The importance of assessing and supplementing vitamin D has bombarded the medical literature and lay press, greatly affecting the practice of most clinicians. Concern has been raised that there is inadequate data to support the cost of ubiquitous testing, and without the benefit of randomized controlled trials, there may be unanticipated consequences to aggressive repletion. The Institute of Medicine (IOM) recently proffered recommendations for daily intake and optimal levels of vitamin D based on an extensive review of the existing literature. 1 Their recommendations for vitamin D intake are higher than prior dietary reference levels for intake, but considerably lower than levels proposed by many in the field. 2,3 This commentary will attempt to clarify the controversy and present evidence to inform practice decisions.
VITAMIN D SOURCES AND METABOLISMVitamin D is not commonly consumed in the diet of the general population. Most plants and meats contain little vitamin D except for oily fish. Most vitamin D is derived through action of solar ultraviolet B radiation acting on 7-dehydrocholesterol in the skin to form previtamin D 3, which is quickly converted to vitamin D 3 . Vitamin D 2 is similarly produced by solar irradiation of marine plankton or yeast and molds. 4,5 Given its endocrine functions, its limited supply in food sources, and the ability of mammals to synthesize it, vitamin D is not truly a vitamin, but rather a prehormone. 4 Ingested or skin-derived vitamin D enters the bloodstream and is hydroxylated to 25-hydroxyvitamin D 2 (or D 3 ) (25-vit D) in the liver by the activating cytochromes, CYP2R1 and CYP27A1. 6 Although having little metabolic activity, 25-vit D has high affinity for vitamin D binding protein, rendering it very stable in circulation with a half-life of 2 weeks. 6,7 The relatively long half-life and high concentration in blood makes 25-vit D the optimal form to measure and assess vitamin D sufficiency. 5,6 In the kidney, 25-vit D is converted to its most active form, 1,25-dihydroxyvitamin D 2 or D 3 (1,25-vit D) by the enzyme 25-hydroxyvitamin D-1␣-hydroxylase, also known as CYP27B1. Although the kidney is the major site of 1,25-vit D production, there is clear evidence that CYP27B1 is present and functioning in other cells, leading to local, extrarenal 1,25-vit D production. 8 The formation of 1,25-vit D is greatly influenced by serum levels of other hormones and ions, such as parathyroid hormone (PTH), fibroblast growth factor 23, calcium, and phosphorus. Because of its very short circulating half-life, and the minute quantities present in the blood (approximately 1000 times less than 25-vit D), 1,25-vit D is an inferior measure of vitamin D adequacy. 2,5,6 Circulating 1,25-vit D induces the cytochrome P 450 enzyme, CYP24, which catabolizes both 25-vit D and 1,25-vit D into 24,25(OH) 2 vitamin D and other metabolites. 4,6 Elevated levels of 1,25-vit D inhibit CYP27B1, further downregulating its own production.
MEASUREMENT OF 25-VITAMIN DLevels of 25-vit D are generally measured e...