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Novel roles of vitamin D in disease: What is new in 2011?

      Abstract

      Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of genes. Until recently its main known role was to control bone metabolism and calcium and phosphorus homeostasis. During the last 2 decades it has been realized that vitamin D deficiency, which is really common worldwide, could be a new risk factor for many chronic diseases, such as the metabolic syndrome and its components, the whole spectrum of cardiovascular diseases, several auto-immune conditions, and many types of cancer as well as all-cause mortality. Except for the great number of epidemiological studies that support the above presumptions, vitamin D receptors (VDRs) have been identified in many tissues and cells. The effect of vitamin D supplementation remains controversial and the need for more persuasive study outcomes is intense.

      Keywords

      1. Introduction and background

      In recent years emphasis has been given on the role of vitamin D in areas beyond bone metabolism and calcium homeostasis [
      • Peterlik M.
      • Cross H.S.
      Vitamin D and calcium deficits predispose for multiple chronic diseases.
      ]. In this context, vitamin D deficiency has been associated with risk factors for cardiovascular disease, the metabolic syndrome and its components (i.e. hypertension, atherogenic dyslipidemia, diabetes mellitus, impaired glucose tolerance, central obesity), and even with cancer, autoimmune diseases, infections and overall mortality [
      • Nadir M.A.
      • Szwejkowski B.R.
      • Witham M.D.
      Vitamin D and cardiovascular prevention.
      ,
      • Melamed M.L.
      • Michos E.D.
      • Post W.
      • Astor B.
      25-hydroxyvitamin D levels and the risk of mortality in the general population.
      ].
      The aims of this review are to summarize the most recent data regarding these associations and try to clarify whether and to what extent oral vitamin D supplementation could be used as a beneficial intervention in such diseases.

      1.1 Search methods

      We searched the PubMed up to 15 January 2011 using combinations of the following keywords: vitamin D deficiency/insufficiency and mortality, metabolic syndrome, cardiovascular disease, immune system and cancer.
      Randomized controlled trials, original papers and review articles are included in the present review. Also the references of those reviews were scanned for relevant articles.

      1.2 Sources and metabolism of vitamin D

      Fig. 1 summarizes the sources and metabolism of vitamin D as well as its main sites of action [
      • Muszkat P.
      • Camargo M.B.
      • Griz L.H.
      • Lazaretti-Castro M.
      Evidence-based non-skeletal actions of vitamin D.
      ,
      • Reddy Vanga S.
      • Good M.
      • Howard P.A.
      • Vacek J.L.
      Role of vitamin D in cardiovascular health.
      ,
      • Florentin M.
      • Elisaf M.S.
      • Mikhailidis D.P.
      • Liberopoulos E.N.
      Vitamin D and metabolic syndrome: is there a link?.
      ].
      Figure thumbnail gr1
      Fig. 1Synthesis and effects of vitamin D. The majority of body's vitamin D (80–90%) comes from endogenous production in the skin through ultraviolet irradiation of the precursor, 7-dehydrocholesterol. Other main sources of vitamin D are fatty fish, eggs and dairy products, as well as dietary supplements
      [
      • Muszkat P.
      • Camargo M.B.
      • Griz L.H.
      • Lazaretti-Castro M.
      Evidence-based non-skeletal actions of vitamin D.
      ]
      . Both endogenous and ingested vitamin D is stored in fat tissue, since it is a fat-soluble molecule, and then it is released into circulation, bound to a vitamin D-binding protein. Vitamin D undergoes first a hepatic 25-hydroxylation, and then a renal 1-α-hydroxylation to produce the active hormone 1,25(OH)2Vit D. The second hydroxylation is tightly regulated by serum parathyroid hormone (PTH), calcium and phosphorus levels. 1,25(OH)2Vit D itself induces the expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24), which catabolizes both 25(OH)Vit D and 1,25(OH)2Vit D into biologically inactive, water-soluble calcitroic acid. The biological functions of vitamin D are exerted through the interaction of the steroid hormone 1,25(OH)2Vit D with a single vitamin D receptor (VDR) in the cell nucleus that functions as a ligand-dependent transcription factor. Subsequently it regulates the expression of many target genes for the production of several molecules such as osteocalcin, osteopontin, calbindin-D28K, calbindin-D9K, TGF-β2 and vitamin D 24-hydrohylase. Therefore, it was hypothesized that the vitamin D endocrine system has additional physiological functions [
      • Muszkat P.
      • Camargo M.B.
      • Griz L.H.
      • Lazaretti-Castro M.
      Evidence-based non-skeletal actions of vitamin D.
      ,
      • Reddy Vanga S.
      • Good M.
      • Howard P.A.
      • Vacek J.L.
      Role of vitamin D in cardiovascular health.
      ,
      • Florentin M.
      • Elisaf M.S.
      • Mikhailidis D.P.
      • Liberopoulos E.N.
      Vitamin D and metabolic syndrome: is there a link?.
      ].

      1.3 Definition, prevalence and risk factors for vitamin D deficiency

      The most commonly used cut-points for serum 25(OH) Vit D levels in adults are: >75 nmol/L (>30 ng/mL) for vitamin D sufficiency, 50–70 nmol/L (20–28 ng/mL) for insufficiency and <50 nmol/L (<20 ng/mL) for deficiency. It has been estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency [
      • Holick M.F.
      Vitamin D deficiency.
      ,
      • Bischoff-Ferrari H.A.
      • Giovannucci E.
      • Willett W.C.
      • Dietrich T.
      • Dawson-Hughes B.
      Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.
      ]. The Third National Health and Nutrition Examination Survey (NHANES III) reported the prevalence of vitamin D deficiency in United States adults to be 25–57% [
      • Looker A.C.
      • Dawson-Hughes B.
      • Calvo M.S.
      • Gunter E.W.
      • Sahyoun N.R.
      Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.
      ].
      Furthermore, 40–100% of U.S. and European non institutionalized elderly people are vitamin D deficient, mainly because aging is associated with decreased concentrations of 7-dehydrocholesterol in the skin [
      • Nadir M.A.
      • Szwejkowski B.R.
      • Witham M.D.
      Vitamin D and cardiovascular prevention.
      ,
      • Michos E.D.
      • Reis J.P.
      • Melamed M.L.
      Vitamin D status and cardiovascular health: a 2009 update.
      ]. Obesity is another strong risk factor for vitamin D deficiency, because fat cells sequester vitamin D. Lower vitamin D levels among older and obese people may also stem from reduced outdoor activity and sunlight exposure [
      • Michos E.D.
      • Reis J.P.
      • Melamed M.L.
      Vitamin D status and cardiovascular health: a 2009 update.
      ,
      • Scragg R.
      • Camargo Jr., C.A.
      Frequency of leisure-time physical activity and serum 25-hydroxyvitamin D levels in the US population: results from the Third National Health and Nutrition Examination Survey.
      ]. Additionally, at particular risk are race/ethnic groups with darker skin coloring living in the Northern hemisphere, since melanin skin pigmentation absorbs UVB light, thus reducing vitamin D synthesis [
      • Michos E.D.
      • Reis J.P.
      • Melamed M.L.
      Vitamin D status and cardiovascular health: a 2009 update.
      ,
      • Martins D.
      • Wolf M.
      • Pan D.
      • Zadshir A.
      • Tareen N.
      • Thadhani R.
      • et al.
      Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey.
      ]. In addition, children and young adults, as well as pregnant and lactating women and their infants, especially when there is multiparity, short spacing between pregnancies, non-white maternal skin and exclusive breast feeding, are also potentially at risk for vitamin D deficiency [
      • Pearce S.H.
      • Cheetham T.D.
      Diagnosis and management of vitamin D deficiency.
      ].

      2. Vitamin D and all-cause mortality

      Several studies and meta-analyses suggest that vitamin D deficiency has a negative association with survival, while supplementation may decrease overall mortality [
      • Reddy Vanga S.
      • Good M.
      • Howard P.A.
      • Vacek J.L.
      Role of vitamin D in cardiovascular health.
      ,
      • Stechschulte S.A.
      • Kirsner R.S.
      • Federman D.G.
      Vitamin D: bone and beyond, rationale and recommendations for supplementation.
      ]. A recent meta-analysis of 18 randomized controlled trials (n=57,000) showed that supplementation with vitamin D (300 to 2000 IU/day) resulted in significant reduction in mortality from any cause [relative risk (RR) 0.93, 95% confidence interval (CI) 0.92 to 1.18] [
      • Nadir M.A.
      • Szwejkowski B.R.
      • Witham M.D.
      Vitamin D and cardiovascular prevention.
      ,
      • Autier P.
      • Gandini S.
      Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
      ]. In addition, among 13,331 US adults participating in NHANES III study, those in the lowest quartile of 25(OH)Vit D (<18 ng/mL; <45 nmol/L) had a 26% increased risk of all-cause death during a follow-up period of 8.7 years compared with those in the highest quartile [
      • Melamed M.L.
      • Michos E.D.
      • Post W.
      • Astor B.
      25-hydroxyvitamin D levels and the risk of mortality in the general population.
      ,
      • Michos E.D.
      • Reis J.P.
      • Melamed M.L.
      Vitamin D status and cardiovascular health: a 2009 update.
      ].

      3. Vitamin D and the metabolic syndrome

      The metabolic syndrome (MetS), describing the cluster of abdominal obesity, hypertension, dyslipidemia and hyperglycemia, is a constellation of vascular risk factors associated with increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [
      • Liberopoulos E.N.
      • Mikhailidis D.P.
      • Elisaf M.S.
      Diagnosis and management of the metabolic syndrome in obesity.
      ,
      • Grundy S.M.
      Metabolic syndrome: a multiplex cardiovascular risk factor.
      ]. NHANES III and NHANES 2003–2004 studies have shown a significant inverse association between serum vitamin D concentrations and MetS as a whole, as well as with each one of its diagnostic criteria [
      • Florentin M.
      • Elisaf M.S.
      • Mikhailidis D.P.
      • Liberopoulos E.N.
      Vitamin D and metabolic syndrome: is there a link?.
      ,
      • Ford E.S.
      • Ajani U.A.
      • McGuire L.C.
      • Liu S.
      Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults.
      ,
      • Reis J.P.
      • von Muhlen D.
      • Miller 3rd, E.R.
      Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults.
      ]. So far, there is no data on the effects of vitamin D supplementation on the prevalence of MetS in vitamin D deficient patients [
      • Florentin M.
      • Elisaf M.S.
      • Mikhailidis D.P.
      • Liberopoulos E.N.
      Vitamin D and metabolic syndrome: is there a link?.
      ].

      4. Vitamin D and hypertension

      Epidemiological observations, like the incidence of hypertension increasing with higher latitude, higher recordings of blood pressure (BP) in winter months [
      • Nadir M.A.
      • Szwejkowski B.R.
      • Witham M.D.
      Vitamin D and cardiovascular prevention.
      ,
      • Woodhouse P.R.
      • Khaw K.T.
      • Plummer M.
      Seasonal variation of blood pressure and its relationship to ambient temperature in an elderly population.
      ] and racial/ethnic differences in 25(OH)Vit D levels explaining approximately half of the increased hypertension prevalence in non-Hispanic blacks compared with whites, support an association between vitamin D and blood pressure (BP) [
      • Michos E.D.
      • Reis J.P.
      • Melamed M.L.
      Vitamin D status and cardiovascular health: a 2009 update.
      ]. Furthermore, the cross-sectional study NHANES III showed that participants in the highest 25(OH)Vit D quartile (>85.7 nmol/L) had systolic BP (SBP) and diastolic BP (DBP) 3.0 and 1.6 mm Hg lower, respectively, compared with those in the lowest 25(OH)Vit D quartile (<40.4 nmol/L) [
      • Scragg R.
      • Sowers M.
      • Bell C.
      Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey.
      ]. In the large prospective cohort studies of the Health Professionals' Follow up (HPFS) (n=613) and the Nurses' Health Study (NHS) (n=1198 women), an increased risk of incident hypertension was demonstrated in subjects with vitamin D insufficiency (<37.5 nmol/L) compared with vitamin D sufficient people (>75 nmol/L) [
      • Forman J.P.
      • Giovannucci E.
      • Holmes M.D.
      • Bischoff-Ferrari H.A.
      • Tworoger S.S.
      • Willett W.C.
      • et al.
      Plasma 25-hydroxyvitamin D levels and risk of incident hypertension.
      ].
      Several potential mechanisms have been proposed to explain the vitamin D's implication in the regulation of BP. In rodents 1,25(OH)2Vit D was proved a negative regulator of the renin-angiotensin system [
      • Li Y.C.
      • Kong J.
      • Wei M.
      • Chen Z.F.
      • Liu S.Q.
      • Cao L.P.
      1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
      ]. Also, vitamin D may have a direct vascular effect, as implied by the presence of 1α-hydroxylase activity in vascular smooth muscle and endothelial cells, and by the presence of VDRs in endothelial cells [
      • Florentin M.
      • Elisaf M.S.
      • Mikhailidis D.P.
      • Liberopoulos E.N.
      Vitamin D and metabolic syndrome: is there a link?.
      ]. To date, only a small number of randomized control trials have reported data on BP with vitamin D supplementation. In Pfeifer's et al. study, there was a 7 mm Hg reduction in SBP in the vitamin D group compared with controls (p=0.02) [
      • Pfeifer M.
      • Begerow B.
      • Minne H.W.
      • Nachtigall D.
      • Hansen C.
      Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women.
      ]. A recent meta-analysis comparing vitamin D with placebo found a small but significant drop in DBP (3 mm Hg) among those taking vitamin D, but only in contestants who were hypertensive at baseline [
      • Witham M.D.
      • Nadir M.A.
      • Struthers A.D.
      Effect of vitamin D on blood pressure: a systematic review and meta-analysis.
      ]. Yet, the largest trial to date, the Women's Health Initiative (WHI), failed to show any significant impact of a small dose of vitamin D (400 IU) plus 1000 mg calcium/day on SBP or DBP after a mean follow-up of 7 years in post-menopausal women [
      • Margolis K.L.
      • Ray R.M.
      • Van Horn L.
      • Manson J.E.
      • Allison M.A.
      • Black H.R.
      • et al.
      Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial.
      ]. However, the lack of effect may have been due to the low doses of vitamin D and poor adherence (59%) to the medication, in a population not hypertensive at baseline [
      • Margolis K.L.
      • Ray R.M.
      • Van Horn L.
      • Manson J.E.
      • Allison M.A.
      • Black H.R.
      • et al.
      Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial.
      ]. Overall, the current evidence to support the role of vitamin D supplementation in reducing BP is weak, and further randomized trials are needed to explore this possibility.

      5. Vitamin D and glucose metabolism

      Vitamin D may play a role in maintaining insulin function. Several studies have found a cross-sectional association between low 25(OH)Vit D levels and obesity, glucose intolerance, hyperinsulinemia and type 2 diabetes [
      • Melamed M.L.
      • Michos E.D.
      • Post W.
      • Astor B.
      25-hydroxyvitamin D levels and the risk of mortality in the general population.
      ,
      • Michos E.D.
      • Reis J.P.
      • Melamed M.L.
      Vitamin D status and cardiovascular health: a 2009 update.
      ,
      • Ford E.S.
      • Ajani U.A.
      • McGuire L.C.
      • Liu S.
      Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults.
      ,
      • Bayens K.C.
      • Boucher B.J.
      • Feskens E.J.
      • Kromhout D.
      Vitamin D, glucose intolerance, and insulinemia in elderly men.
      ]. Although fat cells sequester vitamin D, the cross-sectional association of 25(OH)Vit D deficiency with diabetes remains even after body mass index, physical activity, and other potential confounding factors are taken into account [
      • Melamed M.L.
      • Michos E.D.
      • Post W.
      • Astor B.
      25-hydroxyvitamin D levels and the risk of mortality in the general population.
      ].
      Vitamin D seems to affect the glucose-induced insulin secretion, both directly and indirectly [
      • Bourlon P.M.
      • Billaudel B.
      • Faure-Dussert A.
      Influence of vitamin D3 deficiency and 1,25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas.
      ,
      • Zeitz U.
      • Weber K.
      • Soegiarto D.W.
      • Wolf E.
      • Balling R.
      • Erben R.G.
      Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor.
      ]. The direct effects are probably mediated by the binding of circulating or locally, within the β-cell, produced 1,25(OH)2Vit D to β-cell VDRs [
      • Johnson J.A.
      • Grande J.P.
      • Kumar R.
      Immunohistochemical localization of the 1,25(OH)2Vit D3 receptor and calbidin D28k in human and rat pancreas.
      ,
      • Maestro B.
      • Molero S.
      • Bajo S.
      • Davila N.
      • Calle C.
      Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D3.
      ,
      • Bland R.
      • Markovic D.
      • Hills C.E.
      • Hughes S.V.
      • Chan S.L.
      • Squires P.E.
      • et al.
      Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets.
      ]. The indirect effects may be associated with the regulation of calcium flux through β-cells [
      • Bland R.
      • Markovic D.
      • Hills C.E.
      • Hughes S.V.
      • Chan S.L.
      • Squires P.E.
      • et al.
      Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets.
      ,
      • Sooy K.
      • Schermerhorn T.
      • Noda M.
      Calbidin-D(28 k) controls [Ca(2+)] (i) and insulin release. Evidence obtained from calbidin-d (28 k) knockout mice and beta cell lines.
      ], as insulin secretion is calcium dependent [
      • Milner R.D.
      • Hales C.N.
      The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro.
      ]. Also, in peripheral insulin target tissues, vitamin D may enhance insulin sensitivity by stimulating the expression of insulin receptors [
      • Maestro B.
      • Campion J.
      • Davila N.
      • Calle C.
      Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells.
      ], or by the regulation of free fatty acid metabolism in skeletal muscles and adipose tissue [
      • Luquet S.
      • Gaudel C.
      • Holst D.
      Roles of PPAR delta in lipid absorption and metabolism: a new target for treatment of type 2 diabetes.
      ] via the vitamin D-induced expression of the nuclear peroxisome proliferators-activated receptor (PPAR)-δ [
      • Dunlop T.W.
      • Vaisanen S.
      • Frank C.
      • Molnar F.
      • Sinkkonen L.
      • Carlberg C.
      The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dixydroxyvitamin D3 and nuclear receptor.
      ].
      Replenishing vitamin D in patients with type 2 diabetes was found to improve insulin secretion, peripheral insulin sensitivity and glycosylated hemoglobin levels [
      • Borissova A.M.
      • Tankova T.
      • Kirilov G.
      • Dakovska L.
      • Kovacheva R.
      The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients.
      ,
      • Chiu K.C.
      • Chu A.
      • Go V.L.
      • Saad M.F.
      Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.
      ,
      • Schwalfenberg G.
      Vitamin D and diabetes: improvement of glycemic control with vitamin D3 repletion.
      ]. However, the expected benefit from vitamin D repletion on fasting blood glucose, glucose tolerance, or insulin sensitivity was not observed in some studies [
      • Tai K.
      • Need A.G.
      • Horowitz M.
      • Chapman I.M.
      Glucose tolerance and vitamin D: effects of treating vitamin D deficiency.
      ,
      • Fliser D.
      • Stefanski A.
      • Franek E.
      No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects.
      ]. This inconsistency may be due to ethnic differences or VDR polymorphisms [
      • Malecki M.T.
      • Frey J.
      • Moczulski D.
      • Klupa T.
      • Kozek E.
      • Sieradzki J.
      Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population.
      ]. For example, among women in the Nurses' Health Study (NHS), over a 20-year follow up, there was no association between total vitamin D intake and type 2 diabetes, but the combined calcium (>1200 mg/day) and vitamin D (>800 IU/day) intake was associated with a 33% lower risk compared with intakes <600 mg and 400 IU, respectively [
      • Pittas A.G.
      • Dawson-Hughes B.
      • Li T.
      • Van Dam R.M.
      • Willett W.C.
      • Manson J.E.
      • et al.
      Vitamin D and calcium intake in relation to type 2 diabetes in women.
      ]. Also, a post-hoc analysis of the large Women's Health Initiative (WHI) randomized placebo-controlled trial (n=33,951) showed that calcium supplementation (1000 mg) plus 400 IU of vitamin D/day did not reduce the risk of incident diabetes over a 7-year follow-up, while no changes in fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were observed [
      • de Boer I.H.
      • Tinker L.F.
      • Connelly S.
      • Curb J.D.
      • Howard B.V.
      • Kestenbaum B.
      • et al.
      Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative.
      ]. However, there were limitations in this study including the low vitamin D dose, concomitant therapy with calcium and cross-contamination with controls also taking vitamin D supplementation.
      In another study with healthy volunteers who were not vitamin D deficient at baseline, high-dose of calcitriol (1.5 μg/day for 7 days) did not increase insulin sensitivity, as measured by euglycemic clamp, compared with placebo subjects [
      • Fliser D.
      • Stefanski A.
      • Franek E.
      No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects.
      ]. On the contrary, high-dose (4000 IU/day) vitamin D supplementation improved insulin sensitivity in South Asians with insulin resistance [
      • von Hurst P.R.
      • Stonehouse W.
      • Coad J.
      Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient — a randomized, placebo-controlled trial.
      ]. Similarly, in another study, the combination of vitamin D with calcium over a 3-year time attenuated the rise of fasting plasma glucose (FPG) only in subjects with impaired FPG at baseline [
      • Pittas A.G.
      • Harris S.S.
      • Stark P.C.
      • Dawson-Hughes B.
      The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults.
      ]. Thus, vitamin D supplementation may be effective mainly in patients with impaired glucose metabolism and low levels of circulating vitamin D [
      • Borissova A.M.
      • Tankova T.
      • Kirilov G.
      • Dakovska L.
      • Kovacheva R.
      The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients.
      ,
      • Cade C.
      • Norman A.W.
      Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo.
      ,
      • Kumar S.
      • Davies M.
      • Zakaria Y.
      • Mawer E.B.
      • Gordon C.
      • Olukoga A.O.
      • et al.
      Improvement in glucose tolerance and beta-cell function in a patient with vitamin D deficiency during treatment with vitamin D.
      ,
      • Isaia G.
      • Giorgino R.
      • Adami S.
      High prevalence of hypovitaminosis D in female type 2 diabetic population.
      ].
      Clinical studies designed specifically to assess the effect of vitamin D supplementation with large doses of vitamin D (2000–7000 IU) in high-risk populations with both vitamin D deficiency and impaired glucose metabolism are currently underway [
      • Baz-Hecht M.
      • Goldfine A.B.
      The impact of vitamin D deficiency on diabetes and cardiovascular risk.
      ].

      6. Vitamin D and lipid metabolism

      Some studies reported an association between vitamin D status and/or supplementation with lipids. Specifically, another analysis of the NHANES III examining several CVD risk factors, including lipids, in US adults (n=15,088) found the adjusted prevalence of high serum triglyceride levels (OR 1.47) to be higher in the first compared to the fourth quartile of serum 25(OH)Vit D levels (p<0.001) [
      • Martins D.
      • Wolf M.
      • Pan D.
      • Zadshir A.
      • Tareen N.
      • Thadhani R.
      • et al.
      Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey.
      ]. However, these findings are not in accordance with a study using data from NHANES 2003–2004 (n=1654) which showed a positive relationship between vitamin D and high density lipoprotein cholesterol (HDL-C) (p=0.004) but not with triglycerides [
      • Reis J.P.
      • von Muhlen D.
      • Miller 3rd, E.R.
      Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults.
      ]. On the contrary, in a European large cohort (n=6810) serum 25(OH)Vit D was inversely associated with triglyceride levels (p<0.004) after adjustment for insulin growth factor (IGF)-1, obesity, social and lifestyle variations [
      • Hypponen E.
      • Boucher B.J.
      • Berry D.J.
      • Power C.
      25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort.
      ]. Moreover, 25(OH)Vit D was positively correlated with HDL-C levels (p<0.01) in 381 young adults and inversely related with low density lipoprotein cholesterol (LDL-C) only in males (n=201) (p=0.007) [
      • Gannage-Yared M.H.
      • Chedid R.
      • Khalife S.
      • Azzi E.
      • Zoghbi F.
      • Halaby G.
      Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population.
      ]. Furthermore, 25(OH)Vit D was positively associated with apolipoprotein A-I (p<0.03), and negatively correlated with the LDL-C to HDL-C ratio (p<0.044) in 51 healthy subjects [
      • Carbone L.D.
      • Rosenberg E.W.
      • Tolley E.A.
      • Holick M.F.
      • Hughes T.A.
      • Watsky M.A.
      • et al.
      25-Hydroxyvitamin D, cholesterol, and ultraviolet irradiation.
      ]. Others report inverse correlations of serum 1,25(OH)2Vit D with very low density lipoprotein cholesterol (VLDL-C) and triglyceride levels [
      • Lind L.
      • Hanni A.
      • Lithell H.
      • Hvarfner A.
      • Sorensen O.H.
      • Ljunghall S.
      Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men.
      ]. Overall, vitamin D deficiency seems to alter the lipid profile by increasing peripheral insulin resistance [
      • Reddy Vanga S.
      • Good M.
      • Howard P.A.
      • Vacek J.L.
      Role of vitamin D in cardiovascular health.
      ].
      Oral supplements of vitamin D in postmenopausal women did not improve total cholesterol, LDL-C or HDL-C over 12 months [
      • Heikkinen A.M.
      • Tuppurainen M.T.
      • Niskanen L.
      • Komulainen M.
      • Penttila I.
      • Saarikoski S.
      Long-term vitamin D3 supplementation may have adverse effects on serum lipids during postmenopausal hormone replacement therapy.
      ]. In contrast, calcium plus vitamin D supplementation (600 mg and 200 IU/day, respectively) along with a 15-week weight-loss intervention program resulted in pronounced reductions in total cholesterol to LDL-C and LDL-C to HDL-C ratios (p<0.01 for both) as well as LDL-C levels (p<0.05) compared with placebo in overweight/obese women (n=63). The decrease in lipid and lipoprotein concentrations could partly be attributed to calcium intake through various mechanisms [
      • Major G.C.
      • Alarie F.
      • Dore J.
      • Phouttama S.
      • Tremblay A.
      Supplementation with calcium+vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations.
      ]. In another study, when vitamin D was added to a weight loss program, led to greater reduction in triglycerides than weight loss alone, but paradoxically led to an increase in LDL-C levels compared with placebo [
      • Zittermann A.
      • Frisch S.
      • Berthold H.K.
      • Gotting C.
      • Kuhn J.
      • Kleesiek K.
      • et al.
      Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers.
      ]. Overall, the data from these studies are not sufficient to either confirm or refute any benefit from vitamin D and/or calcium supplementation on lipids and future prospective studies are needed to address this issue.

      7. Vitamin D and cardiovascular effects

      Many coronary risk factors, including hypertension, diabetes mellitus, and dyslipidemia as well as endothelial cell function [
      • Tarcin O.
      • Yavuz D.G.
      • Ozben B.
      • Telli A.
      • Ogunc A.V.
      • Yuksel M.
      • et al.
      Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects.
      ] and vascular calcification [
      • Zittermann A.
      • Fischer J.
      • Schleithoff S.S.
      • Tenderich G.
      • Fuchs U.
      • Koerfer R.
      Patients with congestive heart failure and healthy controls differ in vitamin D-associated lifestyle factors.
      ] may be affected by vitamin D. Vitamin D deficiency is currently regarded as an independent cardiovascular disease (CVD) risk factor [
      • Baz-Hecht M.
      • Goldfine A.B.
      The impact of vitamin D deficiency on diabetes and cardiovascular risk.
      ], based on earlier observations of geographic and seasonal differences in mortality from ischemic heart disease [
      • Fleck A.
      Latitude and ischaemic heart disease.
      ] and results from large, cross-sectional studies using the NHANES databases (n=16,603), where the frequency of ischemic heart disease and stroke was related to 25(OH)Vit D deficiency (p<0.0001) [
      • Kendrick J.
      • Targher G.
      • Smits G.
      • Chonchol M.
      25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.
      ]. Also, an analysis involving 8351 adults showed a high prevalence of vitamin D deficiency (74%) in patients with coronary artery disease and heart failure [
      • Kim D.H.
      • Sabour S.
      • Sagar U.N.
      • Adams S.
      • Whellan D.J.
      Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004).
      ].
      Many studies evaluated prospectively the relation of vitamin D with long-term cardiovascular outcomes in subjects with no history of cardiovascular disease. Vitamin D deficiency (<15 ng/mL) was associated with a 2-fold increased rate of myocardial infarction over a 10-year period in healthy male professionals (n=18,225) [
      • Grandi N.C.
      • Breitling L.P.
      • Brenner H.
      Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies.
      ], or with increased risk of myocardial infarction, coronary insufficiency, cerebrovascular events, claudication, or heart failure in the Framingham Offspring study compared with those with levels >15 ng/mL, after adjustment for age and conventional risk factors [
      • Wang T.J.
      • Pencina M.J.
      • Booth S.L.
      • Jacques P.F.
      • Ingelsson E.
      • Lanier K.
      • et al.
      Vitamin D deficiency and risk of cardiovascular disease.
      ]. Also, a recent meta-analysis report was in support of an overall association of 25(OH)Vit D baseline levels in the lowest compared with the highest categories with cardiovascular events [pooled hazard ratio (HR)=1.54, 95% CI 1.22–1.95]. This association did not differ significantly across studies. A significant association of low 25(OH)Vit D levels with cardiovascular mortality (HR=1.38, 95% CI 1.19–2.80) was also seen in this meta-analysis [
      • Grandi N.C.
      • Breitling L.P.
      • Brenner H.
      Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies.
      ].
      In addition to the effect on classical cardiovascular risk factors, vitamin D may influence cardiac function and atherosclerosis through multiple other mechanisms. Vitamin D deficiency is related to increased activity of the renin-angiotensin-aldosterone system [
      • Milliez P.
      • Girerd X.
      • Plouin P.F.
      • Blacher J.
      • Safar M.E.
      • Mourad J.J.
      Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.
      ], cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation [
      • Achinger S.G.
      • Ayus J.C.
      The role of vitamin D in left ventricular hypertrophy and cardiac function.
      ] and has direct effects on vascular smooth muscle cell calcification and proliferation [
      • Cardus A.
      • Parisi E.
      • Gallego C.
      1,25-Dixydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway.
      ]. Furthermore, hypovitaminosis D may correlate with chronic subacute inflammation, NF-κB activation [
      • Cohen-Lahav M.
      • Shany S.
      • Tobvin D.
      Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels.
      ], and loss of suppression of foam cell formation [
      • Cohen-Lahav M.
      • Douvdevani A.
      • Chaimovitz C.
      • Shany S.
      The anti-inflammatory activity of 1,25-dihydroxyvitamin D3 in macrophages.
      ], thereby promoting atherosclerotic lesions.
      Vitamin D and calcium supplementation has not been shown to alter either coronary or cerebrovascular risk over a 7-year period in the WHI study [
      • Hsia J.
      • Heiss G.
      • Ren H.
      • Allison M.
      • Dolan N.C.
      • Greenland P.
      • et al.
      Calcium/vitamin D supplementation and cardiovascular events.
      ,
      Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group.
      ]. One should cautiously interpret these results due to the small dose and poor compliance with vitamin D as well as the fact that some data suggest that calcium supplementation may lead to an increase in myocardial infarction rates [
      • Bolland M.J.
      • Barber P.A.
      • Doughty R.N.
      • Mason B.
      • Horne A.
      • Ames R.
      • et al.
      Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial.
      ]. Despite this, resent data point out that women who consistently received supplementation with calcium and vitamin D did not experience more cardiovascular events or deaths than women who received minimal supplementation [
      • Shah S.M.
      • Carey I.M.
      • Harris T.
      • DeWilde S.
      • Cook D.G.
      Calcium supplementation, cardiovascular disease and mortality in older women.
      ].
      Conclusively, it is suggested that vitamin D deficiency represents an important new cardiovascular (CV) risk factor. More clinical trials are urgently needed to determine whether there is a causal association and whether vitamin D replenishment could reduce the increase in CV risk. Unfortunately, the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial was recently postponed due to rosiglitazone withdrawal. This study aimed to compare the effect of rosiglitazone vs placebo and vitamin D vs placebo on CV events. Consequently, the Vitamin D and Omega-3 Trial (VITAL), a 5-year, randomized, placebo-controlled trial involving 20,000 U.S. people, is the only project to date aiming to examine whether vitamin D supplementation (2000 IU/d) with or without addition of omega-3 fatty acids, could play a role in the primary prevention of cancer and cardiovascular disease [
      • Manson J.E.
      Vitamin D and the heart: why we need large-scale clinical trials.
      ].

      8. Vitamin D and heart failure

      Observational studies have shown that low serum 25(OH)Vit D levels are common in patients with congestive heart failure [
      • Shane E.
      • Mancini D.
      • Aaronson K.
      • Silverberg S.J.
      • Seibel M.J.
      • Addesso V.
      • et al.
      Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.
      ]. The NHANES III showed that adults with very low vitamin D serum levels (n=13,131) had more than triple the risk of death from heart failure over 8 years compared with those with normal levels [
      • Liu Lea
      Serum 25-hydroxyvitamin D concentration: heart failure mortality and premature death from all causes in US adults: an eight-year follow-up study.
      ]. Moreover, in the German Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort study, which prospectively followed individuals referred for coronary angiography, low levels of 25(OH)Vit D and 1,25(OH)2Vit D were associated with increased risk of death from heart failure or sudden cardiac death [
      • Pilz S.
      • Marz W.
      • Wellnitz B.
      • Seelhorst U.
      • Fahrleitner-Pammer A.
      • Dimai H.P.
      • et al.
      Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
      ]. Also, 25(OH)Vit D levels were negatively correlated with pro-B-natriuretic peptide and inversely associated with impaired left ventricular function [
      • Pilz S.
      • Marz W.
      • Wellnitz B.
      • Seelhorst U.
      • Fahrleitner-Pammer A.
      • Dimai H.P.
      • et al.
      Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
      ]. Of note, reverse causation (i.e. the sickest patients having the lowest vitamin D levels) could still in part account for the above described association. Supplementation with 2000 IU/d of vitamin D reduced inflammatory markers in patients with heart failure and improved serum parathyroid hormone levels in one study without any significant direct survival benefit [
      • Schleithoff S.S.
      • Zittermann A.
      • Tenderich G.
      • Berthold H.K.
      • Stehle P.
      • Koerfer R.
      Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
      ]. Further studies are needed to ascertain whether vitamin D supplementation can improve symptoms and prognosis in heart failure.

      9. Vitamin D and stroke

      The Ludwigshafen Risk and Cardiovascular Health (LURIC) prospective study showed that low levels of both 25(OH)Vit D and 1,25(OH)2Vit D were independently predictive for fatal strokes, during a median of 8 years follow-up [
      • Pilz S.
      • Dobnig H.
      • Fischer J.E.
      • Wellnitz B.
      • Seelhorst U.
      • Boehm B.O.
      • et al.
      Low vitamin d levels predict stroke in patients referred to coronary angiography.
      ]. The most recent data coming from NHANES (n~8000) show that over a median of 14 years, whites with levels of 25(OH)Vit D <15 ng/mL had double the risk of dying from stroke compared with those having higher levels [
      • Brewer L.C.
      • Michos E.D.
      • Reis J.P.
      Vitamin D in atherosclerosis, vascular disease, and endothelial function.
      ]. However, no such association was found in black NHANES participants despite their lower overall vitamin D levels and greater fatal stroke risk compared with whites. This quite surprising finding could possibly be attributed to adaptive resistance to the adverse effects of hypovitaminosis D probably developed in African Americans [
      • Brewer L.C.
      • Michos E.D.
      • Reis J.P.
      Vitamin D in atherosclerosis, vascular disease, and endothelial function.
      ].

      10. Vitamin D and renal disease

      Low levels of 25(OH)Vit D were associated with albuminuria in a cross sectional analysis of NHANES [
      • de Boer I.H.
      • Ioannou G.N.
      • Kestenbaum B.
      • Brunzell J.D.
      • Weiss N.S.
      25-hydroxyvitamin d levels and albuminuria in the third national health and nutrition examination survey (NHANES III).
      ]. Furthermore, observational data show that the use of activated vitamin D analogs in patients with end-stage renal disease may lower mortality [
      • Tentori F.
      • Hunt W.C.
      • Stidley C.A.
      • Rohrscheib M.R.
      • Bedrick E.J.
      • Meyer K.B.
      • et al.
      Mortality risk among hemodialysis patients receiving different vitamin D analogs.
      ]. Also, treatment with such analogs decreased proteinuria in two randomized clinical trials [
      • Alborzi P.
      • Patel N.A.
      • Peterson C.
      • Bills J.E.
      • Bekele D.M.
      • Bunaye Z.
      • et al.
      Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial.
      ,
      • Agarwal R.
      • Acharya M.
      • Tian J.
      • Hippensteel R.L.
      • Melnick J.Z.
      • Qiu P.
      • et al.
      Antiproteinuric effect of oral paricalcitol in chronic kidney disease.
      ]. The Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL) study has shown that the addition of a vitamin D-receptor activator, paricalcitol (Zemplar, Abbot Laboratories) to therapy in patients with diabetic nephropathy reduces albuminuria without risking hypercalcemia or hyperphosphatemia and calcification of diabetic vessels [
      • de Zeeuw D.
      • Agarwal R.
      • Amdahl M.
      • Audhya P.
      • Coyne D.
      • Garimella T.
      • et al.
      Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial.
      ,
      • Thomas M.C.
      • Cooper M.E.
      Into the light? Diabetic nephropathy and vitamin D.
      ].

      11. Vitamin D and immune system effects

      In the 1980s, researchers observed high expression of VDRs in lymphocytes and macrophages, sparking interest for a potential role of vitamin D in immunity [
      • Deluca H.F.
      • Cantorna M.T.
      Vitamin D: its role and uses in immunology.
      ]. It has been shown that the overall effect of 1,25(OH)2Vit D is the enhancement of protective innate immune responses, while maintaining self-tolerance by dampening over-zealous adaptive immune responses [
      • Kamen D.L.
      Vitamin D in Lupus. New kid on the block?.
      ].
      Many studies have shown that the majority of patients with systemic lupus erythematosus (SLE) have insufficient levels of 25(OH)Vit D, even when taking vitamin D supplementation [
      • Toloza S.M.
      • Cole D.E.
      • Gladman D.D.
      • Ibanez D.
      • Urowitz M.B.
      Vitamin D insufficiency in a large female SLE cohort.
      ]. The two largest studies to date both report a significant correlation between higher disease activity and lower 25(OH)VitD [
      • Ben-Zvi I.
      • Aranow C.
      • Mackay M.
      The impact of vitamin D on dendtritic cell function in patients with systemic lupus erythematosus.
      ,
      • Amital H.
      • Szekanecz Z.
      • Szucs G.
      • Danko K.
      • Nagy E.
      • Csepany T.
      • et al.
      Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D?.
      ]. Interestingly, in another study anti-vitamin D antibodies were found in 4% of patients with SLE, possibly contributing to increased vitamin D clearance [
      • Carvalho J.F.
      • Blank M.
      • Kiss E.
      • Tarr T.
      • Amital H.
      • Shoenfeld Y.
      Anti-vitamin D, vitamin D in SLE: preliminary results.
      ].
      Recent clinical studies have shown that vitamin D levels are lower among patients with multiple sclerosis (MS) and that exposure to ultraviolet (UV) light or calcitriol administration reduce disease symptoms [
      • Grant W.B.
      Epidemiology of disease risks in relation to vitamin D insufficiency.
      ]. Also, low serum vitamin D at the time of a first demyelinating event increases the risk of subsequent multiple sclerosis in children, strengthening the argument that vitamin D deficiency plays a causal role in MS by placing the deficiency so close to onset [
      • Hanwell H.E.
      • Banwell B.
      Assessment of evidence for a protective role of vitamin D in multiple sclerosis.
      ].
      Vitamin D deficiency has been associated with type 1 diabetes mellitus (T1DM) as well. Interestingly, T1DM incidence was reported to increase when vitamin D deficiency was present in the first month of life [
      • Grant W.B.
      Epidemiology of disease risks in relation to vitamin D insufficiency.
      ], whereas increasing vitamin D intake during pregnancy reduced the development of islet auto-antibodies in offspring [
      • Chiu K.C.
      • Chu A.
      • Go V.L.
      • Saad M.F.
      Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.
      ]. Possibly VDR gene polymorphisms may be associated with the risk of developing T1DM, but the data available up to now have been conflicting [
      • Ponsonby A.L.
      • Pezic A.
      • Ellis J.
      • Morley R.
      • Cameron F.
      • Carlin J.
      • et al.
      Variation in associations between allelic variants of the vitamin D receptor gene and onset of type 1 diabetes mellitus by ambient winter ultraviolet radiation levels: a meta-regression analysis.
      ].
      Continued research will help us to better understand the key role of vitamin D as immunomodulatory agent, and the way we could probably use it as a disease-suppressing intervention for auto-immune diseases.

      12. Vitamin D and cancer

      Both prospective and retrospective epidemiological studies indicate that people living at higher latitudes are at increased risk for colon, breast, prostate, pancreatic, ovarian and other cancers as well as Hodgkin's lymphoma, and are more likely to die from them as compared with people living at lower latitudes [
      • Holick M.F.
      Vitamin D deficiency.
      ,
      • Giovannucci E.
      • Liu Y.
      • Rimm E.B.
      • Hollis B.W.
      • Fuchs C.S.
      • Stampfer M.J.
      • et al.
      Prospective study of predictors of vitamin D status and cancer incidence and mortality in men.
      ,
      • Garland C.F.
      • Garland F.C.
      • Gorham E.D.
      • Lipkin M.
      • Newmark H.
      • Mohr S.B.
      • et al.
      The role of vitamin D in cancer prevention.
      ]. One likely hypothesis is that since those specific tissues express 25-hydroxyvitamin D-1α-hydroxylase they can produce 1,25(OH)2Vit D locally, and then control more than 200 genes, including those responsible for the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis [
      • Holick M.F.
      Vitamin D deficiency.
      ,
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      ,
      • Mantell D.J.
      • Owens P.E.
      • Bundred N.J.
      • Mawer E.B.
      • Canfield A.E.
      1α,25-dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo.
      ].
      Meta-analyses for the 2008 IARC (International Agency for Research on Cancer) report revealed inverse relationships between 25(OH)Vit D levels and carcinoma or adenoma of the bowel [
      • Zeeb H.
      • Greinert R.
      The role of vitamin D in cancer prevention: does UV protection conflict with the need to raise low levels of vitamin D?.
      ,
      IARC working group on vitamin D: vitamin D and cancer.
      ]. Moreover, an analysis from the NHS cohort (n=32,826) showed that the odd ratios for colorectal cancer were inversely associated with median serum levels of 25(OH)Vit D, whereas serum 1,25(OH)2Vit D had no association [
      • Feskanich D.
      • Ma J.
      • Fuchs C.S.
      • Kirkner G.J.
      • Hankinson S.E.
      • Hollis B.W.
      • et al.
      Plasma vitamin D metabolites and risk of colorectal cancer in women.
      ]. On the other hand, the WHI study showed that daily supplementation of calcium (1000 mg) plus vitamin D (400 IU) for 7 years had no effect on the incidence of colorectal cancer among postmenopausal women [
      • Wactawski-Wende J.
      • Kotchen J.M.
      • Anderson G.L.
      • Assaf A.R.
      • Brunner R.L.
      • O'Sullivan M.J.
      • et al.
      Calcium plus vitamin D supplementation and the risk of colorectal cancer.
      ]. However, participants in the same study who at baseline had a 25(OH)Vit D concentration <12 ng/mL had a 253% increase in the incidence of colorectal cancer relative to those in the highest quartile (>23 ng/mL) over a follow-up period of 8 years [
      • Holick M.F.
      Calcium plus vitamin D and the risk of colorectal cancer.
      ]. Also, an intake of 2000 IU/day of vitamin D was estimated to reduce by 27% the incidence of colorectal cancer in some studies [
      • Wactawski-Wende J.
      • Kotchen J.M.
      • Anderson G.L.
      • Assaf A.R.
      • Brunner R.L.
      • O'Sullivan M.J.
      • et al.
      Calcium plus vitamin D supplementation and the risk of colorectal cancer.
      ,
      • Garlan C.F.
      • Gorham E.D.
      • Mohr S.
      • Garland F.
      Vitamin D for cancer prevention: global perspective.
      ].
      Furthermore, the 2008 IARC report for breast cancer stated that vitamin D has a protective effect with a RR of 0.85 (95% CI 0.71–1.02) for each 25 nmol/L rise in the serum vitamin D level [
      IARC working group on vitamin D: vitamin D and cancer.
      ]. Also, a meta-analysis regarding vitamin D and the prevention of breast cancer demonstrated a 45% decrease in breast cancer risk for those in the highest quartile of circulating 25(OH)Vit D (>60 nmol/L) compared with those at the lowest, but no relationship was found between circulating 1,25(OH)2Vit D and breast cancer [
      • Chen P.
      • Hu P.
      • Xie D.
      • Qin Y.
      • Wang F.
      • Wang H.
      Meta-analysis of vitamin D, calcium and the prevention of breast cancer.
      ]. Recently, a clinical trial (n=1179) showed that the incidence of breast cancer was lowered by daily supplementation with 1000 IU of vitamin D plus calcium in postmenopausal women [
      • Lappe J.M.
      • Travers-Gustafson D.
      • Davies K.M.
      • Recker R.R.
      • Heaney R.P.
      Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.
      ].
      Epidemiological studies have shown that increased exposure to UV light may be protective against prostate cancer [
      • Luscombe C.J.
      • Fryer A.A.
      • French M.E.
      • Liu S.
      • Saxby M.F.
      • Jones P.W.
      • et al.
      Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer.
      ]. Also, in vitro studies have demonstrated that 1,25(OH)2Vit D and its synthetic analogs inhibit the proliferation of prostate cancer cell lines [
      • Nagpal S.
      • Na S.
      • Rathnachalam R.
      Noncalcemic actions of vitamin D receptor ligands.
      ]. On the other hand, in the 2008 IARC report for prostate cancer no protective effect could be determined [
      IARC working group on vitamin D: vitamin D and cancer.
      ]. Furthermore, polymorphisms of the VDR gene may modify vitamin's D biological activity and confer different susceptibility to prostate cancer as well as the local metabolism of hormonal vitamin D, which seems to play an important role in the development and progression of prostate cancer [
      • Lou Y.R.
      • Qiao S.
      • Talonpoika R.
      • Syvala H.
      • Tuohimaa P.
      The role of vitamin D3 metabolism in prostate cancer.
      ].
      Also, epidemiological studies show that children and young adults who are exposed to the most sunlight have reduced risk of non-Hodgkin's lymphoma [
      • Chang E.T.
      • Smedby K.E.
      • Hjalgrim H.
      • Porwit-MacDonald A.
      • Roos G.
      • Glimelius B.
      • et al.
      Family history of hematopoietic malignancy and risk of lymphoma.
      ]. Despite that, clinical trials up to now have failed to obtain good results in clinical management of myelodysplastic syndromes and myeloid leukemia by using 1,25(OH)2Vit D or analogs [
      • Bouillon R.
      • Bischoff-Ferrari H.
      • Willett W.
      Vitamin D and health: perspectives from mice and man.
      ].
      Conclusively, although there is already some evidence for a protective effect of vitamin D against some types of cancer, much research still needs to be done.

      13. Vitamin D supplementation and safety issues

      Supplementation of up to 2000 IU vitamin D daily has been deemed by the U.S. Food and Drug Administration's nutritional guidelines to be generally recognized as more effective and safe [
      • Hathcock J.N.
      • Shao A.
      • Vieth R.
      • Heaney R.
      Risk assessment for vitamin D.
      ]. On the contrary higher levels have not definitely been shown to confer greater benefits and sometimes they have been linked with health problems.
      The most common symptoms of vitamin D intoxication are those related with hypercalcemia (i.e. thirst, itchiness, diarrhea, malaise, wasting, polyuria and diminished appetite) resulting from primary renal failure. Also, calcification especially in the kidney, aorta, heart, lung and subcutaneous tissue can occur [
      • Deluca H.F.
      • Prahl J.M.
      • Plum L.A.
      1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25-hydroxyvitamin D.
      ]. All the reports show that hypercalcemia results only when 25(OH)VitD levels have consistently been above 375–500 nmol/L [
      • Jones G.
      Pharmacokinetics of vitamin D toxicity.
      ], which requires a daily intake of 40.000 IU [
      • Vieth R.
      Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.
      ]. A recent review concluded that the safe upper limit for vitamin D consumption is 10,000 IU/day [
      • Hathcock J.N.
      • Shao A.
      • Vieth R.
      • Heaney R.
      Risk assessment for vitamin D.
      ]. Doses above this limit increase the risk of renal calculi formation, especially in patients with absorptive hypercalciuria and end-stage renal disease on dialysis [
      • Daudon M.
      • Jungers P.
      Drug-induced renal calculi: epidemiology, prevention and management.
      ].
      It is noteworthy that in both the Framingham cohort study [
      • Wang T.J.
      • Pencina M.J.
      • Booth S.L.
      • Jacques P.F.
      • Ingelsson E.
      • Lanier K.
      • et al.
      Vitamin D deficiency and risk of cardiovascular disease.
      ] and in the overall NHANES-III study [
      • Melamed M.L.
      • Michos E.D.
      • Post W.
      • Astor B.
      25-hydroxyvitamin D levels and the risk of mortality in the general population.
      ] there was a suggestion of a U-shaped curve with a trend towards increased risk for CVD and mortality also at high levels of 25(OH)VitD, which did not meet statistical significance, as few individuals had very high 25(OH)VitD levels. What is more, Bolland et al. presented evidence coming from a new analysis of the WHI and two other studies, pointing to a roughly 20% increased risk of both myocardial infarction and stroke in people taking both calcium and vitamin D [
      • Bolland M.J.
      • Grey A.
      • Avenell A.
      • Gamble G.D.
      • Reid I.R.
      Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis.
      ]. Also, a small case–control study in patients with ischemic heart disease found that very elevated 25(OH)VitD levels (>89 ng/mL) were actually harmful (adjusted OR=3.18) [
      • Rajasree S.
      • Rajpal K.
      • Kartha C.C.
      • Sarma P.S.
      • Kutty V.R.
      • Iyer C.S.
      • et al.
      Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease.
      ]. Moreover, some individuals may be adversely affected by elevated 25(OH)Vit D concentrations with respect to risk of cancers of the prostate [
      • Tuohimaa P.
      • Tenkanen L.
      • Ahonen M.
      • Summe S.
      • Jellum E.
      • Hallmans G.
      • et al.
      Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case–control study in the Nordic countries.
      ,
      • Ahn J.
      • Peters U.
      • Albanes D.
      • Purdue M.P.
      • Abnet C.C.
      • Chatterjee N.
      • et al.
      Serum vitamin D concentration and prostate cancer risk: a nested case–control study.
      ], breast [
      • Goodwin P.J.
      • Ennis M.
      • Pritchard K.I.
      • Koo J.
      • Hood N.
      Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer.
      ], pancreas [
      • Stolzenberg-Solomon R.Z.
      • Vieth R.
      • Azad A.
      • Pietinen P.
      • Taylor P.R.
      • Virtamo J.
      • et al.
      A prospective nested case–control study of vitamin D status and pancreatic cancer risk in male smokers.
      ,
      • Stolzenberg-Solomon R.Z.
      • Hayes R.B.
      • Horst R.L.
      • Anderson K.E.
      • Hollis B.W.
      • Silverman D.T.
      Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial.
      ] and esophagus [
      • Chen W.
      • Dawsey S.M.
      • Qiao Y.L.
      • Mark S.D.
      • Dong Z.W.
      • Taylor P.R.
      • et al.
      Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers.
      ,
      • Abnet C.C.
      • Chen W.
      • Dawsey S.M.
      • Wei W.
      • Roth M.J.
      • Liu B.
      • et al.
      Serum 25(OH)-vitamin D concentration and risk of esophageal squamous dysplasia.
      ].
      In fact, continued investigation is necessary to ensure that vitamin D intake recommendations are targeted to individuals who are more likely to benefit most, while simultaneously protecting vulnerable subgroups from risk of overexposure to high vitamin D serum concentrations.

      14. Conclusion

      During the last 20 years, vitamin D and its non-classical actions have taken an important place in the clinical scenario. Indeed, many epidemiological and interventional studies have proved the benefits of vitamin D sufficiency status in improving health. Yet, as already mentioned, there is still demand for further research to clarify the promising clinical use of vitamin D in the prevention and treatment of various chronic diseases.

      Learning points

      • 1 billion people worldwide are vitamin D deficient
      • the metabolic syndrome and its components are inversely related to serum 25(OH)VitD levels
      • vitamin D deficient people may have increased risk for hypertension, impaired glucose tolerance or diabetes mellitus and dyslipidemia, but there is still not enough evidence that vitamin D supplementation could ameliorate these diseases
      • vitamin D deficiency is regarded a new cardiovascular risk factor
      • low vitamin D is associated with albuminuria, which is decreased by the use of activated vitamin D analogs
      • vitamin D deficiency may be a risk factor for auto-immune diseases and for some types of cancer
      • Table 1 summarizes the diseases possibly associated with vitamin D deficiency
        Table 1Non-skeletal diseases associated with hypovitaminosis D.
        All cause mortality
        Metabolic syndrome
        Hypertension
        Impaired glucose metabolism and type 2 diabetes
        Dyslipidemia
        Cardiovascular diseases (myocardial infarction, coronary insufficiency, coronary calcification, increased carotid intima median thickness)
        Heart failure
        Peripheral arterial disease
        Stroke
        Renal disease
        Autoimmune diseases (lupus erythematosus, multiple sclerosis, type 1 diabetes)
        Cancer (bowel, breast, prostate, non-Hodgkin lymphoma)
        Respiratory diseases (wheezing illness, autoimmune interstitial lung diseases)
        Liver fibrosis
        Psychiatric diseases (depression, autism, schizophrenia)
        Loss of gait performance and falls in the elderly
        Lower androgen levels

      Conflict of interest

      We state herein that this review was conducted independently; no company or institution supported it financially. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies. We have had no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.

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