Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contact us Login 
  • Users Online:359
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 229-236

Vitamin D deficiency and cardiometabolic syndrome: Is the evidence solid?

1 Department of Dietetics and Nutrition, Hamad Medical Corporation, Doha, Qatar
2 Department of Columbus County Health, Nutrition and WIC, North Carolina, USA

Date of Web Publication15-Dec-2017

Correspondence Address:
Lubna A.G. Mahmood
Department of Dietetics and Nutrition, Hamad Medical Corporation, Doha
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_80_17

Rights and Permissions

Vitamin D is a fat-soluble vitamin which has an important role in bone metabolism with some anti-inflammatory and immune-modulating properties. It is very unique since it can be made in the skin from exposure to sunlight. Cardiometabolic syndrome (CMS) is a group of metabolic abnormalities that can increase the risk of cardiovascular disease and type 2 diabetes. It develops in an individual with any three of the following risk factors including obesity, diabetes, hypertension, dyslipidemia, and thrombosis. Both dietary and environmental factors, when combined with a sedentary lifestyle, lead to metabolic syndrome (MS) risk factors. The research outcomes propose to increase the current Vitamin D fortification level in foods to reduce the risk factors of the MS. Further researches are needed before clinical practice can recommend a Vitamin D prescription as a treatment for CMS in the general population.

Keywords: Cardiometabolic, deficiency, syndrome, Vitamin D

How to cite this article:
Mahmood LA, Al Saadi R, Matthews L. Vitamin D deficiency and cardiometabolic syndrome: Is the evidence solid?. Arch Med Health Sci 2017;5:229-36

How to cite this URL:
Mahmood LA, Al Saadi R, Matthews L. Vitamin D deficiency and cardiometabolic syndrome: Is the evidence solid?. Arch Med Health Sci [serial online] 2017 [cited 2022 Jan 22];5:229-36. Available from: https://www.amhsjournal.org/text.asp?2017/5/2/229/220833

  Introduction Top

Cardiometabolic syndrome (CMS) or commonly referred to as metabolic syndrome (MS) is a group of metabolic abnormalities that can increase the risk of cardiovascular disease (CVD) and type 2 diabetes. It affects over one-third of American adults and accounts for high health-care costs annually.[1],[2] It develops in an individual with any three of the following risk factors: obesity, diabetes, hypertension (HTN), dyslipidemia, and thrombosis. Recent evidence has suggested that inadequate Vitamin D may play a role in the development of some of these risk factors.[3] MS is more common in western societies compared to underdeveloped countries. In western societies, individuals frequently consume a high-calorie diet that lacks essential nutrients, and coupled with limited sun exposure can restrict their Vitamin D synthesis.[4] Both dietary and environmental factors, along with the sedentary lifestyle, can lead to MS risk factors. Active research has revealed the role of inadequate Vitamin D in the development of obesity, diabetes, inflammation, and HTN. In contrast, limited research has been done on the role of Vitamin D in other risk factors such as thrombosis and dyslipidemia.[5] Research outcomes propose to increase the current Vitamin D fortification level in foods to reduce the risk factors of MS.[6] The aim of this paper is to provide an overview of existing research studies and their approaches concerning the relationship between Vitamin D intake and the development of CMS.

Research criteria and methodology

A search of periodical literature by the author involving Vitamin D and CMS was carried out. Items were identified initially through health-oriented indexing services such as Medline, Health STAR and Cinahl, using the identifiers “Vitamin D”, “CMS” “obesity,” “diabetes,” “blood pressure (BP),” “lipid profile,” “pregnancy,” and “toxicity.” An extensive search was also carried out on educational database ERIC. Through an electronic search, 55 studies were identified

Overview of “Vitamin D”?

Vitamin D is a fat-soluble vitamin which has an important role in bone metabolism with some anti-inflammatory and immune-modulating properties. It is very unique since it can be made in the skin from exposure to sunlight. It is a hormone precursor which presents in two forms: Ergocalciferol or Vitamin D2 is found in plants and some fish and seafood cholecalciferol or Vitamin D3 which is synthesized in the skin by sunlight. Vitamin D3 is synthesized from 7-dehydrocholesterol in the skin and transported to the liver by Vitamin D-binding protein where it undergoes hydroxylation to 25(OH)D (the inactive form of Vitamin D), and then, it is hydrolyzed in the kidney by the enzyme 1-hydroxylase to 1,25(OH)D into its active form [Figure 1].[7] The half-life of Vitamin D in the liver is about 3 weeks. Humans can fulfill their Vitamin D requirements normally by either being exposed to the sun for enough time to produce adequate amounts or ingesting Vitamin D. Vitamin D works with parathyroid hormone (PTH) to mediate skeletal mineralization by controlling calcium absorption in the small intestine and maintaining calcium homeostasis in the bloodstream. Good food sources of Vitamin D include certain kinds of fish, egg yolks, and milk, and it can also be added to some food types such as fortified products including margarine, milk, rice, oats, and juices.[8]
Figure 1: Vitamin D synthesis and metabolism

Click here to view

Vitamin D is the most natural form of the vitamin since ultraviolet B (UVB) light from the sun strikes the skin and promotes synthesis of Vitamin D3.[9] Vitamin D, whether from the skin or diet, requires its first hydroxylation in the liver by Vitamin D-25-hydroxylase (25-OHase) to 25(OH)D. However, 25(OH)D requires a further hydroxylation in the kidneys by the 25(OH)D-1-OHase (CYP27B1) for the formation of the biologically active form of Vitamin D 1,25(OH)2D. Without Vitamin D, only 60% of phosphorus and 10%–15% of dietary calcium are absorbed since Vitamin D sufficiency enhances calcium and phosphorus absorption by 30%–40% and 80%, respectively.[10]

Recent epidemiological studies have noted the relationship between low Vitamin D levels and multiple disease states. Low Vitamin D levels are associated with increased level of diseases. Vitamin D deficiency (VDD) has been defined by the Institute of Medicine as a 25(OH)D of <20 ng/mL while Vitamin D insufficiency has been defined as a 25(OH)D of 20–29.9 ng/mL.[11] It has been found that VDD is common in Australia, the Middle East, India, Africa, and South America, children and young- and middle-aged adults are all at equally high risk for developing Vitamin D deficiency worldwide, while pregnant and lactating women who take a prenatal vitamin and calcium supplements with Vitamin D remain at high risk for VDD [Table 1] and [Table 2].[12]
Table 1: Vitamin D status by measuring the amount of 25D in the blood

Click here to view
Table 2: Recommended intake levels of Vitamin D

Click here to view

Vitamin D deficiency (VD) is a well-recognized condition which is prevalent worldwide, particularly at northern latitudes, because of the low levels of UVB light exposure in winter at these latitudes. Several European studies [6],[7] have shown variation in Vitamin D status within countries, which could be explained by factors such as reduced sunlight exposure, low dietary intake of foods rich in Vitamin D, fortification of food with Vitamin D, low physical health status, or differences in biochemical assays used to measure Vitamin D levels.[8] A study published in 2001 reported a prevalence of Vitamin D deficiency from 2% to 30% of European adults but found that it increased to 75% or more in institutionalized older persons.[9] Data from the Third National Health and Nutrition Survey (NHANES III) showed that approximately one-quarter to one-half of American adolescents and adults are deficient in Vitamin D if one uses a threshold of 25 ng/mL.[10] Data from various studies on postmenopausal women revealed that the levels of 1, 25 DHCC below 75 nmol/L (30 ng/mL) ranged from 42% in Brazilian women [11] to 92% in South Korean women.[12] Very deficient levels (≤10 ng/mL) are most prevalent in South Asia and the Middle East,[13] possibly because of cultural dress that limits sun exposure and extended periods of breastfeeding without Vitamin D supplementation.

Cardiometabolic syndrome

The CMS, an interesting constellation of maladaptive cardiovascular, metabolic, prothrombotic, and inflammatory abnormalities, is recognized as a disease entity by the American Society of Endocrinology and the World Health Organization. “MS” is the term generally used to indicate a clinical condition represented by the co-occurrence of HTN, impaired glucose tolerance, dyslipidemia (elevated or abnormal triglycerides [TG], decreased high-density lipoprotein cholesterol [HDL-C], and increased low-density lipoprotein [LDL] cholesterol along with total cholesterol [TC] concentrations), prothrombotic, inflammatory states, central fat accumulation, and insulin resistance (IR). These multiple cardiovascular and metabolic disorders that clusters together in the same individual more often than might be expected by chance lead to an increased probability of suffering from CVD and type 2 diabetes mellitus (T2DM).[13],[14]

These cardiovascular and metabolic abnormalities can lead to substantial increases in CVD morbidity and mortality, making this syndrome an established and strong risk factor for premature and severe CVD and stroke. Established and evolving medical/nutritional treatment strategies, including weight reduction, rigorous BP control, moderate physical activity, and control hyperglycemia and dyslipidemia, have proven beneficial in reversing these abnormal responses and decreasing the CVD risk.[15]

According to the American Heart Association and the National Heart, Lung, and Blood Institute, the exact definition of CMS can be identified as the presence of 3 or more of the following components: (1) elevated TG (<150 mg/dL), cholesterol (>200 mg/dL), and LDL cholesterol (>100 mg/dL); (2) obesity with >30 kg/m 2 and waist circumference >102 cm in men and >88 cm in women; (3) elevated BP systolic and/or diastolic BP >130/85 mmHg); (4) elevated fasting glucose (>100 mg/dL, including prediabetes and diabetes); and (5) reduced HDL-C (<40 mg/dL in men, <50 mg/dL in women).[16],[17]

Vitamin D and obesity

Obesity is defined by the World Health Organization as a body mass index (BMI) of 30 kg/m 2 or more. There is a consistent association in the published literature between increasing and lower serum 25-hydroxyVitamin D (25D) concentrations which can be related to many problems. Each unit increase in BMI levels is associated with 1.15% lower concentration of 25(OH)D, with adjusted age and sex.[18] Some studies reported an association between obesity, high concentrations of PTH, and 1, 25-dihydroxyVitamin D (1,25D) with low serum 25D concentrations.[19] This might be related to various reasons including: low Vitamin D intake as it has been reported that Vitamin D intake as being lower in obese men when compared to their nonobese counterparts; low calcium intake along with Vitamin D intake has also been associated with obesity in both men and women, but this association does not appear to indicate a causal relationship.[20]

Altered behaviors, low synthetic capacity, intestinal absorption, and altered metabolism can all play a major role in controlling Vitamin D levels. Obese individuals tend to expose themselves less to the sun than nonobese individuals, resulting in reduced synthesis of Vitamin D. However, another study found no association in a study of individuals aged >65 years. This is related to the decline in cutaneous Vitamin D synthetic capacity associated with age.[21] A reduced level of Vitamin D is also noticed in those who have had gastric bypass or bariatric procedures, in which a malabsorptive state is intentionally induced.[22] This consideration is improved with increasing frequency for weight reduction. Gastric bypass or bariatric procedures or the combination of both reduced preoperative vitamin concentration and malabsorption may lead to severe Vitamin D deficiencies. Supplementation with Vitamin D should be considered before and after surgery.[23] One study done among 77 overweight and obese women for receiving either 1000 IU of Vitamin D daily or a placebo. Vitamin D supplementation caused a significant drop in body fat mass compared with the placebo. A significant rise in 25D concentrations and changes in both 25D concentration and fat mass were inversely correlated.[24] There is also evidence that weight reduction leads to increased 25D concentrations that in turn provide extra protection against chronic disease. Data collected from 383 overweight or obese women who participated in a 2-year clinical trial of a weight-loss program indicated that 25D levels increased by 2.7 ng/mL (6.8 nmol/L) for those who lost 5%–10% of baseline weight and by 5.0 ng/mL (12.5 nmol/L) for those who lost >10% of baseline weight (P = 0.014). These findings proposed that weight loss is associated with improved serum 25D concentration in overweight or obese women [Table 3].[25]
Table 3: Previous studies indications of Vitamin D supplementation

Click here to view

Vitamin D and cardiovascular diseases

Epidemiologic studies have recently linked low levels of Vitamin D with increased risk of cardiovascular events. They have suggested that 25(OH)D deficiency plays a role in diabetic CVD, myocardial infarction (MI), heart failure, and peripheral vascular disease. One study showed that a decreased Vitamin D level is significantly associated with high prevalence of coronary artery disease (CAD). Low Vitamin D is linked to a 3-fold increase in the rate of MI among males with HTN making the risk of developing CAD eight times higher with low Vitamin D regardless of gender in Arab Gulf countries.[26] Technology, sedentary activity, and unhealthy dietary patterns are all factors have led to a higher prevalence of low Vitamin D despite the presence of sun most of the year. In addition, a high level of Vitamin D deficiency has been recognized in Middle Eastern females as a result of the cultural habit of remaining covered.[27]

A clear association between Vitamin D status and the occurrence of acute MI and coronary heart disease (CHD) has not been firmly established. In a study that compared healthy participants with 128 patients having either acute MI or angina, overall 25(OH)D levels were similar between groups.[26] However, in another study, where 25(OH)D levels between 15 patients with acute MI and 60 age-matched control patients were compared, the Vitamin D levels did not differ significantly between groups.[24] In the analysis of a cohort study, 454 men who reported nonfatal acute MI or fatal CHD had significantly lower levels of 25(OH)D when compared with 900 matched controls without CVD. This risk remained significant after adjustment for other risk factors including MI, diabetes, HTN, race/ethnicity, BMI, and other factors.[27]

The rate of cardiovascular complications including MI and heart failure was 53%–80%, respectively, higher in individuals with Vitamin D deficiency that were followed for about 5 years. There are several mechanisms that can explain the association between Vitamin D level and CVD development.[27],[28] Impaired levels of 25-hydroxycholecalciferol lead to some changes in the smooth muscle of the vascular wall along with inflammation and thrombosis which could explain cardiovascular complications. Vitamin D deficiency may also trigger secondary hyperparathyroidism. Consequently, PTH can promote myocyte hypertrophy and vascular remodeling. While, others suggested that PTH has a pro-inflammatory effect and stimulates the release of cytokines by vascular smooth muscle cells.[28] Both Vitamin D receptor (VDR) and 1-a-hydroxylase which convert Vitamin D into the hormonal 1, 25-OHD2 (calcitriol) form are actively expressed in cardiovascular tissues, including endothelial, cardiomyocytes, and vascular smooth muscle cells. A study where rats had been fed a Vitamin D and a reduction in calcium levels. These effects were readily corrected by Vitamin D analogs.[29] Vitamin D metabolites reduced both endothelium-dependent vascular smooth muscle contractions along with vascular tone in hypertensive models, and an effect mediated through affecting calcium influx across endothelial cells.[30]

A study that included people above 65 years of age suggested an increased risk of Vitamin D deficiency in overweight and higher body fat percentages.[44] As previously mentioned, studies also support an inverse relationship between weight loss and Vitamin D serum changes. This is shown to be effective in eliminating obesity-related inflammation since significant reductions in levels of interleukin-6 (IL-6), an IL that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine, were noted with intervention combining Vitamin D3 supplementation and a weight-loss program. Low serum 25(OH)D was found to be significantly associated with high serum IL-6 in overweight/obese children, and with increased high-sensitivity C-reactive protein (CRP) in obese children, 1, 25(OH)2D3 is also found to have a strong inhibitory effect on nuclear factor κB (NFκB) signaling in human adipocytes. NFκB proteins are a family of five structurally related transcription factors and the proteins synthesized as precursors.[26]

On the contrary, a meta-analysis conclusive of 13 randomized controlled trials (RCT) suggests that Vitamin D supplementation does not affect inflammatory markers: CRP, tumor necrosis factor-alpha, and IL-6 in overweight or obese participants. Some studies do not support any link between Vitamin D supplementation and obesity. Supplementation with Vitamin D showed no effect on adiposity measures in adults. An increase in serum levels of 25(OH)D or other inflammatory markers was not observed in overweight and obese youths with 150,000 IU supplemented every 3 months. Further investigation regarding potential dosage and frequency is needed [30],[31] since another trial with dosage as low as 400 IU up to 4800 IU daily yielded serum changes when administered for 12 months.

In 1739 participants in the Framingham Offspring Study, participants were free of CVD at baseline while the rate of major disease events was 53%–80% higher among those with reduced Vitamin D levels, with the increased risk magnified among those with HTN. However, this study suggested a slightly increased risk at higher 25(OH)D levels.[26] On the other hand, in an analysis of 13,331 adult participants from the NHANES III study who were followed for about 8.7 years, mortality was inversely linked with Vitamin D levels. Twenty-six percent showed increased mortality compared with the highest quartile with the lowest quartile of 25(OH)D (17.8 ng/ml).[31]

The association between Vitamin D and dyslipidemia

It is reasonable that dyslipidemia should also be considered as a potential link with Vitamin D status because dyslipidemia is a well-described independent risk factor for CVD. Observational studies have indicated that high 25-hydroxyVitamin D (25(OH)D) levels were associated with a favorable serum lipid profile. However, a solid rationale for such association is difficult to determine unless there is an effect of Vitamin D supplementation on serum lipids in placebo-controlled randomized trials. Unfortunately, the intervention studies gave divergent results with some showing a positive and some a negative effect.[32] The association between Vitamin D and CVD could be explained by a lipid-lowering effect of Vitamin D. This has been substantiated in several cross-sectional studies, and there is a general agreement that high serum 25(OH)D levels are associated with a favorable serum lipid profile. However, associations derived from observational studies are no proof of causality, particularly for Vitamin D. A meta-analysis study of RCTs indicated that Vitamin D supplementation provided a statistically significant increase in LDL-C (3.23 mg/dl). There was also a tendency toward an increase in TC (1.52 mg/dl) with supplementation of Vitamin D, and the reductions in HDL-C (−0.14 mg/dl) and TG (−1.92 mg/dl) were both nonsignificant. The effect of Vitamin D supplement on serum LDL-C levels seemed more significant in obese participants and in studies with relatively shorter durations while studies with longer durations only showed a significant reduction in HDL-C levels (−2.01 mg/dl).[33]

More interesting, however, are the results from the interventional or longitudinal part of the study. Among the 108,711 participants, 6260 had serum 25(OH)D levels <20 ng/mL that after 4–26 weeks had increased to between 30 and 100 ng/mL (repletion group). In the control group, 2332 patients had 25(OH)D levels <20 ng/mL at both measurements. In the repletion group, there was an increase in serum 25(OH)D of 27.3 ng/mL whereas the increase in the control group was only 0.9 ng/mL. The assay used by the authors separated 25(OH)D2 (which almost exclusively comes from Vitamin D2 supplements) from 25(OH)D3 (which comes from cutaneous Vitamin D3 production). About 81% of the increase in 25(OH)D in the repletion group represented 25(OH)D2. This shows that the increase in the repletion group was mainly the result of Vitamin D2 supplementation, and if Vitamin D supplementation has any clinically significant effect on serum lipids, one should in this setting have a reasonably good chance of detecting it.[34]

Good quality prospective trials assessing adequate doses of Vitamin D supplementation in individuals with relatively low serum levels of Vitamin D levels are needed to understand the role of Vitamin D in the prevention of CVD. It appears that VD has emerged as an independent risk factor for various CVD s including MI and CHD.

Vitamin D benefits in glucose intolerance

T2DM is considered a state of IR (beta-cell compensation), and insulinopenia (beta-cell decompensation) is characterized by progressive deterioration in beta-cell function and eventual loss of beta cell mass. The mechanism by which Vitamin D deficiency and T2DM are related is not well known.[35] Poor Vitamin D status may play a role in the development of type 2 diabetes because cross-sectional epidemiologic studies have found that low Vitamin D status is associated with increased risk of glucose intolerance or diabetes. Furthermore, longitudinal studies have shown that poorer Vitamin D status is associated with an increased incidence of type 2 diabetes. However, there is no strong evidence from randomized clinical trials that Vitamin D supplementation affects glucose homeostasis. Altered calcium and Vitamin D homeostasis are associated with IR, reduced β-cell function, MS, glucose intolerance, and diabetes.[36]

Vitamin D has a very important role in ensuring adequate calcium influx through cell membranes, which is required to preserve various insulin-mediated processes in insulin-responsive tissues, such as skeletal muscle and adipose tissue. Supporting this finding is an intriguing correlation between Vitamin D deficiency and type 1 diabetes. This may be due to the ability of Vitamin D to preserve insulin release modulating the extracellular and intracellular calcium pools. Further, both T2DM and VD share similar risk factors, including obesity, physical inactivity (which may correspond with decreased time outdoors and reduced exposure to sunlight), age, and nonwhite ethnicity. Finally, both glucose levels and serum 25(OH)D vary seasonally. It has been further suggested that the seasonal variation reported for blood glucose may be due to the seasonal variation seen with serum 25(OH)D, which is lower in winter because of decreased sun exposure.[37]

Previous studies have documented an association between 25-hydroxy Vitamin D (25-OH-D) levels and glucose intolerance, but few have focused on community norms. A culturally unique and medically underserved community in which traditional dress is worn may limit sun exposure and dietary preferences may further contribute to 25(OH)D deficiency. Animal and in vitro studies provide compelling evidence that Vitamin D may play a functional role in the preservation of glucose tolerance through its effects on insulin secretion and insulin sensitivity. Vitamin D deficient rabbits present with impaired insulin secretion, and supplementation with Vitamin D corrects the defect. Mice with mutations in the VDR have impaired insulin secretion and lower glucose tolerance than those with functional receptors in vitro. Vitamin D induces the biosynthesis of insulin in rat pancreatic islet cells and in another study inhibited free fatty acid-induced IR (i.e., improved glucose uptake) in cultured myocytes in a dose-dependent manner. The insulin-sensitizing effects were mediated by a reduction in c-Jun N-terminal protein kinase (JNK) activation. JNK is a key regulator of many cellular events, including programmed cell death (apoptosis).[37] Vitamin D deficiency may influence its effects on insulin secretion and sensitivity through its effects on intracellular calcium. Elevated intracellular calcium impairs postreceptor binding insulin action, such as the dephosphorylation of glycogen synthase and of insulin-regulatable glucose transporter-4. Vitamin D deficiency results in elevated PTH, which in turn is known to elevate intracellular calcium. Sustained elevations of intracellular calcium may inhibit insulin target cells from sensing the brisk intracellular calcium fluxes necessary for insulin action, such as glucose transport. Pancreatic cells also depend on an acute intracellular calcium increase for insulin secretion, which may also be attenuated with elevated cytosolic calcium.[38] However, most of the interventional studies discussed above are done on small sample sizes; this might be responsible for the contradictory nature of the results. Thus, well-planned RCTs are required to shed more light on the nature of association between VD and T2DM.

The role of Vitamin D in hypertension

Vitamin D deficiency is highly prevalent and may contribute to arterial HTN. The antihypertensive effects of Vitamin D include suppression of renin and PTH levels and renoprotective, anti-inflammatory, and vasculoprotective properties. Low 25-hydroxyVitamin D levels, which are used to classify the Vitamin D status, are an independent risk factor for incident arterial HTN. Meta-analyses of controlled trials showed that Vitamin D supplementation reduces systolic BP by 2–6 mmHg. However, further studies are needed before drawing a final conclusion on the effect of Vitamin D therapy on BP and cardiovascular risk.[39] Several epidemiologic and clinical studies have suggested an association between Vitamin D deficiency and cardiovascular risk factors (e.g., HTN), and it is now widely accepted that patients with Vitamin D plasma levels below the recommended 75 nmol/L (30 ng/mL) have higher systolic and diastolic BP levels.[40]

Several mechanisms might explain the observed association of Vitamin D plasma levels and HTN. Vitamin D and its analogs inhibit renin secretion and activity, thereby acting as a negative endocrine regulator of the renin-angiotensin system.[41] Inhibition of 1, 25-dihydroxyVitamin D3 synthesis increased renin expression, whereas 1, 25(OH)2D3 injection leads to renin suppression. Vitamin D regulation of renin expression is independent of calcium. Fifty clinical trials report metabolism and 1, 25(OH)2D3 suppresses renin transcription by a VDR-mediated mechanism in cell cultures. Moreover, Vitamin D has direct effects on the vascular wall where it exerts antiproliferative effects on vascular smooth muscle cells.[42] In a recent meta-analysis of 18 independent RCTs on Vitamin D supplementation, including 57,311 participants, the authors report that even a supplementation with ordinary doses of Vitamin D decreases total mortality. Daily doses of Vitamin D supplements ranged from 300 to 2000 IU with a mean dose in all trials of 528 IU. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87–0.99). However, the specific cause of death and optimal Vitamin D dosing were not considered.[43] Data from cross-sectional studies reported that low 25-hydroxyVitamin D is associated with higher systolic BP and higher incidence of HTN. Large observational studies show a weaker, yet similar association, but they have not accounted for the change in Vitamin D levels over time. Randomized control trials conflict with observational data probably due to differences in populations studied, doses of Vitamin D used, and unmeasured confounders. Further research is needed before clinical practice recommends Vitamin D prescription as treatment for HTN in the general population.[44] In 2010, a large systematic review was published in which an analysis of 13 observational studies and 18 randomized trials was made. It noted that while in a meta-analysis of three cohorts, lower 25(OH)D concentration was associated with incident HTN; while in another meta-analysis of 10 trials, the supplementation with Vitamin D did not bring about a significant reduction in systolic BP and there was no effect on diastolic BP.[42] Thus, the association between VD and HTN is not firmly established. However, in the backdrop of some of the evaluated studies suggesting that VD may be a risk factor for HTN, good quality randomized trials are required to elucidate the exact role of VD in the development of HTN.

Vitamin D supplementation during pregnancy

The function of Vitamin D during pregnancy for both mother and fetus remains largely undefined. Vitamin D is known to be involved in skeletal homeostasis during pregnancy as evidenced by a recent publication dealing with craniotabes in the newborn, and severe Vitamin D deficiency may lead to neonatal seizures in those neonates with profound hypocalcemia.[48] Vitamin D requirements are probably greater in pregnancy, as evidenced by physiologically higher 1,25-dihydroxyVitamin D levels seen in the second and third trimesters. While 1,25(OH)2D levels do not correlate directly with 25-hydroxyVitamin D concentrations, the physiological rise in the active metabolite, the enhanced intestinal calcium absorption, and enhanced fetal requirement of calcium (250 mg/day in the third trimester) all point to the importance of Vitamin D biology in pregnancy.[51]

A RCT done on women with a singleton pregnancy at 12–16 weeks' gestation received 400, 2000, or 4000 IU Vitamin D3/day until delivery. The primary outcome was maternal/neonatal circulating 25(OH)D at delivery, with secondary outcomes 25(OH)D ≥80 nmol/L achieved and 25(OH)D concentration required to achieve maximal 1,25(OH)2D production. The results indicated that Vitamin D supplementation of 4000 IU/day for pregnant women was safe and most effective in achieving sufficiency in all women and their neonates regardless of race while the current estimated average requirement was comparatively ineffective at achieving adequate circulating 25(OH)D, especially in African Americans.[49]

Another meta-analysis studied the effects of oral Vitamin D supplementation (alone or in combination with other vitamins and minerals) during pregnancy on maternal 25(OH)D levels and risk of developing preeclampsia, gestational diabetes, preterm birth, impaired glucose tolerance, cesarean section, gestational HTN, and other adverse conditions. It concluded that supplementing pregnant women with Vitamin D led to significantly higher levels of 25(OH)D at term compared to placebo/control, but results were inconsistent. Vitamin D supplementation, with or without calcium, may be related to lower risk of preeclampsia, but more studies are needed to confirm this.[50]

At this time, there is insufficient evidence to support a recommendation for screening all pregnant women for Vitamin D deficiency. For pregnant women thought to be at increased risk of Vitamin D deficiency, maternal serum 25-OH-D levels can be considered and should be interpreted in the context of the individual clinical circumstance.[51]

Toxicity and over supplementation of Vitamin D

The main consequence of Vitamin D toxicity is a buildup of calcium in the blood (hypercalcemia).

Patients usually present with nausea, vomiting, weakness, and altered level of consciousness. Polyuria, excessive thirst, and other manifestations such as painful periarticular calcinosis, nephrocalcinosis, HTN, renal failure or band keratopathy, and hearing loss have been reported. The symptoms of Vitamin D toxicity can stem from the deposition of calcium phosphate crystals in soft tissues throughout the body, which can occur once the calcium phosphate product is >60.[52]

The mechanism of Vitamin D toxicity in hypervitaminosis D is postulated to be an overwhelming of the Vitamin D signal transduction process, whereby the catabolic system is unable to keep up with the target cell levels of activated Vitamin D metabolites. Three major theories have been put forth by researchers about the mechanisms of Vitamin D toxicity. All involve increased concentrations of a Vitamin D metabolite reaching the VDR in the nucleus of target cells and causing exaggerated gene expression.[53]

Vitamin D intoxication is a treatable cause of hypercalcemia. Calcitriol-induced hypercalcemia usually lasts only one to 2 days due to the short biologic half-life of the compound. Discontinuing the calcitriol, increasing salt and fluid intake or additional hydration with intravenous saline may be the only treatment needed. In contrast, hypercalcemia induced by intoxication with longer lasting preparations such as dihydrotachysterol, Vitamin D3, and Vitamin D2 takes longer to resolve because of deposition of ingested Vitamin D in fat and its consequent slow release. Therefore, more aggressive therapy including intravenous hydration, diuretics, and glucocorticoids is needed. Since the hypercalcemia of Vitamin D intoxication results from increased intestinal absorption of calcium and from the direct effect of 1,25(OH)2D3 to increase resorption of bone in severe cases, therefore, bisphosphonate therapy can be usefully added to the therapeutic regimen of hydration and omission of dietary calcium.[53],[54]

  Conclusion Top

Vitamin D deficiency (VDD) has been classically associated with decreased health. When it comes to supplementation with Vitamin D, the question addressed by intervention studies has been primarily whether Vitamin D supplementation may be effective for either the treatment or prevention of various conditions. However, it is important to recognize that the majority of recommendations regarding Vitamin D supplementation have in focused on the role of Vitamin D in bone health. New guidelines for supplementation with Vitamin D, beyond just the skeletal manifestations of VD, have the potential for an enormous public health improvement. Until such guidelines are confirmed and published, practitioners should focus on maintaining adequate serum concentrations of Vitamin D in their patients by means of adequate nutrition or when indicated supplementation in patients at risk of developing cardiometabolic disorders, to achieve better treatment results and improved health.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Calvo MS, Whiting SJ, Barton CN. Vitamin D intake: A global perspective of current status. J Nutr 2005;135:310-6.  Back to cited text no. 1
Norman AW. From Vitamin D to hormone D: Fundamentals of the Vitamin D endocrine system essential for good health. Am J Clin Nutr 2008;88:491S-9S.  Back to cited text no. 2
Grundy SM. Metabolic syndrome pande myocardial infarctionc. Arterioscler Thromb Vasc Biol 2008;28:629-36.  Back to cited text no. 3
Goodpaster BH, Krishnaswami S, Harris TB, Katsiaras A, Kritchevsky SB, Simonsick EM, et al. Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. Arch Intern Med 2005;165:777-83.  Back to cited text no. 4
Rosen CJ, Adams JS, Bikle D, Black DM, Demay MB, Manson JE, Murad MH, Kovacs CS. The nonskeletal effects of Vitamin D: An endocrine society scientific statement. Endocr Rev 2012;33:456-92.  Back to cited text no. 5
Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, et al. The urgent need to recommend an intake of Vitamin D that is effective. Am J Clin Nutr 2007;85:649-50.  Back to cited text no. 6
Brannon PM, Yetley EA, Bailey RL, Picciano MF. Overview of the conference “Vitamin D and health in the 21st century: An update”. Am J Clin Nutr 2008;88:483S-90S.  Back to cited text no. 7
Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007;72:1004-13.  Back to cited text no. 8
Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L, Maalouf G, et al. The prevalence of Vitamin D inadequacy amongst women with osteoporosis: An international epidemiological investigation. J Intern Med 2006;260:245-54.  Back to cited text no. 9
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am J Clin Nutr 2007;85:1586-91.  Back to cited text no. 10
Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003;22:142-6.  Back to cited text no. 11
Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM, et al. Vitamin D insufficiency: Disease or no disease? J Bone Miner Res 2008;23:1052-60.  Back to cited text no. 12
Isomaa B, Almgren P, Tuomi T, Forsén B, Lahti K, Nissén M, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683-9.  Back to cited text no. 13
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-16.  Back to cited text no. 14
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: Findings from the third national health and nutrition examination survey. JAMA 2002;287:356-9.  Back to cited text no. 15
Reppert A, Steiner BF, Chapman-Novakofski K. Prevalence of metabolic syndrome and associated risk factors in illinois. Am J Health Promot 2008;23:130-8.  Back to cited text no. 16
Vasudevan AR, Ballantyne CM. Cardiometabolic risk assessment: An approach to the prevention of cardiovascular disease and diabetes mellitus. Clin Cornerstone 2005;7:7-16.  Back to cited text no. 17
Pi-Sunyer FX. The obesity epidemic: Pathophysiology and consequences of obesity. Obes Res 2002;10 Suppl 2:97S-104S.  Back to cited text no. 18
Lagunova Z, Porojnicu AC, Lindberg F, Hexeberg S, Moan J. The dependency of Vitamin D status on body mass index, gender, age and season. Anticancer Res 2009;29:3713-20.  Back to cited text no. 19
Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone level is associated with body mass index. The 5th tromsø study. Eur J Endocrinol 2004;151:167-72.  Back to cited text no. 20
Harris SS, Dawson-Hughes B. Reduced sun exposure does not explain the inverse association of 25-hydroxyvitamin D with percent body fat in older adults. J Clin Endocrinol Metab 2007;92:3155-7.  Back to cited text no. 21
Shapses SA, Sukumar D, Schneider SH, Schlussel Y, Brolin RE, Taich L, et al. Hormonal and dietary influences on true fractional calcium absorption in women: Role of obesity. Osteoporos Int 2012;23:2607-14.  Back to cited text no. 22
Jorde R, Sneve M, Torjesen P, Figenschau Y. No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with Vitamin D3 for 1 year. J Intern Med 2010;267:462-72.  Back to cited text no. 23
Salehpour A, Hosseinpanah F, Shidfar F, Vafa M, Razaghi M, Dehghani S, et al. A 12-week double-blind randomized clinical trial of Vitamin D3 supplementation on body fat mass in healthy overweight and obese women. Nutr J 2012;11:78.  Back to cited text no. 24
Rock CL, Emond JA, Flatt SW, Heath DD, Karanja N, Pakiz B, et al. Weight loss is associated with increased serum 25-hydroxyvitamin D in overweight or obese women. Obesity (Silver Spring) 2012;20:2296-301.  Back to cited text no. 25
Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-11.  Back to cited text no. 26
Fields J, Trivedi NJ, Horton E, Mechanick JI. Vitamin D in the Persian Gulf: Integrative physiology and socioeconomic factors. Curr Osteoporos Rep 2011;9:243-50.  Back to cited text no. 27
Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, et al. Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: A novel autocrine determinant of vascular cell adhesion. J Am Soc Nephrol 2002;13:621-9.  Back to cited text no. 28
Chen S, Law CS, Grigsby CL, Olsen K, Hong TT, Zhang Y, et al. Cardiomyocyte-specific deletion of the Vitamin D receptor gene results in cardiac hypertrophy. Circulation 2011;124:1838-47.  Back to cited text no. 29
Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, et al. Activated Vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci U S A 2007;104:16810-5.  Back to cited text no. 30
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-37.  Back to cited text no. 31
Jorde R, Grimnes G. Vitamin D and metabolic health with special reference to the effect of Vitamin D on serum lipids. Prog Lipid Res 2011;50:303-12.  Back to cited text no. 32
Wang H, Xia N, Yang Y, Peng DQ. Influence of Vitamin D supplementation on plasma lipid profiles: A meta-analysis of randomized controlled trials. Lipids Health Dis 2012;11:42.  Back to cited text no. 33
Jorde R, Grimnes G. Vitamin D and lipids: Do we really need more studies? Circulation 2012;126:252-4.  Back to cited text no. 34
Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006;116:1802-12.  Back to cited text no. 35
Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of Vitamin D and risk of type 1 diabetes: A birth-cohort study. Lancet 2001;358:1500-3.  Back to cited text no. 36
Zhou QG, Hou FF, Guo ZJ, Liang M, Wang GB, Zhang X, et al. 1,25-dihydroxyvitamin D improved the free fatty-acid-induced insulin resistance in cultured C2C12 cells. Diabetes Metab Res Rev 2008;24:459-64.  Back to cited text no. 37
Worrall DS, Olefsky JM. The effects of intracellular calcium depletion on insulin signaling in 3T3-L1 adipocytes. Mol Endocrinol 2002;16:378-89.  Back to cited text no. 38
Pilz S, Tomaschitz A. Role of Vitamin D in arterial hypertension. Expert Rev Cardiovasc Ther 2010;8:1599-608.  Back to cited text no. 39
Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007;49:1063-9.  Back to cited text no. 40
Forman JP, Bischoff-Ferrari HA, Willett WC, Stampfer MJ, Curhan GC. Vitamin D intake and risk of incident hypertension: Results from three large prospective cohort studies. Hypertension 2005;46:676-82.  Back to cited text no. 41
Yamamoto T, Kozawa O, Tanabe K, Akamatsu S, Matsuno H, Dohi S, Hirose H, Uematsu T. 1, 25-dihydroxyVitamin D3 stimulates vascular endothelial growth factor release in aortic smooth muscle cells: Role of p38 Myocardial Infarctiontogen-activated protein kinase. Arch Biochem Biophys 2002;398:1-6.  Back to cited text no. 42
Autier P, Gandini S. Vitamin D supplementation and total mortality: A meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730-7.  Back to cited text no. 43
Tamez H, Thadhani RI. Vitamin D and hypertension: An update and review. Curr Opin Nephrol Hypertens 2012;21:492-9.  Back to cited text no. 44
Mehmood ZH, Papandreou D. An updated mini review of Vitamin D and obesity: Adipogenesis and inflammation state. Open Access Maced J Med Sci 2016;4:526-32.  Back to cited text no. 45
Alkharfy KM, Al-Daghri NM, Sabico SB, Al-Othman A, Moharram O, Alokail MS, et al. Vitamin D supplementation in patients with diabetes mellitus type 2 on different therapeutic regimens: A one-year prospective study. Cardiovasc Diabetol 2013;12:113.  Back to cited text no. 46
Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, et al. Effect of monthly high-dose Vitamin D supplementation on cardiovascular disease in the Vitamin D assessment study: A Randomized clinical trial. JAMA Cardiol 2017;2:608-16.  Back to cited text no. 47
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding, American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and Vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142-52.  Back to cited text no. 48
Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: Double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res 2011;26:2341-57.  Back to cited text no. 49
Palacios C, De-Regil LM, Lombardo LK, Peña-Rosas JP. Vitamin D supplementation during pregnancy: Updated meta-analysis on maternal outcomes. J Steroid Biochem Mol Biol 2016;164:148-55.  Back to cited text no. 50
Specker BL. Does Vitamin D during pregnancy impact offspring growth and bone? Proc Nutr Soc 2012;71:38-45.  Back to cited text no. 51
Joshi R. Hypercalcemia due to hypervitaminosis D: Report of seven patients. J Trop Pediatr 2009;55:396-8.  Back to cited text no. 52
Jones G. Vitamin D in the 21st century: An update- Pharmacokinetics of Vitamin D toxicity. Am J Clin Nutr 2008;88:582S-6S.  Back to cited text no. 53
Jensterle M, Pfeifer M, Sever M, Kocjan T. Dihydrotachysterol intoxication treated with pamidronate: A case report. Cases J 2010;3:78.  Back to cited text no. 54


  [Figure 1]

  [Table 1], [Table 2], [Table 3]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded276    
    Comments [Add]    

Recommend this journal