Open AccessA new detection system for serum fragmented cytokeratin 18 as a biomarker reflecting histologic activities of human nonalcoholic steatohepatitis
Author(s) -
Eguchi Akiko,
Iwasa Motoh,
Yamada Minori,
Tamai Yasuyuki,
Shigefuku Ryuta,
Hasegawa Hiroshi,
Hirokawa Yoshifumi,
Hayashi Akinobu,
Okuno Koji,
Matsushita Yuki,
Nakatsuka Takuma,
Enooku Kenichiro,
Sakaguchi Koji,
Kobayashi Yoshinao,
Yamaguchi Tetsuji,
Watanabe Masatoshi,
Takei Yoshiyuki,
Nakagawa Hayato
Publication year - 2022
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1971
Subject(s) - nonalcoholic fatty liver disease , medicine , gastroenterology , biomarker , alanine transaminase , cytokeratin , fatty liver , steatohepatitis , cohort , immunohistochemistry , disease , biology , biochemistry
Caspase‐generated 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‐off values under the current enzyme‐linked 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‐glutamyl 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 3–4 vs. NAFL type 1–2). 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‐4 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.