Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but can cause immune‑mediated hepatotoxicity (IMH), a potentially serious immune‑related adverse event. This review summarizes current understanding of risk factors and predictive biomarkers for IMH. Risk factors include female sex, younger age, Asian ethnicity, extreme BMI, chronic liver disease (especially HBV and NAFLD), specific cancer types (melanoma, HCC, biliary tract cancer, gastric cancer), dual ICI therapy, prior ICI exposure, and concurrent hepatotoxic drugs (e.g., acetaminophen, statins). Potential biomarkers include circulating blood cells (e.g., eosinophils, lymphocytes, NLR), serum proteins (CRP, albumin, AFP), autoantibodies (ANA, TPOAb), cytokines (IL‑1β, IL‑6, CXCL10), genetic variants (SNPs in EDIL3, SEMA5A, GABRP, SLCO1B1, SMAD3), HLA genotypes (HLA‑A*26:01, HLA‑DR4, HLA‑B27:04), and gut microbiome (e.g., Veillonella). However, no definitive biomarker is clinically available. Large prospective studies are needed to validate these candidates and enable early identification and individualized management of IMH.
Introduction
ICIs (anti‑CTLA‑4, anti‑PD‑1/PD‑L1) are widely used for various cancers. Immune‑mediated hepatotoxicity (IMH) – manifesting as asymptomatic ALT/AST/ALP elevations – occurs in 1–15% of patients and can be severe, even fatal. IMH contributed to 20.2% of ICI‑related deaths. Current management relies on ICI discontinuation and glucocorticoids, but no reliable tools exist to predict IMH before treatment. Identifying risk factors and biomarkers is urgently needed.
Potential Mechanisms of IMH
ICIs block CTLA‑4 (priming phase) or PD‑1/PD‑L1 (effector phase), activating CD8⁺ T cells. In the liver, disruption of immune tolerance leads to: (1) direct CTL activation and epitope spreading to hepatocytes; (2) Th1/Th17 expansion and Treg impairment; (3) B‑cell activation and autoantibody production; (4) inflammatory cytokines (IFN‑γ, TNF‑α, IL‑1β, IL‑6) and NLRP3 inflammasome activation; and (5) monocyte/macrophage recruitment.
Risk Factors for IMH
Patient‑associated : Female sex (OR 2.54), younger age (SMD ‑0.18), Asian ethnicity (higher incidence in China/Japan/Korea), extreme BMI (underweight or obesity), chronic HBV infection (pooled OR 2.46), NAFLD (HR 29.34), high baseline AST/ALT, low baseline ALP.
Tumor‑associated : Melanoma (OR 11.6), HCC (OR 2.1–7.9), biliary tract cancer, gastric cancer. Liver metastasis is controversial.
Drug‑associated : Dual ICI therapy (OR 10.95), prior ICI history (pooled OR 3.09), ipilimumab dose (10 mg/kg worse), combination with chemotherapy, targeted agents (osimertinib, sotorasib), or hepatotoxic drugs (acetaminophen OR 2.14, statins OR 4.71).
Predictive Biomarkers for IMH
Circulating blood cells : Baseline eosinophil ≥130/µL (HR 3.01), high lymphocytes, low NLR (<3) or high NLR (>5) depending on tumor type, on‑treatment reduction in CD4⁺/CD8⁺ T and B cells in severe IMH, expansion of Ki67⁺CD8⁺ T cells. Inconsistent across studies; dynamic changes may be more informative.
Serum proteins : Elevated CRP at onset (≥8.2 mg/L) predicts grade ≥3 IMH; CRAFTY score (CRP + AFP) predicts IMH in HCC; low albumin associated with higher IMH risk.
Autoantibodies : ANA positivity (especially with pembrolizumab, OR 7.83) linked to IMH; TPOAb also associated. Liver‑specific autoantibodies (ASMA, AMA, LKM) are not reliable predictors.
Cytokines : Elevated IL‑1β, IL‑6 (at onset), CXCL9/10/11, IL‑18, and TNF‑α correlate with IMH severity. A panel of 11 cytokines (CYTOX score) predicted severe irAEs. Longitudinal monitoring is essential.
Genetic markers : SNPs in EDIL3, SEMA5A, GABRP, SLCO1B1, SMAD3, PACRG are associated with IMH (OR 2.08–9.17). Copy number variations in CD274 and SLCO1B1 also linked.
HLA genotypes : HLA‑A homozygosity, HLA‑A 26:01 (OR 2.67), HLA‑DR4, HLA‑B 27:04 associated with IMH, but not all studies confirm.
Gut microbiome : Veillonella abundance correlated with ICI‑related hepatotoxicity; gut‑liver axis may provide further biomarkers.
Future Perspectives
No single biomarker is sufficiently reliable for clinical use. Most studies are retrospective, heterogeneous, and lack longitudinal data. Future research should: (1) conduct large, prospective, multicenter cohorts; (2) integrate multi‑omics (genomics, transcriptomics, proteomics, metabolomics) with AI/machine learning; (3) implement longitudinal monitoring from baseline through treatment; (4) develop validated composite prediction models combining clinical risk factors, blood cells, cytokines, genetics, and microbiome.
Conclusions
IMH risk is associated with female sex, young age, Asian ethnicity, chronic liver disease, specific cancers (melanoma, HCC), dual ICI therapy, and concurrent hepatotoxic drugs. Promising biomarkers include blood cell counts, CRP, autoantibodies, cytokines, SNPs, HLA types, and gut microbes. However, none are ready for clinical use. Large‑scale prospective studies with integrated multi‑dimensional approaches are urgently needed to enable pre‑emptive risk stratification and improve the safety of cancer immunotherapy.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00622
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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Journal of Clinical and Translational Hepatology
Risk Factors and Biomarkers for Immune Checkpoint Inhibitor-mediated Hepatotoxicity: Emerging Insights and Future Perspectives
23-Jan-2026