High-dose vitamin D3 reduces circulating hepcidin concentrations: A pilot, randomized, double-blind, placebo-controlled trial in healthy adults

      Summary

      Background & aims

      In vitro studies suggest that vitamin D may reduce hepcidin expression and pro-inflammatory cytokine release from monocytes. However, data assessing the vitamin D-mediated effects on iron recycling in healthy individuals are lacking. We aimed to examine the effect of high-dose vitamin D3 on plasma hepcidin, inflammatory cytokine, and ferritin concentrations in healthy adults.

      Methods

      This was a pilot, double-blind, placebo-controlled trial in healthy adults (N = 28) randomized to receive a one-time oral dose of 250,000 IU of vitamin D3 or placebo. Between- and within-group differences in plasma hepcidin, pro-inflammatory cytokine [interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], and ferritin concentrations at baseline and 1 week were determined using two-sample and paired t-tests, respectively.

      Results

      At baseline, plasma 25-hydroxyvitamin D [25(OH)D], hepcidin, pro-inflammatory cytokine, and ferritin concentrations did not differ between the two groups, and greater than 70% of subjects in both groups were vitamin D deficient (25(OH)D < 20 ng/mL). After 1 week, plasma hepcidin concentrations decreased by 73% from baseline in those who received vitamin D3 (geometric mean ratio [GMR] = 0.27 (95% CI: 0.11–0.62); P = 0.005); there was no significant change in the placebo group (GMR = 0.73 (95% CI: 0.49–1.09); P = 0.11). Plasma cytokine and ferritin concentrations did not change significantly in either group.

      Conclusions

      High-dose vitamin D3 significantly reduced plasma hepcidin concentrations in healthy adults 1 week post-dosing, without a change in plasma pro-inflammatory cytokine or ferritin concentrations. These data suggest that vitamin D may have a role in regulating iron recycling by acting independently of changes in pro-inflammatory markers.

      Keywords

      Abbreviations:

      1,25(OH)2D (1,25-dihydroxyvitamin D), 25(OH)D (25-hydroxyvitamin D), BMI (body mass index), CKD (chronic kidney disease), GMR (geometric mean ratio), IL-1β (interleukin-1β), IL-6 (interleukin-6), IL-8 (interleukin-8), MCP-1 (monocyte chemoattractant protein-1)
      To read this article in full you will need to make a payment
      Subscribe to Clinical Nutrition
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ganji V.
        • Zhang X.
        • Tangpricha V.
        Serum 25-hydroxyvitamin D concentrations and prevalence estimates of hypovitaminosis D in the U.S. population based on assay-adjusted data.
        J Nutr. 2012; 142: 498-507
        • Kassebaum N.J.
        • Jasrasaria R.
        • Naghavi M.
        • Wulf S.K.
        • Johns N.
        • Lozano R.
        • et al.
        A systematic analysis of global anemia burden from 1990 to 2010.
        Blood. 2014; 123: 615-624
        • Holick M.F.
        Vitamin D deficiency.
        N Engl J Med. 2007; 357: 266-281
        • Camaschella C.
        Iron-deficiency anemia.
        N Engl J Med. 2015; 372: 1832-1843
        • Hsu C.Y.
        • McCulloch C.E.
        • Curhan G.C.
        Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey.
        J Am Soc Nephrol. 2002; 13: 504-510
        • LaClair R.E.
        • Hellman R.N.
        • Karp S.L.
        • Kraus M.
        • Ofner S.
        • Li Q.
        • et al.
        Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States.
        Am J Kidney Dis. 2005; 45: 1026-1033
        • Groenveld H.F.
        • Januzzi J.L.
        • Damman K.
        • van Wijngaarden J.
        • Hillege H.L.
        • van Veldhuisen D.J.
        • et al.
        Anemia and mortality in heart failure patients a systematic review and meta-analysis.
        J Am Coll Cardiol. 2008; 52: 818-827
        • Kim D.H.
        • Sabour S.
        • Sagar U.N.
        • Adams S.
        • Whellan D.J.
        Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004).
        Am J Cardiol. 2008; 102: 1540-1544
        • Perlstein T.S.
        • Pande R.
        • Berliner N.
        • Vanasse G.J.
        Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation.
        Blood. 2011; 117: 2800-2806
        • Smith E.M.
        • Alvarez J.A.
        • Martin G.S.
        • Zughaier S.M.
        • Ziegler T.R.
        • Tangpricha V.
        Vitamin D deficiency is associated with anaemia among African Americans in a US cohort.
        Br J Nutr. 2015; 113: 1732-1740
        • Nemeth E.
        • Ganz T.
        Anemia of inflammation.
        Hematol Oncol Clin North Am. 2014; 28: 671-681, vi
        • Ganz T.
        Systemic iron homeostasis.
        Physiol Rev. 2013; 93: 1721-1741
        • Smith E.M.
        • Tangpricha V.
        Vitamin D and anemia: insights into an emerging association.
        Curr Opin Endocrinol Diabetes Obes. 2015; 22: 432-438
        • Zughaier S.M.
        • Alvarez J.A.
        • Sloan J.H.
        • Konrad R.J.
        • Tangpricha V.
        The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes.
        J Clin Transl Endocrinol. 2014; 1: 19-25
        • Bacchetta J.
        • Zaritsky J.J.
        • Sea J.L.
        • Chun R.F.
        • Lisse T.S.
        • Zavala K.
        • et al.
        Suppression of iron-regulatory hepcidin by vitamin D.
        J Am Soc Nephrol. 2014; 25: 564-572
        • Kearns M.D.
        • Binongo J.N.
        • Watson D.
        • Alvarez J.A.
        • Lodin D.
        • Ziegler T.R.
        • et al.
        The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.
        Eur J Clin Nutr. 2015; 69: 193-197
        • Looker A.C.
        • Dallman P.R.
        • Carroll M.D.
        • Gunter E.W.
        • Johnson C.L.
        Prevalence of iron deficiency in the United States.
        JAMA. 1997; 277: 973-976
        • Butterfield A.M.
        • Luan P.
        • Witcher D.R.
        • Manetta J.
        • Murphy A.T.
        • Wroblewski V.J.
        • et al.
        A dual-monoclonal sandwich ELISA specific for hepcidin-25.
        Clin Chem. 2010; 56: 1725-1732
        • Troutt J.S.
        • Rudling M.
        • Persson L.
        • Stahle L.
        • Angelin B.
        • Butterfield A.M.
        • et al.
        Circulating human hepcidin-25 concentrations display a diurnal rhythm, increase with prolonged fasting, and are reduced by growth hormone administration.
        Clin Chem. 2012; 58: 1225-1232
        • Bacchetta J.
        • Chun R.F.
        • Gales B.
        • Zaritsky J.J.
        • Leroy S.
        • Wesseling-Perry K.
        • et al.
        Antibacterial responses by peritoneal macrophages are enhanced following vitamin D supplementation.
        PLoS One. 2014; 9: e116530
        • Thomas C.E.
        • Guillet R.
        • Queenan R.A.
        • Cooper E.M.
        • Kent T.R.
        • Pressman E.K.
        • et al.
        Vitamin D status is inversely associated with anemia and serum erythropoietin during pregnancy.
        Am J Clin Nutr. 2015; 102: 1088-1095
        • Carvalho C.
        • Isakova T.
        • Collerone G.
        • Olbina G.
        • Wolf M.
        • Westerman M.
        • et al.
        Hepcidin and disordered mineral metabolism in chronic kidney disease.
        Clin Nephrol. 2011; 76: 90-98
        • Yin K.
        • Agrawal D.K.
        Vitamin D and inflammatory diseases.
        J Inflamm Res. 2014; 7: 69-87
        • von Drygalski A.
        • Adamson J.W.
        Iron metabolism in man.
        J Parenter Enter Nutr. 2013; 37: 599-606
        • Atkinson M.A.
        • Kim J.Y.
        • Roy C.N.
        • Warady B.A.
        • White C.T.
        • Furth S.L.
        Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort.
        Pediatr Nephrol. 2015; 30: 635-643
        • Ernst J.B.
        • Tomaschitz A.
        • Grubler M.R.
        • Gaksch M.
        • Kienreich K.
        • Verheyen N.
        • et al.
        Vitamin D supplementation and hemoglobin levels in hypertensive patients: a randomized controlled trial.
        Int J Endocrinol. 2016; 2016: 6836402
        • Riccio E.
        • Sabbatini M.
        • Bruzzese D.
        • Capuano I.
        • Migliaccio S.
        • Andreucci M.
        • et al.
        Effect of paricalcitol vs calcitriol on hemoglobin levels in chronic kidney disease patients: a randomized trial.
        PLoS One. 2015; 10: e0118174
        • Sooragonda B.
        • Bhadada S.K.
        • Shah V.N.
        • Malhotra P.
        • Ahluwalia J.
        • Sachdeva N.
        Effect of vitamin D replacement on hemoglobin concentration in subjects with concurrent iron-deficiency anemia and vitamin D deficiency: a randomized, single-blinded, placebo-controlled trial.
        Acta Haematol. 2015; 133: 31-35
        • Albitar S.
        • Genin R.
        • Fen-Chong M.
        • Serveaux M.O.
        • Schohn D.
        • Chuet C.
        High-dose alfacalcidol improves anaemia in patients on haemodialysis.
        Nephrol Dial Transpl. 1997; 12: 514-518
        • Goicoechea M.
        • Vazquez M.I.
        • Ruiz M.A.
        • Gomez-Campdera F.
        • Perez-Garcia R.
        • Valderrabano F.
        Intravenous calcitriol improves anaemia and reduces the need for erythropoietin in haemodialysis patients.
        Nephron. 1998; 78: 23-27
        • Lin C.L.
        • Hung C.C.
        • Yang C.T.
        • Huang C.C.
        Improved anemia and reduced erythropoietin need by medical or surgical intervention of secondary hyperparathyroidism in hemodialysis patients.
        Ren Fail. 2004; 26: 289-295