{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:27Z","timestamp":1787022087388,"version":"build-2736575974"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I\/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs\/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (\n                      <jats:italic>N<\/jats:italic>\n                      = 17;\n                      <jats:italic>M<\/jats:italic>\n                      = 217, 95% CI 145\u2013324 for immunotoxicity,\n                      <jats:italic>N<\/jats:italic>\n                      = 103;\n                      <jats:italic>M<\/jats:italic>\n                      = 74, 95% CI 59\u201392 for other causes; ratio of means 0.34, 95% CI 0.19\u20130.60, p = &lt;0.001) and higher ALT:AST ratio (M = 1.27, 95% CI 0.78\u20132.06 for immunotoxicity, M = 0.69, 95% CI 0.59\u20130.80 for other causes, ratio of means 0.54, 95% CI 0.36\u20130.82, p = 0.004). Immunotoxicity was more often seen in patients with prior CPI exposure (41.2% of immunotoxicity vs 15.9% of patients without, p = 0.01), anti-CTLA-4 \u2013containing ICI treatments (29.4% of immunotoxicity vs 6.8% of patients without, p = &lt;0.001) and other organ immunotoxicity (76.5% of immunotoxicity vs 19.2% of patients without, p = &lt;0.001). Cause for enzyme elevation was established in most patients after non-invasive investigation. Liver biopsy was reserved for four patients with atypical treatment response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT\/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0253070","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T13:26:26Z","timestamp":1623417986000},"page":"e0253070","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":32,"title":["Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-9523","authenticated-orcid":true,"given":"Morven","family":"Cunningham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Iafolla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yada","family":"Kanjanapan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orlando","family":"Cerocchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian L.","family":"Siu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe L.","family":"Bedard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendra","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Spreafico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan J.","family":"Feld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"pone.0253070.ref001","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ctrv.2016.02.001","article-title":"Management of toxicities of immune checkpoint inhibitors","volume":"44","author":"L Spain","year":"2016","journal-title":"Cancer Treat 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