{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T22:40:45Z","timestamp":1773700845081,"version":"3.50.1"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"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:p>Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM \u226512.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (\u226512.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM \u226512.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA<jats:sup>+<\/jats:sup>-Mac-2 BP) as the factors that were significantly and independently associated with LSM \u226512.5 kPa. Thus, the formula was constructed as follows: score = \u22126.154 + 1.166 \u00d7 ln type IV collagen 7S + 0.526 \u00d7 ln hyaluronic acid + 1.069 \u00d7 WFA<jats:sup>+<\/jats:sup>-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, \u22120.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM \u226512.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 \u00d7 10<jats:sup>\u221281<\/jats:sup> and 1.88 \u00d7 10<jats:sup>\u221248<\/jats:sup>, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.<\/jats:p>","DOI":"10.1371\/journal.pone.0257166","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T17:52:24Z","timestamp":1631296344000},"page":"e0257166","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["A novel noninvasive formula for predicting cirrhosis in patients with chronic hepatitis C"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-7111","authenticated-orcid":true,"given":"Masanori","family":"Atsukawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihito","family":"Tsubota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chisa","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sawako","family":"Uchida-Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Takaguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akemi","family":"Tsutsui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akito","family":"Nozaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Chuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isao","family":"Hidaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motoh","family":"Iwasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8012-8578","authenticated-orcid":true,"given":"Yasuyuki","family":"Tamai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Tobari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Matsuura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihito","family":"Nagura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Abe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keizo","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomomi","family":"Okubo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taeang","family":"Arai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Itokawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidenori","family":"Toyoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaru","family":"Enomoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Tamori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":true,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norifumi","family":"Kawada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Takei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuhiko","family":"Iwakiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"pone.0257166.ref001","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1053\/j.gastro.2017.03.016","article-title":"American Gastroenterological Association Institute Technical Review on the Role of Elastography in Chronic Liver Diseases","volume":"152","author":"S Singh","year":"2017","journal-title":"Gastroenterology"},{"key":"pone.0257166.ref002","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S1386-6346(98)00075-8","article-title":"Platelet count reflects stage of chronic hepatitis C","volume":"15","author":"E Ono","year":"1999","journal-title":"Hepatol Res"},{"key":"pone.0257166.ref003","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1136\/gut.21.1.63","article-title":"Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin","volume":"21","author":"E Hahn","year":"1980","journal-title":"Gut"},{"key":"pone.0257166.ref004","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1002\/hep.1840200403","article-title":"Serum type III procollagen peptide, type IV collagen 7S domain, central triple-helix","volume":"20","author":"Y Murawaki","year":"1994","journal-title":"Hepatology"},{"key":"pone.0257166.ref005","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1111\/j.1699-0463.1988.tb00946.x","article-title":"Serum aminoterminal type III procollagen peptide: relation to biosynthesis of collagen type III in experimental induced granulation tissue in rats","volume":"96","author":"K H\u00f8rslev-Petersen","year":"1988","journal-title":"Acta Pathol Microbiol Immunol Scand"},{"key":"pone.0257166.ref006","first-page":"752","article-title":"Collagen type IV and procollagen type III during granulation tissue formation","volume":"6","author":"K H\u00f8rslev-Petersen","year":"1988","journal-title":"Eur J Clin Invest"},{"key":"pone.0257166.ref007","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3109\/07853899609033126","article-title":"Serum hyaluronan as a disease marker","volume":"28","author":"TC Laurent","year":"1996","journal-title":"Ann Med"},{"key":"pone.0257166.ref008","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/srep01065","article-title":"A serum\u201dsweet-doughnut\u201d protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis","volume":"3","author":"A Kuno","year":"2013","journal-title":"Sci Rep"},{"key":"pone.0257166.ref009","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1002\/hep.27305","article-title":"Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients","volume":"60","author":"K Yamasaki","year":"2014","journal-title":"Hepatology"},{"key":"pone.0257166.ref010","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/s00535-014-1007-2","article-title":"Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease","volume":"50","author":"M Abe","year":"2015","journal-title":"J Gastroenterol"},{"key":"pone.0257166.ref011","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/hepr.12712","article-title":"Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein may predict liver fibrosis and progression to hepatocellular carcinoma in patients with chronic hepatitis B virus infection","volume":"47","author":"Y Ichikawa","year":"2017","journal-title":"Hepatol Res"},{"key":"pone.0257166.ref012","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1111\/hepr.12662","article-title":"Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level in non-alcoholic steatohepatitis","volume":"46","author":"H Nishikawa","year":"2016","journal-title":"Hepatol Res"},{"key":"pone.0257166.ref013","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1053\/jhep.2003.50346","article-title":"A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C","volume":"38","author":"CT Wai","year":"2003","journal-title":"Hepatology"},{"key":"pone.0257166.ref014","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/hep.21669","article-title":"FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest","volume":"46","author":"A Vallet-Pichard","year":"2007","journal-title":"Hepatology"},{"key":"pone.0257166.ref015","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/S0140-6736(00)04258-6","article-title":"Biochemical markers of liver fibrosis in patients with hepatitis C virus infections: a prospective study","volume":"357","author":"F Imbert-Bismut","year":"2001","journal-title":"Lancet"},{"key":"pone.0257166.ref016","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/hep.20506","article-title":"Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C","volume":"41","author":"M Ziol","year":"2005","journal-title":"Hepatology"},{"key":"pone.0257166.ref017","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1053\/j.gastro.2004.11.018","article-title":"Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C","volume":"128","author":"L Cast\u00e9ra","year":"2005","journal-title":"Gastroenterology"},{"key":"pone.0257166.ref018","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1002\/hep.22870","article-title":"Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography","author":"R Masuzaki","year":"2009","journal-title":"Hepatology"},{"key":"pone.0257166.ref019","doi-asserted-by":"crossref","first-page":"11567","DOI":"10.3748\/wjg.v21.i41.11567","article-title":"Non-invasive diagnosis of liver fibrosis and cirrhosis","volume":"21","author":"Y Lurie","year":"2015","journal-title":"World J Gastroenterol"},{"key":"pone.0257166.ref020","doi-asserted-by":"crossref","first-page":"16820","DOI":"10.3748\/wjg.v20.i45.16820","article-title":"Non-invasive diagnosis of advanced fibrosis and cirrhosis","volume":"20","author":"S Sharma","year":"2014","journal-title":"World J Gastroenterol"},{"key":"pone.0257166.ref021","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1136\/gutjnl-2018-317593","article-title":"Advances in non-invasive assessment of hepatic fibrosis","volume":"69","author":"R Loomba","year":"2020","journal-title":"Gut"},{"key":"pone.0257166.ref022","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1056\/NEJMoa1702417","article-title":"Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection","volume":"378","author":"S Zeuzem","year":"2018","journal-title":"N Engl J Med"},{"key":"pone.0257166.ref023","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1111\/jvh.12312","article-title":"Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial","volume":"21","author":"M Omata","year":"2014","journal-title":"J Viral Hepat"},{"key":"pone.0257166.ref024","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1056\/NEJMoa1402454","article-title":"Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection","volume":"370","author":"N Afdhal","year":"2014","journal-title":"N Engl J Med"},{"key":"pone.0257166.ref025","doi-asserted-by":"crossref","first-page":"ofz185","DOI":"10.1093\/ofid\/ofz185","article-title":"Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10688 Patients in Japan","volume":"6","author":"H Toyoda","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"pone.0257166.ref026","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/jgh.14447","article-title":"Efficacy and safety of elbasvir\/grazoprevir for Japanese patients with genotype 1b chronic hepatitis C complicated by chronic kidney disease, including those undergoing hemodialysis: A post hoc analysis of a multicenter study","volume":"34","author":"M Atsukawa","year":"2019","journal-title":"J Gastroenterol Hepatol"},{"key":"pone.0257166.ref027","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/hepr.13292","article-title":"Efficacy and safety of ombitasvir\/paritaprevir\/ritonavir and ribavirin for chronic hepatitis patients infected with genotype 2a in Japan","volume":"49","author":"M Atsukawa","year":"2019","journal-title":"Hepatol Res"},{"key":"pone.0257166.ref028","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1111\/apt.15218","article-title":"The efficacy and safety of glecaprevir plus pibrentasvir in 141 patients with severe renal impairment: a prospective, multicenter study","volume":"49","author":"M Atsukawa","year":"2019","journal-title":"Aliment Pharmacol Ther"},{"key":"pone.0257166.ref029","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s40121-020-00329-y","article-title":"Sofosbuvir\/Velpatasvir Treatment for Decompensated Cirrhotic Patients with Genotype 1 and 2: A Prospective, Multicenter Study","volume":"9","author":"M Atsukawa","year":"2020","journal-title":"Infect Dis Ther"},{"key":"pone.0257166.ref030","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1111\/jvh.13170","article-title":"Evaluation of 8-week glecaprevir\/pibrentasvir treatment in direct-acting antiviral-na\u00efve noncirrhotic HCV genotype 1 and 2infected patients in a real-world setting in Japan","volume":"26","author":"H Ikeda","year":"2019","journal-title":"J Viral Hepat"},{"key":"pone.0257166.ref031","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/hepr.13256","article-title":"Efficacy of direct-acting antiviral treatment in patients with compensated liver cirrhosis: A multicenter study","volume":"49","author":"N Itokawa","year":"2019","journal-title":"Hepatol Res"},{"key":"pone.0257166.ref032","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.jhep.2020.08.018","article-title":"EASL recommendations on treatment of hepatitis C: Final update of the series","volume":"73","author":"European Association for the Study of the Liver","year":"2020","journal-title":"J Hepatol"},{"key":"pone.0257166.ref033","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1111\/hepr.13503","article-title":"Japan Society of Hepatology guidelines for the management of hepatitis C virus infection: 2019 update","volume":"50","author":"Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology","year":"2020","journal-title":"Hepatol Res"},{"key":"pone.0257166.ref034","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s12072-016-9736-3","article-title":"APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing","volume":"10","author":"M Omata","year":"2016","journal-title":"Hepatol Int"},{"key":"pone.0257166.ref035","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hep.28535","article-title":"Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection","volume":"64","author":"HB El-Serag","year":"2016","journal-title":"Hepatology"},{"key":"pone.0257166.ref036","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/apt.14380","article-title":"Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment","volume":"47","author":"E Ogawa","year":"2018","journal-title":"Aliment Pharmacol Ther"},{"key":"pone.0257166.ref037","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.jhep.2018.07.024","article-title":"Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C","volume":"69","author":"GN Ioannou","year":"2018","journal-title":"J Hepatol"},{"key":"pone.0257166.ref038","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1053\/j.gastro.2017.06.012","article-title":"Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents","volume":"153","author":"F Kanwal","year":"2017","journal-title":"Gastroenterology"},{"key":"pone.0257166.ref039","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0168-8278(97)80279-6","article-title":"Time course of histological changes in patients with a sustained biochemical and virological response to interferon-alpha therapy for chronic hepatitis C virus infection","volume":"27","author":"A Tsubota","year":"1997","journal-title":"J Hepatol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0257166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T17:52:52Z","timestamp":1631296372000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0257166"}},"subtitle":[],"editor":[{"given":"Tatsuo","family":"Kanda","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,10]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0257166","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,10]]}}}