Here Comes the Sun—Is Vitamin D a Cure For All That Ails Us?

Deficiency of 25-hydroxyvitamin D (25[OH]D) has received a great deal of attention in the past several years for its potential nontraditional effects, outside of the skeleton. Vitamin D deficiency has been touted to be associated with increased risk of everything from cancer (1), to diabetes (2) and cardiovascular disease (CVD) (3), and even overall mortality (4). In this issue of the JCEM, Juonala et al (5) address the relationship between vitamin D deficiency and CVD. 25[OH]D deficiency has been associated with incident CVD in multiple adult studies (3, 6), but a large meta-analysis of randomized clinical trials of vitamin D supplementation did not show beneficial effects on stroke or myocardial infarction (7). Juonala et al (5) attempt to determine whether vitamin D deficiency during youth predisposes to increased CVD risk as an adult. The effects of vitamin D in the body are widespread. 25[OH]D represents overall vitamin D stores, but calcitriol or 1,25-dihydroxyvitamin D (1,25[OH]2D) is the biologically active form of vitamin D. PTH stimulates the hydroxylation of 25[OH]D to 1,25[OH]2D in the kidneys.Calcitriol hasmultiplebiological effects, andvitamin D response elements have been found in the promoters of numerous genes. In fact, a recent genome-wide array study showed that vitamin D supplementation affected gene expression in more than 160 biological pathways (8). Furthermore, calcitriol can have both paracrine and autocrine actions, and the latter may relate to its nontraditional effects. Not only do most cells in the human body express vitamin D receptor, most also express the enzyme necessary to convert 25[OH]D to 1,25[OH]2D (9, 10). Thus, in response to an external signal, 25[OH]D might be triggered for intracellular conversion to 1,25[OH]2D, exerting a local action unrelated to PTH levels. If substantiated, this would allow for 25[OH]D to bring about tissue-specific effects. Pathophysiological mechanisms corroborate the plausibility of a relationship between mineral metabolism and CVD. Vitamin D receptors are present on many different tissue types, including myocardium, endothelium, and vascular smooth muscle (11). In humans, 1,25[OH]2D inhibits renin synthesis; thus, its deficiency could contribute to hypertension (12). In addition, vitamin D deficiency leads to hypertrophy of vascular and left ventricular smooth muscle cells (13). Increased PTH, resulting from chronic vitamin D deficiency, is associated with increased blood pressure and myocardial contractility, which can lead to hypertrophy, apoptosis, and fibrosis in the vascular smooth muscle and left ventricle (11, 13). Decreased 25[OH]D and increased PTH both increase inflammation, as evidenced by increased C-reactive protein and IL-10, (13) and increase the risk of CVD events (14). 25[OH]D deficiency has been associated with increased insulin resistance and pancreatic -cell dysfunction as well (15). However, one source of confusion for many clinicians is that scientists cannot agree on what a “normal” 25[OH]D is. Although the Institute of Medicine (16) and the Pediatric Endocrine Society (17) define 25[OH]D sufficiency as a level 20 ng/mL (50 nmol/L), others such as The Endocrine Society consider 25[OH]D sufficiency to be levels 30 ng/mL (75 nmol/L), insufficiency to be values of 20–29 ng/mL (50–72.4 nmol/L), and deficiency to be 20 ng/mL (18). These different definitions could be due to the fact that optimal cutoffs for 25[OH]D may vary depending on the associated outcome. For example, the optimal level for bone health may differ from the level associated with decreased CVD risk. Studies have at-