{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:53:40Z","timestamp":1768319620828,"version":"3.49.0"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Although total 25-hydroxyvitamin D (25(OH)D) measurements may not accurately reflect functional vitamin D status, vitamin D deficiency is common in hepatocellular carcinoma (HCC). The contribution of altered vitamin D-binding protein (VDBP) and albumin to impaired bioavailability is poorly characterized in liver cancer. Methods: We measured total, free, and bioavailable 25(OH)D, VDBP, and albumin in 46 HCC patients and 87 healthy controls during winter and summer. Correlations with Child\u2013Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, and disease aetiology were evaluated. Results: HCC patients exhibited significantly lower VDBP (177.3 \u00b1 237.0 vs. 239.9 \u00b1 141.9 mg\/L, p &lt; 0.001) and albumin (35.9 \u00b1 5.4 vs. 48.0 \u00b1 3.9 g\/L, p &lt; 0.001) compared to winter controls. Total 25(OH)D was lower in HCC (39.3 \u00b1 22.1 nmol\/L) versus summer controls (75.0 \u00b1 22.8 nmol\/L, p &lt; 0.001) but comparable to winter controls (p = 0.061). HCC patients lacked seasonal variation in vitamin D fractions, unlike the controls. VDBP negatively correlated with free (\u03c1 = \u22120.606, p &lt; 0.001) and bioavailable 25(OH)D (\u03c1 = \u22120.541, p &lt; 0.001). Child\u2013Pugh score correlated positively with BCLC stage (\u03c1 = 0.378, p = 0.012) and inversely with albumin (\u03c1 = \u22120.565, p &lt; 0.001). Conclusions: Free and bioavailable vitamin D are profoundly compromised in HCC, reflecting impaired hepatic synthetic function and systemic inflammation. These fractions may serve as novel metabolic biomarkers superior to total 25(OH)D for assessing vitamin D deficiency and guiding individualized supplementation strategies in patients with liver cancer.<\/jats:p>","DOI":"10.3390\/molecules31020273","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T10:13:51Z","timestamp":1768299231000},"page":"273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disrupted Vitamin D Metabolism in Hepatocellular Carcinoma: Free and Bioavailable 25(OH)D as Novel Biomarkers of Hepatic Reserve and Clinical Risk"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1839-2415","authenticated-orcid":false,"given":"Jo\u0161ko","family":"Osredkar","sequence":"first","affiliation":[{"name":"Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, A\u0161ker\u010deva 7, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8044-3527","authenticated-orcid":false,"given":"Matej","family":"Rakusa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes and Metabolic Disease, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6748-7082","authenticated-orcid":false,"given":"Ale\u0161","family":"Jerin","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, A\u0161ker\u010deva 7, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borut","family":"\u0160tabuc","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"},{"name":"Department of Gastroenterology, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Zaplotnik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"},{"name":"Department of Gastroenterology, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sa\u0161a","family":"\u0160tupar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"},{"name":"Department of Gastroenterology, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3686-0411","authenticated-orcid":false,"given":"Darko","family":"Siuka","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"},{"name":"Department of Gastroenterology, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nrc3691","article-title":"The role of vitamin D in reducing cancer risk and progression","volume":"14","author":"Feldman","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/nrc2196","article-title":"Vitamin D signalling pathways in cancer: Potential for anticancer therapeutics","volume":"7","author":"Deeb","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","unstructured":"Feingold, K.R., Adler, R.A., Ahmed, S.F., Anawalt, B., Blackman, M.R., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., and Dungan, K. (2025). Vitamin D: Production, metabolism, and mechanisms of action. Endotext, MDText.com."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dallavalasa, S., Tulimilli, S.V., Bettada, V.G., Karnik, M., Uthaiah, C.A., Anantharaju, P.G., Nataraj, S.M., Ramashetty, R., Sukocheva, O.A., and Tse, E. (2024). Vitaminqw D in Cancer Prevention and Treatment: A Review of Epidemiological, Preclinical, and Cellular Studies. Cancers, 16.","DOI":"10.3390\/cancers16183211"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Adelani, I.B., Rotimi, O.A., Maduagwu, E.N., and Rotimi, S.O. (2021). Vitamin D: Possible Therapeutic Roles in Hepatocellular Carcinoma. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.642653"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3325\/cmj.2022.63.187","article-title":"Vitamin D in liver cancer: Novel insights and future perspectives","volume":"63","author":"Kelava","year":"2022","journal-title":"Croat. Med. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jsbmb.2015.06.008","article-title":"Hepatocellular carcinoma cells express 25OHD-1-hydroxylase and are able to convert 25OHD to 1,25OH2D, leading to the 25OHD-induced growth inhibition","volume":"154","author":"Chiang","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jhep.2013.03.024","article-title":"Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease","volume":"59","author":"Ouziel","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01635581.2020.1797127","article-title":"Serum Vitamin D Levels and Risk of Liver Cancer: A Systematic Review and Dose-Response Meta-Analysis of Cohort Studies","volume":"73","author":"Zhang","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.chembiol.2013.12.016","article-title":"Vitamin D metabolism, mechanism of action, and clinical applications","volume":"21","author":"Bikle","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1002\/hep.25930","article-title":"Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: Relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus","volume":"56","author":"Barchetta","year":"2012","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.jsbmb.2017.01.007","article-title":"Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status?","volume":"173","author":"Bikle","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1210\/jc.2018-00295","article-title":"Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations","volume":"103","author":"Schwartz","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","first-page":"112315","article-title":"Beyond bones: Revisiting the role of vitamin D in chronic liver disease","volume":"17","author":"Tejeda","year":"2025","journal-title":"World J. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pop, T.L., S\u00eerbe, C., Ben\u0163a, G., Mititelu, A., and Grama, A. (2022). The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810705"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/cei.13316","article-title":"IL-17 and TNF-\u03b1 co-operation contributes to the proinflammatory response of hepatic stellate cells","volume":"198","author":"Beringer","year":"2019","journal-title":"Clin. Exp. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/hep.31013","article-title":"Serum Bioavailable, Rather Than Total, 25-hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival","volume":"72","author":"Fang","year":"2020","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1111\/apt.12731","article-title":"Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma\u2014A prospective cohort study","volume":"39","author":"Finkelmeier","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1530\/EJE-15-1089","article-title":"Effects of vitamin D binding protein phenotypes and vitamin D supplementation on serum total 25(OH)D and directly measured free 25(OH)D","volume":"174","author":"Sollid","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bikle, D.D., and Schwartz, J. (2019). Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00317"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17562848251338669","DOI":"10.1177\/17562848251338669","article-title":"Nonlinear associations of serum vitamin D levels with advanced liver disease and mortality: A US Cohort Study","volume":"18","author":"Tseng","year":"2025","journal-title":"Therap. Adv. Gastroenterol."},{"key":"ref_22","first-page":"e85075","article-title":"Vitamin D receptor FOK I Polymorphism and Risk of Hepatocellular Carcinoma in HBV-Infected Patients","volume":"19","author":"Rao","year":"2019","journal-title":"Hepat. Mon."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1056\/NEJMoa1306357","article-title":"Vitamin D-binding protein and vitamin D status of black Americans and white Americans","volume":"369","author":"Powe","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"981581","DOI":"10.1155\/2014\/981581","article-title":"Vitamin D Binding Protein Impact on 25-Hydroxyvitamin D Levels under Different Physiologic and Pathologic Conditions","volume":"2014","author":"Yousefzadeh","year":"2014","journal-title":"Int. J. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1210\/jc.2008-1454","article-title":"Nonclassical actions of vitamin D","volume":"94","author":"Bikle","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1111\/liv.12819","article-title":"Total 25 (OH) vitamin D, free 25 (OH) vitamin D and markers of bone turnover in cirrhotics with and without synthetic dysfunction","volume":"35","author":"Lai","year":"2015","journal-title":"Liver Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhu, A., Kuznia, S., Boakye, D., Sch\u00f6ttker, B., and Brenner, H. (2022). Vitamin D-Binding Protein, Bioavailable, and Free 25(OH)D, and Mortality: A Systematic Review and Meta-Analysis. Nutrients, 14.","DOI":"10.3390\/nu14193894"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gaksch, M., Jorde, R., Grimnes, G., Joakimsen, R., Schirmer, H., Wilsgaard, T., Mathiesen, E.B., Nj\u00f8lstad, I., L\u00f8chen, M.L., and M\u00e4rz, W. (2017). Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170791"},{"key":"ref_29","first-page":"105","article-title":"Effects of vitamin D level on survival in patients with hepatocellular carcinoma","volume":"1","author":"Bilgen","year":"2020","journal-title":"Hepatol. Forum"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1210\/jcem.84.10.6079","article-title":"A critical evaluation of simple methods for the estimation of free testosterone in serum","volume":"84","author":"Vermeulen","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.2215\/CJN.01160308","article-title":"Vitamin D in health and disease","volume":"3","author":"Heaney","year":"2008","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJM199908053410603","article-title":"Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis","volume":"341","author":"Sort","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1056\/NEJMra035021","article-title":"Management of cirrhosis and ascites","volume":"350","author":"Arroyo","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_34","first-page":"297","article-title":"Vitamin D deficiency in patients with liver cirrhosis","volume":"29","author":"Konstantakis","year":"2016","journal-title":"Ann. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1111\/bph.15424","article-title":"Vitamin D regulation of energy metabolism in cancer","volume":"179","author":"Sheeley","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1080\/00365521.2021.1873412","article-title":"Low serum vitamin D level associated with incident advanced liver disease in the general population\u2014A prospective study","volume":"56","author":"Jula","year":"2021","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Gupta, A., Zorzi, J., Ho, W.J., Baretti, M., Azad, N.S., Griffith, P., Dao, D., Kim, A., Philosophe, B., and Georgiades, C. (2023). Relationship of Hepatocellular Carcinoma Stage and Hepatic Function to Health-Related Quality of Life: A Single Center Analysis. Healthcare, 11.","DOI":"10.3390\/healthcare11182571"},{"key":"ref_38","unstructured":"(2025, August 31). Available online: https:\/\/www.cancerresearchuk.org\/about-cancer\/liver-cancer\/stages\/bclc-staging-system-child-pugh-system."},{"key":"ref_39","unstructured":"National Comprehensive Cancer Network (2024). NCCN Clinical Practice Guidelines in Oncology. Hepatocellular Carcinoma, National Comprehensive Cancer Network. Available online: https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=1&id=1514."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1210\/jc.2011-0385","article-title":"Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society Clinical Practice Guideline","volume":"96","author":"Holick","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","unstructured":"(2020). LIAISON\u00ae 25 OH Vitamin D TOTAL Assay, DiaSorin SpA."},{"key":"ref_42","unstructured":"R&D Systems (2022). Human VDBP\/GC-Globulin Quantikine ELISA Kit, R&D Systems, Inc."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Siuka, D., Rakusa, M., Vodenik, A., Vodnik, L., \u0160tabuc, B., \u0160tubljar, D., Drobne, D., Jerin, A., Mateli\u010d, H., and Osredkar, J. (2025). Free and Bioavailable Vitamin D Are Correlated with Disease Severity in Acute Pancreatitis: A Single-Center, Prospective Study. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202505.1905.v1"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/2\/273\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T10:14:09Z","timestamp":1768299249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/2\/273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["molecules31020273"],"URL":"https:\/\/doi.org\/10.3390\/molecules31020273","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,13]]}}}