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Vitamin D

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Vitamin D

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For other uses, see Vitamin D (disambiguation).
Cholecalciferol (D3)
Calcium regulation in the human body.[1] The role of vitamin D is shown in orange.

Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).[2] Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylation reactions to be activated in the body. Calcitriol (1,25-Dihydroxycholecalciferol) is the active form of vitamin D found in the body. The term vitamin D also refers to these metabolites and other analogues of these substances.

Calcitriol plays an important role in the maintenance of several organ systems.[3] However, its major role is to increase the flow of calcium into the bloodstream, by promoting absorption of calcium and phosphorus from food in the intestines, and reabsorption of calcium in the kidneys; enabling normal mineralization of bone and preventing hypocalcemic tetany. It is also necessary for bone growth and bone remodeling by osteoblasts and osteoclasts.[4][5]

Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Deficiency can arise from inadequate intake coupled with inadequate sunlight exposure; disorders that limit its absorption; conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders; or, rarely, by a number of hereditary disorders. Vitamin D deficiency results in impaired bone mineralization and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis.[3]

Vitamin D plays a number of other roles in human health including inhibition of calcitonin release from the thyroid gland. Calcitonin acts directly on osteoclasts, resulting in inhibition of bone resorption and cartilage degradation. Vitamin D can also inhibit parathyroid hormone secretion from the parathyroid gland, modulate neuromuscular and immune function and reduce inflammation.[6][7][8]

Contents

[edit] Forms

Name Chemical composition Structure
Vitamin D1 molecular compound of ergocalciferol with lumisterol, 1:1
Vitamin D2 ergocalciferol (made from ergosterol) Note double bond at top center.
Vitamin D3 cholecalciferol (made from 7-dehydrocholesterol in the skin). Cholecalciferol.svg
Vitamin D4 22-dihydroergocalciferol 22-Dihydroergocalciferol.png
Vitamin D5 sitocalciferol (made from 7-dehydrositosterol) VitaminD5 structure.png

Several forms (vitamers) of vitamin D have been discovered (see table). The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. These are known collectively as calciferol.[9] Vitamin D2 was chemically characterized in 1932. In 1936 the chemical structure of vitamin D3 was established and resulted from the ultraviolet irradiation of 7-dehydrocholesterol.[10]

Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.[11] The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.

Vitamin D2 (made from ergosterol) is produced by invertebrates, fungus and plants in response to UV irradiation; it is not produced by vertebrates. Little is known about the biologic function of vitamin D2 in nonvertebrate species. Because ergosterol can more efficiently absorb the ultraviolet radiation that can damage DNA, RNA and protein it has been suggested that ergosterol serves as a sunscreening system that protects organisms from damaging high energy ultraviolet radiation.[12]

Vitamin D3 is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm.[13][14] These wavelengths are present in sunlight when the UV index is greater than 3. At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin after only ten to fifteen minutes of sun exposure every day of the week to almost the entire body, in noon-day sun without sunscreen. This is assuming that the person is living at the approximate right "latitude" for their skin colour. However, season, geographic latitude, time of day, cloud cover, skin cover, skin color, smog, and sunscreen affect UV ray absorption and vitamin D synthesis. For example, sunlight exposure from November through February in Boston is insufficient to produce significant vitamin D synthesis in the skin.[15] With longer exposure to UVB rays, an equilibrium is achieved in the skin, and excess vitamin D simply degrades as fast as it is generated.[16]

Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.[17] In humans, D3 is as effective as D2 in vitamin D hormone activity in circulation,[18] although others state that D3 is more effective than D2.[19] However, in some species, such as rats, vitamin D2 is more effective than D3.[20]

[edit] Biochemistry

Vitamin D is a prohormone, meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism. Production of vitamin D in nature always appears to require the presence of some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, from mushrooms to animals, which are not able to synthesize it except through the action of sunlight at some point in the synthetic chain. For example, fish contain vitamin D only because they ultimately exist on calories from ocean algae which synthesize vitamin D in shallow waters from the action of solar UV.[citation needed]

[edit] Production in the skin

The epidermal strata of the skin. Production is greatest in the stratum basale (colored red in the illustration) and stratum spinosum (colored orange).

The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.

Cholecalciferol is produced photochemically in the skin from 7-dehydrocholesterol; 7-dehydrocholesterol is produced in relatively large quantities in the skin of most vertebrate animals, including humans. The few exceptions are some bat species, mole rats, cats, and dogs,[12] which produce little vitamin D.[21] In most animals the highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum.[13] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is less.

Synthesis in the skin involves UVB radiation, which effectively penetrates only the epidermal layers of skin. While 7-dehydrocholesterol absorbs UV light at wavelengths between 270–300 nm, optimal synthesis occurs in a narrow band of UVB spectra between 295-300 nm. Peak isomerization is found at 297 nm. This narrow segment is sometimes referred to as D-UV.[14] The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum.[13]

A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 µg/cm² of skin) are available in the stratum spinosum and stratum basale of the skin to meet the body's vitamin D requirements,[13] and melanin content does not alter the amount of vitamin D that can be produced.[22] Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. The amount of time an individual requires to produce a given amount of vitamin D may also depend upon the person's distance from the equator and on the season of the year.

In some animals, the presence of fur or feathers blocks the UV rays from reaching the skin. In birds and fur-bearing mammals, vitamin D is generated from the oily secretions of the skin deposited onto the fur and obtained orally during grooming.[23]

In 1923, Harry Goldblatt and Katherine Soames established that when 7-dehydrocholesterol (a precursor of vitamin D in the skin) is irradiated with light, a form of a fat-soluble vitamin is produced. Alfred Fabian Hess and Mildred Weinstock further substantiated that "[sun]light equals vitamin D".[24] Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928, for his work on the constitution of sterols and their connection with vitamins.[25] In 1930s, he clarified further the chemical structures of the vitamins D.

[edit] Synthesis mechanism (form 3)

7-dehydrocholesterol, a derivative of cholesterol, is photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is pre-vitamin D3.

Reaction-Dehydrocholesterol-PrevitaminD3.png
Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a antarafacial hydride [1,7] Sigmatropic shift. At room temperature the transformation of previtamin-D3 to vitamin D3 takes about 12 days to complete.[12]

Reaction-PrevitaminD3-VitaminD3.png
Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes. This hydroxylation reaction occurs in the endoplasmic reticulum and requires NADPH, O2 and Mg2+ yet it is not a cytochrome P450 enzyme. Once made the product is stored in the hepatocytes until it is needed and then can be released into the plasma where it will be bound to an α-globulin.

25-hydroxycholecalciferol is then transported to the proximal tubules of the kidneys where it can be hydroxylated by one of two enzymes to different forms of vitamin D, one of which is active vitamin D (1,25-OH D) and another which is inactive vitamin D (24,25-OH D). The enzyme 1α-hydroxylase which is activated by parathyroid hormone (and additionally by low calcium or phosphate) forms the main biologically active vitamin D hormone with a C1 hydroxylation forming 1,25-dihydroxycholecalciferol (1,25(OH)2D3, also known as calcitriol). A separate enzyme hydroxylates the C24 atom forming 24R,25(OH)2D3 when 1α-hydroxylase is not active, this inactivates the molecule from any biological activity. Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end).

Reaction-VitaminiD3-Calcitriol.png

[edit] Mechanism of action

After vitamin D is produced in the middle layers of skin or consumed in food, it is converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D), the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). This physiologically active form of vitamin D is known as calcitriol. Following this conversion, calcitriol is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs.[11]

The physiologically active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[11] The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine.

The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.[26]

The VDR is known to be involved in cell proliferation and differentiation. Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells.[17]

Apart from VDR activation, various alternative mechanisms of action are known. An important one of these is its role as a natural inhibitor of signal transduction by hedgehog (a hormone involved in morphogenesis).[27][28]

[edit] Nutrition

Milk and cereal grains are often fortified with vitamin D.

Vitamin D is naturally produced by the human body when exposed to direct sunlight. Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet. Extra vitamin D is also recommended for older adults and people with dark skin. Individuals having a high risk of deficiency should consume 25 μg (1000 IU) of vitamin D daily to maintain adequate blood concentrations of 25-hydroxyvitamin D.[2]

As civilization and the Industrial Revolution enabled humans to work indoors and wear more clothes when outdoors, these cultural changes reduced natural production of vitamin D and caused deficiency diseases. In many countries, such foods as milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency.[29] In the United States and Canada, for example, fortified milk typically provides 100 IU per cup, or a quarter of the estimated adequate intake for adults over age 50.[2] A 1992 study, however, found that the actual vitamin D content of milk varies widely. Supplementation of 100 IU (2.5 microgram) vitamin D3 raises blood calcidiol levels by 2.5 nmol/litre (1 ng/ml).[30]

[edit] Natural sources

Fatty fish, such as salmon, are natural sources of vitamin D.

Natural sources of vitamin D include:[2]

  • Fish liver oils, such as cod liver oil, 1 Tbs. (15 ml) provides 1,360 IU (one IU equals 25 ng)
  • Fatty fish species, such as:
    • Herring, 85 g (3 ounces (oz)) provides 1383 IU
    • Catfish, 85 g (3 oz) provides 425 IU
    • Salmon, cooked, 100 g (3.5 oz]) provides 360 IU
    • Mackerel, cooked, 100 g (3.5 oz]), 345 IU
    • Sardines, canned in oil, drained, 50 g (1.75 oz), 250 IU
    • Tuna, canned in oil, 85 g (3 oz), 200 IU
    • Eel, cooked, 100 g (3.5 oz), 200 IU
  • A whole egg, provides 20 IU
  • Beef liver, cooked, 100 g (3.5 oz), provides 15 IU
  • UV-irradiated mushrooms (Vitamin D2)[31][32]

In the United States (U.S.), the 100% Daily Value used for product labels is 800 IU/day (as of new 2009 data) and typical diets provide about 100 IU/day. Although milk is usually fortified, the average daily consumption by most Americans is insufficient in obtaining levels of vitamin D recommended by various medical authorities.[33] While adequate intake has been defined as 200 IU/day for ages infant to 50, 400/day for 51-70, and 600/day over 70, the American Academy of Pediatrics argues that these recommendations are insufficient and recommends a minimum of 400 IU, even for infants.[34] The NIH has set the safe upper limit at 2000 IU, but acknowledges newer data supporting a UL as high as 10,000 IU/day.[35] Some experts have recommended greatly increasing vitamin D intake. [36] The Institute Of Medicine is revisiting vitamin D and calcium recommendations with a report expected to be released before the end of summer 2010.[37]

[edit] Measuring nutritional status

A blood calcidiol (25-hydroxy-vitamin D) level is a satisfactory way to determine the cumulative effect of sun and diet in relation to vitamin D[38] although serum 25(OH)D levels do not indicate the amount of vitamin D stored in other body tissues.[39] A concentration of over 15 ng/ml (>37.5 nmol/L) is recommended. Higher levels (>30 ng/ml or >75 nmol/L) are proposed by some as desirable for achieving optimum health but there is not enough evidence to support them.[40][41]

[edit] Deficiency

Main article: Hypovitaminosis D

Low blood calcidiol (25-hydroxy-vitamin D) can result from inadequate sun exposure, although deficiency can exist with abundant sunshine,[42] Dietry intake can supply vitamin D but few foods contain a significant amount. Disorders that limit absorption from the gastrointestinal tract and conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders can result in vitamin D deficiency, excess body fat can also lower levels. Skin colour has also been associated with low 25(OH)D, especially in Africans living in countries with a temperate climate. For example 25-OHD under 10ng/mL (25 nmol/l) in 44% of asymptomatic East African children living in Melbourne[43][44] However a study of healthy young Ethiopians living in Addis Ababa (10 degrees N) found average 25(OH)D levels of 23.5nmol/L.[45] A review of Vitamin D in Africa[46] gives the median levels for equatorial countries: Kenya 65.5 nmol/L and Zaire 65nmol/L, concluding that it remains to be established if associations between vitamin D status and health outcomes identified in Western countries can be replicated in African countries. Vitamin D levels are approximately 30% higher in northern Europe than in central and southern Europe, higher vitamin D concentrations in northern countries may have a genetic basis.[47][48] In a meta-analysis of cross-sectional studies on serum 25(OH)D concentrations globally the levels averaged 54 nmol/l and were higher in women than men, and higher in Caucasians than in non-Caucasians. There was no trend in serum 25(OH)D level with latitude.[49] African Americans often have a very low circulating 25(OH)D level, however those of African descent have higher parathyroid hormone and 1,25-Dihydroxycholecalciferol associated with lower 25-hydroxyvitamin D than other ethnic groups, moreover they have the greatest bone density[50] and lowest risk of fragility fractures compared to other populations.[51][52][53] Frank deficiency of vitamin D can result from a number of hereditary disorders.[3] Deficiency results in impaired bone mineralization, and leads to bone softening diseases[54] including:

  • Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones which can be caused by calcium or phosphorus deficiency as well as a lack of vitamin D.[55][56] Rickets was first described in the 17th century by Francis Glisson who stated in 1650 that it had first appeared about 30 years previously in the counties of Dorset and Somerset.[57] In 1857 John Snow (physician) suggested the rickets then widespread in Britain was being caused by the adulteration of bakers bread with alum.[58] The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920.[59] By altering the diets of dogs raised in the absence of sunlight, he was able to establish unequivocally that rickets was linked with diet, and identified cod liver oil as an excellent anti-rachitic agent and phytic acid as a rachitic agent.[60][61][62] Nutritional rickets exists in countries with intense year round sunlight such as Nigeria and can occur without vitamin D deficiency.[63][64] In 1921 Elmer McCollum identified a substance found in certain fats that could prevent rickets. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, the fortification of milk with 10 micrograms (400 IU) of vitamin D per quart in the 1930s led to a dramatic decline in the number of rickets cases.[26] Rickets is now rare in Britain however there have been outbreaks in some immigrant communities.[65][66] although the sufferers did not conform to the steriotype of concealing clothing. Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals.[67] In Britain dietry risk factors for rickets are independent of the low vitamin D content of most foods and appear to result from interactions between constituents of animal foods and the intermediary metabolism of endogenously-synthesized vitamin D.[68]



  • Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain.[69] A number of reports thus indicate that vitamin D deficiency may be related to various types of pain,[70] but of the five small double-blind randomized controlled trials, only one found a reduction in pain after supplementation, and there is no persuasive evidence of lower vitamin D status in chronic pain sufferers compared to controls.[71]


Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases, such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, osteoporosis, chronic pain, seasonal affective disorder,[72][73] peripheral artery disease[74], cognitive impairment which includes memory loss and foggy brain,[75] and several autoimmune diseases including type 1 diabetes (see role in immunomodulation).[8][26] There is an association between low vitamin D levels and Parkinson's disease, but whether Parkinson's causes low vitamin D levels, or whether low vitamin D levels play a role in the pathogenesis of Parkinson's disease has not been established.[76]

One leading proponent of the view that the optimal concentration of 25(OH)D is at least 30 ng/ml [77] defines vitamin D deficiency as a 25(OH)D level of under 20 ng/ml (50 nmol/l), applying this criterion he regards 30% to 50% of the United States population as suffering from vitamin D deficiency.[78] This includes areas with abundant sun exposure, such as Hawaii and southern Arizona where over 50% of inhabitants have 25(OH)D level of under 20 ng/ml.[79][80] Such metrics[81] depart from more typical definitions of vitamin deficiency which are based on prevention of overt deficiency symptoms or comparable biologic indicators.[82]

[edit] Overdose

For more details on this topic, see hypervitaminosis D.

Vitamin D is stored in the human body as calcidiol (25-hydroxy-vitamin D) which has a large volume of distribution and a half-life of about 20 to 29 days.[17] Ordinarily, the synthesis of bioactive vitamin D hormone is tightly regulated, and prevalent thinking is that vitamin D toxicity usually occurs only if excessive doses (prescription forms or rodenticide analogs) are taken.[83] Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose.[3]

The exact long-term safe dose of vitamin D is not known. In 1997 the U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults was set at 50 micrograms/day (2,000 IU)[84], but this is viewed by some researchers as outdated and overly restrictive.[85] A 2007 risk assessment was made by two employees of the dietary supplement trade association Council for Responsible Nutrition,[85] that represents companies including Amway, Bayer AG and GlaxoSmithKline,[86] and their two colleagues, who declared that they had no personal or financial conflicts of interest. They suggested that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit.[85] In adults, sustained intake of 1250 micrograms/day (50,000 IU) can produce toxicity within a few months.[3] For infants (birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. Other sources indicate that the threshold for vitamin D toxicity in humans is 500 to 600 micrograms per kilogram body weight per day."[87] In rats an oral LD50 of 619 mg/kg is noted.[88] All known cases of vitamin D toxicity with hypercalcemia have involved intake of over 1,000 micrograms/day (40,000 IU)[89].

Although normal food and pill vitamin D concentration levels are far too low to be toxic in adults, people taking multiples of the normal dose of codliver oil may reach toxic levels of vitamin A, not vitamin D,[90] if taken in an attempt to increase the levels of vitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.[89] In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004 (a randomly selected year), leading to 1 death.[91]

Some symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure.[92] Gastrointestinal symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop.[3] In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity.[93] Another study showed elevated risk of ischemic heart disease when serum 25-hydroxyvitamin D was above 89 ng/mL.[94] Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.[3]

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.[89] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[16] According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day.[89] According to Holick, "the skin has a large capacity to produce cholecalciferol"; his experiments indicate that,

"[W]hole-body exposure to one minimal erythemal dose of simulated solar ultraviolet radiation is comparable with taking an oral dose of between 250 and 625 micrograms (10 000 and 25 000 IU) vitamin D."[16]

[edit] Health effects

[edit] Immunomodulation

The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects.[95]

VDR ligands have been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages.[17] Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi.[96] Vitamin D deficiency tends to increase the risk of infections, such as influenza[97] and tuberculosis[98][99][100]. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.[101]

Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns.[102] VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression.[103]

These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes); central nervous systems diseases (multiple sclerosis); and in preventing organ transplant rejection.[95]

A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of multiple sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D.[104] Further research conducted in 2009 indicates that vitamin D is required to activate a histocompatibility gene (HLA-DRB1*1501) necessary for differentiating between self and foreign proteins in a subgroup of individuals genetically predisposed to MS.[105] Suggestions that pregnant women take vitamin D during their pregnancy, especially during winter months, is beginning to show merit to lessen the likelihood of the child developing MS later in life.[106][107]

[edit] Cancer

The vitamin D hormone, calcitriol, has been found to induce death of cancer cells in vitro and in vivo. The anti-cancer activity of vitamin D is thought to result from its role as a nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a wide range of cellular mechanisms central to the development of cancer.[108] These effects may be mediated through vitamin D receptors expressed in cancer cells.[17]

In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast and ovarian cancer risks by 30%.[109][110][111] A scientific review undertaken by the National Cancer Institute found that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels of 80 nmol/L or higher associated with a 72% risk reduction. However, the same study found no link between baseline vitamin D status and overall cancer mortality.[112]

A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers.[113] Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight.[114] Another 2006 study found that taking the U.S. RDA of vitamin D (400 IU per day) cut the risk of pancreatic cancer by 43% in a sample of more than 120,000 people from two long-term health surveys.[115][116] A randomized intervention study involving 1,200 women, published in June 2007, reports that vitamin D supplementation (1,100 international units (IU)/day) resulted in a 60% reduction in cancer incidence, during a four-year clinical trial, rising to a 77% reduction for cancers diagnosed after the first year (and therefore excluding those cancers more likely to have originated prior to the vitamin D intervention).[117][118] Research has also indicated beneficial effects of high levels of calcitriol on patients with advanced prostate cancer.[119]

Low levels of vitamin D in serum have also been correlated with breast cancer disease progression and bone metastases,[120] and studies suggest that increased intake of vitamin D reduces the risk of breast cancer in premenopausal women.[121] Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an increased risk of breast cancer.[120] Impairment of the VDR-mediated gene expression is thought to alter mammary gland development or function and may predispose cells to malignant transformation. Women with homozygous FOK1 mutations in the VDR gene had an increased risk of breast cancer compared with the women who did not. FOK1 mutation has also been associated with decreasing bone mineral density which in turn may be associated with an increase in the risk of breast cancer.[122]

The Canadian Cancer Society was the first to recommend, in 2007, that all of its adult citizens begin taking 1,000 IU per day of vitamin D. The country's northern latitude was a factor in the decision, as was the growing body of evidence showing the vitamin's effectiveness in lowering instances of cancer.[123][124]

[edit] Cardiovascular disease

Research indicates that vitamin D may play a role in preventing or reversing coronary disease.[125][126] Vitamin D deficiency is associated with an increase in high blood pressure and cardiovascular risk. Numerous observational studies show this link, but no randomized trial has proven the impact of vitamin D supplementation.[127] The precise mechanism for cardiovascular regulation is still under investigation; possibilities include blood pressure regulation through the renin-angiotensin system, parathyroid hormone levels, direct impact on heart muscle function, inflammation, and vascular calcification.[128]

When researchers monitored the vitamin D levels, blood pressure and other cardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years, they found that those people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels.[129] Low levels of vitamin D have also been implicated in hypertension, elevated VLDL triglycerides, and impaired insulin metabolism.[130]

A report from the National Health and Nutrition Examination Survey (NHANES) involving nearly 5,000 participants found that low levels of vitamin D were associated with an increased risk of peripheral artery disease (PAD). The incidence of PAD was 80% higher in participants with the lowest vitamin D levels (<17.8 ng/mL).[74] Cholesterol levels were found to be reduced in gardeners in the UK during the summer months.[131] Heart attacks peak in winter and decline in summer in temperate[132] but not tropical latitudes.[133]

The issue of vitamin D in heart health has not yet been settled. Exercise may account for some of the benefit attributed to vitamin D, since vitamin D levels are generally higher in physically active persons.[134] Moreover, there may be an upper limit after which cardiac benefits decline. One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL.[94] These sun-living groups results do not generalize to sun-deprived urban dwellers. Among a group with heavy sun exposure, taking supplemental vitamin D is unlikely to result in blood levels over the ideal range, while urban dwellers not taking supplemental vitamin D may fall under the levels recognized as ideal. A review of vitamin D status in India[135] concluded that studies uniformly point to low 25(OH)D levels in Indians despite abundant sunshine, and suggested a public health need to fortify Indian foods with vitamin D might exist. However the levels found in India are consistent with many other studies of tropical populations which have found that even an extreme amount of sun exposure, such as incured by rural Indians, does not raise 25(OH)D levels to the levels typically found in Europeans,[136][137][138][139]

[edit] Mortality

Using information from the National Health and Nutrition Examination Survey a group of researchers concluded that having low levels of vitamin D (<17.8 ng/ml) was independently associated with an increase in all-cause mortality in the general population.[140] The study evaluated whether low serum vitamin D levels were associated with all-cause mortality, cancer, and cardiovascular disease (CVD) mortality among 13,331 diverse American adults who were 20 years or older. Vitamin D levels of these participants were collected over a 6-year period (from 1988 through 1994), and individuals were passively followed for mortality through the year 2000.

Among many factors that may be responsible for certain levels of vitamin D having a beneficial effect on all-cause mortality is its effect on telomeres and its potential effect on slowing aging, overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.[141][142][143] Shortening of leukocyte telomeres is a marker of aging. Leukocyte telomere length (LTL) predicts the development of aging-related disease, and length of these telomeres decreases with each cell division and with increased inflammation (more common in the elderly). Research indicates that vitamin D is a potent inhibitor of the proinflammatory response and slows the turnover of leukocytes. Higher than average vitamin D levels were also associated with longer leukocyte telomere length, indicating that optimal vitamin D concentrations could play a role in preventing age-related diseases.[144]

[edit] See also

[edit] References

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