{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:20:38Z","timestamp":1790839238060,"version":"4.1.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T00:00:00Z","timestamp":1550102400000},"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":[[2019,8]]},"abstract":"<jats:p>Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low\u2010molecular\u2010weight metabolites by new high\u2010throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20\/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19\u20109 (CA 19\u20109) and alpha\u2010fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy\u2010proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14\u201015 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.<\/jats:p>","DOI":"10.1002\/hep.30319","type":"journal-article","created":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T14:07:29Z","timestamp":1539698849000},"page":"547-562","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":165,"title":["Serum Metabolites as Diagnostic Biomarkers for Cholangiocarcinoma, Hepatocellular Carcinoma, and Primary Sclerosing Cholangitis"],"prefix":"10.1097","volume":"70","author":[{"given":"Jesus M.","family":"Banales","sequence":"first","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU),San Sebastian,Spain"},{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"IKERBASQUE,Basque Foundation for Science,Bilbao,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"I\u00f1arrairaegui","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"Liver Unit,Cl\u00ednica Universidad de Navarra\u2010IDISNA,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ander","family":"Arbelaiz","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU),San Sebastian,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery,Medical University of Warsaw,Warsaw,Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Muntan\u00e9","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"Department of General Surgery \u201cVirgen del Roc\u00edo\u201d University Hospital\/IBiS\/CSIC\/University of Seville,Seville,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Mu\u00f1oz\u2010Bellvis","sequence":"additional","affiliation":[{"name":"Service of General and Gastrointestinal Surgery,University Hospital of Salamanca, Biomedical Research Institute of 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Metabolomics,Bizkaia Technology Park,Derio,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibon","family":"Mart\u00ednez\u2010Arranz","sequence":"additional","affiliation":[{"name":"OWL Metabolomics,Bizkaia Technology Park,Derio,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Lapitz","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU),San Sebastian,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvaro","family":"Santos\u2010Laso","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU),San Sebastian,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias A.","family":"Avila","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"Program of Hepatology, Center for Applied Medical Research (CIMA),University of Navarra\u2010IDISNA,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Mart\u00ednez\u2010Chantar","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"CIC bioGUNE,Bizkaia Technology Park,Derio,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Bujanda","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU),San Sebastian,Spain"},{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose J.G.","family":"Marin","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM),University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL),Salamanca,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sangro","sequence":"additional","affiliation":[{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute),Madrid,Spain"},{"name":"Liver Unit,Cl\u00ednica Universidad de 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