Is vitamin D deficiency contributing to high predisposition to non-communicable diseases in Indians? A review article

BACKGROUND

Vitamin D, a fat-soluble vitamin, is necessary in humans to maintain calcium and phosphorus homeostasis.¹ The chief source of vitamin D is exposure to ultraviolet B (UVB) from sunlight or artificial light. This makes dark-skinned people more vulnerable to Vitamin D deficiency (VDD) as skin pigment melanin renders action of sunlight in production of vitamin D less effective. This makes Indians very prone to develop this particular deficiency, which is largely diagnosed only when patients present with clinically overt symptoms like rickets and osteomalacia, which represent the tip of the iceberg. This may be further complemented by inadequate sun exposure and a vitamin D deficient diet. The main circulating storage form of vitamin D is 25-hydroxyvitamin D [25(OH)D] and so vitamin D deficiency has been defined as a 25(OH) D level of <20 ng/ml (50 nmol/l), vitamin D insufficiency as 21 to 29 ng/ml severe vitamin D deficiency as <10 ng/ml and the optimal concentration of 25(OH) D is at least 30 ng/ml.² It has been observed that 25(OH) D is often as low as 30% to 50% in otherwise healthy middle-aged to elderly adults.^3-6 This is of serious concern as Vitamin D is not only crucial to maintaining musculoskeletal health but also has a role in cardiovascular diseases, cancers and even psychiatric morbidities.

PHYSIOLOGY

Vitamin D has two forms: vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). While vitamin D₂ is found in plants and is consumed as a supplement or used in fortified foods, vitamin D₃ is produced by action of UVB radiation on 7-dehydrocholesterol in the skin, which forms previtamin D₃.⁷ Previtamin D₃ is rapidly converted to vitamin D₃ leading to its metabolization in the liver to form 25-hydroxyvitamin D_3. In the kidney, 25(OH)D is converted by 1-hydroxylase to its active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D], which is the hormonal form of vitamin D.⁷ Vitamin D receptors are present in most tissues, including endothelium, vascular smooth muscle, and myocardium.⁸ More than 200 genes are is believed to be regulated by 1,25(OH)₂D, including those involved in renin production in the kidney, insulin production in the pancreas, release of cytokines from lymphocytes, production of cathelicidin in macrophages, and growth and proliferation of both vascular smooth muscle cells and cardiomyocytes.⁷ Though 1,25(OH)₂D circulates throughout the body depending on its serum levels for estimating overall vitamin D status can be misleading as they do not correlate well.⁷

RISK FACTORS OF VITAMIN D DEFICIENCY

Darkly pigmented skin, winter season, increased distance from the equator, time of day, aging, institutionalized patients, indoor lifestyles, covered-up clothing and sunscreen use reduces the cutaneous production of vitamin D₃.² Some medical risk factors are liver and kidney disease, obesity, use of anticonvulsants, glucocorticoids and antiretroviral medications.²

VITAMIN D DEFICIENCY IN PREGNANCY AND ITS OUTCOMES

The need for calcium increases in pregnancy and lactation. Vitamin D deficiency in pregnant women may affect the mother and the child and cause high bone turn over, bone loss, osteomalacia, and hypovitaminosis D myopathy in the mother.^9,10 If severe, vitamin D deficiency during pregnancy effects calcium homeostasis and skeletal mineralization of the fetus and may even lead to congenital rickets, craniotabes.^11,12 The predominant and often the only source of vitamin D for a baby during gestational period and exclusive breast-feeding period is the mother. So, maternal vitamin D deficiency during this time affect the functional characteristics of various tissues of the body, which, in later life makes the person more prone to develop various non-communicable diseases (NCDs) including mental health problems like schizophrenia.^13,14

VITAMIN D AND CARDIOVASCULAR AND CEREBROVASCULAR DISEASES

There are several hypotheses to explain the role of vitamin D in cardiovascular diseases (CVDs). Firstly, 1,25(OH)₂D is a novel negative endocrine regulator of renin-angiotensin system and plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis thereby making vitamin D deficiency major risk factor for hypertension, heart attack, and stroke. ^[15] Also, vitamin D deficiency reduces intestinal calcium absorption by more than 50% which triggers PTH release.⁷ And so, chronic vitamin D deficiency causes secondary hyperparathyroidism which may lead to poor cardiovascular health.

Though several studies hypothesized the role of vitamin D in morbidity and mortality from various cardiovascular diseases (CVDs) as early as the 1980s, it was not until the National Health and Nutritional Examination Surveys (NHANES) (1988–1994, 2000–2004) conducted in the United States that this hypothesis was seriously considered.^16,17 In NHANES, they observed that people with vitamin D deficiency [25(OH)D <20 ng/ml] had higher prevalence of self-reported angina, myocardial infarction, and heart failure compared with individuals with higher levels of vitamin D.¹⁸ Several cardiovascular risk factors and CVDs have been associated with lower vitamin D status, including obesity (body mass index >30 kg/m²), hypertension (HTN), diabetes mellitus (DM), coronary heart disease (CHD), heart failure (HF), peripheral vascular disease (PVD), elevated triglyceride (TG) level, and microalbuminuria.^19-21 In the Framingham offspring study, a cohort with no history of CVD was followed up for 5 years and it was observed that incidence of CVD in subjects with 25(OH)D <10 ng/ml was higher as compared with subjects with 25(OH)D >15 ng/ml. Those subjects with lower serum vitamin D levels elicited a hazard ratio of 1.80 for developing CVDs.²² Severe vitamin D deficiency in patients undergoing coronary angiography has 3 to 5 times risk of dying from sudden cardiac death or heart failure and a 50% increase in fatal stroke compared to patients with no vitamin D deficiency.^23-24

VITAMIN D AND DIABETES MELLITUS

Vitamin D plays an important role in the functional regulation of the endocrine pancreas, particularly the beta cells.²⁵ Several studies have suggested that vitamin D deficiency is associated with insulin resistance and impaired insulin secretion.^26,27 The prevalence of type 2 diabetes in individuals suffering from vitamin D deficiency is observed to be higher than in vitamin D-sufficient individuals. In the same study, it was elicited that administration of high doses of 1,25 (OH)₂ D₃ could prevent type 1 diabetes.²⁸ In a birth cohort study of 31 years of follow-up done in 10,366 children in Finland, it was observed that children who were administered 2,000 IU of vitamin D₃ per day throughout the first year of life experienced a 78% reduced risk of type 1 diabetes.²⁹

VITAMIN D DEFICIENCY AND CANCER

Several studies suggest possible association between vitamin D and an increased risk of developing cancer. In studies conducted in rodents, vitamin D has been found to have several activities that might slow or prevent the development of cancer, including promoting cellular differentiation, decreasing cancer cell growth, stimulating apoptosis or cell death, and reducing angiogenesis or formation of blood vessel in malignant growth.^30-32 There are studies showing that higher vitamin D intake and adequate serum levels of vitamin D are associated with a reduced risk of colorectal cancer.^33-36 Breast cancer has been linked with low exposure to sun and low serum vitamin D levels.^37-39 It was elicited that mice and rats with high intake of vitamin D and calcium-rich diet had markedly reduced incidence of breast cancer.^40,41 Vitamin D was attributed to reduced mortality resulting from ovarian cancer.^42,43 Similar associations have been found with prostate cancers too.^43-47

CONCLUSION

Various sun-avoidance strategies like use of sunscreen, staying indoors increases the risk of vitamin D deficiency, which is otherwise completely preventable. Since, it has been shown in various studies that vitamin D has a wide and varied role in the body; vitamin D deficiency is destined to have serious consequences. The occurrence of several non-communicable diseases like hypertension, obesity, ischemic heart diseases, peripheral vascular diseases, multiple sclerosis, stroke, diabetes mellitus, cancers and also psychiatric illnesses can be reduced if adequate vitamin D levels are maintained in the body. As seen, Indians are predisposed to vitamin D deficiency as endowed owing to their darker skin tone. Unfortunately, Indians are also at an increased risk of having various NCDs, with or without vitamin D deficiency. However, unlike some Scandinavian countries amongst others, Indian climate favours vitamin D synthesis in the body. Maintaining optimum levels of vitamin D in the body does not need any costly intervention but a sensible exposure (neither over nor under) to the sun daily or for most days of the week would suffice provided the person is not wearing clothes baring face, arms and legs which are not smeared with sunscreen. However, if this exercise is not applicable, reasonable amount of vitamin D-enriched food like cod liver oil or mackerel and sardines can be taken. This can be supplemented by vitamin D-fortified foods. Monitoring serum 25-hydroxyvitamin D concentrations yearly should help reveal vitamin D deficiencies and if detected vitamin D analogues can be used after consulting the physicians. This is particularly important for persons who are at an increased risk of developing the deficiency like patients with liver and kidney disease, obesity or those on anticonvulsants, glucocorticoids, immunosupressants and anti-retroviral therapy amongst others. Also, some physiological conditions like pregnancy and aging warrant the same measure.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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