Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known
Caiyun Zheng1,2, Shunmin Huang2,3, Meimei Lin1
1Fuqing City Hospital Affiliated to Fujian Medical University, Fuzhou, China.
Background:
This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment.
Methods:
PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms.
Results:
The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3-5 hepatotoxicity than PD-1 inhibitors.
Conclusions:
The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.
Insights
Immune checkpoint inhibitors (ICIs) for cancer treatment can cause liver injury. Triple ICI therapy poses the highest risk of hepatotoxicity and fatal liver events, while PD-1 and CTLA-4 inhibitors show similar risks in monotherapy.
Area of Science:
- Oncology
- Immunology
- Hepatology
Background:
- Immune checkpoint inhibitors (ICIs) like PD-1, PD-L1, and CTLA-4 are crucial in cancer therapy.
- Understanding the hepatotoxicity profile of these agents is vital for patient safety.
- This review synthesizes safety data on ICI-induced liver injury.
Approach:
- A systematic review and network meta-analysis was conducted.
- Included 106 randomized controlled trials with 164,782 participants.
- Analyzed data on PD-1, PD-L1, and CTLA-4 inhibitors versus conventional therapy.
Key Points:
- Overall hepatotoxicity incidence was 4.06%, with a 0.07% fatality rate.
- Triple ICI therapy (PD-L1 inhibitor + targeted therapy + chemotherapy) showed the highest risk for liver enzyme elevations.
- CTLA-4 inhibitors were linked to a higher risk of severe (grade 3-5) hepatotoxicity compared to PD-1 inhibitors.
Conclusions:
- Triple ICI therapy demonstrated the highest incidence of hepatotoxicity and fatality.
- Hepatotoxicity risk was similar between dual ICI regimens.
- For monotherapy, CTLA-4 and PD-1 inhibitors showed comparable risks of immune-mediated hepatotoxicity.
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