Update in vitamin D

Abstract

The past decade, particularly the last 18 months, witnessed a vigorous increase in interest in vitamin D from both the lay and biomedical worlds. Much of the growing interest in vitamin D is powered by new data being extracted from the National Health and Nutrition Examination Survey (NHANES). The newest statistics demonstrate that more than 90% of the pigmented populace of the United States (Blacks, Hispanics, and Asians) now suffer from vitamin D insufficiency (25-hydroxyvitamin D <30 ng/ml), with nearly three fourths of the white population in this country also being vitamin D insufficient. This represents a near doubling of the prevalence of vitamin D insufficiency seen just 10 yr ago in the same population. This review attempts to provide some explanation for: 1) the rapid decline in vitamin D status in the United States; 2) the adverse impact of vitamin D insufficiency on skeletal, infectious/inflammatory, and metabolic health in humans; and 3) the therapeutic rationale and reliable means for vigorous supplementation of our diets with vitamin D.

Figures

Figure 1

A, Summary of distinctions between the two, phylogentically discrete functions of vitamin D (see Footnote 1), one as a circulating hormone (left) and the other as a locally produced, locally active cytokine made by monocyte-macrophages (right). B, Schematic tracing the serial endocrine responses to a diminishment in vitamin D-directed intestinal calcium absorption as might be seen in humans with acquired vitamin D insufficiency/deficiency; the final step in the process is 1,25-dihydroxyvitamin D (1,25-D) stimulation of genes controlling calcium absorption from the gut, mobilization of calcium from the skeleton and, finally, synthesis and release of FGF23, which acts to return previously enhanced PTH and CYP27B1-hydroxylase gene expression to normal. DBP, Vitamin D binding protein; RXR, retinoid X receptor.

Figure 2

Shown is a schematic of a human macrophage responding to pathogen-associated membrane patterns (PAMPs), shed from wall of M. tuberculosis via the pattern recognition, TLR dimmer pair, TLR1–TLR2. Signaling through the TLRs leads to induction of expression of the endogenous CYP27B1-hydroxylase and VDR. Provided that adequate amounts of substrate 25-hydroxyvitamin D (25D), circulated to the monocyte-macrophage bound to the serum vitamin D binding protein (DBP), are available to the mitochondrial CYP27B1 for intracrine conversion to 1,25-dihydroxyvitamin D (1,25D), the 1,25D ligand activates the VDR; instigates its dimerization with retinoid X receptor (RXR) and nuclear localization of the VDR-RXR; and promotes expression of the cathelicidin antimicrobial gene. In turn, the cathelicidin gene product, LL37, supports the phagolysosomal killing of ingested mycobacterium.

Figure 3

A, Proposed schema linking low serum 25D levels and secondary hyperparathyroidism with 1,25-dihydroxyvitamin D (1,25D)-driven fat accumulation amplifying the state of vitamin D depletion, while at the same time generating an increase in the serum leptin concentration, which exerts feedback inhibition on the synthesis of 1,25D. B, Schematic of the regimen for vitamin D replacement and maintenance therapy in subjects with serum 25D levels less than 30 ng/ml. The regimen calls for: 1) delivery of 500,000 to 1,000,000 IU vitamin D (see Footnote 1) orally over 4–5 wk; 2) a similarly timed period of no vitamin D to permit ascertainment and confirmation of steady-state 25D levels; and 3) maintenance therapy of 50,000 IU vitamin D orally every month thereafter to maintain a vitamin D sufficiency.