Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers



The risk factors and clinical characteristics of ICI-induced immune-mediated hepatotoxicity (IMH) are not fully understood. Thus, the present study sought to clarify the clinical features of IMH.


All patients treated with ICIs between September 2014 and April 2019 at our institution were included. Clinical data were retrospectively collected from medical records. The frequency of grade ≥ 2 liver damage, clinical characteristics, and risk factors for developing IMH were examined.


Overall, 250 patients (median age 71 years; range 30–87 years; 202 males and 48 females) were included in the analyses. Forty-five patients had elevated transaminase levels (> threefold the upper limit of normal). Of these, 21 were considered to have IMH. The remaining 24 patients had other causes of elevated transaminase levels. Steroids were administered to 13/21 patients with IMH. Although all patients exhibited improvement, IMH was not associated with the anticancer efficacy of the ICIs or OS. A multivariable analysis revealed that IMH was significantly associated with malignant melanoma (odds ratio [OR] 11.6; 95% confidence interval [CI] 3.5–38.0; P = 0.0002) and ipilimumab–nivolumab combination therapy (OR 61.2; 95% CI 7.9–1275.3; P < 0.0001).


Immune-mediated hepatotoxicity occurred in 9.5% of patients treated with ICIs. Appropriate therapeutic interventions are important to avoid affecting the patient’s prognosis, and accurate diagnosis of IMH is essential for this purpose. The frequency of IMH varied according to the type of cancer and the drug used, and was significantly higher in patients with malignant melanoma and in patients given ipilimumab–nivolumab combination therapy.

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Fig. 1
Fig. 2

Availability of data and materials

All data generated or analyzed during this study are included in this published article.



Alanine aminotransferase


Antinuclear antibody


Aspartate aminotransferase


Confidence interval


Common terminology criteria for adverse events


Cytotoxic T lymphocyte-associated molecule-4


Disease control rate


Eastern Cooperative Oncology Group performance status




Immune checkpoint inhibitor


Immune-mediated hepatotoxicity


International normalized ratio


Immune-related adverse reaction


Malignant melanoma


Mycophenolate mofetil


Non-small cell lung cancer


Odds ratio


Overall survival


Programmed cell death receptor-1


Programmed cell death ligand-1


Response evaluation criteria in solid tumors


Renal cell carcinoma


Response rate


Ursodeoxycholic acid


Upper limit of the institutional normal


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We thank Stallard Scientific Editing ( for editing a draft of this manuscript.


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Author information




Study conception and design were performed AY, YY and YU. Material preparation and data collection were performed by AY, EY, YH, HH, RY and NA. Analysis was performed by AY. The first draft of the manuscript was written by AY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yoshihiko Yano.

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The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study was carried out in accordance with the Declaration of Helsinki and was approved by the institutional review board of the Kobe University Graduate School of Medicine and by the institutional review boards of the participating hospitals (no. B200118). The need to collect informed consent from the patients was waived because this was a retrospective study. Information about this study was published in our institute, and patients could ask for their data to be withdrawn from the analysis.

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Yamamoto, A., Yano, Y., Ueda, Y. et al. Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers. J Cancer Res Clin Oncol (2020).

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  • Immune checkpoint inhibitors
  • Immune-related adverse events
  • Liver injury
  • Immune-mediated hepatotoxicity
  • Risk factors