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- Table 1 Diabetes Mellitus
- Table 2 Tuberculosis
- Table 3 Hypertension
- Table 4 Cardiovascular Diseases
- Table 5 Osteoporosis
- Table 6 Multiple Sclerosis
- Table 7 Cognition
- Table 8 Chronic Pain
- Table 9 Colon Cancer
- Table 10 Breast cancer
- Table 11 Prostate cancer
- Table 12 Vitamin D levels recommended
- Table 13 Age and vitamin D
PDF is attached at the bottom of this page
Department of Internal Medicine, Karnataka Institute of Medical Sciences, Hubli, India.
Dr. Ram. S. Kaulgud
Department of Internal Medicine,
Karnataka Institute of Medical Sciences, Hubli, India.
Vitamin D has been found to be useful for a number of conditions. Various studies have found it useful in different disorders to varying degree. It is being prescribed very frequently in clinical practice. So, we decided to conduct review to clarify its role in prevention and treatment of different disorders. We found more than thousand articles and reviewed relevant literatute from databases like Cochrane, Pubmed, Medline that tested role of this vitamin in various spectra of diseases. We found vitamin D to be efficacious in conditions like cardiovascular diseases, diabetes mellitus, osteoporosis; but its role in treatment of certain conditions like multiple sclerosis, cognition needs to be assessed further studies.
Keywords: Vitamin D3, diabetes mellitus, osteoporosis, cognition
Vitamin D, also known as sunshine vitamin, until recently was known mainly for its effect on musculoskeletal system. However as more research has been carried out about the pivotal role it plays in functioning of several other organ systems, now there is abundant literature available regarding its vital role in prevention of various spectra of diseases. Here is brief evidence based review of the various diseases in which role of this vitamin has been tested and proven.
1.1 Vitamin D and Diabetes Mellitus: Vitamin D3 is the active form of Vitamin D. Receptors to this active form have now been found in beta cells of pancreas. Vitamin D plays a role in functioning of beta cells of pancreas by binding of active form of Vitamin D to its receptor on beta cells. Vitamin D deficiency has been proposed to predispose to development of both types 1 as well as type 2 diabetes mellitus. Lots of research studies have been carried out to identify its role in pathogenesis as well as in the treatment of diabetes.
Several studies point to a link between deficiency of this vitamin in early life & later onset of Type I diabetes.11 12 Prospective observational study by Hypponen et al1 in Finland conducted with Vitamin D supplementation during infancy, "regular" vs. "none", followed the children up to 14 yrs. They found that relative risk 0.12 of later onset of type 1 diabetes in infants who were given regular Vitamin D compared to the one who were not given any supplementation. Vitamin D deficiency may predispose to glucose intolerance, altered insulin secretion & Type 2 diabetes mellitus. There are Vitamin D receptors & Vitamin D binding protein in pancreatic tissue and they are related to glucose intolerance and insulin secretion. Studies showed a consistent association between low Vitamin D status, calcium daily intake and prevalence of Type 2 diabetes or metabolic syndrome. Liu et al. conducted Women's Health study (US) in 52 middle aged women and classified into low and high Vitamin D intake groups. Mean follow up in the study was 9yrs. This study reported relative risk 0.13 of developing type 2 diabetes in higher Vitamin D intake group as compared to lower intake. Similar study was done by Pittas et al.1 in [Nurses' Health Study] in 46 young women. This study reported the relative risk 0.81 of type 2 diabetes in higher vitamin D intake group as compared to lower intake. Thus, the available literature clearly proves the important role of vitamin D in the prevention as well as treatment of Type 1, type 2 as well as gestational diabetes. The table below summarizes important studies.
Table 1 Vitamin D and Diabetes Mellitus
1.2 Tuberculosis and vitamin D deficiency : Vitamin D and its active form 1, 25 vitamin D induce antibacterial peptides in vitro that effectively inhibit tuberculosis (TB). Early studies in 1985 showed that vitamin D treatment of murine and human macrophages could potentiate the effects of IFN-y to inhibit TB in vitro.13 Till recently Vitamin D deficiency was considered uncommon in India. Following an original observation of Vitamin D deficiency in patients with Tuberculosis a controlled study was done to verify that in Kerala.14 Vitamin D levels in patients with recently diagnosed active Tuberculosis and matched healthy controls were compared. Adequacy of dietary intake of Vitamin D and adequacy sun exposure was studied in the two groups. This study concluded that Vitamin D deficiency was present in all patients with tuberculosis. Deficiency was also noted in healthy controls even though the level was higher compared to patients. The incidence of TB is higher among subjects with relatively low serum vitamin D levels, such as the elderly, uremic patients, and Asian immigrants in the U.K.15 Several other studies from different parts of world support important role of vitamin D in immunity against tuberculosis as shown in table 2.
Table 2 Role of vitamin D in immunity against tuberculosis
Systemic review and meta analysis by Kelechi E Nnoaham et al26 concluded that Low serum vitamin D levels are associated with higher risk of active tuberculosis. Since Vitamin D has a role in cell mediated immunity. It's deficiency could be one of the causes for the infection. This has been supported by epidemiologic data which suggest that low vitamin D is associated with TB severity or susceptibility.27 Genes also probably contribute to this as shown by a meta- analysis showing a positive association between VDR polymorphisms and host susceptibility to tuberculosis.27 Patients with untreated TB, particularly those from a temperate climate, have lower serum vitamin D levels than healthy subjects.15 Recently, a double blind, randomized and placebo controlled trial used three high- dose (1,00,000 I.U.) vitamin D supplements in Tuberculosis patients.28 The study showed no beneficial effect in clinical outcome or mortality in Tuberculosis. Another recent report in patients on dialysis showed no correlation between vitamin D supplementation and decreased risk of Tuberculosis infection.29 So, in spite of several studies supporting role of vitamin D in body defence against tuberculosis, evidence from large scale placebo controlled trials is lacking. And, there is not adequate information available to claim vitamin D as an anti-infective agent.30 Hence, as of today, vitamin D cannot be recommended for prevention or as part of treatment of tuberculosis.
1.3 Vitamin D and Cardiovascular diseases: Vitamin D deficiency has been associated with cardiovascular diseases.31'32 Several mechanisms have been proposed to explain how vitamin D could affect CVD risk. Probable mechanisms are- due to effect of vitamin D on vascular smooth muscle cell proliferation, inflammation, vascular calcification, and blood pressure through the RAS. Third National Health and Nutrition Examination Survey data analysis showed an inverse association between vitamin D levels and blood pressure.33 In this study, during 4 years of follow-up, men and women who had plasma vitamin D levels less than 15 ng/mL were 3 times as likely to have a new diagnosis of hypertension in the next 4 years compared with those with vitamin D levels greater than 30 ng/mL. Important studies regarding role of vitamin D in hypertension have been listed below in table 3.
Table 3 Role of vitamin D in hypertension
Various study reports have linked vitamin D deficiency to such cardiovascular conditions as hypertension, diabetes mellitus, obesity and the metabolic syndrome, left ventricular hypertrophy, heart failure, coronary heart disease, renal disease, and mortality.43- 47 In small clinical trials, vitamin D supplementation has promoted reductions in blood pressure,48, 49 left ventricular hypertrophy,50 and inflammatory cytokines.51 Park et al,50 showed regression of LV hypertrophy in hemodialysis patients treated with vitamin D. Cohort study by Annamari Kilkkinen et al.52 provided evidence that a low circulating level of vitamin D may predict a higher risk of cardiovascular disease death. In this study, subjects in the highest quintile of serum vitamin D level had less than half the risk of cerebrovascular death as those in the lowest quintile. 54Among participants in the Framingham Offspring Study cohort, vitamin D deficiency was associated with an increased risk of CVD. The association was observed only in hypertensive subjects, not in those without hypertension.53 In the Health Professionals Follow-up Study, men with a high circulating level of vitamin D had half the risk of myocardial infarction as men with vitamin D insufficiency.54 Vitamin D deficiency is associated with increased mortality rates in the setting of chronic kidney disease55, and repleting vitamin D in such patients improves outcomes. Yadav and collegues,56 in their study on chronic kidney disease patients, found Vitamin D deficiency to be correlating with preclinical atherosclerotic changes. There is also emerging evidence that treatment with vitamin D analogues reduces mortality in hemodialysis patients. Lower vitamin D levels have been observed in individuals with acute myocardial infarction,57 stroke,58 heart failure,59,60and cardiovascular disease, 61 peripheral arterial disease 62 in several small cross sectional studies.
Though many studies have highlighted the protective role of vitamin D in prevention of cardiovascular diseases, there is no unanimity. Hsia and colleagues 63 recently reported that use of calcium and vitamin D supplements was not associated with a reduction in cardiovascular events in the Women's Health Initiative. Recent cohort study based on data from the Third National Health and Nutrition Examination Survey, Melamed et al64 could not find a statistically significant association between vitamin D status and cardiovascular disease mortality in the general population. Systematic review by Anastassios G. Pittas et al. of 13 observational studies (14 cohorts) and 18 trials concluded that association between vitamin D status and cardiometabolic outcomes is uncertain.65 Results of the studies assessing role of vitamin D in cardiovascular diseases has been listed in table 4.
Table 4 Studies assessing role of vitamin D in cardiovascular diseases
It is too early to know if the beneficial effect of vitamin D treatment is mediated by effects on cardiac function; there is, however, sufficient literature to support the notion that vitamin D has a beneficial effect on cardiac tissue. Evidence from data available till now suggests that vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects.74 Vitamin D deficiency, thus, probably represents an important new cardiovascular risk factor and, may be an etiologic factor in the development of cardiovascular risk factors and cardiovascular diseases and adverse events, including death.75
1.4 Vitamin D and Osteoporosis: Osteoporosis is the most common metabolic bone disease in the world. Vitamin D plays a key role in bone formation. A low vitamin D level is an established risk factor for osteoporosis. Vitamin D deficiency will decrease the active trans-cellular absorption of calcium. Vitamin D supplementation of more than 400 IU daily has been found to reduce incidence of non-vertebral fractures as shown by a meta analysis.76 The effect was dose dependent and was not significant if doses were <400 IU daily.
Table 5 Role of Vitamin D in Osteoporosis
Results of several important studies favour vitamin D supplementation for prevention and treatment of osteoporosis (table 5). Thus prescribing vitamin D supplements in patients with osteoporosis seems to be adequately justified.
1.5 Vitamin D and Multiple Sclerosis 87' 88: Vitamin D is important for normal immune response of the body. It affects the growth and differentiation of immune-modulator cells like T and B lymphocytes, antigen presenting cells like macrophages, dendritic cells. This action has implications for a variety of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosis,89 type 1 DM, inflammatory bowel disease, and Multiple Sclerosis.87 Vitamin D supplementation may help prevent the development of MS and may be a useful addition to therapy.90 Higher serum vitamin D levels are protective against MS as shown by a case-control study which showed that for every 10-nmol/L increase of serum vitamin D level the odds of MS was reduced by 19% in women.91 Several other studies have supported the finding that lower levels of vitamin D in MS patients are associated with more severe disability. Lower levels during relapses have also been reported in patients with relapse-remitting MS. A large observational study in the United States that followed the Nurses' Health Study involving 92,253 women and the Nurses' Health Study II 92 involving 95,310 women—found that vitamin D supplementation in the form of a multivitamin seemed to lower their MS risk by 40%. However, several methodological weaknesses in study design made the results inconclusive.93 Vitamin D supplementation at appropriate dosage has been shown to reduce gadolinium-enhancing lesions on magnetic resonance imaging without causing hypercalcemia, hypercalciuria, or other complication. 93 Support for vitamin D supplementation in MS patients is also given by A Finnish study which found that, compared with patients without MS, patients with MS had lower serum vitamin D levels during the 94
Table 6 Role of Vitamin D in Multiple Sclerosis
From the table above, we can observe that vitamin D deficiency is associated with worse clinical course of multiple sclerosis, with more frequent relapses and disease exacerbations. A link between dietary intake of vitamin D and the incidence of MS has also been suggested. The Atlantic coastal areas of Norway have a lower incidence of MS than the rest of Scandinavia, which is thought to be due to the high amount of vitamin D from fish in the local diet.104 So, the measures to increase blood levels of vitamin D either by diet or supplementation may be used to improve the course and prognosis of multiple sclerosis.
1.6 Vitamin D and Cognition: Vitamin D levels have been found to correlate with score on mental status examination in a study.105 The biological plausibility of this relationship includes vitamin D's anti-oxidative effects and the presence of vitamin D receptors in the hippocampus, which has been seen in rats and humans. Vitamin D is needed for normal cognition and deficiency of this vitamin has been proposed to predispose to cognitive disorders like Alzheimers' disease (table 7).
Table 7 Role of Vitamin D in Cognition
But this notion has not been supported by well designed randomized control trials till today. Hence, till evidence from such large and well designed studies is available, vitamin D supplementation cannot be recommended for either prevention or treatment of multiple sclerosis.
1.7 Vitamin D and Chronic Pain: Because of the important role vitamin D plays in bone homeostasis, it is only logical to think that vitamin D deficiency may correlate with chronic pain syndromes, including chronic low back pain. Most of the times Vitamin D deficiency occurs without any symptoms, if at all any symptoms present it indicates severe deficiency (<5ng/ml). Severe vitamin D deficiency leads to osteomalacic myopathy, as characterized in a case series demonstrating severe myalgia and muscle weakness in individuals with low serum concentration of vitamin D, with prompt resolution of symptoms following vitamin D replacement.116 Several case series and observational studies have suggested that vitamin D inadequacy may represent a source of nociception and impaired neuromuscular functioning among patients with chronic pain. Patients often complain of aching nonspecific symptoms such as bones and myalgia. Such patients are often misdiagnosed with fibromyalgia, chronic fatigue syndrome, myositis, or other nonspecific collagen vascular diseases. It is estimated that 40-60% of patients with fibromyalgia may have some component of vitamin D deficiency and osteomalacia.117-121
Table 8 Role Vitamin D in Chronic Pain
Vitamin D deficiency often presents as musculoskeletal pain severity of which increases with lower vitamin D levels. Treatment of vitamin D deficiency produces an increase in muscle strength and a marked decrease in back and lower-limb pain within few months. However the verdict on this topic will remain undecided until this is evaluated by double-blind, randomized, controlled trials stratified by baseline vitamin D level with defined treatments and comparison placebo groups.
2. The Role of Vitamin D in Cancer Prevention: Role of vitamin D is being researched by studies around all over. More than 1000 laboratory and epidemiological studies have been published concerning the association between vitamin D and its metabolites and cancer. Emphasis is being paid on vitamin D in cancer prevention and treatment because of the easy availability and low cost of this molecule in addition to its positive results from lots of studies. The evidence suggests that efforts to improve vitamin D status could result in less cancer incidence and mortality at low cost, with few or no adverse effects. Raising serum vitamin D to appropriate level can prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year.132 In a cohort study by Edward Giovannucci et al, a vitamin D increment of 25 nmol/L was associated with a 17% reduction in total cancer incidence, a 29% reduction in total cancer mortality, and a 43% and 45% reduction in incidence and mortality, respectively, of digestive-system cancers.133 Digestive system cancer incidence as well as mortality in men has been found to be associated with low levels of vitamin D.135 Vitamin D synthesis34 and serum vitamin D levels135 are inversely correlated with latitude and directly with sunlight, consistent with higher incidence or mortality rates for colon136 and breast cancer,137 especially in areas 37° or more from the equator. There are also north-south gradients for ovarian 138 and prostate cancer.139'140
2.1 Vitamin D and colon cancer: Relation between vitamin D deficiency and colon cancer has been subjected to various studies. Individuals with low circulating vitamin D levels have been shown to be at increased risk of colon cancer in various studies (table 9).
Table 9 Role of Vitamin D in Colon Cancer
Several epidemiological studies like Western Electric Cohort Study, the Nurses' Health Study, the Male Health Professionals' Follow-Up Study have reported higher risk of colon malignancy in individuals consuming lower amounts of vitamin D.142 Both human and animal studies-interventional as well as non-interventional support protective notion that vitamin D can reduce the risk of colon cancer related to high dietary fat intake.151-154 Daily intake of 1000-2000 IU/day of vitamin D3 could reduce the incidence of colorectal without any significant risk.145 Population serum vitamin D level of 40
to 60 ng/mL has been found to be adequate to obtain various health benefits of this vitamin, which is obtained from intake of approximately 2000 IU per day of vitamin D3.
2.2 Vitamin D and breast cancer: Western-style diet, which contains low calcium and vitamin D and increased fat content has been found to induce hyper-proliferation and hyperplasia in mammary gland and colonic epithelium in short-term studies; dietary calcium supplementation inhibited those changes.155 Breast cancer death rates tend to be lower in areas with better sunshine. Women with lower serum Vitamin D levels (< 75nmol/l) have been found to have higher risk of breast cancer than those in whom vitamin D levels are in normal range. Lower vitamin D levels have also been associated with faster progression of metastatic breast cancer.156 Several epidemiologic and experimental studies have now suggested that high dietary fat and decreased calcium and vitamin D intake have associations with mammary gland carcinogenesis.157-159
Table 10 Role of Vitamin D in breast cancer
2.3 Vitamin D and prostate cancer: Vitamin D has been proposed to have beneficial effect in prevention and treatment of prostatic cancer. Several studies have been carried to study this association. The results have been mixed as shown in table below. But, no large scale placebo controlled study has been carried out yet.
Table 11 Role of Vitamin D in prostate cancer
Thus, though theoretically vitamin D is likely to have beneficial effects on prostatic cancer, in the absence of strong evidence to prove its therapeutic utility, no definite recommendations can be made for its use in prostatic cancer.
In addition to being associated with specific diseases and morbidity associated with those conditions, lower vitamin D levels also have been associated with increase in all cause mortality as noted from cardiovascular disease (CVD) mortality in 13331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files.177 And Intake of usual doses of vitamin D supplements seems to be adequate to reduce these death rates.178 3. Serum levels recommended:
Table 12 Serum levels recommended
In patients with documented vitamin D deficiency, a cumulative dose of at least 6 lakh units administered over several weeks is essential to replenish stores.179 According to mayoclinic, for type 2 diabetes patients, 400-5714 IU of vitamin D is recommended to be taken by mouth daily for 2 months to several years. According to KDOQI guidelines, in patients with chronic kidney disease, monthly intake of 50,000 IU orally is recommended. 10-15 min whole-body exposure to peak summer sun will generate and release up to 20,000 IU vitamin D-3 into the circulation. So, exposure to sunlight is very simple and effective measure to prevent vitamin D deficiency. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.180
Table 13 Age group Vitamin D sufficient Vitamin D deficient
Vitamin D has definite beneficial role in prevention and treatment of cardiovascular disease, osteoporosis, type 1 diabetes, type 2 diabetes, gestational diabetes. Intake of vitamin D is associated with reduced incidence and death rates of colon, breast, prostate, and ovarian cancers. It is probably also beneficial for chronic pain. But its role in cognitive disorders, multiple sclerosis and tuberculosis requires further research. Because of the overall health benefits of this vitamin for various diseases, measures to prevent deficiency of this vitamin like exposure to sunlight, dietary supplementation need to be encouraged in all the individuals.
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37. Davide Carrara, Matteo Bernini, Alessandra Bacca. Ilaria Rugani. Cholecalciferol administration blunts the systemic renin-angiotensin system in essential hypertensives with hypovitaminosis D. Journal of Renin-Angiotensin-Aldosterone System 2013 Jan 2. [Epub ahead of print]
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