Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

Eleonora De Martin; Jean-Marie Michot; Olivier Rosmorduc; Catherine Guettier; Didier Samuel

doi:10.1016/j.jhepr.2020.100170

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

JHEP Rep. 2020 Aug 11;2(6):100170. doi: 10.1016/j.jhepr.2020.100170. eCollection 2020 Dec.

Authors

Eleonora De Martin¹, Jean-Marie Michot², Olivier Rosmorduc^{1

3}, Catherine Guettier⁴, Didier Samuel¹

Affiliations

¹ AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, Univ Paris-Sud, Université Paris-Saclay, FHU Hépatinov, Villejuif, F-94800, France.
² Département d'innovation thérapeutique et d'Essais Précoces (DITEP), Institut Gustave-Roussy, Université Paris Saclay, Villejuif, France.
³ Sorbonne-Université.
⁴ AP-HP Hôpital Bicêtre, Laboratoire Anatomie Pathologique, Le Kremlin-Bicêtre, France, Univ Paris-Sud, UMR-S 1193, Université Paris-Saclay, France.

Abstract

Immune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.

Keywords: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibodies; ASMA, anti-smooth muscles antibodies; AST, aspartate aminotransferase; CTLA-4, cytotoxic T lymphocyte-associated protein 4; Corticosteroid therapy; DCR, disease control rate; DILI, drug-induced liver injury; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; INR, international normalised ratio; Immune-mediated hepatitis; Immunotherapy; Liver biopsy; MMF, mycophenolate mofetil; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death 1; PD-L1-2, programmed cell death ligands 1-2; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; anti-LC1, anti-liver cytosol type-1 antibodies; anti-LKM, anti-liver-kidney microsomal antibodies; anti-SLA, anti-soluble liver antigen antibodies; irAE, immune-related adverse event; trAE, treatment-related adverse event.

Publication types

Review