Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting immune checkpoint molecules. ICIs are an immunotherapy for the treatment of many advanced malignancies. The advent of ICIs has been a major breakthrough in the field of oncology, a fact recognized by the 2018 Nobel Prize in Physiology or Medicine being awarded for the discovery. The Food and Drug Administration approved the first ICI, ipilimumab, in 2011 for the treatment of metastatic melanoma. Seven ICIs are now used in clinical practice, including nivolumab and pembrolizumab for treatment of advanced hepatocellular carcinoma. ICIs are increasingly used across the spectrum of hepatobiliary neoplasia. The utility of ICI therapy has been limited by immune‐related adverse reactions (irAEs) affecting multiple organ systems. Hepatotoxicity is an important irAE, occurring in up to 16% of patients receiving ICIs. Optimizing outcomes in patients receiving ICI therapy requires awareness of and familiarity with diagnosing and management of ICI‐induced immune‐mediated hepatotoxicity (IMH), including approaches to treatment and ICI dose management. The aim of this review article is to (1) provide a comprehensive, evidence‐based review of IMH; (2) perform a systematic review of the management of IMH; and (3) present algorithms for the diagnosis and management of IMH.

Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis

“…However, ICIs are associated with immune-mediated hepatotoxicity whose severity is unpredictable. The hepatotoxicity can range from mild to life-threatening, and it is not completely known in patients with cirrhosis [ 29 , 30 ].…”

“…Lack of data regarding all-cause SAEs for Nivolumab may have affected our analyses. However, reported data for Pembrolizumab led to a more accurate assessment of overall tolerability of ICIs in patients with liver disease [ 30 ].…”

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

“…Termed immune related adverse events (irAEs), the side effects of these novel therapeutic antibodies result from the loss of immune homeostasis and off-target effects in peripheral tissues [2,3]. Although the skin, endocrine glands and digestive tract are mostly affected, pulmonary [4][5][6], neurologic [7][8][9][10], hepatic [11][12][13] and cardiologic [14][15][16][17][18][19] side effects have also been described and may be life-threatening.…”

<p>Adverse Effects of Immune-Checkpoint Inhibitors in Hepatocellular Carcinoma</p>

“…60 Mycophenolate mofetil, azathioprine, budesonide, cyclosporine, tacrolimus, ursodeoxycholic acid (UDCA), antithymocyte globulin (ATG), tocilizumab (IL-6 receptor antagonist), and plasma exchange could be used as an additional immunosuppressant to treat steroid refractory hepatotoxicity. 60 Because of the concern for anti-TNF induced liver injury, most guidelines do not support infliximab as a treatment for steroid-refractory toxicity, however, no such cases have been reported.…”