To the Editor:
Arabi et al. report in the recent systematic review and meta-analysis of the effect of vitamin D supplementation on hemoglobin concentration that supplementation with vitamin D had no significant effect on hemoglobin and ferritin levels, while positive effects on transferrin saturation and iron status were observed [1]. There is concern that the studies in this meta-analysis included highly variable patient cohorts and vitamin D dosing, acute and chronic treatment strategies, and not all patients had anemia.
The potential beneficial impact of vitamin D on hemoglobin in patients with anemia was not separately examined. Vitamin D supplementation may provide a safe, simple and cost-effective therapy for prevention and/or treatment of anemia. There is concern that the conclusion of this meta-analysis “… vitamin D had no significant effect on hemoglobin levels” is not meaningful based on the wide diversity of studies included. Why would vitamin D impact on hemoglobin if hemoglobin levels are normal?
Did the authors consider assessment of the total vitamin D dose in each of the studies, and separate analysis of the trials in anemic patients? The Table below confirms the wide variability in total dose and duration in these randomized clinical trials, which makes it challenging to discern an impact of vitamin D on hemoglobin in anemic patients.
It has clearly been documented that high-dose vitamin D is required for hepcidin suppression, which is required for optimal increase in endogenous erythropoiesis and subsequent increase in hemoglobin in anemic patients who have high hepcidin levels and anemia of inflammation or chronic kidney disease [2,3,4,5,6,7]. We would like to highlight the very important finding in Fig. 2 (effect of vitamin D on hemoglobin) in 2.3.6 “Critically ill patients”, that the placebo cohort mean hemoglobin was 6.7 g/dL vs. 11.25 g/dL in the high-dose (500,000 units total, 100,000 units daily for 5 days) vitamin D intervention cohort.
It should also be noted that in Table 1 for the Smith study in mechanically ventilated critically ill adults, the duration of the vitamin D intervention was listed as “4 weeks”, but the study drug was administered in 5 equal doses over 5 days, not 4 weeks. There are additional errors in that Table regarding drug dosing, duration and year of publication, all corrected in the Table below.
Availability of data and materials
Not applicable.
References
Arabi MA, Ranjbar G, Bahrami LS, Vafa M, Norouzy A. The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analylsis. Nutr J. 2020;19:11. https://doi.org/10.1186/s12937-020-0526-3.
Ganz T. Anemia of inflammation. N Engl J Med. 2019;381:1148–57.
Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K, Nayak A, Wesseling-Perry K, Westerman M, Hollis BW, Salusky IB, Hewison M. Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol. 2014;25(3):564–72. https://doi.org/10.1681/ASN.2013040355.
Cherry-Bukowiec JR, Engoren M, Wiktor A, Raghavendran K, Napolitano LM. Hepcidin and Anemia in surgical critical care: a prospective cohort study. Crit Care Med. 2018;46(6):e567–74. https://doi.org/10.1097/CCM.0000000000003089.
Sihler KC, Raghavendran K, Westerman M, Ye W, Napolitano LM. Hepcidin in trauma: linking injury, inflammation, and anemia. J Trauma. 2010;69(4):831–7. https://doi.org/10.1097/TA.0b013e3181f066d5 PMID: 20938270.
Smith EM, Jones JL, Han JE, Alvarez JA, Sloan JH, Konrad RJ, Zughaier SM, Martin GS, Ziegler TR, Tangpricha V. High-dose vitamin D3 administration is associated with increases in hemoglobin concentrations in mechanically ventilated critically ill adults: a pilot double-blind, randomized, placebo-controlled trial. J Parenter Enter Nutr. 2018;42(1):87–94. https://doi.org/10.1177/0148607116678197 PMID: 29505145.
Smith EM, Alvarez JA, Kearns MD, Hao L, Sloan JH, Konrad RJ, Ziegler TR, Zughaier SM, Tangpricha V. high-dose vitamin D3 reduces circulating hepcidin concentrations: a pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr. 2017;36(4):980–5. https://doi.org/10.1016/j.clnu.2016.06.015 PMID: 27402475.
Acknowledgements
Not applicable.
Funding
None.
Author information
Authors and Affiliations
Contributions
LMN conceived and wrote the paper and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
None.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Napolitano, L.M. Vitamin D supplementation and hemoglobin: dosing matters in prevention/treatment of anemia. Nutr J 20, 23 (2021). https://doi.org/10.1186/s12937-021-00680-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12937-021-00680-x