{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:06:56Z","timestamp":1791216416747,"version":"4.1.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":335,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>There is no clinically applicable biomarker for surveillance of hepatocellular carcinoma (HCC), because the sensitivity of serum alpha-fetoprotein (AFP) is too low for this purpose. Here, we determined the diagnostic performance of a panel of urinary metabolites of HCC patients from West Africa. Urine samples were collected from Nigerian and Gambian patients recruited on the case-control platform of the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) program. Urinary proton nuclear magnetic resonance (<jats:sup>1<\/jats:sup>H-NMR) spectroscopy was used to metabolically phenotype 290 subjects: 63 with HCC; 32 with cirrhosis (Cir); 107 with noncirrhotic liver disease (DC); and 88 normal control (NC) healthy volunteers. Urine samples from a further cohort of 463 subjects (141 HCC, 56 Cir, 178 DC, and 88 NC) were analyzed, the results of which validated the initial cohort. The urinary metabotype of patients with HCC was distinct from those with Cir, DC, and NC with areas under the receiver operating characteristic (AUROC) curves of 0.86 (0.78\u20130.94), 0.93 (0.89\u20130.97), and 0.89 (0.80\u20130.98) in the training set and 0.81 (0.73\u20130.89), 0.96 (0.94\u20130.99), and 0.90 (0.85\u20130.96), respectively, in the validation cohort. A urinary metabolite panel, comprising inosine, indole-3-acetate, galactose, and an N-acetylated amino acid (NAA), showed a high sensitivity (86.9% [75.8\u201394.2]) and specificity (90.3% [74.2\u201398.0]) in the discrimination of HCC from cirrhosis, a finding that was corroborated in a validation cohort (AUROC: urinary panel = 0.72; AFP = 0.58). Metabolites that were significantly increased in urine of HCC patients, and which correlated with clinical stage of HCC, were NAA, dimethylglycine, 1-methylnicotinamide, methionine, acetylcarnitine, 2-oxoglutarate, choline, and creatine. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: The urinary metabotyping of this West African cohort identified and validated a metabolite panel that diagnostically outperforms serum AFP. (Hepatology 2014;60:1291\u20131301)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.27264","type":"journal-article","created":{"date-parts":[[2014,6,13]],"date-time":"2014-06-13T08:14:19Z","timestamp":1402647259000},"page":"1291-1301","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":80,"title":["Discovery and validation of urinary metabotypes for the diagnosis of hepatocellular carcinoma in West Africans"],"prefix":"10.1097","volume":"60","author":[{"given":"Nimzing G.","family":"Ladep","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony C.","family":"Dona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M.E.","family":"Crossey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Lemoine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Okeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Shimakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Duguru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harr F.","family":"Njai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haddy K.S.","family":"Fye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makie","family":"Taal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Chetwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Kasstan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid A.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Garside","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisha","family":"Wijeyesekera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew V.","family":"Thillainayagam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund","family":"Banwat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Thursz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy K.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramou","family":"Njie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon D.","family":"Taylor-Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-22-20250207","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1002\/ijc.21731","article-title":"The global health burden of infectionassociated cancers in the year 2002.","volume":"118","author":"Parkin","year":"2006","journal-title":"Int J Cancer"},{"key":"R2-22-20250207","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3322\/canjclin.55.2.74","article-title":"Global cancer statistics, 2002.","volume":"55","author":"Parkin","year":"2005","journal-title":"CA Cancer J Clin"},{"key":"R3-22-20250207","first-page":"311","article-title":"World Gastroenterology Organisation Guideline. Hepatocellular carcinoma (HCC): a global perspective.","volume":"19","author":"Ferenci","year":"2010","journal-title":"J Gastrointestin Liver Dis"},{"key":"R4-22-20250207","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S0168-8278(02)00297-0","article-title":"Changing international trends in mortality rates for liver, biliary and pancreatic tumours.","volume":"37","author":"Khan","year":"2002","journal-title":"J Hepatol"},{"key":"R5-22-20250207","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1053\/j.gastro.2007.04.061","article-title":"Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.","volume":"132","author":"ElSerag","year":"2007","journal-title":"Gastroenterology"},{"key":"R6-22-20250207","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1053\/j.gastro.2003.10.065","article-title":"Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.","volume":"126","author":"ElSerag","year":"2004","journal-title":"Gastroenterology"},{"key":"R9-22-20250207","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1021\/pr070063h","article-title":"Metabonomic studies of human hepatocellular carcinoma using highresolution magicangle spinning 1H NMR spectroscopy in conjunction with multivariate data analysis.","volume":"6","author":"Yang","year":"2007","journal-title":"J Proteome Res"},{"key":"R10-22-20250207","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature11708","article-title":"Metabolic phenotyping in clinical and surgical environments.","volume":"491","author":"Nicholson","year":"2012","journal-title":"Nature"},{"key":"R11-22-20250207","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.aca.2011.02.038","article-title":"Fecal metabolome profiling of liver cirrhosis and hepatocellular carcinoma patients by ultra performance liquid chromatographymass spectrometry.","volume":"691","author":"Cao","year":"2011","journal-title":"Anal Chim Acta"},{"key":"R12-22-20250207","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1007\/s00216-011-5245-3","article-title":"Identification of serum biomarkers of hepatocarcinoma through liquid chromatographymass spectrometrybased metabonomic method.","volume":"401","author":"Chen","year":"2011","journal-title":"Anal Bioanal Chem"},{"key":"R13-22-20250207","first-page":"M110","article-title":"Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma.","volume":"10","author":"Chen","year":"2011","journal-title":"Mol Cell Proteomics"},{"key":"R14-22-20250207","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1039\/b820224a","article-title":"A metabonomic study of hepatitis Binduced liver cirrhosis and hepatocellular carcinoma by using RPLC and HILIC coupled with mass spectrometry.","volume":"5","author":"Yin","year":"2009","journal-title":"Mol Biosyst"},{"key":"R15-22-20250207","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00216-012-5782-4","article-title":"Serum metabolomics reveals the deregulation of fatty acids metabolism in hepatocellular carcinoma and chronic liver diseases.","volume":"403","author":"Zhou","year":"2012","journal-title":"Anal Bioanal Chem"},{"key":"R16-22-20250207","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.aca.2009.06.033","article-title":"Metabolomic profiling of human urine in hepatocellular carcinoma patients using gas chromatographymass spectrometry.","volume":"648","author":"Wu","year":"2009","journal-title":"Anal Chim Acta"},{"key":"R17-22-20250207","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1021\/pr300502v","article-title":"Analysis of urinary metabolic signatures of early hepatocellular carcinoma recurrence after surgical removal using gas chromatographymass spectrometry.","volume":"11","author":"Ye","year":"2012","journal-title":"J Proteome Res"},{"key":"R18-22-20250207","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cca.2012.12.024","article-title":"Urinary metabolic profiling identifies a key role for glycocholic acid in human liver cancer by ultraperformance liquidchromatography coupled with highdefinition mass spectrometry.","volume":"418","author":"Wang","year":"2013","journal-title":"Clin Chim Acta"},{"key":"R19-22-20250207","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1002\/hep.24199","article-title":"Management of hepatocellular carcinoma: an update.","volume":"53","author":"Bruix","year":"2011","journal-title":"Hepatology"},{"key":"R20-22-20250207","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1021\/pr901058t","article-title":"Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy in a Nigerian population.","volume":"9","author":"Shariff","year":"2010","journal-title":"J Proteome Res"},{"key":"R21-22-20250207","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1021\/pr101096f","article-title":"Urinary metabolic biomarkers of hepatocellular carcinoma in an egyptian population: a validation study.","volume":"10","author":"Shariff","year":"2011","journal-title":"J Proteome Res"},{"key":"R23-22-20250207","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1055\/s-2007-1007122","article-title":"Prognosis of hepatocellular carcinoma: the BCLC staging classification.","volume":"19","author":"Llovet","year":"1999","journal-title":"Semin Liver Dis"},{"key":"R24-22-20250207","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1038\/nprot.2007.376","article-title":"Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts.","volume":"2","author":"Beckonert","year":"2007","journal-title":"Nat Protoc"},{"key":"R25-22-20250207","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.taap.2004.06.031","article-title":"Comparative metabonomics of differential hydrazine toxicity in the rat and mouse.","volume":"204","author":"Bollard","year":"2005","journal-title":"Toxicol Appl Pharmacol"},{"key":"R26-22-20250207","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1021\/ac00101a004","article-title":"750 MHz 1H and 1H13C NMR spectroscopy of human blood plasma.","volume":"67","author":"Nicholson","year":"1995","journal-title":"Anal Chem"},{"key":"R27-22-20250207","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1021\/ac048630x","article-title":"Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1H NMR data sets.","volume":"77","author":"Cloarec","year":"2005","journal-title":"Anal Chem"},{"key":"R28-22-20250207","first-page":"1","article-title":"A list of candidate cancer biomarkers for targeted proteomics.","volume":"1","author":"Polanski","year":"2007","journal-title":"Biomark Insights"},{"key":"R29-22-20250207","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.7314\/APJCP.2012.13.9.4695","article-title":"Urinary concentrations of human epidydimis secretory protein 4 (He4) in the diagnosis of ovarian cancer: a casecontrol study.","volume":"13","author":"Macuks","year":"2012","journal-title":"Asian Pac J Cancer Prev"},{"key":"R30-22-20250207","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1746-1596-8-45","article-title":"The endothelial lipase protein is promising urinary biomarker for diagnosis of gastric cancer.","volume":"8","author":"Dong","year":"2013","journal-title":"Diagn Pathol"},{"key":"R31-22-20250207","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1021\/pr901058t","article-title":"Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy in a Nigerian population.","volume":"9","author":"Shariff","year":"2010","journal-title":"J Proteome Res"},{"key":"R32-22-20250207","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.4161\/cc.22137","article-title":"Ketone body utilization drives tumor growth and metastasis.","volume":"11","author":"MartinezOutschoorn","year":"2012","journal-title":"Cell Cycle"},{"key":"R33-22-20250207","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/nrc3162","article-title":"Choline metabolism in malignant transformation.","volume":"11","author":"Glunde","year":"2011","journal-title":"Nat Rev Cancer"},{"key":"R34-22-20250207","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/(SICI)1099-1492(1998110)11:7<354::AID-NBM515>3.0.CO;2-N","article-title":"Metabolic changes underlying 31P MR spectral alterations in human hepatic tumours.","volume":"11","author":"Bell","year":"1998","journal-title":"NMR Biomed"},{"key":"R35-22-20250207","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ccr.2012.02.014","article-title":"Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.","volume":"21","author":"Ward","year":"2012","journal-title":"Cancer Cell"},{"key":"R36-22-20250207","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s10555-011-9334-8","article-title":"The geneticmetabolic transformation concept of carcinogenesis.","volume":"31","author":"Costello","year":"2012","journal-title":"Cancer Metastasis Rev"},{"key":"R37-22-20250207","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1007\/s12603-009-0204-9","article-title":"Sarcopenia: clinical evaluation, biological markers and other evaluation tools.","volume":"13","author":"Pahor","year":"2009","journal-title":"J Nutr Health Aging"},{"key":"R38-22-20250207","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1021\/pr2005764","article-title":"Stability and robustness of human metabolic phenotypes in response to sequential food challenges.","volume":"11","author":"Heinzmann","year":"2012","journal-title":"J Proteome Res"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27264","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27264","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201410000-00022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T16:48:17Z","timestamp":1738946897000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201410000-00022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2014]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.27264","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2014,10]]}}}