{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:48:59Z","timestamp":1792003739215,"version":"4.4.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"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":["Hepatology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>NAFLD is the most common liver disease worldwide. NASH, the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes. We searched for their noninvasive biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      Global RNA sequencing of liver tissue from 98 patients with biopsy\u2010proven NAFLD was performed. Unsupervised hierarchical clustering well distinguished NASH from nonalcoholic fatty liver (NAFL), and patients with NASH exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified proteins up\u2010regulated in NASH and\/or advanced fibrosis (stage F3\u2010F4), including matricellular glycoprotein thrombospondin\u20102 (TSP\u20102), encoded by the thrombospondin 2 (\n                      <jats:italic toggle=\"yes\">THBS2<\/jats:italic>\n                      ) gene. The intrahepatic\n                      <jats:italic toggle=\"yes\">THBS2<\/jats:italic>\n                      expression level showed the highest areas under the receiver operating characteristic curves (AUROCs) of 0.915 and 0.957 for diagnosing NASH and advanced fibrosis, respectively.\n                      <jats:italic toggle=\"yes\">THBS2<\/jats:italic>\n                      positively correlated with inflammation and ballooning according to NAFLD activity score, serum aspartate aminotransferase and hyaluronic acid (HA) levels, and NAFLD Fibrosis Score (NFS).\n                      <jats:italic toggle=\"yes\">THBS2<\/jats:italic>\n                      was associated with extracellular matrix and collagen biosynthesis, platelet activation, caspase\u2010mediated cleavage of cytoskeletal proteins, and immune cell infiltration. Serum TSP\u20102 expression was measured in 213 patients with biopsy\u2010proven NAFLD, was significantly higher in NASH than in NAFL, and increased parallel to fibrosis stage. The AUROCs for predicting NASH and advanced fibrosis were 0.776 and 0.856, respectively, which were comparable to Fibrosis\u20104 index, serum HA level, and NFS in advanced fibrosis diagnosis. Serum TSP\u20102 level and platelet count were independent predictors of NASH and advanced fibrosis. Serum TSP\u20102 levels could stratify patients with NAFLD according to the risk of hepatic complications, including liver cancer and decompensated cirrhotic events.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TSP\u20102 may be a useful biomarker for NASH and advanced fibrosis diagnosis in patients with NAFLD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31995","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T08:30:27Z","timestamp":1623227427000},"page":"2452-2466","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":159,"title":["Transcriptomics Identify Thrombospondin\u20102 as a Biomarker for NASH and Advanced Liver Fibrosis"],"prefix":"10.1097","volume":"74","author":[{"given":"Kazuhiro","family":"Kozumi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6250-1324","authenticated-orcid":false,"given":"Takahiro","family":"Kodama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Murai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadatsugu","family":"Sakane","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Govaere","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute,Faculty of Medical Sciences,Newcastle University,Newcastle Upon Tyne,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Cockell","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute,Faculty of Medical Sciences,Newcastle University,Newcastle Upon Tyne,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Motooka","sequence":"additional","affiliation":[{"name":"Genome Information Research Center,Research Institute for Microbial Diseases,Osaka University,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naruyasu","family":"Kakita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Kaizuka City Hospital,Osaka,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinori","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Kaizuka City Hospital,Osaka,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5935-4346","authenticated-orcid":false,"given":"Yasuteru","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Hepatology,Sendai Kousei Hospital,Sendai,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tahata","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Hikita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1580-607X","authenticated-orcid":false,"given":"Ryotaro","family":"Sakamori","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kamada","sequence":"additional","affiliation":[{"name":"Department of Advanced Metabolic Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann K.","family":"Daly","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute,Faculty of Medical Sciences,Newcastle University,Newcastle Upon Tyne,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9518-0088","authenticated-orcid":false,"given":"Quentin M.","family":"Anstee","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute,Faculty of Medical Sciences,Newcastle University,Newcastle Upon Tyne,United Kingdom"},{"name":"Newcastle National Institute for Health Research Biomedical Research Centre,Newcastle Upon Tyne Hospitals National Health Service Foundation Trust,Newcastle Upon Tyne,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Morii","sequence":"additional","affiliation":[{"name":"Department of Pathology,Osaka University Graduate School of Medicine,Osaka,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Takehara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Osaka University Graduate School of Medicine,Suita,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8,21]]},"reference":[{"key":"hep31995-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1053\/j.gastro.2020.01.052","article-title":"Nonalcoholic fatty liver disease 2020: the state of the disease","volume":"158","year":"2020","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1053\/j.gastro.2018.12.036","article-title":"Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease","volume":"156","year":"2019","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver fibrosis, but no other histologic features, is associated with long\u2010term outcomes of patients with nonalcoholic fatty liver disease","volume":"149","year":"2015","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jhep.2017.07.027","article-title":"Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy\u2010proven NAFLD","volume":"67","year":"2017","journal-title":"J Hepatol"},{"key":"hep31995-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1053\/j.gastro.2020.01.043","article-title":"Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta\u2010analysis","volume":"158","year":"2020","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1053\/j.gastro.2005.03.084","article-title":"Sampling variability of liver biopsy in nonalcoholic fatty liver disease","volume":"128","year":"2005","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/hep.26661","article-title":"Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep31995-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1053\/j.gastro.2016.05.051","article-title":"Comparison of gene expression patterns between mouse models of nonalcoholic fatty liver disease and liver tissues from patients","volume":"151","year":"2016","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"G462","DOI":"10.1152\/ajpgi.00358.2018","article-title":"Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal\u2010weight individuals","volume":"316","year":"2019","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep31995-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"12541","DOI":"10.1038\/s41598-019-48746-5","article-title":"Gene expression predicts histological severity and reveals distinct molecular profiles of nonalcoholic fatty liver disease","volume":"9","year":"2019","journal-title":"Sci Rep"},{"key":"hep31995-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s42255-019-0076-1","article-title":"Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution","volume":"1","year":"2019","journal-title":"Nat Metab"},{"key":"hep31995-bib-0012-20250824","article-title":"Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis","volume":"12","year":"2020","journal-title":"Sci Transl Med"},{"key":"hep31995-bib-0013-20250824","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","year":"2005","journal-title":"Hepatology"},{"key":"hep31995-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity","volume":"116","year":"1999","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0015-20250824","first-page":"E10417","article-title":"Molecular profiling of nonalcoholic fatty liver disease\u2010associated hepatocellular carcinoma using SB transposon mutagenesis","volume":"115","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep31995-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"106175","DOI":"10.1016\/j.cct.2020.106175","article-title":"The European NAFLD registry: a real\u2010world longitudinal cohort study of nonalcoholic fatty liver disease","volume":"98","year":"2020","journal-title":"Contemp Clin Trials"},{"key":"hep31995-bib-0017-20250824","article-title":"A subcellular map of the human proteome","volume":"356","year":"2017","journal-title":"Science"},{"key":"hep31995-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","article-title":"Mechanisms of fibrosis development in nonalcoholic steatohepatitis","volume":"158","year":"2020","journal-title":"Gastroenterology"},{"key":"hep31995-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41575-019-0160-8","article-title":"The effects of platelet accumulation in fatty liver disease","volume":"16","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep31995-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1038\/ncomms4083","article-title":"Genome\u2010scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non\u2010alcoholic fatty liver disease","volume":"5","year":"2014","journal-title":"Nat Commun"},{"key":"hep31995-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1002\/hep.23050","article-title":"Cytokeratin\u201018 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study","volume":"50","year":"2009","journal-title":"Hepatology"},{"key":"hep31995-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-7493-1_12","article-title":"Profiling tumor infiltrating immune cells with CIBERSORT","volume":"1711","year":"2018","journal-title":"Methods Mol Biol"},{"key":"hep31995-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"hep31995-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/liv.14776","article-title":"Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD","volume":"41","year":"2021","journal-title":"Liver Int"},{"key":"hep31995-bib-0025-20250824","article-title":"The thrombospondins","volume":"3","year":"2011","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"hep31995-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1083\/jcb.140.2.419","article-title":"Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis","volume":"140","year":"1998","journal-title":"J Cell Biol"},{"key":"hep31995-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of liver fibrosis and its regression","volume":"18","year":"2021","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep31995-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"G744","DOI":"10.1152\/ajpgi.00339.2018","article-title":"Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology","volume":"316","year":"2019","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep31995-bib-0029-20250824","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s00535-007-2014-3","article-title":"Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage","volume":"42","year":"2007","journal-title":"J Gastroenterol"},{"key":"hep31995-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1002\/hep.28860","article-title":"Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep31995-bib-0031-20250824","first-page":"109\u2010","article-title":"Laminin: loss\u2010of\u2010function studies","volume":"74","year":"2017","journal-title":"Cell Mol Life Sci"},{"key":"hep31995-bib-0032-20250824","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1002\/ar.23567","article-title":"Basement membrane type IV collagen and laminin: an overview of their biology and value as fibrosis biomarkers of liver disease","volume":"300","year":"2017","journal-title":"Anat Rec (Hoboken)"},{"key":"hep31995-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1210\/js.2018-00122","article-title":"Transcriptomic profiling of obesity\u2010related nonalcoholic steatohepatitis reveals a core set of fibrosis\u2010specific genes","volume":"2","year":"2018","journal-title":"J Endocr Soc"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31995","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31995","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31995","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:09:06Z","timestamp":1756076946000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,21]]},"references-count":33,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31995","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,21]]},"assertion":[{"value":"2021-01-07","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-09","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}