Vitamin D is a fat-soluble vitamin that functions as a pro-hormone — it is converted in the liver to 25-hydroxyvitamin D3 (calcidiol, the major circulating form that is used to assess vitamin D status) and in the kidney to 1,25-dihydroxyvitamin D3 (calcitriol, the hormonally active form that binds to the vitamin D receptor (VDR)). The VDR is a nuclear receptor that is expressed in virtually every cell in the body, and when calcitriol binds to the VDR, the activated VDR dimerises with the retinoic X receptor (RXR) and binds to the vitamin D response elements (VDREs) in the promoters of vitamin D-responsive genes, regulating the transcription of genes that control calcium absorption, bone mineralisation, cell proliferation, immune function, and a vast array of other physiological processes. This vitamin D-VDR signalling system is one of the most important regulatory mechanisms in human physiology, and its dysfunction is implicated in some of the most common diseases of modern civilisation, including osteoporosis, rickets, osteomalacia, autoimmune disease, cancer, and the immune dysfunction that is associated with vitamin D deficiency.
The Vitamin D Endocrine System
The vitamin D endocrine system consists of the skin (where vitamin D3 is synthesised from 7-dehydrocholesterol upon UV-B exposure), the liver (where vitamin D3 is converted to 25-hydroxyvitamin D3 by the vitamin D-25-hydroxylase), the kidney (where 25-hydroxyvitamin D3 is converted to the active 1,25-dihydroxyvitamin D3 by the 1-alpha-hydroxylase enzyme, CYP27B1), and the target tissues (where the VDR mediates the transcriptional effects of 1,25-dihydroxyvitamin D3). The activity of the renal 1-alpha-hydroxylase is regulated by parathyroid hormone (PTH), by the FGF23 hormone, and by the circulating 1,25-dihydroxyvitamin D3 itself, through a feedback loop that maintains calcium homeostasis. When blood calcium is low, PTH stimulates the renal 1-alpha-hydroxylase to produce more 1,25-dihydroxyvitamin D3, which then increases calcium absorption from the gut, increases calcium reabsorption in the kidney, and stimulates bone resorption — all of which act to restore blood calcium to normal levels. This vitamin D-PTH-calcium axis is the primary regulatory system for calcium homeostasis.
The clinical importance of the vitamin D endocrine system is underscored by the conditions that result from its dysfunction. In vitamin D deficiency, the production of 1,25-dihydroxyvitamin D3 is increased (in an attempt to compensate for the low calcium absorption), but without adequate substrate vitamin D, the blood calcium cannot be maintained at normal levels, and the PTH is elevated in secondary hyperparathyroidism. In rickets (the childhood vitamin D deficiency disease), the inadequate mineralisation of the growth plate cartilage and of the osteoid tissue produces the characteristic skeletal deformities — including bowing of the legs, rachitic rosary (costochondral beading), craniotabes (softening of the skull), and delayed fontanelle closure. In osteomalacia (the adult vitamin D deficiency disease), the inadequate mineralisation of the osteoid produces bone pain, muscle weakness, and the pseudofractures (Looser zones) that are the radiographic hallmark of osteomalacia.
Vitamin D and Immune Function
Vitamin D has important immunomodulatory effects that are mediated through the VDR, which is expressed in many immune cells including the monocytes, the dendritic cells, and the T lymphocytes. The active form of vitamin D (1,25-dihydroxyvitamin D3) has been shown to inhibit the differentiation of monocytes to dendritic cells, to inhibit the production of the Th1 cytokines (including interferon-gamma and IL-2), and to promote the differentiation of regulatory T cells (Tregs). These immunomodulatory effects of vitamin D are the basis for the observed association between vitamin D deficiency and autoimmune diseases — including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease — and for the hypothesis that vitamin D supplementation may reduce the risk of these autoimmune conditions. Large randomised controlled trials of vitamin D supplementation for the prevention of autoimmune diseases are currently underway, and the results of these trials will clarify the role of vitamin D in autoimmune disease prevention.
Practical Application
For general vitamin D supplementation, the evidence-based approach is to supplement with vitamin D3 (cholecalciferol) at 1,000-4,000 IU daily (which is sufficient to maintain blood 25-hydroxyvitamin D levels above 30ng/mL, the threshold for vitamin D sufficiency, in the majority of the adult population). The optimal blood level of 25-hydroxyvitamin D for bone health and for the other physiological functions of vitamin D is approximately 40-60ng/mL, and to achieve this level from a starting point of severe deficiency may require doses of 5,000-10,000 IU daily for 3-6 months, followed by a maintenance dose of 2,000-4,000 IU daily. Vitamin D should be taken with a fat-containing meal because it is fat-soluble and requires bile acids for optimal absorption. For comprehensive calcium and bone health support, vitamin D pairs well with calcium (which is the primary mineral component of bone), with vitamin K2 (which directs calcium to bone and away from soft tissues by activating osteocalcin and MGP), with magnesium (which is required for the activity of the renal 1-alpha-hydroxylase and for the function of the vitamin D receptor), and with the weight-bearing exercise programme (which is the most effective non-pharmacological intervention for the maintenance of bone mass).
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