Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes.

Many arguments are favouring a renewed interest in vitamin D physiology, with a consequent increase in the number of scientific publications and media reports (1). Not surprisingly, TIME magazine nominated vitamin D as one of the “top medical breakthroughs” in the December issue of 2007. This vigorous increase of interest in vitamin D is powered by the spectacular insights into the pivotal regulatory role of vitamin D with regard to pleiotropic functions, by the data on worldwide trend to nutritional vitamin insufficiency (2) and by new knowledge on intracrine and paracrine actions of vitamin D metabolites (3). Despite the fact that vitamin D is still called and known as a vitamin, it actually comprises a group of very closely interrelated hormonal compounds also related to the other main calciotropic hormone, the parathyroid hormone. Therefore, vitamin D is now viewed from a controller of calcium homeostasis (calciotropic) to an hormone with pleiotropic actions. Vitamin D is synthesized in human skin after the photoisomerization of 7-dehydrocolesterol to pre-vitamin D3 under the influence of UV B radiation (wavelength, 280-315 nm) (Fig. 1). The major factors influencing this process are either environmental (latitude, season, time of day, ozone and clouds, reflectivity of the surface) or personal (skin type, age, clothing, use of sunscreen, genetics). From the skin, parental vitamin D3 find its way into the general circulation and it is then metabolized in the liver to 25-hydroxyvitamin D3 [25(OH)D3] (calcifediol) by one of several, high capacity cytochrome P450s (Fig. 1). 25(OH)D3 is an immediate precursor metabolite to the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], that is the product of the mitochondrial CYP27B1-hydroxylase confined primarily but not entirely to the proximal tubular epithelial cell of the kidney (Fig. 1). 1,25(OH)2D3 synthesis in the kidney is stimulated by parathyroid hormone (PTH) and inhibited by fibroblast growth factor 23 (FGF23) made by osteocytes (4). As vitamin D has a much shorter half-life than 25(OH)D3 (1-2 days versus 2-3 weeks), 25(OH)D3 was favoured as the best indicator of vitamin D status. Other reasons for 25(OH)D3 becoming the parameter of choice for estimating the vitamin D status include: it enters the host, either by cutaneous synthesis or by ingestion in the diet and it is the most abundant and stable vitamin D metabolite in human serum, as determined by its high affinity to vitamin D binding protein and by other members of the albumin superfamily of circulating proteins. Conversely, 1,25(OH)2D3 circulates in the serum at concentrations that are about 0.1% of those of the prohormone 25(OH)D3 and its synthesis is tightly regulated by the endocrine system. For these reasons 1,25(OH)2D3 levels in the serum are not used to evaluate the vitamin D status in humans (Fig. 2). Using 25(OH)D3 circulating values and increases in serum PTH levels as markers of inadequacy and deficiency, it was possible to define the different cut-off values for the definition of the vitamin D status (Fig. 2). It is now generally agreed that the serum PTH will start to rise significantly when the serum 25(OH)D3 drops to less than 30 ng/ml; values of 25(OH)D3 between 30 ng/ml and 20 ng/ml are considered to represent vitamin D inadequacy, while those less than 20 ng/ml fall into the vitamin deficiency (Fig. 3). In this latter condition it is likely to observe clinical evidence of osteomalacia. There is growing evidence about high prevalence of unrecognized vitamin D deficiency worldwide in different age groups (2, 5-7).