{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:55:23Z","timestamp":1789754123052,"version":"4.0.1"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3\/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (\u03c1 = \u22120.49, p &lt; 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0\/F1 (median 4753 ng\/mL) to F2\u2013F3\u2013F4 (2760 ng\/mL) and in cirrhotic subjects (1418 ng\/mL). The diagnostic performance of FCN-2 in detecting F \u2265 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate\/advanced) significantly improving the fibrosis diagnostic algorithms.<\/jats:p>","DOI":"10.3390\/ijms23052813","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:38:16Z","timestamp":1646599096000},"page":"2813","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2852-6648","authenticated-orcid":false,"given":"Pablo J.","family":"Giraudi","sequence":"first","affiliation":[{"name":"Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6394-2383","authenticated-orcid":false,"given":"Noel","family":"Salvoza","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy"},{"name":"Philippine Council for Health Research and Development, DOST Compound, Bicutan Taguig City 1631, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5605-6711","authenticated-orcid":false,"given":"Deborah","family":"Bonazza","sequence":"additional","affiliation":[{"name":"Surgical Pathology Unit, Cattinara Hospital, ASUGI, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Saitta","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Medicine and Hepatology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Lombardo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Medicine and Hepatology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4280-1725","authenticated-orcid":false,"given":"Biagio","family":"Casagranda","sequence":"additional","affiliation":[{"name":"Surgical Clinic Division, Cattinara Hospital, ASUGI, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8362-9044","authenticated-orcid":false,"given":"Nicol\u00f2","family":"de Manzini","sequence":"additional","affiliation":[{"name":"Surgical Clinic Division, Cattinara Hospital, ASUGI, 34149 Trieste, Italy"},{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Pollicino","sequence":"additional","affiliation":[{"name":"Department of Human Pathology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Raimondo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Medicine and Hepatology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-4258","authenticated-orcid":false,"given":"Silvia","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy"},{"name":"Surgical Clinic Division, Cattinara Hospital, ASUGI, 34149 Trieste, Italy"},{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4251-3547","authenticated-orcid":false,"given":"Natalia","family":"Rosso","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease-Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1053\/j.gastro.2014.11.039","article-title":"Nonalcoholic Steatohepatitis Is the Second Leading Etiology of Liver Disease among Adults Awaiting Liver Transplantation in the United States","volume":"148","author":"Wong","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Jarvis, H., Craig, D., Barker, R., Spiers, G., Stow, D., Anstee, Q.M., and Hanratty, B. (2020). Metabolic Risk Factors and Incident Advanced Liver Disease in Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic Review and Meta-Analysis of Population-Based Observational Studies. PLoS Med., 17.","DOI":"10.1371\/journal.pmed.1003100"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1053\/j.gastro.2005.04.014","article-title":"The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study","volume":"129","author":"Adams","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/hep.29085","article-title":"Increased Risk of Mortality by Fibrosis Stage in Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis","volume":"65","author":"Dulai","year":"2017","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"IV1","DOI":"10.1136\/gut.45.2008.iv1","article-title":"Guidelines on the Use of Liver Biopsy in Clinical Practice","volume":"45","author":"Grant","year":"1999","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a Simple Noninvasive Index to Predict Significant Fibrosis in Patients with HIV\/HCV Coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.jhepr.2019.06.004","article-title":"Performance of the PRO-C3 Collagen Neo-Epitope Biomarker in Non-Alcoholic Fatty Liver Disease","volume":"1","author":"Boyle","year":"2019","journal-title":"JHEP Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/hep.29721","article-title":"Diagnostic Modalities for Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Associated Fibrosis","volume":"68","author":"Younossi","year":"2018","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/s41575-018-0007-8","article-title":"Systems Biology in Hepatology: Approaches and Applications","volume":"15","author":"Mardinoglu","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Page, S., Birerdinc, A., Estep, M., Stepanova, M., Afendy, A., Petricoin, E., Younossi, Z., Chandhoke, V., and Baranova, A. (2013). Knowledge-Based Identification of Soluble Biomarkers: Hepatic Fibrosis in NAFLD as an Example. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056009"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1111\/hepr.12877","article-title":"Identification of Core Gene Networks and Hub Genes Associated with Progression of Non-Alcoholic Fatty Liver Disease by RNA Sequencing","volume":"14","author":"Hotta","year":"2017","journal-title":"Hepatol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12361","DOI":"10.1038\/s41598-017-10930-w","article-title":"Human Hepatic Gene Expression Signature of Non-Alcoholic Fatty Liver Disease Progression, a Meta-Analysis","volume":"7","author":"Ryaboshapkina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_15","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","author":"Estes","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13098-020-00570-y","article-title":"NAFLD as a Continuum: From Obesity to Metabolic Syndrome and Diabetes","volume":"12","author":"Valerio","year":"2020","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.metabol.2018.11.014","article-title":"Obesity and Nonalcoholic Fatty Liver Disease: From Pathophysiology to Therapeutics","volume":"92","author":"Polyzos","year":"2019","journal-title":"Metab. Clin. Exp."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.jhep.2006.06.013","article-title":"Hepatic Histology in Obese Patients Undergoing Bariatric Surgery","volume":"45","author":"Machado","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1111\/liv.14473","article-title":"Occult Hepatitis B Virus Infection Predicts Non-Alcoholic Steatohepatitis in Severely Obese Individuals from Italy","volume":"40","author":"Raimondo","year":"2020","journal-title":"Liver Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1089\/omi.2018.0179","article-title":"Serum Proteomic Changes as Candidate Biomarkers of Intermediate Liver Fibrosis in Chronic Hepatitis B Infection","volume":"23","author":"Dai","year":"2019","journal-title":"OMICS J. Integr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s12250-015-3605-4","article-title":"Serum Ficolin-2 Concentrations Are Significantly Changed in Patients with Hepatitis B Virus Infection and Liver Diseases","volume":"30","author":"Chen","year":"2015","journal-title":"Virol. Sin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/cmi.2009.32","article-title":"Specifically Binding of L-Ficolin to N -Glycans of HCV Envelope Glycoproteins E1 and E2 Leads to Complement Activation","volume":"6","author":"Liu","year":"2009","journal-title":"Cell. Mol. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"138797","DOI":"10.1155\/2012\/138797","article-title":"Human L-Ficolin (Ficolin-2) and Its Clinical Significance","volume":"2012","author":"Kilpatrick","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.molimm.2010.09.019","article-title":"Ficolins and FIBCD1: Soluble and Membrane Bound Pattern Recognition Molecules with Acetyl Group Selectivity","volume":"48","author":"Thomsen","year":"2011","journal-title":"Mol. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.molimm.2008.07.025","article-title":"Two Factors of the Lectin Pathway of Complement, l-Ficolin and Mannan-Binding Lectin, and Their Associations with Prematurity, Low Birthweight and Infections in a Large Cohort of Polish Neonates","volume":"46","author":"Swierzko","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/S2468-1253(20)30252-1","article-title":"A Blood-Based Biomarker Panel (NIS4) for Non-Invasive Diagnosis of Non-Alcoholic Steatohepatitis and Liver Fibrosis: A Prospective Derivation and Global Validation Study","volume":"5","author":"Harrison","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"106175","DOI":"10.1016\/j.cct.2020.106175","article-title":"The European NAFLD Registry: A Real-World Longitudinal Cohort Study of Nonalcoholic Fatty Liver Disease","volume":"98","author":"Hardy","year":"2020","journal-title":"Contemp. Clin. Trials"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/eurheartj\/ehz486","article-title":"2019 ESC Guidelines on Diabetes, Pre-Diabetes, and Cardiovascular Diseases Developed in Collaboration with the EASD","volume":"41","author":"Cosentino","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/liv.13505","article-title":"A Simple in Silico Strategy Identifies Candidate Biomarkers for the Diagnosis of Liver Fibrosis in Morbidly Obese Subjects","volume":"38","author":"Giraudi","year":"2018","journal-title":"Liver Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2813\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:31:55Z","timestamp":1760135515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":30,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052813"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052813","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-1250728\/v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,4]]}}}