Authors :
Diya Yohannan; Gowri Sudha; Meenu Maria Sunny; Nalin Aaditya Dharmalingam; Adithya Krishna Kezhuppilly Ramakrishnan; Subrahmaniyan Sujitha Lekshmi
Volume/Issue :
Volume 10 - 2025, Issue 10 - October
Google Scholar :
https://tinyurl.com/3h7v5h23
Scribd :
https://tinyurl.com/yxexcy4w
DOI :
https://doi.org/10.38124/ijisrt/25oct1473
Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.
Note : Google Scholar may take 30 to 40 days to display the article.
Abstract :
The identification of the role of vitamin D in the human body has evolved drastically over the years. Now
considered an essential vitamin, D was previously labelled as a hormone. The synthesis is initiated within the keratinocytes
due to the sunlight exposure and is transformed into an active form through a series of reactions in the liver and kidney,
where the enzymes required for this conversion are present. As a result of restricted production or availability, vitamin D
deficiency is a concerning issue in children and adults. Along with this, certain genetic, molecular and metabolic disturbances
result in the development of vitamin D resistance. The role of pathogens and environmental toxins that result in this condition
is also asserted. The review also explores the mechanism of vitamin D resistance in chronic diseases, such as the reduced
enzyme activity due to a variety of factors, leading to chronic kidney disease. Impaired hydroxylation in the liver contributes
to chronic lung disease, and how obesity, endocrine, and inflammatory disorders impact this mechanism is also
acknowledged. The clinical consequences of vitamin D dysfunction are wide, such as effects on bone, teeth and even muscles.
It also plays a role in the pathogenesis of Multiple Sclerosis and may lead to associated symptoms. The review also discusses
the diagnostic methods, which mainly focus on clinical and biochemical studies. The management and therapeutic strategies
that underlie the importance of vitamin D supplementation and the use of enzyme analogues and symptomatic management.
Keywords :
“Vitamin D Resistance” “Vitamin D Deficiency” “VDR polymorphism” “Rickets” “Sarcopenia” “Osteomalacia”.
References :
- Sarathi V, Dhananjaya MS, Karlekar M, Lila AR. Vitamin D deficiency or resistance and hypophosphatemia. Best Pract Res Clin Endocrinol Metab. 2024 Mar;38(2):101876. doi: 10.1016/j.beem.2024.101876. Epub 2024 Jan 30. PMID: 38365463.
- Carlberg C, Raczyk M, Zawrotna N. Vitamin D: A master example of nutrigenomics. Redox Biol. 2023 Jun;62:102695. doi: 10.1016/j.redox.2023.102695. Epub 2023 Apr 5. PMID: 37043983; PMCID: PMC10119805.
- Janoušek J, Pilařová V, Macáková K, Nomura A, Veiga-Matos J, et al. Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites. Crit Rev Clin Lab Sci. 2022 Dec;59(8):517-554. doi: 10.1080/10408363.2022.2070595. Epub 2022 May 16. PMID: 35575431.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–81. doi:10.1056/NEJMra070553.
- Malloy PJ, Feldman D. Vitamin D resistance. Am J Med. 1999 Mar;106(3):355-70. doi:10.1016/S0002-9343(98)00419-7
- Ito N, Hidaka N, Kato H. The pathophysiology of hypophosphatemia. Best Pract Res Clin Endocrinol Metab. 2024 Mar;38(2):101851. doi: 10.1016/j.beem.2023.101851. Epub 2023 Nov 30. PMID: 38087658.
- Grant WB, Wimalawansa SJ, Pludowski P, Cheng RZ. Vitamin D: Evidence-Based Health Benefits and Recommendations for Population Guidelines. Nutrients. 2025 Jan 14;17(2):277. doi: 10.3390/nu17020277. PMID: 39861407; PMCID: PMC11767646.
- Dominguez LJ, Veronese N, Ragusa FS, Baio SM, Sgrò F, et al. The Importance of Vitamin D and Magnesium in Athletes. Nutrients. 2025 May 13;17(10):1655. doi: 10.3390/nu17101655. PMID: 40431395; PMCID: PMC12114196.
- Uçar N, Holick MF. Illuminating the Connection: Cutaneous Vitamin D3 Synthesis and Its Role in Skin Cancer Prevention. Nutrients. 2025 Jan 22;17(3):386. doi: 10.3390/nu17030386. PMID: 39940244; PMCID: PMC11821240.
- Bikle DD. Vitamin D: Production, Metabolism, and Mechanism of Action. 2025 Jun 15. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905172.
- Gasperini B, Visconti VV, Ciccacci C, Falvino A, Gasbarra E, et al. Role of the Vitamin D Receptor (VDR) in the Pathogenesis of Osteoporosis: A Genetic, Epigenetic and Molecular Pilot Study. Genes (Basel). 2023 Feb 21;14(3):542. doi: 10.3390/genes14030542. PMID: 36980815; PMCID: PMC10048253.
- Aggeletopoulou I, Tsounis EP, Mouzaki A, Triantos C. Exploring the role of vitamin D and the vitamin D receptor in the composition of the gut microbiota. Front Biosci (Landmark Ed). 2023;28(6):116. doi:10.31083/j.fbl2806116
- Lei M, Liu Z, Guo J. The emerging role of vitamin D and vitamin D receptor in diabetic nephropathy. Biomed Res Int. 2020;2020:4137268. doi:10.1155/2020/4137268.
- Laird E, Ward M, McSorley E, Strain JJ, Wallace J. Vitamin D and bone health: potential mechanisms. Nutrients. 2010 Jul;2(7):693-724. doi: 10.3390/nu2070693. Epub 2010 Jul 5. PMID: 22254049; PMCID: PMC3257679.
- Rejnmark L. Effects of vitamin d on muscle function and performance: a review of evidence from randomized controlled trials. Ther Adv Chronic Dis. 2011 Jan;2(1):25-37. doi: 10.1177/2040622310381934. PMID: 23251739; PMCID: PMC3513873.
- Latham CM, Brightwell CR, Keeble AR, Munson BD, Thomas NT, et al. Vitamin D Promotes Skeletal Muscle Regeneration and Mitochondrial Health. Front Physiol. 2021;12:660498. doi:10.3389/fphys.2021.660498.
- Lemke D, Klement RJ, Schweiger F, Schweiger B, Spitz J. Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol. Front Immunol. 2021 Apr 7;12:655739. doi: 10.3389/fimmu.2021.655739. PMID: 33897704; PMCID: PMC8058406.
- Feldman D, J Malloy P. Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets. Bonekey Rep. 2014 Mar 5;3:510. doi: 10.1038/bonekey.2014.5. PMID: 24818002; PMCID: PMC4015455.
- Lee SM, Meyer MB, Benkusky NA, O'Brien CA, Pike JW. The impact of VDR expression and regulation in vivo. J Steroid Biochem Mol Biol. 2018 Mar;177:36-45. doi: 10.1016/j.jsbmb.2017.06.002. Epub 2017 Jun 9. PMID: 28602960; PMCID: PMC5723236.
- Stokes, C. S., Volmer, D. A., Grünhage, et al(2013). Vitamin D in chronic liver disease. Liver International, 33(3), 338-352. https://doi.org/10.1111/liv.12106
- Rozmus D, Ciesielska A, Płomiński J, Grzybowski R, Fiedorowicz E, et al. Vitamin D Binding Protein (VDBP) and Its Gene Polymorphisms-The Risk of Malignant Tumors and Other Diseases. Int J Mol Sci. 2020 Oct 22;21(21):7822. doi: 10.3390/ijms21217822. PMID: 33105665; PMCID: PMC7659952.
- Delrue C, Speeckaert MM. Vitamin D and Vitamin D-Binding Protein in Health and Disease. Int J Mol Sci. 2023 Feb 28;24(5):4642. doi: 10.3390/ijms24054642. PMID: 36902073; PMCID: PMC10003016.
- Christakos, S., Dhawan, P., Verstuyf, et al. (2016). Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiological Reviews, 96(1), 365-408. https://doi.org/10.1152/physrev.00014.2015
- Newton DA, Baatz JE, Kindy MS, Gattoni-Celli S, Shary JR, et al. Vitamin D binding protein polymorphisms significantly impact vitamin D status in children. Pediatr Res. 2019 Nov;86(5):662-669. doi: 10.1038/s41390-019-0322-y. Epub 2019 Feb 2. PMID: 30712059; PMCID: PMC6677641.
- Bikle, D. D., & Schwartz, J. (2019). Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions. Frontiers in Endocrinology, 10, 317. https://doi.org/10.3389/fendo.2019.00317
- Abbas, M. A. (2017). Physiological functions of Vitamin D in adipose tissue. The Journal of Steroid Biochemistry and Molecular Biology, 165(Pt B), 369-381. https://doi.org/10.1016/j.jsbmb.2016.08.004
- Vogt, I., Haffner, D., & Leifheit-Nestler, M. (2019). FGF23 and phosphate—Cardiovascular toxins in CKD. Toxins, 11(11), 647. https://doi.org/10.3390/toxins11110647
- Kitson, M. T., & Roberts, S. K. (2012). D-livering the message: the importance of vitamin D status in chronic liver disease. Journal of Hepatology, 57(4), 897–909. https://doi.org/10.1016/j.jhep.2012.04.033
- Charoenngam, N. (2021). Vitamin D and Rheumatic Diseases: A Review of Clinical Evidence. International Journal of Molecular Sciences, 22(19), 10659. https://doi.org/10.3390/ijms221910659
- Huang HY, Lin TW, Hong ZX, Lim LM. Vitamin D and Diabetic Kidney Disease. Int J Mol Sci. 2023 Feb 13;24(4):3751. doi: 10.3390/ijms24043751. PMID: 36835159; PMCID: PMC9960850.
- Nejla Latic, Reinhold G. Erben, FGF23 and Vitamin D Metabolism, JBMR Plus, Volume 5, Issue 12, 1 December 2021, e10558, https://doi.org/10.1002/jbm4.10558
- Dusso AS. Vitamin D receptor: mechanisms for vitamin D resistance in renal failure. Kidney Int Suppl. 2003 Jun;(85):S6-9. doi: 10.1046/j.1523-1755.63.s85.3.x. PMID: 12753256.
- Iruzubieta P, Terán Á, Crespo J, Fábrega E. Vitamin D deficiency in chronic liver disease. World J Hepatol. 2014 Dec 27;6(12):901-15. doi: 10.4254/wjh.v6.i12.901. PMID: 25544877; PMCID: PMC4269909.
- Cheng, J. B., Motola, D. L., Mangelsdorf, D. J., & Russell, D. W. (2003). De-orphanization of Cytochrome P450 2R1: A MICROSOMAL VITAMIN D 25-HYDROXYLASE. The Journal of Biological Chemistry, 278(39), 38084. https://doi.org/10.1074/jbc.M307028200
- Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases. Int J Mol Sci. 2022 Sep 14;23(18):10705. doi: 10.3390/ijms231810705. PMID: 36142636; PMCID: PMC9503777.
- Zhu F, Lin BR, Lin SH, Yu CH, Yang YM. Hepatic-specific vitamin D receptor downregulation alleviates aging-related metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol. 2025 Apr 14;31(14):104117. doi: 10.3748/wjg.v31.i14.104117. PMID: 40248374; PMCID: PMC12001193.
- Morró M, Vilà L, Franckhauser S, Mallol C, Elias G, et al. Vitamin D Receptor Overexpression in β-Cells Ameliorates Diabetes in Mice. Diabetes. 2020 May;69(5):927-939. doi: 10.2337/db19-0757. Epub 2020 Feb 21. PMID: 32086292; PMCID: PMC7171966.
- Al-Shoumer KA, Al-Essa TM. Is there a relationship between vitamin D with insulin resistance and diabetes mellitus? World J Diabetes 2015; 6(8): 1057-1064 [PMID: 26240702 DOI: 10.4239/wjd.v6.i8.1057]
- Wortsman, J., Matsuoka, L. Y., Chen, T. C., Lu, Z., et al. (2000). Decreased bioavailability of vitamin D in obesity. American Journal of Clinical Nutrition, 72(3), 690-693. https://doi.org/10.1093/ajcn/72.3.690
- Vanlint, S. (2013). Vitamin D and Obesity. Nutrients, 5(3), 949-956. https://doi.org/10.3390/nu5030949
- Jonas MI, Kuryłowicz A, Bartoszewicz Z, Lisik W, Jonas M, et al. Vitamin D Receptor Gene Expression in Adipose Tissue of Obese Individuals is Regulated by miRNA and Correlates with the Pro-Inflammatory Cytokine Level. Int J Mol Sci. 2019 Oct 24;20(21):5272. doi: 10.3390/ijms20215272. PMID: 31652924; PMCID: PMC6862513.
- Mohannad, N., Nassar, E.S., Moaaz, M. et al. Immunological analysis of vitamin D receptor gene expression in Egyptian patients with rheumatoid arthritis: relation to disease activity and functional disability. Egypt Rheumatol Rehabil 47, 44 (2020). https://doi.org/10.1186/s43166-020-00042-1
- Juniku-Shkololli, A., Manxhuka-Kërliu, S., Hamza, V., & Basholli, M. (2023). VDR Immunohistochemistry Expression Is Down-Regulated in Colorectal Cells of Patients with IBD and Could Rank the Patients According to Their Complications Risk. Gastroenterology Insights, 14(3), 342-351. https://doi.org/10.3390/gastroent14030025
- Garg M, Royce SG, Tikellis C, Shallue C, Sluka P, et al. The intestinal vitamin D receptor in inflammatory bowel disease: inverse correlation with inflammation but no relationship with circulating vitamin D status. Therap Adv Gastroenterol. 2019 Jan 18;12:1756284818822566. doi: 10.1177/1756284818822566. PMID: 30719077; PMCID: PMC6348511.
- Bagger-Jörgensen H, Thomsen C, Borrisholt M, Wanders A, Sjöberg K. The Colonic Vitamin D Receptor and Inflammatory Bowel Disease: No Correlation to Histologic or Endoscopic Inflammation. APMIS. 2025 Jan;133(1):e70000. doi: 10.1111/apm.70000. PMID: 39829252; PMCID: PMC11744339.
- Sater MS, Malalla ZHA, Ali ME, Giha HA. Downstream Link of Vitamin D Pathway with Inflammation Irrespective of Plasma 25OHD3: Hints from Vitamin D-Binding Protein (DBP) and Receptor (VDR) Gene Polymorphisms. Biomedicines. 2025 Feb 6;13(2):385. doi: 10.3390/biomedicines13020385. PMID: 40002798; PMCID: PMC11853708.
- Jiménez-Sousa MÁ, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino S. Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease. Front Immunol. 2018 Mar 12;9:458. doi: 10.3389/fimmu.2018.00458. PMID: 29593721; PMCID: PMC5857570.
- Rathored, J., Sharma, S.K., Sreenivas, V. et al. Association of vitamin D receptor mRNA expression, vitamin D deficiency and genetic variant in patients with multi-drug resistant pulmonary tuberculosis. BMC Infect Dis 25, 1334 (2025). https://doi.org/10.1186/s12879-025-11707-7
- Matyjaszek-Matuszek B, Lenart-Lipińska M, Woźniakowska E. Clinical implications of vitamin D deficiency. Prz Menopauzalny. 2015 Jun;14(2):75-81. doi: 10.5114/pm.2015.52149. Epub 2015 Jun 22. PMID: 26327893; PMCID: PMC4498026.
- Bouillon R. Vitamin D resistance. Best Pract Res Clin Endocrinol Metab. 2006;20(4):627-645. doi:10.1016/j.beem.2006.09.008
- Liberman UA. Vitamin D–Resistant Diseases. J Bone Miner Res. 2007;22(S2):S210-S214. doi: 10.1359/JBMR.07S210.
- Kaur J, Khare S, Sizar O, Givler A. Vitamin D Deficiency. 2025 Feb 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 30335299.
- Levine MA. “Diagnosis and Management of Vitamin D Dependent Rickets.” Frontiers in Pediatrics. 2020 Jun 12; 8:315. doi: 10.3389/fped.. 2020.00315.
- Walsh S, Ludlow AT, Metter EJ, Ferrucci L, Roth SM. Replication study of the vitamin D receptor (VDR) genotype association with skeletal muscle traits and sarcopenia. Aging Clin Exp Res. 2016 Jun;28(3):435-42. doi: 10.1007/s40520-015-0447-8. Epub 2015 Sep 28. PMID: 26415498; PMCID: PMC6223620.
- Yao X, Yang L, Li M, Xiao H. Relationship of vitamin D receptor gene polymorphism with sarcopenia and muscle traits based on propensity score matching. J Clin Lab Anal. 2020 Nov;34(11):e23485. doi: 10.1002/jcla 23485. Epub 2020 Jul 22. PMID: 32696506; PMCID: PMC7676216.
- Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit? Isr Med Assoc J. 2017 Jul;19(7):438-443. PMID: 28786260.
- Yu F, Cui LL, Li X, Wang CJ, Ba Y, Wang L, et al The genetic polymorphisms in vitamin D receptor and the risk of type 2 diabetes mellitus: an updated meta-analysis. Asia Pac J Clin Nutr. 2016;25(3):614-24. doi: 10.6133/apjcn.. 092015.12. PMID: 27440697.
- Biasucci G, Donini V, Cannalire G. Rickets types and treatment with vitamin D and analogs. Nutrients. 2024;16(3):416. doi:10.3390/nu16030416
- Khorsandi AA, Amouzegar A, Mir Saeid Ghazi AA, Zarif Yeganeh M, Alamdari S, Amirbaigloo A, et al Hereditary vitamin D-resistant rickets: clinical, laboratory, and genetic characteristics of 2 Iranian siblings. Int J Endocrinol Metab. 2017;15(3):e12384. doi:10.5812/ijem.12384.
- Pludowski P, Grant WB, Karras SN, Zittermann A, Pilz S. Vitamin D supplementation: a review of the evidence arguing for a daily dose of 2000 international units (50 µg) of vitamin D for adults in the general population. Nutrients. 2024;16(3):391. doi:10.3390/nu16030391. PMID: 38337676.
- Galior K, Grebe S, Singh R. Development of vitamin D toxicity from overcorrection of vitamin D deficiency: a review of case reports. Nutrients. 2018 Jul 24;10(8):953. doi: 10.3390/nu10080953. PMID: 30042334; PMCID: PMC6115827.
- Lung BE, Komatsu DE. Calcitriol. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526025/
- Ze Rui, Chao Yan, Zhiwei Wang, Yufeng Yuan, Chunyu Luan, et al. The effects of alfacalcidol combined with calcitonin in the treatment of osteoporosis and its influence on levels of inflammation. Am J Transl Res. 2024 May 15;16(5):1690-1700. doi: 10.62347/ZMAL4724.
- Fenercioglu A. The Anti-Inflammatory Roles of Vitamin D for Improving Human Health. Curr Issues Mol Biol. 2024 Nov 26;46(12):13514–25. doi: 10.3390/cimb46120807.
- Park CY, Han SN. Vitamin D and obesity. In: Advances in Food and Nutrition Research. Vol 109. Elsevier; 2024. p. 221-247. doi: 10.1016/bs.afnr.2023.12.006.
- Mattioli AV, Coppi F, Severino P, Penna C, Pagliaro P, et al. A Personalized Approach to Vitamin D Supplementation in Cardiovascular Health Beyond the Bone: An Expert Consensus by the Italian National Institute for Cardiovascular Research. Nutrients. 2025;17(1):115. doi:10.3390/nu17010115.
- Gupta VK, Sahu L, Sonwal S, Suneetha A, Kim DH,et al. Advances in biomedical applications of vitamin D for VDR-targeted management of obesity and cancer. Biomed Pharmacother. 2024 Aug;177:117001. doi: 10.1016/j.biopha.2024.117001.
The identification of the role of vitamin D in the human body has evolved drastically over the years. Now
considered an essential vitamin, D was previously labelled as a hormone. The synthesis is initiated within the keratinocytes
due to the sunlight exposure and is transformed into an active form through a series of reactions in the liver and kidney,
where the enzymes required for this conversion are present. As a result of restricted production or availability, vitamin D
deficiency is a concerning issue in children and adults. Along with this, certain genetic, molecular and metabolic disturbances
result in the development of vitamin D resistance. The role of pathogens and environmental toxins that result in this condition
is also asserted. The review also explores the mechanism of vitamin D resistance in chronic diseases, such as the reduced
enzyme activity due to a variety of factors, leading to chronic kidney disease. Impaired hydroxylation in the liver contributes
to chronic lung disease, and how obesity, endocrine, and inflammatory disorders impact this mechanism is also
acknowledged. The clinical consequences of vitamin D dysfunction are wide, such as effects on bone, teeth and even muscles.
It also plays a role in the pathogenesis of Multiple Sclerosis and may lead to associated symptoms. The review also discusses
the diagnostic methods, which mainly focus on clinical and biochemical studies. The management and therapeutic strategies
that underlie the importance of vitamin D supplementation and the use of enzyme analogues and symptomatic management.
Keywords :
“Vitamin D Resistance” “Vitamin D Deficiency” “VDR polymorphism” “Rickets” “Sarcopenia” “Osteomalacia”.