{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T10:09:46Z","timestamp":1781690986881,"version":"3.54.5"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Caspase\u2010generated fragmented cytokeratin 18 (fCK18) is recognized as a useful noninvasive biomarker in the diagnosis of nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH). However, fCK18 measurement is not applied clinically due to widely variable cut\u2010off values under the current enzyme\u2010linked immunosorbent assay platform. Therefore, we developed a highly sensitive chemiluminescent enzyme immunoassay using newly developed monoclonal antibodies against fCK18 and investigated its relevance in NASH diagnosis. Serum fCK18 levels were measured in the derivation and validation cohort. The correlation between serum fCK18 levels and NAFLD activity score (NAS), fibrosis stage, and liver function was examined. Serum fCK18 levels were significantly correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma\u2010glutamyl transpeptidase. Serum fCK18 levels were significantly associated with NAS, Brunt's grade\/stage, Matteoni's classification, portal inflammation, and fat accumulation in the liver. Notably, hepatocyte ballooning was the only independent variable significantly associated with serum fCK18 in the multivariate linear regression analysis. Serum fCK18 levels were significantly elevated in patients with NAFLD and nonalcoholic fatty liver (NAFL) compared to healthy individuals. They were also significantly elevated in patients with NAFL compared to NASH defined by NAS or Matteoni's classification, with area under the curve values being 0.961 (NAFLD vs. healthy), 0.913 (NAFL vs. healthy), 0.763 (NASH vs. NAFL), and 0.796 (NASH type 3\u20134 vs. NAFL type 1\u20132). These results were confirmed by a validation cohort. Notably, changes over time in serum fCK18 levels were significantly correlated with changes in ALT, AST, and the fibrosis\u20104 index in 25 patients who underwent lifestyle modification. Serum fCK18 levels were significantly correlated with liver damage associated with NASH pathology. Serum fCK18 levels are accurate in distinguishing patients with NAFL or NASH from healthy individuals and may be useful to monitor NASH over time.<\/jats:p>","DOI":"10.1002\/hep4.1971","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T08:44:20Z","timestamp":1651221860000},"page":"1987-1999","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":17,"title":["A new detection system for serum fragmented cytokeratin 18 as a biomarker reflecting histologic activities of human nonalcoholic steatohepatitis"],"prefix":"10.1097","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0555-2707","authenticated-orcid":false,"given":"Akiko","family":"Eguchi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"},{"name":"JST, PRESTO,Kawaguchi,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5488-2622","authenticated-orcid":false,"given":"Motoh","family":"Iwasa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minori","family":"Yamada","sequence":"additional","affiliation":[{"name":"Bio\u2010Reagent Material Development,Bio\u2010Diagnostic Reagent Technology Center,Sysmex Corporation,Kobe,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Tamai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Shigefuku","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshifumi","family":"Hirokawa","sequence":"additional","affiliation":[{"name":"Department of Oncologic Pathology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinobu","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Oncologic Pathology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Okuno","sequence":"additional","affiliation":[{"name":"Scientific Affairs,Sysmex Corporation,Kobe,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,University of Tokyo,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuma","family":"Nakatsuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,University of Tokyo,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Enooku","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,University of Tokyo,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Bio\u2010Reagent Material Development,Bio\u2010Diagnostic Reagent Technology Center,Sysmex Corporation,Kobe,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinao","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Center for Physical and Mental Health,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuji","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Manufacturing Technology Development 2, Reagent Production,Sysmex Corporation,Kobe,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Oncologic Pathology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Takei","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Graduate School of Medicine,Mie University,Tsu,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"hep41971-bib-0001-20241129","first-page":"743","article-title":"Changing trends in liver transplantation: challenges and solutions","volume":"105","year":"2020","journal-title":"Transplantation"},{"key":"hep41971-bib-0002-20241129","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030","volume":"69","year":"2018","journal-title":"J 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