In Letter to editor doi: 10.3945/ajcn.111.019539.

Serum 25-hydroxyvitamin D is a reliable indicator of vitamin D status

Dear Sir:
Reid et al (1) reported a decrease in plasma 25-hydroxyvitamin D [25(OH)D], both total and free, after knee arthroplasty (1). Baseline 25(OH)D values in their patients averaged 40 nmol/L, well below even the most conservative lower limit of adequacy (2). By5dpost-surgery, this concentration had dropped by more than 25%; and by 3 mo, that deficit had still not been repaired. The authors concluded that serum 25(OH)D is thus not a reliable measure of vitamin D status.

What the authors understood by vitamin D status is unclear. Whatever the reason for the observed decrease after surgery, the serum 25(OH)D is what the peripheral tissues see. Serum 25(OH)D is not simply a convenient biomarker, it is a critical intermediary in the utilization of vitamin D by the body. And because tissue level 1-a-hydroxylases function below their Km values, the ability of extrarenal tissues to synthesize 1,25(OH)2D is strictly limited by substrate [ie, 25(OH)D] concentration. Hence, it would seem that exactly the opposite conclusion would be more appropriate, ie, that plasma 25(OH)D was indeed an accurate and reliable measure of a deteriorating vitamin D status. The preoperative low vitamin D status in these patients had simply worsened after surgery and, given low environmental availability of vitamin D in the Glasgow region, it had not been possible to restore vitamin D status to even the low preoperative levels. The authors discussed possible reasons for the postoperative decrease. None of these seems persuasive.

The 3-wk half-life cited by the authors for serum 25(OH)D (3) is simply an average that prevails under conditions of health and which does not exclude increased 25(OH)D turnover in an already deficient, inflammatory context. Available data indicate that, at levels in the range of reported preoperative values, fat stores of vitamin D would have been low and circulating 25(OH)D would have accounted for a major fraction (approximately one-third) of the total body vitamin D supply (4). Metabolic consumption of vitamin D is a function of both need and concentration. My colleagues and I have shown elsewhere that '4000 IU vitamin D/d are required to sustain a blood concentration of 80 nmol/L (5), and at higher concentrations the body consumes as much as 6000 IU/d (6). Finally, in catabolic states such as that the patients experienced after arthroplasty (with a huge rise in C-reactive protein), there may be up-regulation of hepatic 24-hydroxylation such as occurs in hyperparathyroidism, with resulting additional degradation of 25(OH)D.

But whatever the reason behind the changes described by Reid et al (1), those findings themselves are surely a call for vitamin D supplementation in patients in northern latitudes who are subjected to inflammatory stress.

The author had no conflicts of interest to declare.

Robert P Heaney, Creighton University, 2500 California Plaza, Omaha, NE 68178, E-mail: rheaney at creighton.edu

REFERENCES

1. Reid D, Toole BJ, Knox S, et al. The relation between acute changes in the systematic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroscopy. Am J Clin Nutr.2011;93:1006-11.
2. Institute of Medicine. Dietary Reference Intakes for calcium and vitamin D. Washington, DC: The National Academies Press. 2011.
3. Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008;87(suppl):1087S-91S.
4. Heaney RP, Horst RG, Cullen DR, Armas LAG. Vitamin D3 distribution and status in the body. J Am Coll Nutr 2009;28:252-6.
5. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-10.
6. Heaney RP, Armas LAG, Recker RR, Grote J, Horst RL. Vitamin D3 is more potent than vitamin D2 in humans. J Clin Endocrinol Metab 2011: 96(3);E447-E552.

Reply to RP Heaney

Dear Sir:
Heaney has interpreted the observed decrease of serum 25-hydroxyvitamin D [25(OH)D] after knee arthroplasty reported in our article (1) as reflecting true vitamin D status. His argument is that the serum 25(OH)D is what the peripheral tissues see and is more than simply a convenient biomarker, being a critical intermediary in the utilization of vitamin D by the body. This interpretation, in the presence of the systemic inflammatory response, is unlikely to be sound for the following reasons some of which are outlined in our article.

Heaney states that The 3-wk half-life cited by the authors for serum 25(OH)D is simply an average that prevails under conditions of health and which does not exclude increased 25(OH)D turnover in an already deficient, inflammatory context. However, to explain our results the half-life would have to have decreased to '24 h, and there is, to our knowledge, no evidence from the literature that this could be the case. Rather, as proposed in our article, plasma 25(OH)D is behaving in a fashion similar to other fat-soluble vitamins such as vitamin A. _Vitamin A, which is known to have large liver stores and a half-life of >3 mo, decreased by '50% in the first 24-48 h of the evolution of the systemic inflammatory response after knee arthroplasty (2).__

Heaney states that Available data indicate that, at levels in the range of reported preoperative values, fat stores of vitamin D would have been low and circulating 25(OH)D would have accounted for a major fraction (approximately one-third) of the total body vitamin D supply. However, it was of interest that, in our study, in those patients who could be considered to have adequate plasma 25(OH)D (>50 nmol/L; n — 13) the median preoperative plasma concentration was 73 (range: 50-124) nmol/L, and this decreased by 59% by day 1 (P — 0.003). In those patients who had could be considered to have inadequate plasma 25(OH)D (<50 nmol/L; n — 20) the median preoperative plasma concentration was 33 (range: 12-48) nmol/L, and this decreased by 42% by day 1 (P — 0.002).

It is one thing to disagree on the basis of the decrease of plasma 25(OH)D; it is another to advocate widespread vitamin D supplementation based on these measurements in patients in northern latitudes subjected to inflammatory stress. Indeed, the results we report might explain the observed associations of 25(OH)D with incident disease (3) whereby low plasma 25(OH)D substantially reflects disease activity. Therefore, in the era of evidence-based medicine and without convincing evidence of efficacy from randomized trials, there should be caution in the use of vitamin D supplementation (4).
The authors had no conflicts of interest to declare.

Dinesh Talwar Denis St J O'Reilly
Donald C McMillan
Department of Clinical Biochemistry University of Glasgow, Royal Infirmary Glasgow United Kingdom
University Department of Surgery, Faculty of Medicine, University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
E-mail: d.c.mcmillan at clinmed.gla.ac.uk

REFERENCES

• 1. Reid D, Toole BJ, Knox S, et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr 2011;93: 1006-11.
• 2. Gray A, McMillan DC, Wilson C, Williamson C, O'Reilly DS, Talwar D. The relationship between the acute changes in the systemic inflammatory response, lipid soluble antioxidant vitamins and lipid peroxidation following elective knee arthroplasty. Clin Nutr 2005;24:746-50.
• 3. Welsh P, Peters MJ, Sattar N. Vitamin D in rheumatoid arthritis: a magic bullet or a mirage? The need to improve the evidence base prior to calls for supplementation. Arthritis Rheum (Epub ahead of print 11 March 2011; DOI:10.1002/art.30341).
• 4. Rosen CJ. Vitamin D insufficiency. N Engl J Med 2011;364:248-54.

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