{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:39:43Z","timestamp":1792100383237,"version":"4.4.0"},"reference-count":16,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, but they may cause a wide range of immune-related adverse events (irAEs). Hepatic toxicity occurs in approximately 1\u20136% of patients treated with nivolumab and usually presents with a hepatocellular pattern responsive to corticosteroids. The cholestatic-predominant immune-mediated hepatitis seems to respond poorly to immunosuppression. We describe an 87-year-old man with metastatic melanoma treated with nivolumab who developed steroid-refractory, cholestatic-predominant immune-mediated hepatitis after 18 cycles of therapy. Laboratory tests revealed a mixed but predominantly cholestatic pattern (ALT 585 U\/L, GGT 2261 U\/L, total bilirubin 2.0 mg\/dL). Imaging excluded biliary obstruction or hepatic metastases. Liver biopsy showed acute lobular hepatitis with intracanalicular cholestasis and mild bile duct injury, consistent with immune-mediated, drug-induced injury (Ishak score 5). Mycophenolate mofetil produced only partial biochemical improvement. The patient died one month later from influenza A pneumonia in the context of combined immunosuppressive therapy. This case illustrates a cholestatic-predominant phenotype of nivolumab-induced hepatitis, characterized by poor corticosteroid response and incomplete recovery despite second-line immunosuppression. Recognition of this entity is essential, as early introduction of agents such as mycophenolate may improve outcomes. In elderly and frail patients, however, the risks of intensified immunosuppression must be carefully balanced against infection risk, highlighting the need for individualized management and vigilant monitoring.<\/jats:p>","DOI":"10.3390\/curroncol32120663","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T09:56:02Z","timestamp":1764323762000},"page":"663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Steroid-Refractory Cholestatic Immune-Mediated Hepatitis Following Nivolumab Therapy in an Elderly Patient with Metastatic Melanoma: A Rare and Challenging Presentation"],"prefix":"10.3390","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4606-2316","authenticated-orcid":false,"given":"Luis","family":"Posado-Dominguez","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute for Biomedical Research of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-5332","authenticated-orcid":false,"given":"Jorge","family":"Feito-Perez","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7325-3647","authenticated-orcid":false,"given":"Mar\u00eda","family":"Escribano-Iglesias","sequence":"additional","affiliation":[{"name":"Department of Radiology, University Hospital of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Bragado Pascual","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, University Hospital of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Fonseca S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute for Biomedical Research of Salamanca, 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1080\/21645515.2016.1175694","article-title":"Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers","volume":"12","author":"Rajan","year":"2016","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7953","DOI":"10.3390\/curroncol29100629","article-title":"Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients","volume":"29","author":"Tong","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/hep.31227","article-title":"Hepatotoxicity from Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation","volume":"72","author":"Peeraphatdit","year":"2020","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.jhep.2018.01.033","article-title":"Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors","volume":"68","author":"Michot","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00416","DOI":"10.14309\/crj.0000000000000416","article-title":"Nivolumab-Induced Autoimmune-Like Cholestatic Hepatitis in a Liver Transplant Recipient","volume":"7","author":"Anugwom","year":"2020","journal-title":"ACG Case Rep. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100719","DOI":"10.1016\/j.jhepr.2023.100719","article-title":"Clinical pattern of checkpoint inhibitor-induced liver injury in a multicentre cohort","volume":"5","author":"Hountondji","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3892\/ol.2025.14957","article-title":"Incidence and management of hepatic immune-related adverse events in advanced urologic cancers treated with immune checkpoint inhibitors: A multicenter retrospective study","volume":"29","author":"Park","year":"2025","journal-title":"Oncol. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1159\/000347210","article-title":"Cholestatic liver disease","volume":"31","author":"Lammert","year":"2013","journal-title":"Dig. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"858","DOI":"10.5858\/arpa.2014-0229-RA","article-title":"Pathophysiology and Diseases of the Proximal Pathways of the Biliary System","volume":"139","author":"Nakanishi","year":"2015","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vitale, G., Mattiaccio, A., Conti, A., Berardi, S., Vero, V., Turco, L., Seri, M., and Morelli, M.C. (2023). Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065823"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"847","DOI":"10.2174\/138955709788452676","article-title":"Diagnosis and therapy of autoimmune hepatitis","volume":"9","author":"Granito","year":"2009","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.cgh.2013.08.039","article-title":"Cholestatic phenotypes of autoimmune hepatitis","volume":"12","author":"Czaja","year":"2014","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_13","unstructured":"European Association for the Study of the Liver (2025). EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J. Hepatol., 83, 453\u2013501."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1016\/j.apsb.2021.10.003","article-title":"Mechanisms of immune checkpoint inhibitor-mediated liver injury","volume":"11","author":"Shojaie","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_15","first-page":"83","article-title":"Immune Checkpoint Inhibitor-Induced Hepatic Injury: A Clinicopathologic Review","volume":"2","author":"Taherian","year":"2022","journal-title":"J. Clin. Transl. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/gastro\/goz044","article-title":"Histologic patterns of liver injury induced by anti-PD-1 therapy","volume":"8","author":"Zhang","year":"2020","journal-title":"Gastroenterol. 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