1% to 15%. Because of the lack of specific markers, a diagnosis of exclusion of IMH is critical. Although most IMH is mild and recoverable, several death cases have been reported, which has been increasingly concerned. This review summarizes the current understanding of the pathophysiology, epidemiology, diagnosis, management and prognosis of IMH caused by Immune checkpoint inhibitors. It also discusses the controversial issues in IMH, such as the role of liver biopsy, grading criteria, risk factors, rational treatment strategies with steroids, and the timing of Immune checkpoint inhibitors rechallenging, which may provide helpful information for IMH in future clinical practice.

Keywords: cancer; drug-induced liver injury; hepatitis; immune checkpoint inhibitors; immune-related adverse events; immunotherapy.

FIGURE 1

Mechanisms of T cells activation and immune-mediated hepatitis caused by ICIs. (A) Blockade of CTLA-4 activates T cells at the priming phase. (B) Further anti-tumor effect induced by the blockade of PD-1 and PD-L1 occurs in the effector phase. Once liver self-tolerance impairs, immune cells such as (C) Th cells, (D) Monocytes, (E) Treg cells, and (F) cytotoxic T cells will be involved in the pathophysiological process of immune-mediated hepatitis.

FIGURE 2

Management for immune-mediated hepatitis caused by immune checkpoint inhibitors. LFT, liver function test; ICI, immune checkpoint inhibitor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TBil, total bilirubin; ULN, upper limit of normal; BLV, baseline value; MMF, mycophenolate mofetil; UDCA, ursodeoxycholic acid; ATG, antithymocyte globulin; AZA, azathioprine.