{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T06:21:38Z","timestamp":1781590898116,"version":"3.54.5"},"reference-count":79,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["24K09745"],"award-info":[{"award-number":["24K09745"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Imaging tests, tumor marker (TM) screening, and biochemical tests provide a definitive diagnosis of hepatocellular carcinoma (HCC). However, some patients with HCC may present TM-negative results, warranting a need for developing more sensitive and accurate screening biomarkers. Various diseases exhibit increased blood levels of bile acids, biosynthesized from cholesterol in the liver, and they have been associated with HCC. Herein, we analyzed plasma bile acids using liquid chromatography\/tandem mass spectrometry and integrated them with conventional biomarkers to develop a diagnostic screening model for HCC. Plasma samples were obtained from patients diagnosed with chronic hepatitis, hepatic cirrhosis (HC), and HCC. A QTRAP 6500 mass spectrometer and a Nexera liquid chromatograph with a YMC-Triart C18 analytical column were used. The mobile phase A was a 20 mmol\/L ammonium formate solution, and mobile phase B was a methanol\/acetonitrile mixture (1:1, v\/v) with 20 mmol\/L ammonium formate. After determining the concentrations of 32 bile acids, statistical analysis and diagnostic screening model development were performed. Plasma concentrations of bile acids differed between sample groups, with significant differences observed between patients with HC and HCC. By integrating bile acid results with conventional biochemical tests, a potential diagnostic screening model for HCC was successfully developed. Future studies should increase the sample size and analyze the data in detail to verify the diagnostic efficacy of the model.<\/jats:p>","DOI":"10.3390\/metabo14090513","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T08:54:13Z","timestamp":1727168053000},"page":"513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Liquid Chromatography\/Tandem Mass Spectrometry-Based Simultaneous Analysis of 32 Bile Acids in Plasma and Conventional Biomarker-Integrated Diagnostic Screening Model Development for Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"14","author":[{"given":"Minami","family":"Yamauchi","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6723-0298","authenticated-orcid":false,"given":"Masamitsu","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"},{"name":"Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"},{"name":"Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8807-2417","authenticated-orcid":false,"given":"Toshihiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8979-2408","authenticated-orcid":false,"given":"Yu","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2333-2847","authenticated-orcid":false,"given":"Masaki","family":"Kumondai","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mio","family":"Tsuruoka","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1171-7835","authenticated-orcid":false,"given":"Jun","family":"Inoue","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7184-7282","authenticated-orcid":false,"given":"Atsushi","family":"Masamune","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nariyasu","family":"Mano","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"},{"name":"Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10573","DOI":"10.3748\/wjg.v21.i37.10573","article-title":"Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma","volume":"21","author":"Tsuchiya","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(22)01200-4","article-title":"Hepatocellular Carcinoma","volume":"400","author":"Vogel","year":"2022","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/hepr.13953","article-title":"Report of the 23rd Nationwide Follow-up Survey of Primary Liver Cancer in Japan (2014\u20132015)","volume":"53","author":"Iijima","year":"2023","journal-title":"Hepatol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000514174","article-title":"Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update","volume":"10","author":"Kudo","year":"2021","journal-title":"Liver Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ejrad.2018.01.025","article-title":"Diagnosis and Staging of Hepatocellular Carcinoma (HCC): Current Guidelines","volume":"101","author":"Ayuso","year":"2018","journal-title":"Eur. J. Radiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1148\/radiol.14132362","article-title":"CT and MR Imaging Diagnosis and Staging of Hepatocellular Carcinoma: Part II. Extracellular Agents, Hepatobiliary Agents, and Ancillary Imaging Features","volume":"273","author":"Choi","year":"2014","journal-title":"Radiology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/hep.29487","article-title":"Imaging for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis","volume":"67","author":"Roberts","year":"2018","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.hbpd.2022.08.004","article-title":"The Latest Research Progress on Minimally Invasive Treatments for Hepatocellular Carcinoma","volume":"22","author":"Zou","year":"2023","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1053\/j.gastro.2018.01.064","article-title":"Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis: A Meta-Analysis","volume":"154","author":"Tzartzeva","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1007\/s00261-021-03059-y","article-title":"Contrast-Enhanced Ultrasound (CEUS) in HCC Diagnosis and Assessment of Tumor Response to Locoregional Therapies","volume":"46","author":"Eisenbrey","year":"2021","journal-title":"Abdom. Radiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.3748\/wjg.v24.i22.2348","article-title":"Noninvasive Imaging of Hepatocellular Carcinoma: From Diagnosis to Prognosis","volume":"24","author":"Jiang","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s12253-019-00585-5","article-title":"Current Status and Perspective Biomarkers in AFP Negative HCC: Towards Screening for and Diagnosing Hepatocellular Carcinoma at an Earlier Stage","volume":"26","author":"Luo","year":"2020","journal-title":"Pathol. Oncol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"536","DOI":"10.7150\/ijbs.64537","article-title":"The Landscape of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We?","volume":"18","author":"Hu","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3748\/wjg.v28.i2.216","article-title":"Update on the Applications and Limitations of Alpha-Fetoprotein for Hepatocellular Carcinoma","volume":"28","author":"Hanif","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8392","DOI":"10.1038\/s41467-023-44255-2","article-title":"Proteomics-Driven Noninvasive Screening of Circulating Serum Protein Panels for the Early Diagnosis of Hepatocellular Carcinoma","volume":"14","author":"Xing","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e5811","DOI":"10.1097\/MD.0000000000005811","article-title":"Usefulness of AFP, AFP-L3, and PIVKA-II, and Their Combinations in Diagnosing Hepatocellular Carcinoma","volume":"96","author":"Park","year":"2017","journal-title":"Medicine"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Feng, H., Li, B., Li, Z., Wei, Q., and Ren, L. (2021). PIVKA-II Serves as a Potential Biomarker That Complements AFP for the Diagnosis of Hepatocellular Carcinoma. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08138-3"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3350\/cmh.2022.0212","article-title":"Utility of Combining PIVKA-II and AFP in the Surveillance and Monitoring of Hepatocellular Carcinoma in the Asia-Pacific Region","volume":"29","author":"Kim","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jare.2012.10.004","article-title":"Impact of PIVKA-II in Diagnosis of Hepatocellular Carcinoma","volume":"4","author":"Zakhary","year":"2013","journal-title":"J. Adv. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E27673","DOI":"10.1097\/MD.0000000000027673","article-title":"AFP-L3 for the Diagnosis of Early Hepatocellular Carcinoma: A Meta-Analysis","volume":"100","author":"Zhou","year":"2021","journal-title":"Medicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.jhep.2023.08.020","article-title":"AFP-L3 and DCP Strongly Predict Early Hepatocellular Carcinoma Recurrence after Liver Transplantation","volume":"79","author":"Norman","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1111\/hepr.12277","article-title":"Triple Positive Tumor Markers Predict Recurrence and Survival in Early Stage Hepatocellular Carcinoma","volume":"44","author":"Nakagawa","year":"2014","journal-title":"Hepatol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s11605-017-3394-1","article-title":"Double- and Triple-Positive Tumor Markers Predict Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh Class A","volume":"21","author":"Ryu","year":"2017","journal-title":"J. Gastrointest. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/hepr.13892","article-title":"Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 Version (5th JSH-HCC Guidelines)","volume":"53","author":"Hasegawa","year":"2023","journal-title":"Hepatol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"264","DOI":"10.3350\/cmh.2019.1001","article-title":"Hepatocellular Carcinoma Surveillance in the 21st Century: Saving Lives or Causing Harm?","volume":"25","author":"Hanouneh","year":"2019","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1194\/jlr.R900010-JLR200","article-title":"Bile Acids: Regulation of Synthesis","volume":"50","author":"Chiang","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chiang, J.Y.L. (1998). Regulation of Bile Acid Synthesis. Front. Biosci., 3.","DOI":"10.2741\/A273"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev.biochem.72.121801.161712","article-title":"The Enzymes, Regulation, and Genetics of Bile Acid Synthesis","volume":"72","author":"Russell","year":"2003","journal-title":"Annu. Rev. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jhep.2003.11.006","article-title":"Regulation of Bile Acid Synthesis: Pathways, Nuclear Receptors, and Mechanisms","volume":"40","author":"Chiang","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mce.2012.05.004","article-title":"FXR Signaling in the Enterohepatic System","volume":"368","author":"Matsubara","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1007\/s11695-019-03790-y","article-title":"Changes in Enterohepatic Circulation after Duodenal\u2013Jejunal Bypass and Reabsorption of Bile Acids in the Bilio-Pancreatic Limb","volume":"29","author":"Ise","year":"2019","journal-title":"Obes. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1146\/annurev-nutr-082018-124344","article-title":"Bile Acids as Metabolic Regulators and Nutrient Sensors","volume":"39","author":"Chiang","year":"2019","journal-title":"Annu. Rev. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1152\/physrev.00010.2008","article-title":"Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation","volume":"89","author":"Lefebvre","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Shulpekova, Y., Zharkova, M., Tkachenko, P., Tikhonov, I., Stepanov, A., Synitsyna, A., Izotov, A., Butkova, T., Shulpekova, N., and Lapina, N. (2022). The Role of Bile Acids in the Human Body and in the Development of Diseases. Molecules, 27.","DOI":"10.3390\/molecules27113401"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"(1987). Clayton, P.T.; Lake, B.D.; Hall, N.A.; Shortland, D.B.; Carruthers, R.A.; Lawson, A.M. Plasma Bile Acids in Patients with Peroxisomal Dysfunction Syndromes: Analysis by Capillary Gas Chromatography\u2014Mass Spectrometry. Eur. J. Pediatr., 146, 166\u2013173.","DOI":"10.1007\/BF02343226"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1186\/s13023-021-01887-1","article-title":"Maternal Bile Acid Profile and Subtype Analysis of Intrahepatic Cholestasis of Pregnancy","volume":"16","author":"Shao","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.jchromb.2013.02.003","article-title":"Determination of 3\u03b2-Hydroxy-\u03945-Bile Acids and Related Compounds in Biological Fluids of Patients with Cholestasis by Liquid Chromatography-Tandem Mass Spectrometry","volume":"923\u2013924","author":"Murai","year":"2013","journal-title":"J. Chromatogr. B Analyt. Technol. Biomed. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/BF01797919","article-title":"Inborn Errors of Bile Acid Metabolism","volume":"14","author":"Clayton","year":"1991","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jhep.2017.11.014","article-title":"Lipotoxicity and the Gut-Liver Axis in NASH Pathogenesis","volume":"68","author":"Marra","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1002\/ijc.30219","article-title":"Dysregulated Hepatic Bile Acids Collaboratively Promote Liver Carcinogenesis","volume":"139","author":"Xie","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"154457","DOI":"10.1016\/j.metabol.2020.154457","article-title":"Bile Acids Profile, Histopathological Indices and Genetic Variants for Non-Alcoholic Fatty Liver Disease Progression","volume":"116","author":"Nimer","year":"2021","journal-title":"Metabolism"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/hep.29359","article-title":"The Presence and Severity of Nonalcoholic Steatohepatitis Is Associated with Specific Changes in Circulating Bile Acids","volume":"67","author":"Puri","year":"2018","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"114664","DOI":"10.1016\/j.taap.2019.114664","article-title":"Altered Bile Acid Composition and Disposition in a Mouse Model of Non-Alcoholic Steatohepatitis","volume":"379","author":"Suga","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Shoji, S., Maekawa, M., Ogura, J., Sato, T., and Mano, N. (2022). Identification Cholesterol Metabolites Altered before the Onset of Nonalcoholic Steatohepatitis by Targeted Metabolomics. Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids, 1867.","DOI":"10.1016\/j.bbalip.2022.159135"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.taap.2013.01.022","article-title":"Decreased Hepatotoxic Bile Acid Composition and Altered Synthesis in Progressive Human Nonalcoholic Fatty Liver Disease","volume":"268","author":"Lake","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.4254\/wjh.v14.i9.1730","article-title":"Bile Acids as Drivers and Biomarkers of Hepatocellular Carcinoma","volume":"14","author":"Colosimo","year":"2022","journal-title":"World J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Shen, E.Y.L., Mei Ran Abellona, U., Cox, I.J., and Taylor-Robinson, S.D. (2023). The Role of Mass Spectrometry in Hepatocellular Carcinoma Biomarker Discovery. Metabolites, 13.","DOI":"10.3390\/metabo13101059"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Goicoechea, L., Conde de la Rosa, L., Torres, S., Garc\u00eda-Ruiz, C., and Fern\u00e1ndez-Checa, J.C. (2023). Mitochondrial Cholesterol: Metabolism and Impact on Redox Biology and Disease. Redox Biol., 61.","DOI":"10.1016\/j.redox.2023.102643"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/ijc.33236","article-title":"Metabolic Perturbations Prior to Hepatocellular Carcinoma Diagnosis: Findings from a Prospective Observational Cohort Study","volume":"148","author":"Stepien","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1002\/ijc.33885","article-title":"Prediagnostic Alterations in Circulating Bile Acid Profiles in the Development of Hepatocellular Carcinoma","volume":"150","author":"Stepien","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Khalil, A., ElSheashaey, A., Abdelsameea, E., Obada, M., Bayomy, F.F.M., and El-Said, H. (2022). Value of Bile Acids in Diagnosing Hepatitis C Virus-Induced Liver Cirrhosis and Hepatocellular Carcinoma. Br. J. Biomed. Sci., 79.","DOI":"10.3389\/bjbs.2021.10191"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.aca.2012.07.013","article-title":"Utilization of Metabolomics to Identify Serum Biomarkers for Hepatocellular Carcinoma in Patients with Liver Cirrhosis","volume":"743","author":"Ressom","year":"2012","journal-title":"Anal. Chim. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.cca.2018.10.039","article-title":"Tissue and Serum Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma","volume":"488","author":"Han","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.steroids.2013.11.016","article-title":"Tandem Mass Spectrometric Characterization of Bile Acids and Steroid Conjugates Based on Low-Energy Collision-Induced Dissociation","volume":"80","author":"Maekawa","year":"2014","journal-title":"Steroids"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.steroids.2009.04.007","article-title":"Chemical Synthesis of 3beta-Sulfooxy-7beta-Hydroxy-24-nor-5-Cholenoic Acid: An Internal Standard for Mass Spectrometric Analysis of the Abnormal Delta5-Bile Acids Occurring in Niemann-Pick Disease","volume":"74","author":"Kakiyama","year":"2009","journal-title":"Steroids"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Steiner, C., Othman, A., Saely, C.H., Rein, P., Drexel, H., von Eckardstein, A., and Rentsch, K.M. (2011). Bile Acid Metabolites in Serum: Intraindividual Variation and Associations with Coronary Heart Disease, Metabolic Syndrome and Diabetes Mellitus. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025006"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Danese, E., Negrini, D., Pucci, M., De Nitto, S., Ambrogi, D., Donzelli, S., Lievens, P.M.J., Salvagno, G.L., and Lippi, G. (2020). Bile Acids Quantification by Liquid Chromatography-Tandem Mass Spectrometry: Method Validation, Reference Range, and Interference Study. Diagnostics, 10.","DOI":"10.3390\/diagnostics10070462"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Yin, P., Wan, D., Zhao, C., Chen, J., Zhao, X., Wang, W., Lu, X., Yang, S., Gu, J., and Xu, G. (2009). A Metabonomic Study of Hepatitis B-Induced Liver Cirrhosis and Hepatocellular Carcinoma by Using RP-LC and HILIC Coupled with Mass Spectrometry. Mol. Biosyst., 5.","DOI":"10.1039\/b820224a"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"817","DOI":"10.3349\/ymj.2006.47.6.817","article-title":"Bile Acid Analysis in Biliary Tract Cancer","volume":"47","author":"Park","year":"2006","journal-title":"Yonsei Med. J."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Alonso-Pe\u00f1a, M., Espinosa-Escudero, R., Hermanns, H.M., Briz, O., Herranz, J.M., Garcia-Ruiz, C., Fernandez-Checa, J.C., Juamperez, J., Avila, M., and Argemi, J. (2022). Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation. Cells, 11.","DOI":"10.3390\/cells11243983"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Ge, X., Huang, S., Ren, C., and Zhao, L. (2023). Taurocholic Acid and Glycocholic Acid Inhibit Inflammation and Activate Farnesoid X Receptor Expression in LPS-Stimulated Zebrafish and Macrophages. Molecules, 28.","DOI":"10.3390\/molecules28052005"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1023\/A:1026446008712","article-title":"Apoptosis Induced in Rat Hepatocytes by in Vivo Exposure to Taurochenodeoxycholate","volume":"29","author":"Chieco","year":"1997","journal-title":"Histochem. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5277","DOI":"10.1039\/D3FO00770G","article-title":"Taurochenodeoxycholic Acid Inhibits Intestinal Epithelial Cell Proliferation and Induces Apoptosis Independent of the Farnesoid X Receptor","volume":"14","author":"Liu","year":"2023","journal-title":"Food Funct."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"10899","DOI":"10.1002\/jcp.27905","article-title":"Bile Salt (Glycochenodeoxycholate Acid) Induces Cell Survival and Chemoresistance in Hepatocellular Carcinoma","volume":"234","author":"Wang","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jhep.2022.08.036","article-title":"Blood-Based Biomarkers for Hepatocellular Carcinoma Screening: Approaching the End of the Ultrasound Era?","volume":"78","author":"Parikh","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3944","DOI":"10.1158\/1078-0432.CCR-12-3363","article-title":"Evaluation of Midkine as a Diagnostic Serum Biomarker in Hepatocellular Carcinoma","volume":"19","author":"Zhu","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/hep.24703","article-title":"Identification of Osteopontin as a Novel Marker for Early Hepatocellular Carcinoma","volume":"55","author":"Shang","year":"2012","journal-title":"Hepatology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.clinre.2014.06.008","article-title":"Comparison Osteopontin vs. AFP for the Diagnosis of HCC: A Meta-Analysis","volume":"38","author":"Wan","year":"2014","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8925","DOI":"10.2147\/OTT.S186230","article-title":"Osteopontin versus Alpha-Fetoprotein as a Diagnostic Marker for Hepatocellular Carcinoma: A Meta-Analysis","volume":"11","author":"Sun","year":"2018","journal-title":"Onco Targets Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4867","DOI":"10.1021\/acs.analchem.0c04756","article-title":"High-Speed Screening of Lipoprotein Components Using Online Miniaturized Asymmetrical Flow Field-Flow Fractionation and Electrospray Ionization Tandem Mass Spectrometry: Application to Hepatocellular Carcinoma Plasma Samples","volume":"93","author":"Kim","year":"2021","journal-title":"Anal. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Buechler, C., and Aslanidis, C. (2020). Role of Lipids in Pathophysiology, Diagnosis and Therapy of Hepatocellular Carcinoma. Biochim. Biophys. Acta Mol. Cell. Biol. Lipids, 1865.","DOI":"10.1016\/j.bbalip.2020.158658"},{"key":"ref_73","first-page":"60","article-title":"High Cholinesterase Predicts Tolerance to Sorafenib Treatment and Improved Prognosis in Patients with Transarterial Chemoembolization Refractory Intermediate Stage Hepatocellular Carcinoma","volume":"12","author":"Takaki","year":"2020","journal-title":"Mol. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"999","DOI":"10.3748\/wjg.v30.i9.999","article-title":"Role of Albumin-Bilirubin Score in Non-Malignant Liver Disease","volume":"30","author":"Xu","year":"2024","journal-title":"World J. Gastroenterol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Tian, Y.B., Niu, H., Xu, F., Shang-Guan, P.W., and Song, W.W. (2024). ALBI Score Combined with FIB-4 Index to Predict Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-58205-5"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/260804a0","article-title":"\u03b1 Foetoprotein and Serum Albumin Show Sequence Homology","volume":"260","author":"Ruoslathi","year":"1976","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/apt.17374","article-title":"Improved Prediction of 10-Year Risk of Severe Liver Disease in the General Population Using Commonly Available Biomarkers","volume":"57","author":"Yan","year":"2023","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/liv.12455","article-title":"Circulating Gamma-Glutamyltransferase Fractions in Cirrhosis","volume":"34","author":"Elawdi","year":"2014","journal-title":"Liver Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1136\/gutjnl-2015-309260","article-title":"The Gamma-Glutamyl Transpeptidase to Platelet Ratio (GPR) Predicts Significant Liver Fibrosis and Cirrhosis in Patients with Chronic HBV Infection in West Africa","volume":"65","author":"Lemoine","year":"2016","journal-title":"Gut"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/14\/9\/513\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:00:36Z","timestamp":1760112036000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/14\/9\/513"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":79,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["metabo14090513"],"URL":"https:\/\/doi.org\/10.3390\/metabo14090513","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,23]]}}}