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 [2–7]. 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.
Table 1.
Wide variability in Vitamin D dose and duration, type of patients enrolled, and whether anemia was present or not in randomized clinical trials
| Patients | Anemia | Vitamin D dose | Vitamin D duration | Total Vitamin D dose | |
|---|---|---|---|---|---|
| Trautveffer 2014 | Healthy adults | No | Fortified bread with 400 IU vit D3 daily | 8 weeks | 22,400 IU vit D3 |
| Miskulin 2016a | Adults with CKD | Yes | Oral dose of 50,000 IU vit D2 weekly | 6 months | 1,200,000 IU vit D2 |
| Toxqui 2013 | Adult Women | Yes | Fortified milk with 200 IU vit D3 & 15 mg iron daily | 16 weeks | 22,400 IU vit D3 |
| Sooragonda 2015 | Healthy adults | Yes | 0.6 Lakh Amp vit D3+ Amp iron once | Once | 600,000 IU vit D3 |
| Smith 2017 [7]a | Healthy adults | No | Oral dose of 250,000 IU, vit D3 once | Once | 250,000 IU vit D3 |
| Smith 2018 [6] | Critically ill adults | Yes | Enteral dose of 50,000 IU (I1) or 100,000 IU (I2) vit D3 daily | 5 days |
500,000 IU (I1) vit D3 250,000 IU (I2) vit D3 |
| Madar 2016 | Healthy adults | No |
I1 = tablet 1000 IU, vit D3 daily I2 = tablet 400 IU, vit D3 daily |
16 weeks |
42,000 IU (I1) vit D3 16,800 IU (I2) vit D3 |
| Hennigar 2016 | Healthy adults | No | Fortified bar with 1000 IU vit D3 + 2000 mg calcium, 2 bars per day | 9 weeks | 126,000 IU vit D3 |
| Ernest 2016 | Adults with hypertension | No | Oral dose of 2800 IU vit D3 daily | 8 weeks | 156,800 IU vit D3 |
| Ernest 2017 | Adults with heart failure | Some (23 of 172) | Oral dose of 4000 IU vit D3 daily | 36 months | 4,032,000 IU vit D3 |
| Jastrzebska 2017 | Healthy adults | No | Oral dose of 5000 IU vit D3 daily | 8 weeks | 280,000 IU vit D3 |
| Dahlquist 2017 | Healthy adults | No | Sport drink with 5000 IU vit D3 once | Once | 5000 IU vit D3 |
| Walentukiewicz 2018a | Elderly women | No | Oral dose of 28,000 IU vit D3 weekly | 12 weeks | 336,000 IU vit D3 |
| Panwar 2018 | Adults with CKD | Yes | Oral dose of 0.5 mcg (20 IU vit D3) calcitriol daily | 6 weeks | 840 IU vit D3 |
CKD Chronic kidney disease
aHemoglobin not reported
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LMN conceived and wrote the paper and approved the final manuscript.
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References
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