In recent years, we have witnessed an exponential growth in interest in vitamin D. This is not just for its role in mineral metabolism and bone homeostasis through its renal and intestinal actions, but also because it is a hormone with multiple pleiotropic effects and extraskeletal systemic functions in the cardiovascular system, in innate or acquired immunomodulation, and in the regulation of cellular growth, among others.
In the last two years, its relationship to SARS-CoV-2 infection has also influenced this interest. However, what is most significant is the public health impact of a high prevalence of hypovitaminosis D described in the general population.1, 2 Despite the consensus that measurement of 25(OH)D levels reflects the body’s vitamin D status, the best biomarker that reflects sufficient levels of this vitamin and its function has not been established and nor has the most precise technique for its proper quantification. In addition, the definition of optimal 25(OH)D concentrations remains controversial.3
In this regard, the National Academy of Medicine in the United States of America proposes values above 20 ng/mL for the healthy general population4 whereas the International Osteoporosis Foundation establishes values above 30 ng/mL for patients.5 Regarding these definitions, it has been described that 88% of the population has 25(OH)D concentrations below 30 ng/mL and 37% have values below 20 ng/mL.2 In Spain, the situation is very similar, reaching alarming figures of 80%–100% in individuals older than 65 years when using the threshold value of less than 20 ng/mL. In the population younger than this age, the deficit has been found in 40%.6
However, it should be noted that the studies used to determine the cut-off points of 20 and 30 ng/mL measured levels of 25(OH)D via a competitive protein-binding assay and/or a radioimmunoassay, whose precision and exactness were variable at that time. This represents an important limitation and an assay-dependent definition.7
Due to their hydrophobic nature, vitamin D metabolites, especially 25(OH)D, bind to carrier proteins. The principal protein is the vitamin D-binding protein, which binds to approximately 90% of its circulating concentration. Due to its high concentration in the blood but lower affinity, albumin binds the remaining 10%. A small fraction, less than 0.1% of the total, circulates freely and is unbound.
The quantification of this free fraction is not a common clinical practice, although its measurement instead of total 25(OH)D has been suggested, especially in circumstances in which the levels and/or affinities of binding proteins are physiologically altered (pregnancy), pathologically altered (liver disease, nephrotic syndrome, acute illnesses), or altered due to genetic mutations in the vitamin D carrier protein.8 These possible interferences in the measurement of the total concentration as well as racial differences may influence the overestimation of hypovitaminosis D in the population. In addition, the unbound metabolite is that which passes through cellular membranes and exercises biological actions.
Although it is common to determine the free fraction of other circulating hormones, the measurement of free 25(OH)D is a recent phenomenon due to a lack of a direct measurement method until now. With a direct immunoassay now available, the number of studies as well as their possible clinical applications are growing.8, 9
The study by Fernández-Vicente et al.10 evaluated vitamin D status through the analysis of total 25(OH)D and free 25(OH)D in a series of 206 healthy adults from Burgos and Valencia during two periods (March-April, period of minimum vitamin D synthesis, and October-November, months of maximum synthesis following summer). The mean concentrations of total 25(OH)D were 24.77 ng/mL in summer and 20 ng/mL in winter; they were lower in Burgos. Twenty-five percent of the cohort had sufficient vitamin D, confirming the high prevalence of hypovitaminosis D described in our country.
These suboptimal results in young people, even in those from a region with a sunny climate year-round, point to the fact that the thresholds for defining vitamin D insufficiency and deficiency in the healthy population are not ideal, as the authors speculate. The recommendations of clinical practice guidelines should be reconsidered in the future as additional data become available on the standardization of 25(OH)D and data from other ongoing randomized trials.
The novelty of this work is the simultaneous quantification of free 25(OH)D and the influence of seasonality, climate, and latitude on levels of vitamin D, reporting lower free 25(OH)D concentrations in the winter in Burgos.10 Additional studies that support the free fraction as the most reliable biomarker for real vitamin D status and the standardization of normal values are still necessary before widespread implementation.8, 9
Footnotes
Please cite this article as: Azriel S, ¿Es una quimera la deficiencia de vitamina D en la población sana española? Revista Clínica Española. 2022;222:370–371.
References
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