{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:38:57Z","timestamp":1791567537925,"version":"4.3.4"},"reference-count":30,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Immune check\u2010point inhibitors are known to cause immune\u2010mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second\u2010generation drugs, pembrolizumab (<jats:italic>n<\/jats:italic>\u00a0=\u00a06) and atezolizumab (<jats:italic>n<\/jats:italic>\u00a0=\u00a04), were reviewed. Liver dysfunction developed during a median period of 3.5\u00a0weeks after administration of the check\u2010point inhibitor (3\u00a0days\u20131\u00a0year). Antinuclear antibodies were detected in two patients at a low titre (1\/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (<jats:italic>n<\/jats:italic>\u00a0=\u00a05), cholangiopathic changes (<jats:italic>n<\/jats:italic>\u00a0=\u00a02), granulomatous injury (<jats:italic>n<\/jats:italic>\u00a0=\u00a02) and bland cholestasis (<jats:italic>n<\/jats:italic>\u00a0=\u00a01). Two cases of cholangiopathy (both pembrolizumab\u2010treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab\u2010treated cases, K\u00fcpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8<jats:sup>+<\/jats:sup>\/CD4<jats:sup>+<\/jats:sup> cells was 12.2\u00a0\u00b1\u00a05.1, which was significantly higher than that in autoimmune hepatitis (2.7\u00a0\u00b1\u00a01.1; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) or idiosyncratic drug\u2010induced liver injury (5.0\u00a0\u00b1\u00a01.1; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8<jats:sup>+<\/jats:sup> lymphocytes and macrophages due to blockage of PD\u20101\u2013PD\u2010L1 interaction.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.14000","type":"journal-article","created":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T17:30:56Z","timestamp":1569346256000},"page":"470-480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Immune\u2010related adverse reactions in the hepatobiliary system: second\u2010generation check\u2010point inhibitors highlight diverse histological changes"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8370-6508","authenticated-orcid":false,"given":"Yoh","family":"Zen","sequence":"first","affiliation":[{"name":"Institute of Liver Studies King's College Hospital and King's College London London UK"},{"name":"Department of Diagnostic Pathology Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen\u2010Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Taipei Veterans General Hospital Taipei Taiwan"},{"name":"School of Medicine National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung\u2010Ming","family":"Jeng","sequence":"additional","affiliation":[{"name":"Department of Pathology National Taiwan University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung\u2010Wen","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Pathology National Cheng\u2010Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington School of Medicine Seattle WA USA"},{"name":"Department of Medicine University of Washington School of Medicine Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.60.0379"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.41.6750"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.66.1389"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1606774"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716948"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1501824"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1503093"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1809615"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0013-y"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000453"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-012-2140-5"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30157"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathol.2017.07.010"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-313369"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semdp.2019.07.009"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504030"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdq013"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1584319"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.pas.0000136449.37936.6c"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-016-1163-7"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-017-0453-0"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000759"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000362614"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.4161\/21624011.2014.954506"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.39.3298"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.01.033"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0113051"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158265"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22396"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fhis.14000","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.14000","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/his.14000","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.14000","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T02:20:01Z","timestamp":1694139601000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.14000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":30,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["10.1111\/his.14000"],"URL":"https:\/\/doi.org\/10.1111\/his.14000","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"2019-07-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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