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

ABSTRACT

Introduction: 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
• immune-related adverse events
• immunotherapy-induced hepatotoxicity
• ipilimumab
• nivolumab
• pembrolizumab
• drug-induced autoimmune hepatitis

Article highlights

• Initial reported rates of hepatotoxicity due to immune checkpoint inhibitors show that it is not uncommon – occurring in 2–30% of patients - though severe cases of hepatotoxicity remains very rare.

• Liver injury due to ICIs most often present with a hepatocellular biochemical pattern although cholestatic injury has been reported as well.

• Risk of hepatotoxicity increases when using multiple ICIs and in patients who develop other immune-related adverse events.

• Other risk factors for hepatotoxicity include: underlying chronic liver disease, higher dosages of immune checkpoint inhibitors, and utilizing anti-CTLA-4 agents as opposed to anti-PD-1 or anti-PD-LI agents.

• Patients started on immune checkpoint inhibitors should have serial monitoring (e.g. at least monthly) of their liver associated enzymes to monitor for hepatotoxicity.

• Liver biopsy can be useful in establishing the diagnosis of ICI-IMH – especially when fibrin-ring granulomas are found in patients receiving anti-CTLA-4 therapy.

• Consultation with a liver specialist should be considered for any patient who develops grade 2 hepatotoxicity or greater.

• Liver biopsy may be useful in a subset of patients to identify those with less severe inflammation who may be able to avoid steroids and alternatively be managed with close monitoring of liver-associated enzymes and temporarily holding of the immune checkpoint inhibitor.

• Corticosteroids, when indicated based on the grade of hepatotoxicity, can be used either orally or intravenously depending on severity. Limited data are available on additional or alternatively agents (e.g. budesonide, tacrolimus, mycophenolate mofetil, azathioprine) that may be needed if the injury is refractory to corticosteroids.

• Guidelines from multiple groups agree on the need permanent discontinuation of immune checkpoint inhibitor therapy for grade 4 injury although increasingly restarting ICI treatment has been performed for patients with less severe grade 3 injury.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to acknowledge Dr. Joseph Misdraji of Harvard Medical School for his generous help in providing photomicrographs for this manuscript.

Author contributions

Paper design: J J Jennings, R Mandaliya, J H Lewis. Data collection: J J Jennings, R Mandaliya, A Nakshabandi, J H Lewis. Manuscript drafting: J J Jennings, R Mandaliya, A Nakshabandi, J H Lewis. Critical Review: J J Jennings, R Mandaliya, J H Lewis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.