Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases.
Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.
On November 30, 2010, at the request of the Canadian and US Governments, the Institute of Medicine provided a report addressing conflicting information on vitamin D.1 This report took into consideration >1000 studies and reports and considered testimony from scientists and stakeholders. Outcomes included bone and cardiovascular diseases as well as cancer, diabetes mellitus, inflammation, neuropsychological function, physical performance, preeclampsia, and reproduction. The overall conclusion of this report was that the majority of Americans and Canadians are receiving adequate amounts of both calcium and vitamin D and that too much of these nutrients may be harmful. It further noted that information about health benefits beyond those for bone—benefits often reported in the media—were from studies with mixed and inconclusive results that could not be considered reliable.2 Even before this report, Towler had noted that the effects of vitamin D on cardiovascular health are complex and biphasic, with direct and indirect actions mediating its vasculotropic actions.3 There is not yet evidence from a randomized controlled trial showing a cardiovascular benefit of vitamin D supplementation.4
Until recently, hormonal regulation of calcium-phosphate metabolism by vitamin D metabolites and the parathyroid gland were of little interest to cardiovascular scientists and clinicians. But with new clinical guidelines and media attention, awareness of vitamin D physiology is necessary, especially given that, despite the conclusions of the Institute of Medicine, routine vitamin D testing and supplementation are widely recommended by physicians. As commonly occurs with supplements, it is often used in doses far beyond those directed. Given its extensive actions in human metabolism—both beneficial and harmful—the biochemistry, physiology, and financial motivations surrounding vitamin D warrant attention.
Forms of Vitamin D
From a technical standpoint, the term vitamin D is a misnomer. It is not a true vitamin because the human body has the capacity to synthesize its own cholecalciferol (D 3 ), except in rare instances of complete lack of ultraviolet radiation. It is more accurate to view it as a steroid hormone or an oxysterol. The International Union of Pure and Applied Chemistry’s Commission on the Nomenclature of Biological Chemistry defines vitamin D 3 as a steroid or secosteroid. Its chemical name is 9,10-secocholesta-5,7,10(19)-trien-3beta-ol. Six different steroid hormones go by the name vitamin D, with varying degrees of activity: the endogenous precursor, cholecalciferol (D 3 ), which is derived from cholesterol; its hydroxylated derivative, calcidiol (25(OH)D 3 ), which has partial activity; and its hydroxylated derivative, the active dihydroxy-form, calcitriol (1,25(OH) 2 D 3 ). In addition, there is a plant-derived form, ergocalciferol (D 2 ), which also has the corresponding monohydroxy and dihydroxy metabolites. Since 25(OH)D 3 is longer lasting, it is the level of this hormone—not that of the more active 1,25(OH) 2 D 3 —that is used to diagnose clinical deficiency. Notably, levels of 25(OH)D 3 tend to vary inversely with the levels of the active form, possibly because of displacement of the active metabolite from D-binding protein (DBP).5 In this article, we will use the term vitamin D hormones for all 6 types of steroid hormones and to emphasize their true physiological nature.
Sources of vitamin D hormones include exposure to ultraviolet light, certain foods, and dietary supplements. As one of the 4 fat-soluble vitamins (A, D, E, and K), its lipophilicity requires special mechanisms to pass through the aqueous environment of blood to reach tissues and cells. Separate mechanisms are used for the endogenous D 3 synthesized in sun-exposed skin versus exogenous D 3 obtained from diet or supplements. This may result in distinct pharmacokinetic volumes and targets of distribution (Figure 1).
Figure 1. Vitamin D-hormone metabolism, carriers, and distribution. Because of its lipophilic nature, endogenously produced D 3 is carried in the aqueous environment of blood by D-binding protein (DBP), whereas exogenous (dietary and supplemental) D 3 and D 2 , absorbed from the intestines, are transported within chylomicrons, which are further processed to lipoproteins (eg, VLDL [very-low-density lipoprotein] and LDL [low-density lipoprotein]), many of which continue to carry the exogenous D. The conventional sites of vitamin D-hormone metabolism are the liver and proximal tubules of the kidney, where hydroxylases convert it to its active form. But hydroxylase activity is also found in parenchymal and immune cells, including vascular smooth muscle cells (VSMC) and monocytes, in other tissues. This raises the potential for accumulation of vitamin D hormone within LDL in the subendothelial space, where it may undergo activation in atherosclerotic plaque and possibly influence ectopic differentiation and calcification. UV indicates ultraviolet.
Endogenous Vitamin D Hormone Synthesis, Transport, and Activation
Endogenous vitamin D hormone synthesis occurs by ultraviolet light exposure of 7-dehydrocholesterol within the microvessels of the skin resulting in its conversion into cholecalciferol (D 3 ). But, as a fat-soluble oxysterol, D 3 must be carried in the blood by DBP, a liver-derived apoprotein and a member of the albumin gene family.6 For light-skinned individuals, sun exposure of the face and arms for just 15 minutes per week may produce tens of thousands of units of cholecalciferol. This endogenous production from sun exposure had been the major source for most humans for centuries. The fact that sun-derived D 3 is carried on DBP is a key difference from exogenous D 3 , because of its potential influence on biodistribution.
Exogenous sources of vitamin D hormones include diet (eggs, fish, liver, and marine mammal fat) and supplements. A cup of milk provides ≈100 international units (IU) and a serving of salmon contains ≈400 IU of D 3 . Although the dietary sources may be in the D 3 or D 2 form, supplements typically derive from the plant-derived hormone, ergocalciferol (D 2 ). A key feature of dietary or supplemental sources is that D 3 taken orally is absorbed from the intestinal tract via chylomicrons,7 which pass into the lymphatic circulation before returning to the central venous circulation via the thoracic duct. Eventually, ≈35% of ingested D 3 is carried in lipoproteins,8 rather than DBP.
Activation by Sequential Hydroxylation of D 3
For both endogenous and exogenous sources, the D 3 carried in the bloodstream on either DBP or lipoproteins undergoes a 2-step sequential hydroxylation to active metabolites. First, it is converted by 25-hydroxylase to the monohydroxy-derivative, 25(OH)D 3 , the metabolite that is measured for vitamin D levels. This occurs primarily in the liver but may take place in other tissues as well. Next, 25(OH)D 3 is further hydroxylated by 1-alpha–hydroxylase to the active, dihydroxy-form, 1,25(OH) 2 D 3 .8 This occurs primarily in the capillaries surrounding the proximal convoluted tubules of kidney, but, importantly, the enzyme producing the active form is also found in vascular cells and monocytes among other tissues and cells (Table).
Table. Partial Literature Summary of Vitamin D-Hormone Actions Vitamin D-Hormone Effects Targets Cells that metabolize D 3 Hepatocytes,9 renal cells,10 endothelial cells,11 smooth muscle cells,12 monocytes,13 skeletal muscle cells14 Pathophysiology affected Osteomalacia,15 vascular calcification,16–19 renal and myocardial calcification,19 atherosclerosis,20 heart failure,21 thrombosis22 Tissue content and function affected Calcium balance,23 aortic elastin,24 bile acid synthesis,25 vasoconstrictor response to norepinephrine,26 lipogenesis,27 insulin sensitivity,28 endothelial-dependent contraction29 Cellular functions Osteoblastogenesis,30 osteoclastogenesis,31 chondrogenesis32 Myogenesis,33 adipogenesis,34 hematopoiesis,35 nerve growth36 Smooth muscle cell (SMC) dedifferentiation,37 SMC migration,38 SMC contraction39 Tumor cell differentiation40 Macrophage cholesterol uptake,41 T-lymphocytes42 Apoptosis,43 DNA synthesis,44 arachidonic acid turnover45 Oscillation of inositol phosphate 3 and diacylglycerol production46 Prostaglandin production,47,48 superoxide anion production49 Nitric oxide synthase50 Signaling pathways Protein kinase C-alpha,51 cAMP,52 p38 MAPK (mitogen-activated protein kinase),53 cellular homolog of the oncogene of avian myelocytomatosis virus strain 29,54 c-fos,31 NFAT-1 (nuclear factor of activated T cells 1),55 Wnt,56 nuclear factor-kappa B57 Known interactions Retinoic acid receptors,58 retinoid X receptors,59 glucocorticoid60 Runx-2 (runt related transcription factor–2),61 transforming growth factor-beta,62 insulin-like growth factor binding protein-5,63 vitamin K,64 estrogen65 Protein synthesis and serum levels regulated LDL (low-density lipoprotein),66 prostaglandin synthesis,47 endothelin receptor37 Gene expression Bone morphogenetic protein-2,67 alkaline phosphatase,68 bone sialoprotein,69 collagen I,70 osteopontin,70 osteocalcin,61 tissue plasminogen activator,71 parathyroid hormone,72 fibroblast growth factor-2373 Receptor activator of nuclear factor-kappa B ligand74 Msx-2 (muscle segment homeobox-containing gene; Hox-8)75 Peroxisome proliferator–activated receptor-gamma76 Integrins,77 fibronectin,78 laminin receptor79 Collagenase,80 matrix metalloproteinase81 Granulocyte-macrophage colony stimulating factor,55,60 macrophage-colony stimulating factor,82 tumor necrosis factor-alpha,83 interleukin-884 Insulin receptor85 Vascular endothelial growth factor,86 nerve growth factor87 Type A natriuretic peptide receptor88 Aromatase89 Nephrin58 CYP7A1,90 CYP19A1,89 CYP24A191 p450 cytochrome,92 Mullerian-inhibiting substance93
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Guidelines for Vitamin D Hormone Assessment and Supplementation
Different criteria for vitamin D deficiency have been proposed by the Endocrine Society, Osteoporosis Society, and Institute of Medicine. Normal reference values shown by individual clinical laboratories are not standardized. Conservative definitions define vitamin D deficiency as levels of 25(OH)D 3 <20 ng/mL (<50 nmol/L), and vitamin D insufficiency as 20 to 30 ng/mL (50–75 nmol/L).94 The Institute of Medicine chooses cut off values of <12 ng/mL and >50 ng/mL as levels with increased risk of deficiency and excess, respectively.1 The Institute of Medicine does not recommend specific doses, but, based on bone health indicators, their analysis suggests that the daily use of vitamin D is 600 IU for individuals from 1 to 70 years of age, and 800 IU for individuals 71 and older, some or all of which may be achieved by ordinary sun exposure.1 They further suggest a safe upper limit of dietary vitamin D intake as 4000 IU daily, a level at which risk for toxicity begins to increase. Yet, the Institute of Medicine emphasizes that this upper limit should not be misunderstood as amounts people need or should strive to consume.1
The use of the terms daily and per day in these recommendations may give the false impression that a day without sunshine requires a dose of supplement. Even though adults may use a given amount of cholecalciferol each day, such daily use does not necessarily require daily replacement. 25(OH)D 3 has a half-life of 2 weeks95 to 3 months,96 and is stored primarily in adipose tissue97,98 and, to a lesser extent, in the liver.99 Presumably, this stored source of vitamin D is available for release back into the plasma, as indicated by a long-term study in Norwegians.100 Moreover, cholecalciferol recycles in the enterohepatic circulation.101 Thus, vitamin D hormones may not require daily, weekly or even monthly replenishment. Summer sun exposure may provide enough for the winter.102 Major institutions have used dosing schedules as infrequent as once every 1 to 4 months.103,104 It may be more correct to refer to a monthly requirement, and this requirement may vary depending on age (<70 years or >70 years) or season (ie, summer versus winter).102
Personalized Approach to Vitamin D Hormones
A personalized medicine approach is important in considering vitamin D hormone supplementation because of the influence of differences in body composition, environmental factors, and genetic variations in DBP as well as variations in the intracellular vitamin D receptor (VDR). Although darkly pigmented individuals are believed to require more sun exposure to generate the same amount of vitamin D hormones, they have genetic polymorphisms of the vitamin DBP,105 which change the bioavailability of vitamin D, counteracting the decrease in synthesis.106 The half-life of 25(OH)D 3 in the bloodstream is influenced by genotype of the DBP. Based on in vitro studies, the intracellular VDR, which binds and translocates 1,25(OH) 2 D 3 to the nucleus, has ≈7% read through efficiencies, producing VDR proteoforms that have reduced binding.107 This phenomenon may vary among individuals. High body fat content may decrease availability of fat-soluble 25(OH)D 3 because of sequestration in adipose tissue.108 Conversely, high skeletal muscle content also modulates vitamin D hormone availability; muscle cells internalize DBP and expose it, allowing extensive intracellular uptake and retention of 25(OH)D 3 .109 The elderly may have lower levels because of less outdoor activity and sun exposure.102 Polymorphisms arising in the Inuit Eskimo background limit intestinal D 3 uptake protect against excess D 3 ingestion from the ancestral diet of whale blubber rich in vitamin D hormones. These genetic variations, phenotypic differences, and environmental influences underscore the importance of tailoring any recommendations for vitamin D supplementation to individualized needs.
Both mono- and dihydroxy-forms of vitamin D hormones are delivered to cells either by DBP,124 where entry is mediated by the endocytic receptors, cubilin/megalin,125 or by lipoproteins,8 where entry is mediated by the LDL (low-density lipoprotein) receptor.126 However, during the pathogenesis of atherosclerosis, vitamin D hormones that are consumed in the diet may accompany LDL into the subendothelial space of the artery wall where atherosclerotic lesions form.127 In peripheral tissues that express lipoprotein lipase, the chylomicron metabolizing enzyme, a fraction of vitamin D hormones can be taken up by the tissues. Since 1-alpha–hydroxylase is present in tissues and cells, including vessel walls and monocyte-derived cells, the active form may be produced locally within the artery wall and, conceivably, within monocyte-laden atherosclerotic plaque.128
Targets of Vitamin D Hormones
Cellular and molecular effects of vitamin D hormones are extensive. In addition to homodimerization, VDR heterodimerizes with the retinoid X receptor to activate transcription of a wide range of genes. As steroid hormones, they are related to estrogen, testosterone, mineralocorticoids, and glucocorticoids. Even our limited search of the literature (Table) reveals hundreds of diverse genomic and nongenomic targets of vitamin D hormones, affecting a vast array of physiological functions. Adding further complexity, vitamin D hormones have significant cross talk with steroid and nuclear hormones and their receptors.129 For instance, vitamin D 3 may affect actions of glucocorticoids.130,131 Conversely, steroid and xenobiotic receptors132 as well as peroxisome proliferator-activated receptor-gamma133 inhibit VDR-mediated CYP24 (24-hydroxylase) promoter activity.
Effects of Vitamin D Hormones in the Vasculature
Given that diet-derived 25(OH)D 3 is carried in lipoproteins, and that lipoproteins accumulate in the subendothelial space of arteries leading to atherosclerotic lesions, it is likely that diet-derived 25(OH)D 3 also accumulates in the neointima artery wall and atherosclerotic plaque. Given that vascular smooth muscle cells and monocytes both produce 1-alpha–hydroxylase, it follows that 1,25(OH) 2 D 3 may also accumulate in artery walls and atherosclerosis. Potential effects of this accumulation remain to be determined. One possibility is an acceleration of both atherosclerosis and cardiovascular calcification, based on studies showing that vitamin D receptor deficiency significantly reduces calcific atherosclerosis in hyperlipidemic mice.134 Vitamin D hormones are known to stimulate smooth muscle cell proliferation135 and induce expression of FGF-23 (fibroblast growth factor-23), high levels of which are linked to adverse cardiovascular events.136 With respect to mineralization, effects of vitamin D hormones are double-edged. Although there is convincing evidence that supplements increase bone density,137 any benefit to bone may be at the cost of cardiovascular morbidity and mortality because of calcific vasculopathy and valvulopathy. Cardiovascular calcification has been shown to occur by many of the same cellular and molecular processes as bone mineralization,138 including induction of osteogenic factors by vitamin D hormones.139 Indeed, high dose vitamin D supplements used for several decades as an experimental model reproducibly induces severe aortic calcification, acutely and chronically, over a wide range of conditions in a variety of species in the hands of many different investigators.17,18 The dramatic vascular calcification seen in patients with chronic kidney disease may be due in part to local induction of 1-alpha–hydroxylase in the artery wall.140 The extensive immunomodulatory effects of vitamin D have been reviewed elsewhere.141
Vitamin D-Hormone Toxicity and Benefits
Overuse of vitamin D-hormone supplements carries significant risks that have been known for decades, and these risks have traditionally been associated with those of the resulting hypercalcemia that can occur at 25(OH)D 3 plasma concentrations of >150 ng/mL (>375 nmol/L). Thus, the traditional clinical manifestations of vitamin D-hormone toxicity are those of hypercalcemia, which include generalized (fatigue, weakness), neurological (altered mental status, irritability, coma), gastrointestinal (nausea, vomiting, constipation), and endocrinologic (polyuria, polydipsia) symptoms. Additionally, renal injury as well as the development of kidney stones may occur. As such, studies evaluating the safety of various dosing regimens typically use measurements of serum and urinary calcium to monitor the safety of the administered doses.142,143
However, given the number of cell types and tissues that possess 25-hydroxylase, vitamin D hormones may have effects on these systems without necessarily affecting the serum or urinary calcium levels, and all of the biological processes listed in the Table may be deranged by excess intake. A daily intake of 25(OH)D 3 up to 4000 IU is deemed to be the upper limit of safety,1 as the risk of harm seems to increase above this level. Yet as discussed above, variations in vitamin D-hormone production and metabolism may depend significantly on individual genotype, phenotype, and environmental conditions; thus, a universal upper limit of safety and a universal lower limit of sufficiency for all patients may not necessarily be accurate. Additionally, excess vitamin D-hormone supplements also displace the active form from binding sites, making it more available even when not appropriate.5 Further, given the cross talk with other steroid hormone receptors, vitamin D hormones in excess may have physiological effects similar to those of glucocorticoids, estrogen, or even those of anabolic steroids.144 Nonetheless, in general, it is difficult to categorize any one of the numerous effects of vitamin D as necessarily beneficial or toxic, given the dependence on location as well as physiological and pathological contexts. For instance, osteoblastogenesis may be beneficial in osteoporosis but hazardous in calcific vasculopathy and valvulopathy.
Concluding Remarks
Widely used guidelines for monitoring and supplementing vitamin D hormones resembles the ill-fated call, years ago, for widespread use of another steroid hormone, estradiol, for postmenopausal women based on observational studies. The impact of confounding environmental factors was not recognized. Even after the Women’s Health Initiative showed increased cardiovascular risk in postmenopausal women randomized to hormone replacement therapy,104 recommendations were slow to change. Observational studies are not sufficient to recommend widespread hormonal supplementation, and the same applies to vitamin D hormones. The ongoing randomized clinical trial, VITAL (Vitamin D and Omega-3 Trial), will be helpful in determining whether vitamin D-hormone supplementation provides any benefit in the primary prevention of cancer and cardiovascular disease.145
Decades ago, the pioneering Johns Hopkins cardiologist, Dr Helen Taussig, anticipated the need for a personalized approach to D 3 supplements: “as is so common, the popular belief was that if ‘some is good, more is better.’ The result was the overdosing with vitamin D and adding it to various foods. Then came the recognition of vitamin D intoxication… we are coming to appreciate that there exists an inborn variation in man’s ability to metabolize vitamin D and that some individuals may be injured by doses of vitamin D which are safe for others.”146 For health reasons, many Americans pay extra for bread free of preservatives (such as antioxidants) and meats that are free of steroid hormones. In the next aisle of the store, they buy bottles of antioxidant preservatives and steroid hormones in pill form, labeled as nutritional supplements, including D 3 hormones. Scientists need to use their knowledge of molecular, cellular, and integrative physiology to advocate for the rational use of vitamin D-hormone supplements to prevent adverse consequences to cardiovascular health by overenthusiastic guidelines followed by well-meaning physicians.
Nonstandard Abbreviations and Acronyms 25(OH)D 3 calcidiol 1,25(OH) 2 D 3 calcitriol DBP (vitamin) D-binding protein FGF-23 fibroblast growth factor-23 LDL low-density lipoprotein VDR vitamin D receptor VITAL Vitamin D and OMEGA-3 Trial
Acknowledgments
Without express permission, we wish to acknowledge the late Hywel Davies, MD, FRCP (1924–2017), whose writing and input contributed to this review.
Sources of Funding This study was supported in part by funding from the National Institutes of Health (HL114709, HL121019, HL007895), the Claude D. Pepper Older American Independence Center at UCLA, and an award from the UCLA Specialty Training and Advanced Research Program.
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