{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T01:21:18Z","timestamp":1782955278467,"version":"3.54.5"},"reference-count":16,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2016,9,6]],"date-time":"2016-09-06T00:00:00Z","timestamp":1473120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Regorafenib is the first small\u2010molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (<jats:styled-content style=\"fixed-case\">mCRC<\/jats:styled-content>) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Patients with refractory <jats:styled-content style=\"fixed-case\">mCRC<\/jats:styled-content> treated with regorafenib in our institution were reviewed. Severe treatment\u2010related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4) and uridine diphosphate\u2010glucuronosyltransferase 1A9 (<jats:styled-content style=\"fixed-case\">UGT<\/jats:styled-content>1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto\u2010central bridging and fibrosis in the delayed presentation. None of the patients had <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4 gene mutations. Similar polymorphisms in <jats:styled-content style=\"fixed-case\">UGT<\/jats:styled-content>1A9 gene promoter region (<jats:styled-content style=\"fixed-case\">UGT<\/jats:styled-content>1A9 variant \u2013118T<jats:sub>9&gt;10<\/jats:sub> [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan\u2010based chemotherapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.13217","type":"journal-article","created":{"date-parts":[[2016,8,8]],"date-time":"2016-08-08T18:16:39Z","timestamp":1470680199000},"page":"1590-1594","source":"Crossref","is-referenced-by-count":21,"title":["Regorafenib induced severe toxic hepatitis: characterization and discussion"],"prefix":"10.1111","volume":"36","author":[{"given":"Anne","family":"Sacr\u00e9","sequence":"first","affiliation":[{"name":"Service d'Oncologie m\u00e9dicale Cliniques Universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain (UCL)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Lanthier","sequence":"additional","affiliation":[{"name":"Service d'H\u00e9pato\u2010gastroent\u00e9rologie Cliniques Universitaires Saint\u2010Luc UCL  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Dano","sequence":"additional","affiliation":[{"name":"Service d'anatomie pathologique Cliniques Universitaires Saint\u2010Luc UCL  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selda","family":"Aydin","sequence":"additional","affiliation":[{"name":"Service d'anatomie pathologique Cliniques Universitaires Saint\u2010Luc UCL  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Leggenhager","sequence":"additional","affiliation":[{"name":"Institute of Surgical Pathology University Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Surgical Pathology University Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010France","family":"Dekairelle","sequence":"additional","affiliation":[{"name":"Centre de Technologies Mol\u00e9culaires Appliqu\u00e9es Cliniques Universitaires Saint\u2010Luc UCL  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"De Cuyper","sequence":"additional","affiliation":[{"name":"Service d'Oncologie m\u00e9dicale Cliniques Universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain (UCL)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Luc","family":"Gala","sequence":"additional","affiliation":[{"name":"Centre de Technologies Mol\u00e9culaires Appliqu\u00e9es Cliniques Universitaires Saint\u2010Luc UCL  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Humblet","sequence":"additional","affiliation":[{"name":"Service d'Oncologie m\u00e9dicale Cliniques Universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain (UCL)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Sempoux","sequence":"additional","affiliation":[{"name":"Institut Universitaire de Pathologie\u2010IUP  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Van den Eynde","sequence":"additional","affiliation":[{"name":"Service d'Oncologie m\u00e9dicale Cliniques Universitaires Saint\u2010Luc Universit\u00e9 catholique de Louvain (UCL)  Brussels Belgium"},{"name":"Service d'H\u00e9pato\u2010gastroent\u00e9rologie Cliniques Universitaires Saint\u2010Luc UCL  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,9,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61900-X"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)70156-7"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12231"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2012.09.004"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.153"},{"key":"e_1_2_9_7_1","unstructured":"http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2012\/203085lbl.pdf\u2014Highlights of prescribing information about Stivarga. 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