Skip to main content
Log in

Liver damage related to immune checkpoint inhibitors

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Recently, immune checkpoint inhibitors are becoming one of the key agents of systemic treatment of cancer. The anti-cancer mechanism of this type of agent is totally different from that of conventional therapies; blockade of regulatory receptors and ligand of immune checkpoint molecules arose anti-tumor immunity with durable response. However, owing to its unique action to host immune system, immune checkpoint inhibitors sometimes induce immune-related adverse events (irAEs) which has not been observed for conventional chemotherapies. It has been reported that irAEs are manageable by discontinuation of immune checkpoint inhibitors and corticosteroid. However, severe irAEs might lead to the unsuccessful management of cancer treatment. It is conceivable that irAEs during the treatment of immune checkpoint blockade might mimic the autoimmune disease of the specific organ, such as autoimmune hepatitis (AIH). However, detail of the pathogenesis of irAEs has not been well estimated. In this review, we specially focused on this important issue and discussed the liver toxicity of this type of agent in the context of comparison of clinical and pathological findings of liver damage related to irAEs and AIH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology 2017;92(Suppl 1):40–49

    Article  PubMed  Google Scholar 

  2. Kudo M. Immune checkpoint blockade in hepatocellular carcinoma: 2017 update. Liver Cancer 2016;6:1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kudo M. A new era of systemic therapy for hepatocellular carcinoma with regorafenib and lenvatinib. Liver Cancer 2017;6:177–184

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kudo M. Management of hepatocellular carcinoma in Japan as a world-leading model. Liver Cancer 2018;7:134–147

    Article  PubMed  Google Scholar 

  5. Kudo M. Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials. Oncology 2017;92(Suppl 1):50–62

    Article  PubMed  Google Scholar 

  6. Nishida N, Kudo M. Role of immune checkpoint blockade in the treatment for human hepatocellular carcinoma. Dig Dis 2017;35:618–622

    Article  PubMed  Google Scholar 

  7. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol 2016;2:1346–1353

    Article  PubMed  Google Scholar 

  8. Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol 2018;41:760–765

    Article  CAS  PubMed  Google Scholar 

  9. Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA 2018;320:1702–1703

    Article  PubMed  Google Scholar 

  10. Sanjeevaiah A, Kerr T, Beg MS. Approach and management of checkpoint inhibitor-related immune hepatitis. J Gastrointest Oncol 2018;9:220–224

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nishida N, Kudo M. Oncogenic signal and tumor microenvironment in hepatocellular carcinoma. Oncology 2017;93(Suppl 1):160–164

    Article  PubMed  Google Scholar 

  12. Kudo M. Combination cancer immunotherapy in hepatocellular carcinoma. Liver Cancer 2018;7:20–27

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lin JJ, Chin E, Yeap BY, Ferris LA, Kamesan V, Lennes IT, et al. Brief report: Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small-cell lung cancer. J Thorac Oncol 2019;14:135–140

    Article  PubMed  Google Scholar 

  14. Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 2018;31:965–973

    Article  PubMed  Google Scholar 

  15. Zhang X, Ran Y, Wang K, Zhu Y, Li J. Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. Drug Des Dev Ther 2016;10:3153–3161

    Article  CAS  Google Scholar 

  16. Wang W, Lie P, Guo M, He J. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis of published data. Int J Cancer 2017;141:1018–1028

    Article  CAS  Google Scholar 

  17. Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int 2018;38:976–987

    Article  PubMed  Google Scholar 

  18. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521–2532

    Article  CAS  Google Scholar 

  20. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–1835

    Article  CAS  PubMed  Google Scholar 

  21. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013;368:1365–1366

    Article  CAS  PubMed  Google Scholar 

  22. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:1345–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017;52:512–519

    Article  CAS  PubMed  Google Scholar 

  25. Kudo M, Hatano E, Ohkawa S, Fujii H, Masumoto A, Furuse J, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial. J Gastroenterol 2017;52:494–503

    Article  CAS  PubMed  Google Scholar 

  26. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317–370

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nishida N, Nishimura T, Kaido T, Minaga K, Yamao K, Kamata K, et al. Molecular scoring of hepatocellular carcinoma for predicting metastatic recurrence and requirements of systemic chemotherapy. Cancers (Basel) 2018;10:E367

    Article  Google Scholar 

  28. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492–2502

    Article  CAS  Google Scholar 

  29. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018;19:940–952

    Article  Google Scholar 

  30. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81–88

    Article  CAS  Google Scholar 

  31. De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 2018;68:1181–1190

    Article  CAS  Google Scholar 

  32. Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor-associated colits and hepatitis. Clin Transl Gastroenterol 2018;9:180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nadeau BA, Fecher LA, Owens SR, Razumilava N. Liver toxicity with cancer checkpoint inhibitor therapy. Semin Liver Dis 2018;38:366–378

    Article  CAS  PubMed  Google Scholar 

  34. Ziemer M, Koukoulioti E, Beyer S, Simon JC, Berg T. Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids. J Hepatol 2017;66:657–659

    Article  PubMed  Google Scholar 

  35. Gassmann D, Weiler S, Mertens JC, Reiner CS, Vrugt B, Nageli M, et al. Liver allograft failure after nivolumab treatment-a case report with systematic literature research. Transpl Direct 2018;4:e376

    Article  Google Scholar 

  36. Kuo JC, Lilly LB, Hogg D. Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review. Melanoma Res 2018;28:61–64

    Article  PubMed  Google Scholar 

  37. Biondani P, De Martin E, Samuel D. Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient. Ann Oncol 2018;29:286–287

    Article  CAS  PubMed  Google Scholar 

  38. Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective. J Clin Pathol 2018;71:665–671

    Article  CAS  PubMed  Google Scholar 

  39. Simonelli M, Di Tommaso L, Baretti M, Santoro A. Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Immunotherapy 2016;8:1363–1369

    Article  CAS  PubMed  Google Scholar 

  40. Schmeltzer PA, Russo MW. Clinical narrative: autoimmune hepatitis. Am J Gastroenterol 2018;113:951–958

    Article  PubMed  Google Scholar 

  41. Doherty GJ, Duckworth AM, Davies SE, Mells GF, Brais R, Harden SV, et al. Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury. ESMO Open 2017;2:e000268

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kawakami H, Tanizaki J, Tanaka K, Haratani K, Hayashi H, Takeda M, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Investig New Drugs 2017;35:529–536

    Article  CAS  Google Scholar 

  43. Parlati L, Vallet-Pichard A, Batista R, Hernvann A, Sogni P, Pol S, et al. Incidence of grade 3–4 liver injury under immune checkpoints inhibitors: a retrospective study. J Hepatol 2018;69:1396–1397

    Article  PubMed  Google Scholar 

  44. Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, et al. Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol 2015;39:1075–1084

    Article  PubMed  Google Scholar 

  45. Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol 2017;41:134–137

    Article  PubMed  Google Scholar 

  46. Nishida N, Kudo M. Immune checkpoint blockade for the treatment of human hepatocellular carcinoma. Hepatol Res 2018;48:622–634

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI: 16K09382) from the Japanese Society for the Promotion of Science (N. Nishida) and a Grant from the Smoking Research Foundation (N. Nishida).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Naoshi Nishida.

Ethics declarations

Conflict of interest

Naoshi Nishida and Masatoshi Kudo have no conflicts of interest to disclose.

Ethical approval and informed consent

This is not a research paper involving human participants and/or animals; informed consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nishida, N., Kudo, M. Liver damage related to immune checkpoint inhibitors. Hepatol Int 13, 248–252 (2019). https://doi.org/10.1007/s12072-018-9921-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-018-9921-7

Keywords

Navigation