{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:39:40Z","timestamp":1792100380563,"version":"4.4.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T00:00:00Z","timestamp":1567987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Immune checkpoint inhibitor treatment has been approved by the U.S. Food and Drug Administration for the treatment of a wide range of cancer types, including hepatocellular carcinoma. Workup and management of immune-mediated hepatitis, pancreatitis, or cholangitis that develops during immune checkpoint inhibitor treatment can be challenging. Immune-mediated hepatitis can be particularly challenging if patients have underlying viral hepatitis or autoimmune hepatitis. Patients with positive hepatitis B virus DNA should be referred to a hepatologist for antiviral therapy prior to immune checkpoint inhibitor treatment. With untreated hepatitis C virus (HCV) and elevated liver enzymes, a liver biopsy should be obtained to differentiate between HCV infection and immune-mediated hepatitis due to anti-programmed cell death protein 1 (PD-1) therapy. If autoimmune serologies are negative, then this supports a case of immune-mediated hepatitis secondary to anti-PD-1 therapy, rather than autoimmune hepatitis. In this case, an empiric steroid therapy is reasonable; however, if the patient does not respond to steroid therapy in 3\u20135\u2009days, then liver biopsy should be pursued. The incidence of immune checkpoint-induced pancreatitis is low, but when it does occur, diagnosis is not straightforward. Although routine monitoring of pancreatic enzymes is not generally recommended, when pancreatitis is suspected, serum levels of amylase and lipase should be checked. Once confirmed, a steroid or other immunosuppressant (if steroids are contraindicated) should be administered along with close monitoring, and a slow tapering dosage once the pancreatitis is under control. Patients should then be monitored for recurrent pancreatitis. Finally, immune therapy-related cholangitis involves elevated bilirubin and alkaline phosphatase and, once diagnosed, is managed in the same way as immune-mediated hepatitis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:p>Immune-mediated hepatitis, pancreatitis, and cholangitis are found in patients receiving or who have previously received immune checkpoint inhibitors. To work up immune-mediated hepatitis, viral, and autoimmune serologies, liver imaging will help to differentiate immune-mediated hepatitis from hepatitis of other etiology. Hepatology consult may be considered in patients with a history of chronic liver disease who developed hepatitis during immune checkpoint inhibitor treatment. Liver biopsy should be considered to clarify the diagnosis for case in which the hepatitis is refractory to steroid or immunosuppressant treatment. Immune-mediated pancreatitis is treated with steroid or other immunosuppressant with a slow tapering and should be monitored for recurrence.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1634\/theoncologist.2018-0162","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T19:05:13Z","timestamp":1568055913000},"page":"105-111","source":"Crossref","is-referenced-by-count":40,"title":["Workup and Management of Immune-Mediated Hepatobiliary Pancreatic Toxicities That Develop During Immune Checkpoint Inhibitor Treatment"],"prefix":"10.1093","volume":"25","author":[{"given":"Christine","family":"Hsu","sequence":"first","affiliation":[{"name":"MedStar Georgetown Transplant Institute, Pasquerilla Healthcare Center, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiwu Ruth","family":"He","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,9]]},"reference":[{"key":"2021122510024879000_R1","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1\/2 dose escalation and expansion trial","volume":"389","author":"El-Khoueiry","year":"2017","journal-title":"Lancet"},{"key":"2021122510024879000_R2","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.2147\/DDDT.S115493","article-title":"Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: A meta-analysis","volume":"10","author":"Zhang","year":"2016","journal-title":"Drug Des Devel Ther"},{"key":"2021122510024879000_R3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s40425-016-0166-5","article-title":"Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction","volume":"4","author":"Kanz","year":"2016","journal-title":"J Immunother Cancer"},{"key":"2021122510024879000_R4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/CMR.0000000000000434","article-title":"Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and non-small-cell lung cancer in patients with viral hepatitis: A case series","volume":"28","author":"Kothapalli","year":"2018","journal-title":"Melanoma Res"},{"key":"2021122510024879000_R5","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1097\/QAD.0000000000001599","article-title":"Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy","volume":"31","author":"Lake","year":"2017","journal-title":"AIDS"},{"key":"2021122510024879000_R6","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1186\/s12879-017-2672-6","article-title":"Hepatitis B reactivation characterized by HBsAg negativity and anti-HbsAg antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal","volume":"17","author":"Cerva","year":"2017","journal-title":"BMC Infect Dis"},{"key":"2021122510024879000_R7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/TP.0000000000001870","article-title":"Incidence of hepatitis B viral reactivation after kidney transplantation with low-dose rituximab administration","volume":"102","author":"Masutani","year":"2018","journal-title":"Transplantation"},{"key":"2021122510024879000_R8","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1002\/hep.29022","article-title":"Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study","volume":"65","author":"Seto","year":"2017","journal-title":"Hepatology"},{"key":"2021122510024879000_R9","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0063818","article-title":"A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection","volume":"8","author":"Gardiner","year":"2013","journal-title":"PLoS One"},{"key":"2021122510024879000_R10","first-page":"737389","article-title":"PD-1 blockade in advanced melanoma in patients with hepatitis C and\/or HIV","volume":"2015","author":"Davar","year":"2015","journal-title":"Case Rep Oncol Med"},{"key":"2021122510024879000_R11","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.jhep.2016.04.008","article-title":"Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy","volume":"65","author":"Reig","year":"2016","journal-title":"J Hepatol"},{"key":"2021122510024879000_R12","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1053\/j.gastro.2017.06.012","article-title":"Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents","volume":"153","author":"Kanwal","year":"2017","journal-title":"Gastroenterology"},{"key":"2021122510024879000_R13","article-title":"HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma","author":"Ioannou","year":"2017","journal-title":"J Hepatol"},{"key":"2021122510024879000_R14","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/cei.13159","article-title":"Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody: A novel gut-immune system-based therapy for metaflammation and NASH","volume":"193","author":"Ilan","year":"2018","journal-title":"Clin Exp Immunol"},{"key":"2021122510024879000_R15","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/s41379-018-0013-y","article-title":"Hepatotoxicity of immune checkpoint inhibitors: A histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury","volume":"31","author":"Zen","year":"2018","journal-title":"Mod Pathol"},{"key":"2021122510024879000_R16","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1097\/PAS.0000000000000453","article-title":"Ipilimumab-associated hepatitis: Clinicopathologic characterization in a series of 11 cases","volume":"39","author":"Johncilla","year":"2015","journal-title":"Am J Surg Pathol"},{"key":"2021122510024879000_R17","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1007\/s10620-012-2140-5","article-title":"Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma","volume":"57","author":"Kleiner","year":"2012","journal-title":"Dig Dis Sci"},{"key":"2021122510024879000_R18","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1007\/s10637-013-9939-6","article-title":"Ipilimumab associated hepatitis: Imaging and clinicopathologic findings","volume":"31","author":"Kim","year":"2013","journal-title":"Invest New Drugs"},{"key":"2021122510024879000_R19","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1159\/000471480","article-title":"Successful treatment of sudden hepatitis induced by long-term nivolumab administration","volume":"10","author":"Imafuku","year":"2017","journal-title":"Case Rep Oncol"},{"key":"2021122510024879000_R20","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1093\/jjco\/hyw167","article-title":"Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab","volume":"47","author":"Tanaka","year":"2017","journal-title":"Jpn J Clin Oncol"},{"key":"2021122510024879000_R21","doi-asserted-by":"crossref","DOI":"10.1136\/esmoopen-2017-000268","article-title":"Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury","volume":"2","author":"Doherty","year":"2017","journal-title":"ESMO Open"},{"key":"2021122510024879000_R22","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1136\/gutjnl-2012-302779","article-title":"Classification of acute pancreatitis--2012: Revision of the Atlanta classification and definitions by international consensus","volume":"62","author":"Banks","year":"2013","journal-title":"Gut"},{"key":"2021122510024879000_R23","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1200\/JCO.2012.44.6112","article-title":"Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma","volume":"31","author":"Ribas","year":"2013","journal-title":"J Clin Oncol"},{"key":"2021122510024879000_R24","doi-asserted-by":"crossref","DOI":"10.1016\/S1470-2045(15)70122-1","article-title":"Correction to Lancet Oncol 2015; 16: 522-30. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial","volume":"16","author":"Eggermont","year":"2015","journal-title":"Lancet Oncol"},{"key":"2021122510024879000_R25","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/S1470-2045(17)30446-1","article-title":"Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): A multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial","volume":"18","author":"Maio","year":"2017","journal-title":"Lancet Oncol"},{"key":"2021122510024879000_R26","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S1470-2045(15)70076-8","article-title":"Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial","volume":"16","author":"Weber","year":"2015","journal-title":"Lancet Oncol"},{"key":"2021122510024879000_R27","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/S0140-6736(15)01281-7","article-title":"Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial","volume":"387","author":"Herbst","year":"2016","journal-title":"Lancet"},{"key":"2021122510024879000_R28","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N Engl J Med"},{"key":"2021122510024879000_R29","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/S1470-2045(15)00083-2","article-title":"Pembrolizumab versus investigator-choice chemotherapy for ipilimumab refractory melanoma (KEYNOTE-002): A randomised, controlled","volume":"16","author":"Ribas","year":"2015","journal-title":"phase 2 trial. Lancet Oncol"},{"key":"2021122510024879000_R30","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0140-6736(16)32517-X","article-title":"Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial","volume":"389","author":"Rittmeyer","year":"2017","journal-title":"Lancet"},{"key":"2021122510024879000_R31","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/S1470-2045(16)30366-7","article-title":"Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled","volume":"17","author":"Hodi","year":"2016","journal-title":"phase 2 trial. Lancet Oncol"},{"key":"2021122510024879000_R32","first-page":"1270","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"24","author":"Larkin","year":"2015","journal-title":"N Engl J Med"},{"key":"2021122510024879000_R33","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","article-title":"Pembrolizumab versus ipilimumab in advanced melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N Engl J Med"},{"key":"2021122510024879000_R34","article-title":"Thinking critically about classifying adverse events: Incidence of pancreatitis in patients treated with nivolumab + ipilimumab","volume":"109","author":"Friedman","year":"2016","journal-title":"J Natl Cancer Inst"},{"key":"2021122510024879000_R35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1200\/JCO.2017.72.2850","article-title":"Nivolumab plus ipilimumab in patients with advanced melanoma: Updated survival, response, and safety data in a phase I dose-escalation study","volume":"36","author":"Callahan","year":"2018","journal-title":"J Clin Oncol"},{"key":"2021122510024879000_R36","first-page":"592","article-title":"The role of etiology in the hyperamylasemia of acute liver failure","volume":"104","author":"Cot\u00e9","year":"2009","journal-title":"Am J Gastroenterol"},{"key":"2021122510024879000_R37","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.soard.2014.04.030","article-title":"Roux-en-Y gastric bypass: Hyperamylasemia is associated with small bowel obstruction","volume":"11","author":"Spector","year":"2015","journal-title":"Surg Obes Relat Dis"},{"key":"2021122510024879000_R38","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1111\/j.1572-0241.2000.03279.x","article-title":"Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities","volume":"95","author":"Yadav","year":"2000","journal-title":"Am J Gastroenterol"},{"key":"2021122510024879000_R39","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1111\/j.1572-0241.1999.01074.x","article-title":"Abnormalities of serum amylase and lipase in HIV-positive patients","volume":"94","author":"Argiris","year":"1999","journal-title":"Am J Gastroenterol"},{"key":"2021122510024879000_R40","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J Clin Oncol"},{"key":"2021122510024879000_R41","doi-asserted-by":"crossref","DOI":"10.1097\/CMR.0000000000000611","article-title":"Immune-related pancreatitis associated with checkpoint blockade in melanoma","author":"Kohlmann","year":"2019","journal-title":"Melanoma Res"},{"key":"2021122510024879000_R42","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ejca.2016.02.025","article-title":"Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy","volume":"60","author":"Hofmann","year":"2016","journal-title":"Eur J Cancer"},{"key":"2021122510024879000_R43","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.lungcan.2016.07.001","article-title":"Immune-related pancreatitis secondary to nivolumab in a patient with recurrent lung adenocarcinoma: A case report","volume":"99","author":"Ikeuchi","year":"2016","journal-title":"Lung Cancer"},{"key":"2021122510024879000_R44","doi-asserted-by":"crossref","first-page":"e528","DOI":"10.1097\/RLU.0000000000000940","article-title":"Pancreatitis secondary to anti-programmed death receptor 1 immunotherapy diagnosed by FDG PET\/CT","volume":"40","author":"Alabed","year":"2015","journal-title":"Clin Nucl Med"},{"key":"2021122510024879000_R45","doi-asserted-by":"crossref","DOI":"10.1111\/hepr.13329","article-title":"Secondary sclerosing cholangitis with hemobilia induced by pembrolizumab: Case report and review of published work","author":"Koya","year":"2019","journal-title":"Hepatol Res"},{"key":"2021122510024879000_R46","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.2169\/internalmedicine.1981-18","article-title":"Efficacy and safety of chemotherapy following anti-PD-1 antibody therapy for gastric cancer: A case of sclerosing cholangitis","volume":"58","author":"Kono","year":"2019","journal-title":"Intern Med"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2018-0162","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2018-0162","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/25\/2\/105\/41919373\/oncolo_25_2_105.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/25\/2\/105\/41919373\/oncolo_25_2_105.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,25]],"date-time":"2021-12-25T10:04:55Z","timestamp":1640426695000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/25\/2\/105\/6443035"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,9]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,9,9]]},"published-print":{"date-parts":[[2020,2,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2018-0162","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,2,1]]},"published":{"date-parts":[[2019,9,9]]}}}