Journal Information
Vol. 92. Issue 3.
Pages 167-168 (01 March 2020)
Vol. 92. Issue 3.
Pages 167-168 (01 March 2020)
Scientific letter
DOI: 10.1016/j.anpede.2019.04.016
Open Access
Vitamin D and its receptor: Reflections on the unusual tendency to create supposed diseases
La vitamina D y su receptor. Reflexiones sobre la inusitada tendencia a crear supuestas enfermedades
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Víctor García-Nieto
Corresponding author
, M. Cristina Ontoria Betancort, Pedro Carballo Martin, Mónica Ruiz Pons
Departamento de Pediatría, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Tenerife, Spain
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Since the middle of the last decade, there is consensus that in the adult population, vitamin D deficiency can be defined as levels of calcifediol (25(OH)D) of less than 50 nmol/L (20 ng/mL) and vitamin D insufficiency as levels between 50 and 80 nmol/L (20–32 ng/mL), while values greater than 80 nmol/L are considered sufficient. These thresholds are also taken as valid in everyday paediatric clinical practice.1

The consequence of these definitions is that levels of calcifediol of less than 32 ng/mL may be considered pathological and consequently an indication for replacement therapy, with the drawback that healthy children are considered to be in the stage preceding disease.

In 2017, we gathered the calcifediol measurements recorded in our hospital over a period of 18 months (n = 161). We found that 41 patients (25.5%) had normal levels, 85 (52.8%) insufficient levels and 35 (21.7%) deficient levels. The levels of intact parathyroid hormone (iPTH) were low (<10 pg/mL) in 12 patients (7.5%) and normal (10–65 pg/mL) in the rest. We did not find statistically significant differences in the levels of iPTH in relation to the 3 groups of calcifediol levels (ANOVA).2

Recently, we measured calcifediol levels in 42 obese children. We compared the results with those of a group of 76 healthy children in the same geographical area. The levels of calcifediol in the obese group were lower compared to the other group (24.7 ± 7.9 vs 28.9 ± 7.7 ng/mL, P = .006). In the obese group, 24.4% of children had sufficient levels, 42.9% insufficiency and 35.7% deficiency. In the healthy group, 35.5% had sufficient levels, 55.3% insufficiency and 9.2% deficiency. The differences in the proportion of children corresponding to each range of calcifediol levels were statistically significant (P = .002). None of the children had manifestations compatible with rickets (subclinical vitamin D deficiency) or elevated levels of iPTH.3

How can it be that in 3 different samples of children residing in the island of Tenerife, which receives more than 3000 h a year of sunshine, this many have vitamin D deficiency or insufficiency?

Leaving aside that calcifediol levels do not always accurately reflect the levels of calcitriol, which is the active form of vitamin D, the assessment of vitamin D metabolism should take into account other basic and influential aspects, such as the levels of vitamin D binding protein (DBP), the existence of variants of this transport protein with different affinities for vitamin D metabolites, and the variability in the functionality, density and number of nuclear vitamin D receptors (VDRs). In regard to the latter, a study conducted in 1993 demonstrated that rats with spontaneous hypercalciuria (genetic hypercalciuric stone-forming rats) exhibited increased VDR gene expression in intestinal cells. Yao et al. demonstrated that these animals had hyperresponsiveness of VDR gene expression even at low levels of calcitriol.4

Thus, a child or adult with levels of vitamin D considered insufficient or lower that happens to carry a genetic variant promoting the function of DBP or VDR and/or with an adequate density of VDRs is likely to exhibit adequate intestinal absorption of calcium. While all of these factors cannot be assessed in everyday clinical practice, clinicians should be cautious in prescribing vitamin D replacement based solely on calcifediol levels and consider other clinical or biochemical parameters. We also believe that while awaiting further data, it would be advisable that the “insufficiency” term that often accompanies values in the normal range in laboratory reports no longer be used.

In our region, vitamin D supplementation is frequently used in children and adults with insufficient levels of calcifediol, and we assume that this practice is also widespread in all of Spain. In this regard, the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Agency of Medicines and Medical Devices) recently published an informational note citing cases of hypercalcaemia in children receiving “daily doses much higher than recommended for prevention of vitamin D deficiency.” It is important to consider that this note does not differentiate between overdosing and toxic doses. We must not forget the cases of so-called “idiopathic hypercalcaemia” that emerged in the United Kingdom in the 1950s as a result of vitamin D fortification of foods consumed by children, which gave rise to the novel concept of vitamin D hypersensitivity.5 Let us hope that in upcoming years we will not be reminded of the historic quote that “those who cannot remember the past are condemned to repeat it.”

References
[1]
C.L. Wagner, F.R. Greer.
American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.
Pediatrics., 122 (2008), pp. 1142-1152
[2]
P. Carballo Martin, D. Aracil Hernández, S.T. Moraleda Mesa, V.M. Ferreiro Díaz-Velis, P. Arango Sancho, M.C. Martin Fernández De Basoa, et al.
Relación entre los niveles de calcidiol y de PTH intacta en pacientes pediátricos ingresados en nuestro hospital.
Can Pediatr., 41 (2017),
[3]
R. Molina Suárez, C. Ontoria Betancort, M. Murray Hurtado, J.P. González Díaz, V. García Nieto, M.T. Rodrigo Bello, et al.
Grosor de íntima media carotidea y otros factores de riesgo cardiovascular: estudio de casos y controles.
Rev Esp Pediatr., 73 (2017), pp. 149-150
[4]
J. Yao, P. Kathpalia, D.A. Bushinsky, M.J. Favus.
Hyperresponsiveness of vitamin D receptor gene expression to 1,25-dihydroxyvitamin D3. A new characteristic of genetic hypercalciuric stone-forming rats.
J Clin Invest, 101 (1998), pp. 2223-2232
[5]
R. Lightwood, T. Stapleton.
Idiopathic hypercalcaemia in infants.

Please cite this article as: García-Nieto V, Cristina Ontoria Betancort M, Martin PC, Pons MR. La vitamina D y su receptor. Reflexiones sobre la inusitada tendencia a crear supuestas enfermedades. An Pediatr (Barc). 2020;92:167–168.

Copyright © 2019. Asociación Española de Pediatría
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