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Abstract Vitamin D has emerged from obscurity, and its effects on various organ systems throughout the body down to the cellular level are being discovered. What was once thought to be a simple hormone affecting only bone and calcium metabolism has shifted. We no longer see vitamin D as a "vitamin" important only in childhood, but as a complex hormone that is involved not only in calcium homeostasis but also in the integrity of the innate immune system. Vitamin D deficiency is linked to inflammatory and long-latency diseases such as multiple sclerosis, rheumatoid arthritis, tuberculosis, diabetes, and various cancers, to name a few. In this review, we trace how we came to view vitamin D and how that view led to one of the largest epidemics of nutrient deficiency beginning in the late 20(th) century. We then discuss the needs of vitamin D in the context of the breastfeeding mother and her infant and child, why breastfed infants are particularly at risk, and what to do about it.
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PMID:Does vitamin D make the world go 'round'? 1908 22

Vitamin D has important benefits in reducing the risk of many conditions and diseases. Those diseases for which the benefits are well supported and that have large economic effects include many types of cancer, cardiovascular diseases, diabetes mellitus, several bacterial and viral infections, and autoimmune diseases such as multiple sclerosis. Europeans generally have low serum 25-hydroxyvitamin D [25(OH)D] levels owing to the high latitudes, largely indoor living, low natural dietary sources of vitamin D such as cold-water ocean fish, and lack of effective vitamin D fortification of food in most countries. Vitamin D dose-disease response relations were estimated from observational studies and randomized controlled trials. The reduction in direct plus indirect economic burden of disease was based on increasing the mean serum 25(OH)D level to 40 ng/mL, which could be achieved by a daily intake of 2000-3000 IU of vitamin D. For 2007, the reduction is estimated at euro187,000 million/year. The estimated cost of 2000-3000 IU of vitamin D3/day along with ancillary costs such as education and testing might be about euro10,000 million/year. Sources of vitamin D could include a combination of food fortification, supplements, and natural and artificial UVB irradiation, if properly acquired. Additional randomized controlled trials are warranted to evaluate the benefits and risks of vitamin D supplementation. However, steps to increase serum 25(OH)D levels can be implemented now based on what is already known.
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PMID:Estimated benefit of increased vitamin D status in reducing the economic burden of disease in western Europe. 1926 96

Extrarenal calcifications, particularly affecting the cardiovascular system, are common observations which can be a source of serious complications in patients with chronic renal disease, especially those on dialysis. In these patients, cardiovascular disease - myocardial infarction, arrhythmia, calcified valvulopathy, stroke, peripheral ischemic arteriopathy, calciphylaxy, etc. - is the leading cause of death (more than 50%). These complications are closely related to the presence of vascular calcifications (VC) which are much more frequent, severe, and progressive than in the general population. Previously, these calcifications were considered to arise via a passive process within the context of comorbid conditions without specific signs of gravity: high blood pressure, atherosclerosis, aging, diabetes, smoking, dyslipidemia, chronic micro-inflammation, hyperhomocysteinemia, disorders of calcium-phosphorus metabolism. It is now established that VC arise via a complex, probably regulated, active process analogous to the processes leading to bone formation and/or remodeling. New insight provided by a large body of work designed to ascertain the mechanisms underlying the onset of VC has enabled the development of new diagnostic and therapeutic approaches. It is now possible to identify factors clearly favoring the formation of VC: TNF-alpha (which stimulates cell necrosis/apoptosis), CRP, oxidized lipids, AGEs, leptin, inorganic phosphate, high calcium-phosphorus product (CaxPO(4)), calcium, 1,25-OH(2)D(3) and Vitamin D(3), PTHrP (via an intracrine pathway), cyclic AMP, TGF-beta, bone morphogenic protein 2 (BMP2) and factors protective against the formation of VC: magnesium, HDL, inorganic pyrophosphate, albumin, ahsg/fetuin A, osteopontin (OPN), osteoprotegerin (OPG), osteonectin (ON), bone morphogenic protein 7 (BMP7), klotho, PTHrP (via a paracrine pathway), matrix gla protein (MGP), PTH (via Msx2) and vitamin K. In conclusion, until recently, neglected disorders of calcium-phosphorus metabolism are currently recognized as the main actors in the process leading to vascular mediacalcosis in patients with chronic kidney failure.
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PMID:[Origin of the mediacalcosis in kidney failure]. 1934 26

It is the purpose of this comprehensive report to outline a revolutionary strategy to prevent vitamin D deficiency in our nation. Vitamin D is a unique vitamin. Its metabolic product, calcitriol, is a profound secosteroid hormone that has impact on over 1000 genes in the human body. Recent clinical research has implicated vitamin D deficiency as a major factor in the etiology of rickets, a wide variety of cancers, as well as hypertension, stroke, heart attack, diabetes, bone fractures, periodontal disease, and even multiple sclerosis. There are two forms of vitamin D utilized in the human body: D2 and D3. Measurement of 25(OH)D is the most reliable method of detecting vitamin D deficiency. Several methods, including high-performance liquid chromatography (HPLC), chemoluminescence, and radioimmunoassay (RIA), have been developed for the measurement of total 25(OH)D levels. Prevention and treatment of vitamin D deficiency is accomplished by regulated sun exposure as well as vitamin D, supplementation. This information describing our plan to prevent vitamin D deficiency in the patients and employees of Legacy Health System is a landmark accomplishment that should be replicated in every healthcare setting in our country to prevent vitamin D deficiency.
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PMID:Modern concepts in the diagnosis and treatment of vitamin D deficiency and its clinical consequences. 1939 50

Prevention, or at least delay in onset of type 2 diabetes is possible by intensive lifestyle intervention. This is costly and labour intensive, and alternative methods of preventing diabetes have been sought. Vitamin D has important physiological effects aside from its effects on bone metabolism, including an important role in glucose homeostasis, insulin release and response. Observational data strongly support the role of vitamin D deficiency in the pathogenesis of type 2 diabetes. The time is ripe for a well conducted randomised controlled trial of vitamin D in high risk individuals to test the hypothesis that vitamin D delays the onset of type 2 diabetes.
Prim Care Diabetes 2009 May
PMID:Vitamin D and type 2 diabetes: Is there a link? 1939 31

Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin-megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.
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PMID:Vitamin D and aging. 1944 37

The growing incidence of prediabetes and clinical type 2 diabetes, in part characterised by insulin resistance, is a critical health problem with consequent devastating personal and health-care costs. Vitamin D status, assessed by serum 25-hydroxyvitamin D levels, is inversely associated with diabetes in epidemiological studies. Several clinical intervention studies also support that vitamin D, or its active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D), improves insulin sensitivity, even in subjects with glucose metabolism parameters classified within normal ranges. The mechanisms proposed which may underlie this effect include potential relationships with improvements in lean mass, regulation of insulin release, altered insulin receptor expression and specific effects on insulin action. These actions may be mediated by systemic or local production of 1,25(OH)2D or by suppression of parathyroid hormone, which may function to negatively affect insulin sensitivity. Thus, substantial evidence supports a relationship between vitamin D status and insulin sensitivity; however, the underlying mechanisms require further exploration.
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PMID:Vitamin D: emerging new roles in insulin sensitivity. 1955 19

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Recently vitamin D deficiency has been identified as a potential risk factor for many diseases not traditionally associated with vitamin D, such as cancer and CVD. This review discusses the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms mediating it. Vitamin D deficiency has been associated with CVD risk factors such as hypertension and diabetes mellitus, with markers of subclinical atherosclerosis such as intima-media thickness and coronary calcification as well as with cardiovascular events such as myocardial infarction and stroke as well as congestive heart failure. It could be suggested that vitamin D deficiency contributes to the development of CVD through its association with risk factors, such as diabetes and hypertension. However, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells and vitamin D has been shown to affect inflammation and cell proliferation and differentiation. While much evidence supports a potential antiatherosclerotic effect of vitamin D, prospective, placebo-controlled randomized as well as mechanistic studies are needed to confirm this association. Since vitamin D deficiency is easy to screen for and treat, the confirmation of such an association could have important implications for both, patient care and health policy.
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PMID:Vitamin D and cardiovascular disease. 1960 65

Although diabetes mellitus (DM) disturbs bone metabolism, little is known concerning its effects on laboratory abnormalities in chronic kidney disease-mineral and bone disorders (CKD-MBD). We extracted data for 602 patients from the Osaka Vitamin D Study in patients with CKD (OVIDS-CKD), an observational study enrolling predialysis outpatients. No enrolled patients received vitamin D, bisphosphonate, estrogen or raloxifene. We measured 1- 84 PTH, 25-hydroxyvitamin D (25D), calcitriol, fibroblast growth factor-23 (FGF-23), calcium (Ca), and phosphate (P). Since there were 112 DM patients (group D), we extracted 112 age-, sex-, and eGFR-matched non-DM counterparts (group N). We compared biochemical markers between groups, and then performed multiple regression analyses for all 602 subjects to confirm the results obtained. Group D had significantly higher corrected Ca and P than group N throughout all stages of CKD. In group D, 25D decreased as renal function declined, while in group N it remained constant (interaction P<0.05). Despite higher P and poorer vitamin D status in DM, there were no differences in 1- 84 PTH level between group D and group N stratified by stage of CKD, resulting in significantly lower calcitriol levels in group D in late CKD. Multiple regression analyses revealed that DM was significantly associated with low vitamin D status even with adjustment for urinary protein, and that this poorer vitamin D status in DM was responsible for lower calcitriol level associated with DM. Despite higher P, lower FGF-23 in early CKD (stages 1 + 2) and comparable level of FGF-23 in late stages of CKD (stages 3, 4, and 5) were observed in group D. We interpreted these results to indicate that inappropriate production of FGF-23 in DM might explain higher serum phosphate in DM. Multiple regression analysis with adjustment for covariates confirmed an independent relationship between DM and low FGF-23, implying the existence of dysfunction or decreased density of osteocytes in DM. Given the origin of these phosphaturic hormones, DM may thus have markedly deleterious effects on parathyroid and bone. Poorer vitamin D status and higher CaP product might be partly responsible for functional and structural changes of vasculature, respectively, in DM.
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PMID:The impact of diabetes mellitus on vitamin D metabolism in predialysis patients. 1963 79

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.
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PMID:Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease. 1975 26


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