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Letters to the Editor |
Departments of1
Rheumatology and2
Chemical Pathology, St. George’s Healthcare NHS Trust, London, United Kingdom
3 Chemical Pathology, West Park Hospital, Epsom, Surrey, United Kingdom
aAddress correspondence to this author at: Department of Rheumatology, St. George’s Healthcare NHS Trust, Blackshaw Road, London, SW17 0QT United Kingdom. Fax 44-0208-725-3297; e-mail patrick.kiely{at}stgeorges.nhs.uk.
To the Editor:
Measurement of 25-hydroxyvitamin D (25OHD) is used to assess both vitamin D status and the response to exogenous replacement therapy (1). Inaccurate assays may place patients at risk of either under- or overreplacement, with potential adverse consequences (1)(2).
Significant interassay and interlaboratory variations in measured 25OHD values have been reported (3)(4). The international Vitamin D Quality Assessment Scheme (DEQAS) monitors the performance of vitamin D assays in >100 laboratories in 18 countries (4). Recently, the analysis of samples containing only 25OHD3 was reported by DEQAS to be within 7% of the target value (as determined by gas chromatography–mass spectrometry) for 5 of the 6 methods reported, with a degree of operator-dependent variability. The Nichols Advantage assay, however, yielded consistently higher results, averaging 
31% higher than the mean of the other methods (4). Conversely, in 2 samples containing mostly 25OHD2, the Nichols assay consistently underestimated 25OHD compared with other assays, such as the DiaSorin RIA (4).
In March 2004, we recruited 50 patients with hypovitaminosis D (43 female; mean age, 53 years; range, 29–82 years) to assess the effects of replacement therapy. The baseline vitamin D concentration was <17 nmol/L in 28 patients and 18–35 nmol/L (mean, 24.5 nmol/L) in 22 patients. Each patient received a single intramuscular injection containing 300 000 IU of ergocalciferol. Serum samples were obtained at baseline and 6, 12, and 24 weeks later. The concentration of 25OHD was measured with the Nichols Advantage automated assay at St. George’s Hospital (London, UK). Several samples were stored at –20 °C and subsequently analyzed blind with the DiaSorin assay at West Park Hospital, Epsom (Surrey, UK).
Comparison of DEQAS data for the laboratories at St. George’s and West Park Hospitals confirmed the reported higher values (4) for the Nichols (mean 25OHD concentration, 63 nmol/L) compared with the DiaSorin assay (mean 25OHD concentration, 55.5 nmol/L) for 28 paired nonstudy samples for which 25OHD was likely to be derived from vitamin D3.
The main source of 25OHD at baseline was hard to determine. In general, the source is assumed to be sunlight-derived vitamin D3, but for some patients, limited sunlight exposure, with or without reduced skin exposure, or reduced dermal capacity to synthesize vitamin D3 may mean that dietary vitamin D2 is more important (5)(6)(7)(8)(9)(10)(11)(12). In all of the posttreatment samples, vitamin D2 was assumed to comprise the main source of measured 25OHD.
Paired 25OHD results for the Nichols Advantage and DiaSorin assays were obtained for 10 pretreatment baseline samples and for 4 samples at 6 weeks, 19 samples at 12 weeks, and 14 samples at 24 weeks after ergocalciferol treatment. The mean baseline 25OHD concentration obtained with the Nichols assay was significantly lower (24.7 nmol/L; range, 17.0–35.0 nmol/L) than that obtained with the DiaSorin assay (34.8 nmol/L; range, 19.0–63.0 nmol/L; P = 0.041, Wilcoxon signed-rank tests), as were the individual results for 8 of 10 samples. That is consistent with the predominant source of baseline 25OHD in these patients being vitamin D2, given the DEQAS data (4). In the posttreatment samples, an increase in 25OHD concentration compared with baseline was found with both assays, but the mean values from the DiaSorin assay were significantly higher than the Nichols values at both 12 weeks (54.7 and 30.9 nmol/L, respectively; P <0.001, Wilcoxon signed-rank test) and 24 weeks (56.4 and 34.5 nmol/L, respectively, P = 0.001, Wilcoxon signed-rank test). Furthermore, in every posttreatment sample, the DiaSorin assay yielded a higher 25OHD concentration than the Nichols Advantage assay. A difference plot indicated that the disparity between the 2 assays was greater at higher concentrations (Fig. 1
).
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We conclude that the Nichols assay underestimates 25OHD in patients treated with ergocalciferol and that the increasing disparity between the studied assays at higher concentrations may lead to unnecessary increases in replacement therapy and potential toxicity.
References
The following articles in journals at HighWire Press have cited this article:
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  H. M. Pappa, C. M. Gordon, T. M. Saslowsky, A. Zholudev, B. Horr, M.-C. Shih, and R. J. Grand Vitamin D Status in Children and Young Adults With Inflammatory Bowel Disease Pediatrics, November 1, 2006; 118(5): 1950 - 1961. [Abstract] [Full Text] [PDF]
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 G. L. Lensmeyer, D. A. Wiebe, N. Binkley, and M. K. Drezner HPLC Method for 25-Hydroxyvitamin D Measurement: Comparison with Contemporary Assays Clin. Chem., June 1, 2006; 52(6): 1120 - 1126. [Abstract] [Full Text] [PDF]
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 K. Querings, M. Girndt, J. Geisel, T. Georg, W. Tilgen, and J. Reichrath 25-Hydroxyvitamin D Deficiency in Renal Transplant Recipients J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 526 - 529. [Abstract] [Full Text] [PDF]
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), 12 (
), or 24 (
) weeks after parenteral ergocalciferol therapy.