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Year : 2012  |  Volume : 1  |  Issue : 1  |  Page : 17-26

Vitamin D: Extra-skeletal effects

Department of Endocrinology, Jaslok Hospital and Research Centre, Mumbai, India

Date of Web Publication3-Apr-2012

Correspondence Address:
Vishal Gupta
Department of Endocrinology, Jaslok Hospital and Research Centre, 15-Dr. Deshmukh Marg, Pedder Road, Mumbai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2278-019X.94632

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There is a growing concern of vitamin D deficiency and its relationship with several extra-skeletal pathological states, ranging from immune disorders (systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, and rheumatoid arthritis), cardiovascular disorders (coronary artery disease, atherosclerosis, and hypertension), infections (viral and bacterial), endocrine disorders (growth failure, infertility in males, metabolic syndrome, and type 2 diabetes mellitus), neuro-psychiatric, and neuro-degenerative disorders, renal disorders, chronic lung disorders to cancer. Besides its positive effects on the musculo-skeletal system, vitamin D has shown to take an active part in the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis. It has been shown to control approximately 3% of the human genes directly or indirectly. Although there is a strong body of evidence toward implication of vitamin& D deficiency with several extra-skeletal disorders, it remains unclear if vitamin D supplementation may slow down, halt or even reverse the disease processes. This review aims to discuss the potential associations of vitamin D with various extra-skeletal disorders.

Keywords: Extra-skeletal effects, vitamin D, vitamin D deficiency

How to cite this article:
Gupta V. Vitamin D: Extra-skeletal effects. J Med Nutr Nutraceut 2012;1:17-26

How to cite this URL:
Gupta V. Vitamin D: Extra-skeletal effects. J Med Nutr Nutraceut [serial online] 2012 [cited 2024 Mar 3];1:17-26. Available from: http://www.jmnn.org/text.asp?2012/1/1/17/94632

  Introduction Top

The growing concern of vitamin D deficiency and its relationship with several pathological states has been the recent buzz of the endocrine world, with a few skeptics wondering whether we are overdoing the vitamin D saga. Nevertheless what is obvious is that both the prevalence and incidence of vitamin D deficiency are high and steadily increasing especially in those with persistent musculoskeletal complains (93%). The human being seems to have eclipsed the sun (sunlight), which is the natural source of vitamin D. Holick and colleagues have shown that skin color and modern practices of cosmetic dermatology (sun tan lotions and creams, etc.) have significantly rendered the sun redundant. [1],[2],[3],[4]

Conventionally the vitamin D endocrine system has been thought to be responsible for musculoskeletal health. It is now recognized that the vitamin D receptor is ubiquitously present in most tissue types (immune, endocrine {parathormone, beta-cells of pancreas, rennin producing}, cardiovascular cells, pulmonary, neural, etc.) that respond to active vitamin D (D3; 1,25-dihydroxy (OH)2 vitamin D) exposure. Approximately 3% (more than 200 genes) of the human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system. It also takes an active part in the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis. [5],[6]

Vitamin D physiology

Source of vitamin D and metabolism [Figure 1]
Figure 1: Metabolism of vitamin D

Click here to view

Dietary: There are two forms of vitamin D, erogocalciferol (D2; plant source), which is manufactured from the ultraviolet irradiation of ergosterol (obtained from yeast and mushrooms), and cholecalciferol (D3), which is obtained from fatty fish, milk, and eggs. Unfortunately in order to obtain the recommended daily requirements of vitamin D, a very large quantity of food (approximately 40 eggs; 2.5 liters of milk or 10.5 ounces of fatty fish) needs to be consumed which is both impractical and impossible for most. Additionally one tablespoon of cod liver oil contains 1360 IU, 3.5 oz salmon 360 IU, 3.5 oz mackerel 345 IU, 3.5 oz sardines 270 IU, 3.5 oz eel 200 IU, 1 egg yolk 25 IU, 236 ml milk 100 IU of vitamin D. [1],[3],[5] One way of trying to meet the daily vitamin D requirements is to fortify foods with vitamin D such as milk, breads, cereals, and yogurts as occurs in the United States. In Europe, food fortification got prohibited since 1950s in most countries except Sweden and France, when there were reported outbreaks of vitamin D intoxication in infants. [7],[8]

Skin: The principal source of vitamin D is however the skin. For all practical purposes vitamin D will be referred to both vitamin D2 and D3 unless specified. Ultraviolet irradiation (280-310 nm) of the epidermis results in photochemical isomerization of 7-dehydrocholesterol to form previtamin D3, which is then transported to the liver bound to the vitamin D binding protein or albumin. Excess skin irradiation protects against formation of toxic levels of D3 by converting 7-dehydrocholesterol to lumisterol and tachysterol (both biologically inactive). Lumisterol can reversibly be converted back to previtamin-D3 should it be required. Factors that influence the degree of vitamin D3 formation in the skin include time of day (9 am to 4 pm), season (summer, spring>>winter), latitude (angle of the sun and degree of ozone density), sunscreen use, clothing, and other barriers, skin pigmentation/type and aging. [9],[10],[11],[12],[13]

  1. Time of day: skin production of vitamin D3 starts about 9 am and ceases after 4 pm even during the summer. In countries such as Norway, vitamin D3 production may not start until 11 am even during summer where sunlight is available for 24 hours.
  2. Season: greater vitamin D3 is produced during summer, spring, and fall because of greater availability of sunlight during these seasons. A cloudy environment can reduce the degree of ultraviolet light by as much as 99% compared to a clear day.
  3. Latitude: ozone is thickest in the polar region. It absorbs all ultraviolet B radiation before they reach the earth's surface. As the angle of the sun (zenith angle) increases with increasing latitude, the ultraviolet B photons have to travel a greater distance making it less capable of inducing vitamin D3 production in the skin, e.g., Boston in the winter (previtamin D 3 synthesis begins in March and ends in November). [13]
  4. Sunscreen use: Use of sunscreen over 1/4 th body surface area in a dose of 2 mg/cm 2 skin surface, i.e., about 1 oz or 25% of a 4-oz bottle applied to all sun exposed areas of the skin of a person wearing a bathing suit with a sun protection factor (SPF) of 8, reduces vitamin D3 production by more than 95%. Use of SPF 15 reduced vitamin D3 production by approximately 99%. [14],[15]
  5. Skin type: the skin type of Fitzpatrick is classified from 1 (lightest) to 6 (darkest), with the darkest skin type (African origin) requiring 5 to 10 times the degree of sunlight exposure to manufacture the same quantity of vitamin D3 in the skin. Natural skin melanin acts as a shield that absorbs the UVB photons. Therefore darker the skin lesser is its capacity to generate vitamin D. Despite all these differences once 1 MED (minimal erythemal dose; minimum amount of UVB that produces skin pinkness/redness 24 hours after exposure) of sunlight exposure is attained, the degree of vitamin D3 production seems to be similar across all skin types. [16]
  6. Clothing and other barriers: like transparent glass, absorbs 100% of the UVB radiation and totally prevents the formation of UVB photons and vitamin D.
  7. Aging: a 70-year-old person produces only 25% the capacity of vitamin D3 compared to a 20 year old

In liver vitamin D is enzymatically hydroxylated at carbon position 25 to form 25-hydroxy-D (25-OH-D) by a CYP-450 enzyme (CYP27A1; 25-hydroxylase). CYP27A1 is widely distributed throughout different tissues with highest levels in liver and muscle, but also in kidney, intestine, lung, skin, and bone. 25-OHD is the major circulating form of vitamin D that is biologically inert. Liver hydroxylation of vitamin D is substrate dependent. It is converted to its active form, 1,25-dihydroxyvitamin D (1,25-OH2D) in the kidneys by enzyme 25OHD-1αhydroxylase (CYP27B1) which is regulated by need and not substrate. The principal regulators of CYP27B1 activity in the kidney are parathyroid hormone (PTH), fibroblast growth factor-23(FGF-23), calcium, phosphate, and 1,25-OH2D. Extrarenal production of 1,25-OH2D tends to be stimulated by cytokines such as interferon (INF)-gamma and tumor necrosis factor (TNF)-alfa more effectively than PTH and may be less inhibited by calcium, phosphate, and 1,25-OH2D. 1,25-OHD further binds to the vitamin D receptor (VDR) in order to achieve its biological effects, which will be discussed in detail. [17],[18],[19]

Catabolism and regulation of vitamin D

Excess vitamin D formation is prevented from accumulating in the body by the following three processes:

  1. On prolonged skin exposure toxic levels of previtamin D3 are prevented because of conversion to lumisterol and tachysterol, of which lumisterol can be reconverted back to previtamin D3 should the need arise.
  2. The 24-hydroxylase pathway [Figure 1] which breaks down excess vitamin D2 and D3.
  3. Negative feedback of 1,25-OH2D (renal) on the production of 25-OHD in the liver.
Natural daily production of vitamin D
"Holick's rule" states that sun exposure of 1/4 th of an MED over 1/4 of the body surface generated vitamin D equivalent to approximately 1000 IU of orally consumed vitamin D. [20]

One MED exposure for as little 5-15 minutes between the hours of 10 am and 3 pm in the spring, summer, and fall at latitudes above and below 35° (and all year near the equator) to exposed parts of the body

  1. Other than "body type of bathing suit" produces between 3000 and 5000 IU of vitamin D.
  2. Other than "bikini type bathing suit" produces between 15,000 and 20,000 IU of vitamin D.
  3. Involving "arms, legs and face" as occurs with shorts and short-sleeved shirts (20-25%) produces 1000 IU of vitamin D.
Ideal therapeutic levels

Based on the ability of vitamin D to promote bone health and prevent secondary hyperparathyroidism and osteoporosis, most experts including the Endocrine Society of America and International Osteoporosis Foundation believe that a cut-off of 30 ng/ml (multiply by 2.49 for nmol/l) represents a safe lower limit of vitamin D. These ranges are however only with respect to bone health. [21],[22] The questions that many healthcare practitioners have is that, is the cut off of 30 ng/m enough to achieve sufficient tissue concentration of active vitamin D in order for it to achieve its extra-skeletal effects? One such example is with regard to cancer prevention, which many authors believe follows a U-shaped curve with an increased incidence of cancer with extreme serum concentration of vitamin D. Prolonged vitamin D intake has been associated with an increased risk of prostate cancer in Nordic males, which is probably inherent to that population and cannot be generalized. [23] This finding only adds confusion to setting an optimal vitamin D target; [24] however despite all these idiosyncracies most experts define vitamin D sufficiency, insufficiency, and deficiency as follows:

Vitamin D insufficiency is defined as values between 21 and 29 ng/ml.

Vitamin D deficiency is defined as values 10-20 ng/ml.

Severe vitamin D deficiency is defined as <10 ng/ml.

Vitamin D replacement regimens

In order to raise the serum concentration of vitamin D by approximately 1 ng/ml one must increase the daily vitamin D intake by 100 IU for approximately 4-6 months, e.g., if patient serum vitamin D level is 15 ng/ml and if one was to increase it to approximately 30 ng/ml, the average increase in vitamin D would have to be 1500 IU approximately, in order to achieve the target vitamin D level. [25] Vitamin D may be given as either ergocalciferol or cholecalciferol (40 IU=1 μg). Only cholecalciferol is available in India. Replacement regimens are as follows:

  1. Intermittent bolus "high-dose vitamin D: A total of 300,000 IU every 6 months titrated to serum vitamin D level >30 ng/ml. [26],[27]
  2. Intermittent bolus low-dose vitamin D: A total of 50,000 IU every week for six doses titrated to serum vitamin D level >30 ng/ml, failing which a repeat of the above can be done for vitamin D values persistently <20 ng/ml and for values between 21 and 29 ng/ml, 50,000 IU may be instituted every 2-4 weeks for a further six doses till desired result are achieved.
  3. Daily vitamin D: Depending upon minimum daily need as guided by the Endocrine Society and serum vitamin D levels, the total daily dose can be calculated based on the formula mentioned above, -on an individual basis. For adults the upper limit of vitamin D supplements is set at 10,000 IU/day beyond which vitamin D toxicity may ensue. [1],[3],[4],[21] The recommended daily intake may be as follows [Table 1]:
Table 1: Recommended daily vitamin D intake per day[1,3,4,21]

Click here to view

Parenteral replacement (intramuscular) should be avoided as far as possible as they have consistently showed an unpredictable and prolonged time required to attain the desired serum vitamin D concentration coupled with a lack of adequate suppression of serum parathormone, compared to adequate oral replacement regimens. [27]

Mechanism of action

Vitamin D is responsible for maintaining bone homeostasis via regulating calcium and phosphorous metabolism. It achieves this via a controlled and tightly regulated vitamin D endocrine system, the active metabolite (1,25-OH2D) of which is produced by the kidney. This then acts on the vitamin D receptor to produce its biological effects. At the level of the intestine it is responsible for calcium and phosphorous absorption. The absence of vitamin D results in not more than 10-15% of calcium absorption, which is increased by approximately 40% for calcium and 80% for phosphorous once the vitamin D levels are in the "sufficient" range. It achieves this by stimulating a calcium channel (TrpV6) at the level of intestinal epithelial, cellular calcium binding protein, and calmodulin and calcium-ATPase at the basolateral membrane. [28],[29] Bone is made up of 30% organic substances and 70% inorganic mineral. The inorganic tissue is made up of insoluble calcium and phosphate salts that precipitate as hydroxyapatite on the organic tissue. [30],[31]

Extra-skeletal effects (possible mechanisms and evidence)

A. Muscular system: Vitamin D deficiency is associated with a proximal myopathy and sarcopenia[32] of the appendicular skeleton independent of obesity. It seems to relate directly to the degree of vitamin D deficiency. It is associated with muscle atrophy (type 2 muscle fibers) and poor muscle strength/performance. [33] It may affect muscle function via:

a. Reduced total body calcium levels and calcium-related protein transcription in the muscle.

b. IGF-1 and IGF-BP3: IGF-1 is a 7.5 kDa polypeptide that contains three isoforms (IGF-1Ea, IGF-1Eb, and IGF-1Ec). This system seems to be influenced/regulated by vitamin D3 and several studies have shown a positive correlation between IGF-1 and vitamin D3 levels during growth, of children. IGF- 1Ea is the circulating form of IGF-1 expressed from the liver that stimulates terminal differentiation of muscle cells into myotubes and promotes stem-cell-mediated muscle regeneration. IGF-1Ec, also called mechano-growth factor (MGF), is the tissue isoform expressed from skeletal muscle cells, believed to exert exclusively autocrine/paracrine actions that responds to tissue damage, controls local tissue repair, and causes muscle hypertrophy. IGF-1 circulates in the serum 99% bound to a carrier protein IGFBP-3. Vitamin D3 also seems to be one of the regulators of IGFBP-3 expression. [34],[35],[36] Vitamin D supplementation has been shown to directly correlate with growth and IGF-1 levels.

Adequate replacement of vitamin D has been shown to increase muscle strength by as much as 24.8±8.0%. [37] Stabilization of the musculoskeletal also results in falls prevention. A meta-analysis showed that the minimum dose of vitamin D supplementation required, to prevent falls was 700 IU/day. This resulted in a 19% reduction in fall rate. Similarly the minimum serum concentration of vitamin D required to do the same was a value >=60 nmol/l (24.09 ng/dl). This remains the only extra-skeletal indication that has found place with regard to vitamin D testing and monitoring, by the US Endocrine Society. It becomes more importance due to the fact that one in three elderly people (aged 65 years or older) experiences at least one fall each year and of these about 5-6% translates into a fracture. [38]

B. Endocrine

a. Obesity: The NHANES has shown that there is a growing prevalence of vitamin D deficiency and obesity. Numerous studies have shown an inverse relationship between the two. A serum vitamin D level of less of < 50.0 (20 ng/ml) nmol/l has shown to be significantly associated with new-onset obesity (defined as waist circumference of ≥88 cm for women and ≥102 cm for men) in both in adults and children/adolescents. In the latter the highest incidence of obesity was found with a serum vitamin D of <17 ng/ml. [39],[40] One of the possible mechanisms explaining the association is that a larger fat mass promotes greater storage of vitamin D effectively reducing bioavailable vitamin D. [41]

b. Metabolic syndrome and diabetes mellitus: Obesity is associated with insulin resistance and metabolic syndrome. [42],[43],[44] Whether the insulin resistance is due to vitamin D deficiency and secondary hyperparathyroidism [45] needs to be clarified. Vitamin D has shown to stimulate insulin secretion via regulating intracellular calcium, modulating beta-cell depolarization-stimulated insulin release, and preventing apoptosis. [46-48] This was particularly seen in patients with type 1 diabetes mellitus (T1DM) where significantly low vitamin D levels (<10 ng/ml) were associated with higher insulin requirements suggesting an insulin secretory action of vitamin D. [49] Although debatable, [50] a few pilot studies have demonstrated that vitamin D supplementation may help improve insulin sensitivity and markers of metabolic syndrome. [51]

c. Growth: As outlined above it is clear that vitamin D influences growth linearly in a manner related directly to serum concentrations of IGF-1. IGFBP-3 binds to IGF-I, which augments the half-life and biological actions of IGF on target cells. IGFBP-3 seems to be regulated by specific growth promoters and inhibitors, one of which is vitamin D. A vitamin D receptor-responsive element has been found to be located between 3296 and 3282 upstream of the human IGFBP-3 gene. [52]

d. Fertility: The metabolizing hormones (25 and 1,25 hydroxylase) of vitamin D and their receptor have been seen in round elongated spermatids, mature spermatozoa, epididymis, glandular epithelium of cauda epididymis, testicular tissue, and prostate. Spermatogonia express CYP27B1 (1, 25 hydroxylase; activating hormone) and CYP24A1 (24 hydroxylase; inactivating hormone) without any 25-hydroxylase. Vitamin D augments the synthesis of calcium transporters, calcium pump, calbindin, and calmodulin, all required for sperm function. [53] In a study that assessed the degree of sperm function with serum levels of vitamin D, the authors found that up to 44% of patients with vitamin D deficiency had impaired sperm motility that correlated positively and inversely with serum parathormone levels. Vitamin D supplementation-induced sperm motility and acrosomal reaction indicating that it has an important role in maintaining fertility in males. [54]

C. Cardiovascular system

a. Ischemic heart disease: A number of epidemiological studies have evaluated the risk of developing cardiovascular disease with calcium and vitamin D deficiency. The results are very inconsistent and most experts are unable to form a consensus with regard to the same. Positive studies favoring calcium and vitamin D intake include those conducted by Bostick et al. [55] (higher intake of calcium, but not of vitamin D was associated with reduced ischemic heart disease mortality in postmenopausal women), Kims et al. [56] (NHANES; vitamin D <20 ng/mL was associated with increased prevalence of self-reported coronary heart disease, heart failure, and peripheral vascular disease), Giovannucci et al. [57] (US Health Professionals Follow-up Study; vitamin D <15 ng/ml was associated with twofold increased rate of myocardial infarction), Wang et al. [58] (Framingham Offspring Study; vitamin D <10 ng/ ml was associated with a 1.80-fold increase rate of developing the first cardiovascular event compared with subjects with levels >15 ng/ml), and Pilz et al. [59] (vitamin D levels <10 ng/ml was associated with three to five times risk of sudden cardiac death or heart failure during a 7-year follow-up period). Vitamin D deficiency has been shown to directly relate to coronary calcification even in patients with type 1 diabetes mellitus. [60],[61] To dampen the enthusiasm on the above studies a meta-analysis of calcium intake showed no significant benefits of calcium supplement use in reducing the risk of coronary artery disease or stroke [62] while on the other hand only a slight but statistically nonsignificant reduction in cardiovascular risk was seen in another meta-analysis in patients on moderate to high doses vitamin D supplementation (approximately 1000 IU/day). [63]

The primary mechanisms proposed for the cardiovascular benefit are

1. Renin and angiotensin dowregulation: Vitamin D has shown to regulate the rennin-angiotensin system (RAS) and vitamin D receptor null mice have shown to exhibit high-blood pressure, cardiac hypertrophy, and polyuria. Human studies have shown that vitamin D acts as an endocrine inhibitor of the RAS. Vitamin D insufficiency (15.0-29.9 ng/ml) and deficiency (<15.0 ng/ml) having higher circulating angiotensin II levels and a significantly blunted renal plasma flow response to infused angiotensin II suggesting that low plasma vitamin D may upregulate RAS and induce hypertension contributing to coronary heart disease. [64],[65],[66]

2. Cardiomyocyte: Vitamin D may directly affect myocardial contractility by reducing intramyocardial calcium. [67]

b. Hypertension: Vitamin D supplementation has shown down regulate the RAS and reduce systemic blood pressure. An upregulated RAS has been implicated in the development of beta-cell dysfunction [68] and insulin resistance all contributing the development of hypertension. [69] Short-term vitamin D supplementation (800 IU) was shown to decrease systolic blood pressure by approximately 9% [70] confirming the possible role of vitamin D in cardiovascular protection.

D. Immune system: Vitamin D has shown to inhibit the following:

1. T cell proliferation, in particular the TH1 (T-helper cell 1) response (cytotoxic) by reducing gamma-interferon and interleukin 2.

2. Costimulatory molecules CD40, CD80, CD86 on dendritic cells which leads to reduced secretion of IL-12 (critical for Th1 development).

3. Differentiation of B cell precursors into plasma cells thereby reducing immunoglobulin production.

4. TH17 response: They are a subset of T helper cells that produce interleukin 17 (IL-17) considered developmentally distinct thought to play a key role in autoimmune disease.

5. Antigen presenting dendritic and macrophage cells. Vitamin D deficiency impairs macrophage ability to mature, produce macrophage-specific surface antigens, lysosomal enzyme acid phosphatase, and to secrete hydrogen peroxide, which is essential to their antimicrobial function.

It has shown to up-regulate the following:

1. Protective TH2 (T-helper cell 2) response by increasing IL-4,5 and 10.

2. T-cell regulatory cells (Treg): Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e., autoimmune disease. [71],[72]

a. Autoimmune disorders: Vitamin D deficiency has been implicated in pathogenesis of systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, and rheumatoid arthritis. [73],[74] Up to 77% of patients with multiple sclerosis and >60% with rheumatoid arthritis have vitamin D levels <55 nmol/l. A Finnish study showed that the risk for developing type 1 diabetes mellitus in infants who received daily vitamin D supplementation (50 mg/day) over a 30-year follow-up study was markedly low (relative risk 0.12). [75],[76]

b. Infections


In a survey conducted in London approximately 56% had undetectable levels of vitamin D, and an additional 20% had levels below 9 ng/ml. Vitamin D has shown to inhibit the growth of Mycobacterium tuberculosis via activation of the Toll-like receptor (TLR2/1) which reduces its viability within macrophages and monocytes. [77] Skin infections (staphylococcus aureu,s pseudomonas auroginosa): Keratinocytes treated with vitamin D have been shown to have substantially more killing abilities toward epidermal bacteria mediated by enhanced cathelicidiin expression in human epidermal keratinocytes. Following epidermal injury 1,25-hydroxylase activity in the skin increases suggesting the contributory role of vitamin D in maintaining structural skin integrity by fighting infection. Leprosy: [78] vitamin D has also been shown to have an effect on leprosy either directly through the vitamin D receptors or via other indirect means.

Vitamin D sufficiency is an independent predictor of sustained virological response following antiviral therapy given for chronic hepatitis C infection. [79] An increased associated with the common cold and flu[80] has also been seen with low vitamin D levels with severe infections requiring intensive care associated with the lowest range of vitamin D levels (<20 ng/ml).

E. Cancer Prevention: Vitamin D has shown to reduce the incidence of cancer via inhibiting tumor angiogenesis, stimulating cell adherence by enhancing intercellular communication gap junctions, inhibiting cell proliferation, and inducing tumor cell apoptosis. Vitamin D receptor has several genotypes with "bb" showing the strongest relationship with development of cancer (twice for colon and prostate cancer in men; and twice the risk for breast cancer in women) compared to the "BB" phenotype. [81] A high incidence of vitamin D deficiency has been seen in patients with head and neck, [82] breast, colon, ovarian, and prostate cancer. Severe vitamin D deficiency can be seen in up to 45% of head and neck cancers. Although the evidence with regard to an increased incidence of vitamin D deficiency exists in populations at an increased risk of cancer, it is not clear whether vitamin D or calcium supplementation can reduce the risk of cancer. In the Cancer Prevention Study II Nutrition Cohort (United States), calcium supplementation (but not vitamin D) was associated with a marginal decrease in the risk of colon cancer; [83] however a meta-analysis [84] did not show any benefit of vitamin D supplementation with regard to cancer prevention. To further confuse the issue it has been shown that higher than normal levels can be associated with an increased risk of cancer and that the risk of cancer follows a U-shaped curve with regard to serum vitamin D levels. [23]

F. Neurodegeneration (Alzheimers disease): There is a high prevalence of vitamin D in patients with Alzheimers disease, Parkinson disease, depression, and schizophrenia. The vitamin D receptor has been implicated as a candidate gene in the etiopathogenesis of Parkinsons disease and other developmental brain disorders. Preclinical studies have shown that total gestational deprivation of vitamin D causes mild distortion of the brain, increased lateral ventricular volume, reduced differentiation, and diminished expression of neutropic factors. This may occur as a result of genomic and nongenomic mechanisms, some of which involve nitric oxide synthase, cyco-oxygenase 2, nerve growth factor, L-type calcium channels, and prostaglandins. Vitamin D replacement has shown to positively influence mood and cognitive performance in elderly patients with neurodegenerative brain disorders. The question remains as to whether vitamin D treatment can halt or even reverse the pathology remains to be seen. [85],[86],[87]

G. Pulmonary system: Vitamin D deficiency has been linked to chronic lung conditions such as childhood asthma in patients with maternal vitamin D deficiency, infections such as influenza A and mycobacterial tuberculosis, cyctic fibrosis, interstitial lung disease, and chronic obstructive pulmonary disease. [88] There is a suggestion that there may be a role of vitamin D supplementation in patients with acute exacerbation of severe chronic obstructive pulmonary disease in patients with a baseline vitamin D of <10 ng/ml). [89] Vitamin D deficiency has been also directly related to prolonged requirements of oxygen therapy, worse quality of life scores, tendency to have lower percent predicted forced expiratory volume in 1 seconds (FEV 1 ) during pulmonary rehabilitation. [90]

H. Renal: Vitamin D has shown to have protective effects on the kidneys via its blood pressure lowering ability and also has shown to reduce the albumin excretion rate which is an independent marker of future kidney function. [91] It has also shown to reduce cardiovascular mortality in patients with stage 3/4 chronic kidney disease (21% in the vitamin D group versus 44% in the control group over a 27-month follow-up, at an average vitamin D dose of 1650 IU/day). [92] Possible mechanisms proposed have been antihypertensive effect, renin-angiotensin down-regulation and hence preventing ventricular remodeling and improvement in parathormone-related adverse events. Most of the cardiovascular protective data published so far have shown mixed results, probably because of low-vitamin D doses used in the past, not enough to reach sufficient tissue concentrations. The average dose used in the above study (1650 IU/day) was much higher than previously reported, leaving room for argument that current practices may not have got it entirely correct with regards adequate daily vitamin D doses meant to be used per day.

  Conclusion Top

The saga of vitamin D seems to be unfolding with every passing year. Its deficiency is clearly being implicated in virtually every disease state ranging from cardiovascular disease to autoimmune disorders. Although a clear association exists between several pathology states and vitamin D deficiency it remains to be seen if vitamin D supplementation can slow down, halt or even reverse the disease processes with which they are associated.

Besides the musculo-skeletal effects of vitamin D, most other extra-skeletal effects are a matter of conjecture at this time and robust studies are need to firmly establish justifying vitamin D testing and supplementation other than for muscle or bone-related problems.

  References Top

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