Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies

Expert Opin Drug Metab Toxicol. 2019 Mar;15(3):231-244. doi: 10.1080/17425255.2019.1574744. Epub 2019 Feb 5.


Immune checkpoint inhibitors (ICIs) block cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) receptors that control antitumor activities of lymphocytes. While highly efficacious, these drugs have been associated with several immune-related adverse events (irAEs) due to the disruption of self-tolerance. Immune-mediated hepatitis (IMH) usually presents as mild elevations of liver enzymes though it can rarely be associated with life-threatening hepatic injury. Areas covered: A comprehensive review was performed to define the clinicopathologic forms of liver injury associated with ICIs, comparing the various ICI classes as well as comparing this form of IMH with idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. Liver biopsy has proven very useful in selected patients. A specific form of fibrin ring granulomatous hepatitis appears to be associated with IMH. The current societal treatment algorithms and emerging data were reviewed to determine when to utilize corticosteroids. Expert opinion: Monitoring for severe ICI-IMH is recommended although acute liver failure remains rare. Most patients with grade 3-4 hepatotoxicity respond to corticosteroids, but a subset of patients with mild hepatitis on liver biopsy resolve without steroids and need to be carefully selected in concert with the consultation of a hepatologist.

Keywords: Hepatotoxicity; checkpoint inhibitors; drug-induced autoimmune hepatitis; immune-related adverse events; immunotherapy-induced hepatotoxicity; ipilimumab; nivolumab; pembrolizumab.

Publication types

  • Review

MeSH terms

  • Adrenal Cortex Hormones / administration & dosage
  • Algorithms
  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / adverse effects*
  • Biopsy / methods
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / immunology
  • Humans
  • Immunotherapy / adverse effects*
  • Immunotherapy / methods
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Self Tolerance / immunology


  • Adrenal Cortex Hormones
  • Antineoplastic Agents, Immunological