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RESEARCH




The Science of Vitamin D


There is growing evidence of the vital role Vitamin D plays in multiple aspects of human physiology and that sub-optimal levels may be widespread, potentially contributing to ill-health in a number of ways. Vitamin D is a generic term for the family of cholesterol-like, fat-soluble substances called secosteroids and essentially functions as a ‘pro-hormone’ within the body. It has the potential to be converted into molecules with hormonal functions that can operate in both endocrine and exocrine pathways.

METABOLISM
Vitamin D requires participation from the skin, bloodstream, liver and kidneys to convert it from its biologically inactive precursor molecules, choleclaciferol (vatimin D3) and ergocalciferol (vitamin D2) into the biologically active form calcitriol. The former is synthesised by humans in the skin from 7-Dehydrocholesterol upon exposure to ultraviolet-B radiation from sunlight, whilst the latter is derived from plant sources and therefore can be obtained from the diet.

As a fat-soluble nutrient, dietary vitamin D is primarily absorbed in the small intestine by passive diffusion, delivered to the enterocytes in micelles, and then secreted into the lymphatic system as chylomicrons. From there it enters circulation and is bound to vitamin D binding protein for further transportation to tissues and organs.

A large amount of circulating vitamin D is extracted by the liver cells and metabolised to calcidiol (25-Hydrocholecalciferol). This is the major circulation form of vitamin D. calcidiol then must be biologically activated in the kidneys into calcitriol (1,25-Dihydrocholecalcifero) via the enzyme 25-hydroxyvitamin D-1-alpha hydroxylase. Calcitriol is the active form of vitamin D utilised by the body for a range of biochemical processes. Vitamin D status is generally assessed by measuring circulation calcidiol (calcitriol levels are increased by parathyroid activity and may mask low calcidiol levels).

Although all initial forms of vitamin D are theoretically metabolised in the same way in the body, according to one small scale study (1), vitamin D3 appeared initially to be more effective than D2 at increasing the active (calcitriol) form. However, a more recent study challenges this view, suggesting that D2 is as effective in sustaining levels of calcidiol and calcitriol as D3 (2).

RISK FACTORS FOR VITAMIN DEFICIENCY

  • People with dark coloured skin synthesise less vitamin D on exposure to sunlight
  • Fat malabsorption syndromes: e.g. cystic fibrosis and cholestatic liver disease impair the absorption of dietary vitamin D
  • Infants who are exclusively breast-fed may be at risk of vitamin D deficiency. The American Academy of pediatrics recommends that breast fed infants be given a vitamin D supplement of 200iu/day (3)
  • Aging: The elderly have reduced capacity to synthesise vitamin D in the skin when exposed to UVB radiation
  • Inflammatory bowel disease: People with IBD appear to be at increased risk of vitamin D deficiency, especially those who have had small bowel resections
  • Obesity: Vitamin D is deposited in body fat stores, making it less bioavailable to people with large stores of body fat

 


FUNCTIONS OF VITAMIN D
A major and well-known biological function of Vitamin D is its effect on calcium and phosphorus absorption but it also has recognised effects on regulation of cell differentiation, immunity and autoimmunity, blood pressure and the insulin mechanism.

Many of the biological effects of calcitriol are mediated via the vitamin D receptor (VDR). This triggers small sequences of DNA known as vitamin D response elements (VDREs), initiating a cascade of molecular interactions that modulate the transcription of specific genes. More than 50 genes in tissues throughout the body are known to be regulated by vitamin D as calcitriol.

Serum Calcium Regulation
Maintenance of serum calcium levels within a narrow range is vital for normal functioning of the nervous system.

The parathyroid glands monitor serum calcium levels and secrete parathyroid hormone (PTH) if levels drop. This increases the 1-hydroxylase enzyme in the kidney, thus increasing production of calcitriol. Calcitriol normalises serum calcium by increasing the intestinal absorption of dietary calcium where required, while both calcitriol and PTH together can further stabilise serum calcium by increasing the re-absorption of calcium filtered by the kidneys and mobilising calcium from bone when there is insufficient dietary calcium to maintain normal levels.

Conversely calcitonin, secreted by the parathyroid gland to decrease serum calcium, is rarely used as hypercalcaemia seldom occurs in normal circumstances.

Bone Mineralisation
Calcitriol alone increases intestinal absorption of calcium and, via a feedback loop, also reduces PTH secretion. Without sufficient vitamin D to support calcium utilisation, there is an elevation in PTH secretion by the parathyroid glands resulting in calcium being taken from bones to maintain serum levels. The presence of adequate vitamin D levels normalises the process, resulting in proper maintenance of both serum and bone calcium levels.

The results of most clinical trials suggest that vitamin D supplementation can slow bone density losses or decrease the risk of osteoporotic fracture in men and women. For example post-menopausal women taking at least 600ius of vitamin D per day had a risk of osteoporotic hip fracture that was 37% lower than women who consumed less than 140iu/day (4).

Overall evidence suggest vitamin D at levels of about 800ius per day may be helpful in reducing bone loss and fracture rates in the elderly. For vitamin D supplementation to be effective, adequate calcium is also needed.

Cell Differentiation
Uncontrolled proliferation of cells without differentiation may lead to diseases like cancer. Calcitriol inhibits proliferation and stimulates appropriate differentiation of cells (5).

Many malignant tumours have been found to contain vitamin D receptors, including breast, lung, skin (melanoma), colon, and bone. Calcitriol has been found to induce cell differentiation and/or inhibit proliferation of a number of cancerous and non-cancerous cell types (6). The mechanism of action of the anti-carcinogenic activity of vitamin D is not fully understood, but has been found to induce apoptosis of cancer cells in vitro and in vivo. It may down-regulate the anti-apoptotic bdl-2 protein and up-regulate P53 expression, resulting in tumour cell death. In mice vitamin D supplementation produced tumours that were less ‘vascularised’ (7).

Further evidence of the link between vitamin D and cancer includes a long term study of more that 88,000 women, which found that higher intakes of vitamin D were associated with significantly lower breast cancer risk in premenopausal women but not postmenopausal women (8). Studies on the relationship between vitamin D and prostate cancer risk/incidence are inconclusive. There is mixed evidence on the relationship between colorectal cancer and vitamin D status, but a recent meta-analysis suggests a link between tissue levels of vitamin D and reduced incidence at higher levels of supplementation (9).

Insulin Regulation
Animal studies suggest that calcitriol plays a role in insulin secretion where there is high insulin demand (10). Limited data in humans suggests that insufficient vitamin D levels may have an adverse effect on insulin secretion and glucose tolerance in type 2 diabetes (11). According to one correlational study, higher vitamin D status correlated with a 60% improvement in insulin sensitivity (12). In a recent clinical trial using 1,332 ius/day for only 30 days in 10 women with type 2 diabetes, vitamin D supplementation was shown to improve insulin sensitivity by 21% (13). Finally a cohort study of children born in 1966 and followed up for thirty years found that those who received vitamin D in the first year of life had a significantly lower risk of developing type 1 diabetes (14).

Blood Pressure Control
Renin catalyses Angiotensinogen (produced by the liver) to yield Angiotensin. ACE (Angiotensin converting enzyme) then catalyses Angiotensin to form Angiotensin II, a peptide that can increase blood pressure by inducing constriction of small arteries and increasing sodium and water retention. Calcitriol decreases the expression of the gene which encodes the enzyme rennin and is thus responsible for regulating the rate of Angiotensin II synthesis (15). Epidemiological studies suggest that conditions that decrease vitamin D synthesis in the skin, such as having dark skin and living in temperate latitudes, are associated with increased prevalence of high blood pressure (16). At present, results from controlled clinical trials utilising vitamin D are mixed, but predominantly positive (17,18,19). Higher levels of parathyroid hormone, resulting from low levels of vitamin D, are also linked with hypertension, as well as infarction and stroke (20,21).

Immunity/Autoimmunity
Vitamin D as calcitriol is a potent immune system modulator. The VDR is expressed by most cells of the immune system, including T cells and antigen-presenting cells, such as dendritic cells and macrophages (22). Vitamin D appears to both enhance innate immunity and inhibit the development of autoimmunity (23). In general it has been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin 1 and 2, as well as to suppress immunoglobulin secretion by B lymphocytes. It has been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines. Vitamin D therefore demonstrates both immune-enhancing and immunosuppressive effects (24).

Vitamin D may positively affect autoimmune function by suppressing the activity of dendritic cells (or Langerhan’s cells in the skin) which regulate immune activity by secreting nitric acid. Calcitriol has also been found to modulate T cell responses, such that autoimmune responses are diminished.

Epidemiological studies have found the prevalence of insulin dependent diabetes, multiple sclerosis, and rheumatoid arthritis increases as latitude increases, suggesting vitamin D synthesis may play a role in these autoimmune diseases. In fact calcitriol has been effective in the treatment of psoriasis when applied topically in some double-blind, placebo-controlled trials. This may be due to anti-proliferative effect on the skin keratinocytes (25). There is the potential for oral vitamin D to also support appropriate immune function in those with psoriasis as with other autoimmune conditions such as multiple sclerosis.

Vitamin D supplement use was associated with a significant reduction in the risk of developing MS in two large cohorts of women followed for at lest ten years (26). Mahon gave 800 mg calcium and 1,000 ius of vitamin D per day for six months to 39 patients with MS and noted a modest anti-inflammatory effect (27).

In terms of rheumatoid arthritis, a study noted that postmenopausal women with the highest total vitamin D intakes were at significantly lower risk of developing the condition after eleven years of follow up than those with the lowest levels (28).

Migraine Headaches
Calcium’s role in maintenance of vascular tone may be useful in cases of migraine. Two cases have been reported of a reduction in menstrual migraine attacks following supplementation with calcium and up to 1,600 iu of vitamin D in women with vitamin D deficiency (29).

There is growing evidence of the vital role Vitamin D plays in multiple aspects of human physiology and that sub-optimal levels may be widespread, potentially contributing to ill health in a number of ways. Vitamin D is a generic term for the family of cholesterol-like, fat soluble substances called secosteroids and essentially functions as a ‘pro-hormone’ within the body i.e. it has the potential to be converted into molecules with hormonal functions that can operate in both endocrine and exocrine pathways.

Mood and Depression
Recent research has shown that vitamin D can also have a positive effect on mood. The incidence of depression has increased over the last century which has been linked largely due to our changes in lifestyle, including reducing our exposure to sunlight through changing work practices i.e. working indoors, our use of cars (glass blocks UVB rays) and our use of sun block. In turn this has contributed to reduced vitamin D levels in the blood. According to Klerman and Weissman’s research, major depression increases when vitamin D in the blood dips below normal levels (30). Vitamin D, in two human studies, was found to significantly enhance positive effect and possibly reduce negative affect. In 1999, a study found that 10,000 iu of vitamin D administered in one oral dose improved depression more significantly than light therapy in a group of patients suffering from seasonal affective disorder (SAD) (31).

The mechanism of the possible mood-modulating effect of vitamin D is unclear. It is speculated that it may influence brain serotonin levels (32). Research on Vitamin D, exposure to sunlight and the effect it can play on mood is an area of great potential and one, which can contribute significantly to our understanding of depression.

Musculoskeletal Function
Skeletal muscles have receptors for calcitriol. Aching bones and muscles may be due to vitamin D deficiency. In a cross-sectional study of 150 consecutive patients referred to a clinic in Minnesota for the evaluation of persistent, non-specific musculoskeletal pain, 93% had serum calcidiol levels indicative of vitamin D deficiency (33). Overall low vitamin D levels may be a factor in a range of non-specific joint and muscle disorders and conditions such as fibromyalgia.

Conclusion
Vitamin D has a very wide range of functions in many aspects of physiology. There are ongoing developments in research showing its vital and central role for general health as well as some of the more serious chronic diseases. There is also increasing evidence of epidemiological levels of deficiency or sub-optimal intake of vitamin D especially in northern European countries like the U.K. In future, supplementation of vitamin D is likely to become more and more important in the conventional management of health and disease.

References
1. Armas et al. Vitamin D2 much less effective thatn vitamin D3 inhumans. J clin endocrinol Metab 2004;89:5387-539
2. Holick et al. Vitamin D2 is as effective as Vitamin D3 in maintaining circulatin concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 2008 Mar;93(3): 677-81. Epub 2007 Dec 18
3. Gartner LM, Greer FR. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics. 2003;111(4 Pt 1):908-910
4. Feskanich D, Willett WC, Colditz GA. Calcium, vitamin D milk consumption, and hip fractures: a prospective study among postmenopausal women. Am J Clin Nutr. 2003;77(2):504-511
5. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3)362-371
6. Blutt SE, Weigel NL. Vitamin D and prostate cancer. Proc Soc Exp Eiol Med. 1999;221(2):89-98
7. Mantell DJ, Owens PE, bundred NJ et al. 1alpha, 25-Dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo. Circ Res. 2000; 87:214-220
8. Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst. 2002;94(17):1301-1311
9. Gorham ED, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitive meta analysis. Am J Prev Med 32(3), 2007
10. Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erban RG. Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J. 2003;17(3):509-511
11. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 patients. Int J clin Pract.2003;57(4):258-261
12. Chiu KC, Chu A, Vay Lwg, Saad MF, Hypovitaminosis d is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004; 79:820-5
13. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R.The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 patients Int J Clin Pract. 2003;57(4):258-61
14. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500-1503
15. Sigmund CD. Regulation of rennin expression and blood pressure by vitamin D(3). J Clin Invets. 2002;110(2):155-156
16. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997;30(2 Pt 1):150-156
17. Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998;352(9129):709-10
18. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86(4):1633-1637
19. Pan WH, Wang CY, Li LA, Kao LS, Yeh SH. No significant effect of calcium and vitamin D supplementation on blood pressure and calcium metabolism in elderly Chinese. Chin J Physiol. 1993;36(2):85-94
20. (Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone levels predict coronary heart disease: the Tromso Study. Eur J Cardiovasc Prev Rehabil. 2004;11(1):69-74
21. Sato Y, Kaji M, Metoki N, Satoh K, Iwamoto J. Does compensatory hyperparathyroidism predispose to ischemic stroke? Neurology. 2003;60(4):626-9).
22. Lin R, White JH. The pleiotropic actions of vitamin D. Bioessays. 2004;26(1):21-28
23. Griffin MD, Xing N, Kumar R. Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr. 2003;23:117-145
24. Manoglas SC, Provvedini DM, Tsoukas CD. Interactions of 1, 25-dihydroxyvitamin D3 and the immune system. Mol Cell Endocrinol. 1985;43:113-122
25. Ashcroft DM, Po ALW, Williams HC, Griffiths CEM. Systemic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis. Br Med J. 200;320:963-967
26. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60-65
27. Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT. Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J euro-immunol. 2003;134(1-2):128-32
28. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the lowa Women’s Health Study. Arthritis Rheum. 2004;50(1)72-77
29. Thys-Jacobs S. Vitamin D and calcium in menstrual migraine Headache. 1994 Oct;34(9):544-6
30. Klerman GL. Weismann MM. Increasing rates of depression. JAMA 1989 Apr21;261(15):2229-35[31] Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, non-specific musculoskeletal pain. Mayo Clin Proc. 2003;78(12):1463-1470
31. Gloth et al. Vitamin D vs broad-spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr health Aging. 1999;3(1):5-7
32. Landsdowne ATG, Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacol. 1998; 135:319-323 (a study involving 44 subjects, where supplementation with 400-800 IU per day significantly improved mood within five days of supplementation)
33. Pltnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, non-specific musculoskeletal pain. Mayon Clin Proc. 2003;79(12) 1463-1470

 

Also see: The Truth about supplements and The Essentiality of Fats
 




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