Vitamin D

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 secosteroids, the two major physiologically relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D without a subscript refers to either D2 or D3 or both. Vitamin D3 is produced in the skin of vertebrates after exposure to ultraviolet B light from the sun or artificial sources, and occurs naturally in a small range of foods. In some countries staples such as milk, flour and margarine are artificially fortified with vitamin D, and it is also available as a supplement in pill form.[2] Food sources such as fatty fish, eggs, and meat are rich in vitamin D and are often recommended for consumption to those suffering vitamin D deficiency.[3]

Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcidiol. Circulating calcidiol may then be converted into calcitriol, the biologically active form of vitamin D, either in the kidneys or by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders.[4]

When synthesized in the kidneys, calcitriol circulates as a hormone, regulating, among other things, the concentration of calcium and phosphate in the bloodstream, promoting the healthy mineralization, growth and remodeling of bone, and the prevention of hypocalcemic tetany. Vitamin D insufficiency can result in thin, brittle, or misshapen bones, while sufficiency prevents rickets in children and osteomalacia in adults, and, together with calcium, helps to protect older adults from osteoporosis. Vitamin D also modulates neuromuscular function, reduces inflammation, and influences the action of many genes that regulate the proliferation, differentiation and apoptosis of cells.[5]

Contents

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.[6] 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.[7]

Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.[8] 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.[9] 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.[10]

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.[11] 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, vitamin D3 can be made in the skin. Depending on the intensity of UVB rays and the minutes of exposure, an equilibrium can develop in the skin, and vitamin D degrades as fast as it is generated.[12]

Evolution

The photosynthesis of vitamin D evolved over 750 million years ago; the phytoplankton coccolithophor Emeliani huxleii is an early example. Vitamin D played a critical role in the maintenance of a calcified skeleton in vertebrates as they left their calcium-rich ocean environment for land over 350 million years ago. "Because vitamin D can only be synthesized via a photochemical process, early vertebrates that ventured onto land either had to ingest foods that contained vitamin D or had to be exposed to sunlight to photosynthesize vitamin D in their skin to satisfy their body’s vitamin D requirement."[12]

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 light brown).

Vitamin D3 is made in the skin when 7-dehydrocholesterol absorbs UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm.[11]

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. Vitamin D is produced in the two innermost strata, the stratum basale and stratum spinosum.

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.[13] The naked mole rat appears to be naturally cholecalciferol deficient as serum 25-OH vitamin D levels are undetectable.[14] Interestingly, the naked mole rat is resistant to aging, maintains healthy vascular function[15] and is the longest lived of all rodents.[16]

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.[17]

In 1923, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced. Alfred Fabian Hess showed that "light equals vitamin D".[18] 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.[19] In the 1930s he clarified further the chemical structure of vitamin D.

In 1923, Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials.[20] After irradiating rodent food, Steenbock discovered that the rodents were cured of rickets. It is now known that vitamin D deficiency is a cause of rickets. Using $300 of his own money, Steenbock patented his invention. Steenbock's irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in 1945, rickets had all but been eliminated in the US.[21]

Synthesis mechanism (form 3)

In the skin 7-dehydrocholesterol, a derivative of cholesterol, is photolyzed by ultraviolet light in a 6-electron conrotatory electrocyclic reaction. The product is pre-vitamin D3. Reaction-Dehydrocholesterol-PrevitaminD3.png
Previtamin D3 spontaneously isomerizes to vitamin D3 (cholecalciferol) in a antarafacial sigmatropic [1,7] hydride shift. At room temperature the transformation of previtamin D3 to vitamin D3 takes about 12 days to complete.[10] Reaction-PrevitaminD3-VitaminD3.png
Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is hydroxylated in the liver at position 25 (upper right of the molecule) forming 25-hydroxycholecalciferol (calcidiol). This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase,[22] which is produced by hepatocytes. 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. Reaction - cholecalciferol to calcidiol.png
Calcidiol is transported to the proximal tubules of the kidneys where it is hydroxylated at the 1-α position (lower right of the molecule) forming calcitriol. This product is a potent ligand of the vitamin D receptor (VDR) which mediates most of the physiological actions of the vitamin. The conversion of calcidiol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, the levels of which are increased by parathyroid hormone (and additionally by low calcium or phosphate). Reaction - calcidiol to calcitriol.png

Mechanism of action

Following the final converting step in the kidney, calcitriol (the physiologically active form of vitamin D) is released into the circulation. By binding to vitamin D-binding protein (VDBP), a carrier protein in the plasma, calcitriol is transported to various target organs.[8]

Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[8] 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.[23]

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.[24]

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).[25][26]

Nutrition

Milk and cereal grains are often fortified with vitamin D.

Adequate intake

Adequate intake levels of vitamin D have been established by the Food and Nutrition Board at the Institute of Medicine of The National Academies (formerly National Academy of Sciences). Adequate intakes depend only on age (i.e., they are the same regardless of sex, pregnancy, or lactation).

These intake levels are based on the assumption that the vitamin is not synthesized by exposure to sunlight.

In the United States, typical diets provide about 100 IU/day. The NIH has a "Tolerable Upper Intake Level (UL)" of 2,000 IU/day, while newer studies indicate a UL as high as 10,000 IU/day.[27]

Australian studies into vitamin D deficiency have yielded tables of recommended sunlight intake based on the country's major cities.[3]

Natural sources

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

Natural sources of vitamin D include:[5]

Nutrition Facts labels on food products in the US are not required to list vitamin D content unless a food has been fortified with this nutrient.[5]

Naming of vitamin D

In 1913 American researchers Elmer McCollum and Marguerite Davis discovered a substance in cod liver oil which later came to be called "vitamin A". A British doctor Edward Mellanby noticed that dogs that were fed cod liver oil did not develop rickets and concluded that vitamin A, or a closely associated factor, could prevent the disease. In 1921 Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed. The modified oil cured the sick dogs, so McCollum concluded that the factor in cod liver oil which cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named.[31][32][33] Unlike other vitamins, vitamin D can be synthesised by humans and it is therefore not a vitamin in the strict sense.

Measuring vitamin D status

The serum concentration of 25-hydroxy-vitamin D is typically used to determine vitamin D status. It reflects vitamin D produced in the skin as well as that acquired from the diet, and has a fairly long circulating half-life of 15 days. It does not, however, reveal the amount of vitamin D stored in other body tissues. The level of serum 1,25-dihydroxy-vitamin D is not usually used to determine vitamin D status because it has a short half-life of 15 hours and is tightly regulated by parathyroid hormone, calcium, and phosphate, such that it does not decrease significantly until vitamin D deficiency is already well advanced.[5]

There has been variability in results of laboratory analyses of the level of 25-hydroxy-vitamin D. Falsely low or high values have been obtained depending on the particular test or laboratory used. Beginning in July 2009 a standard reference material became available which should allow laboratories to standardise their procedures.[5]

There is some disagreement concerning the exact levels of 25-hydroxy-vitamin D needed for good health. A level lower than 10 ng/mL (25 nmol/L) is associated with the most severe deficiency diseases: rickets in infants and children, and osteomalacia in adults. A concentration above 15 ng/ml (37.5 nmol/L) is generally considered adequate for those in good health. Levels above 30 ng/ml (75 nmol/L) are proposed by some as desirable for achieving optimum health, but there is not yet enough evidence to support this.[5][34][35]

Levels of 25-hydroxy-vitamin D that are consistently above 200 ng/mL (500 nmol/L) are thought to be potentially toxic, although data from humans is sparse. In animal studies levels up to 400 ng/mL (1,000 nmol/L) were not associated with toxicity.[5] Vitamin D toxicity usually results from taking supplements in excess. Hypercalcemia is typically the cause of symptoms, and levels of 25-hydroxy-vitamin D above 150 ng/mL (375 nmol/L) are usually found, although in some cases 25-hydroxy-vitamin D levels may appear to be normal. It is recommended to periodically measure serum calcium in individuals receiving large doses of vitamin D.[36]

In overweight persons increased fat mass is inversely associated with 25(OH)D levels.[37][38] This association may confound the reported relationships between low vitamin D status and conditions which occur more commonly in obesity[39] as the circulating 25(OH)D underestimates their total body stores.[40]

A study of highly sun exposed (tanned) healthy young skateboarders and surfers in Hawaii found levels below the proposed higher minimum of 30 ng/ml in 51% of the subjects. The highest 25(OH)D concentration was around 60 ng/ml (150nmol/L).[41] A similar <using the same data> study in Hawaii found a range of (11–71 ng/mL) in a population with prolonged extensive skin exposure while as part of the same study Wisconsin breastfeeding mothers were given supplements. The range of circulating 25(OH)D levels in women in the supplementated group was from 12–77 ng/mL. It is noteworthy that the levels in the supplemented population in Wisconsin were higher than the sun exposed group in Hawaii (which again included surfers because it was the same data set).[42]

Deficiency

Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun.[43] Deficiency results in impaired bone mineralization, and leads to bone softening diseases[44] including:

Adequate vitamin D may also be associated with healthy hair follicle growth cycles.[68] There are also associations between low 25(OH)D levels and peripheral vascular disease,[69] certain cancers, multiple sclerosis, rheumatoid arthritis, juvenile diabetes,[23] Parkinson's and Alzheimer's disease.[70] However these associations were found in observational studies and vitamin D vitamin supplements have not been demonstrated to reduce the risks of these diseases.[34]

Research shows that dark-skinned people living in Western societies have lower vitamin D levels.[71][72][72] It has been suggested that dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis, however a recent study has found novel evidence that low vitamin D levels among Africans may be due to other reasons.[73] Recent evidence implicates parathyroid hormone in adverse cardiovascular outcomes, black women have an increase in serum PTH at a lower 25(OH)D level than white women.[74] A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.[75][76]

Overdose by ingestion

In healthy adults, sustained intake of 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months;[77] those with certain medical conditions are far more sensitive to vitamin D and develop hypercalcaemia in response to any increase in vitamin D nutrition, while maternal hypercalcaemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.[78][79] Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. For infants (birth to 12 months) the tolerable Upper Limit (maximum amount that can be tolerated without harm) is set at 25 micrograms/day (1000 IU). 1000 micrograms/day (40,000 IU) in infants has produced toxicity within 1 month.[80] The U.S. Dietary Reference Intake Tolerable Upper Intake Level (upper limit) of vitamin D for children and adults is set at 50 micrograms/day (2,000 IU). Vitamin D overdose causes hypercalcemia and the main symptoms of vitamin D overdose are those of hypercalcemia: anorexia, nausea, and vomiting can occur, frequently followed by polyuria, polydipsia, weakness, nervousness, pruritus, and ultimately renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop.[81] Vitamin D toxicity is treated by discontinuing vitamin D supplementation and restricting calcium intake. Kidney damage may be irreversible.

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.[78] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentrations of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[12] According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day.[78] 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 [a dose that would just begin to produce sunburn in a given individual] 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."[12]

The similar effect of supplementation and whole body exposure to one erythemal dose prompted a researcher [82] to suggest that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit.[82] Supplements and skin synthesis have a different effect on serum 25(OH)D concentrations;[83] endogenously synthesized vitamin D3 travels in plasma almost exclusively on vitamin D-binding protein (VDBP), providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol. Orally administered vitamin D produces swift hepatic delivery and increases in plasma 25-hydroxycholecalciferol. The richest food source of vitamin D — wild salmon — would require 35 ounces a day to provide 10,000IU.[84] Recommending supplementation, when those supposedly in need of it are labeled healthy, has proved contentious, and doubt exists concerning long term effects of attaining and maintaining serum 25(OH)D of at least 80nmol/L by supplementation.[85]

A Toronto study concluded, "skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D". The uniform occurrence of low serum 25(OH)D in Indians living in India.[86] and Chinese in China,[87] does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes; the leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless, saying, "I see no risk, no downside, there's only a potential benefit".[88][89] Whether the toxicity of oral intake of vitamin D is due to that route being unnatural, as suggested by Fraser,[83] is not known, but there is evidence to suggest that dietary vitamin D may be carried by lipoprotein particles[90] into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages.[91] These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk.

Health effects

Immune system

VDR ligands have been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages.[24] Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi.[92][93][94] Suggestions of a link between vitamin D deficiency and the onset of multiple sclerosis posited that this is due to the immune-response suppression properties of Vitamin D[95] and 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.[96] Whether vitamin D supplements during pregnancy can lessen the likelihood of the child developing MS later in life is not known;[97][98] however, vitamin D fortification has been suggested to have caused a pandemic of allergic disease[99] and an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life has been found .[100] Veteran vitamin D researcher Hector DeLuca has cast doubt on whether vitamin D affects MS.[101] For viral infections, other implicated factors include low relative humidities produced by indoor heating and cold temperatures that favor virus spread during winter.[102]

Influenza

Lack of vitamin D synthesis is a possible explanation for high rates of influenza infection during winter; however, see flu season for the factors apart from vitamin D that are also hypothesized to influence rates of infection during winter.[103] Other implicated factors include low relative humidities produced by indoor heating and cold temperatures as features of winter that favor influenza virus spread.

Cancer

The molecular basis for thinking vitamin D has the potential to prevent cancer lies in its role in a wide range of cellular mechanisms central to the development of cancer.[104] These effects may be mediated through vitamin D receptors expressed in cancer cells.[24] Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an increased risk of breast cancer.[105] Women with mutations in the VDR gene had an increased risk of breast cancer.[106]

A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked increase in some cancer risks in countries with less sun and another metastudy found correlations between vitamin D levels and cancer. The authors suggested 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%.[107][108][109][110] Low levels of vitamin D in serum have been correlated with breast cancer disease progression and bone metastases.[105] However, the vitamin D levels of a population do not depend on the solar irradiance to which they are exposed.[111][112][113][114] Moreover, there are genetic factors involved with cancer incidence and mortality which are more common in northern latitudes.[115][116]

A 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.[117][118] However, in male smokers a 3-fold increased risk for pancreatic cancer in the highest compared to lowest quintile of serum 25-hydroxyvitamin D concentration has been found.[119]

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).[120][121] The study was criticized on several grounds[122] including lack of data, use of statistical techniques and comparison with a self-selected (i.e. non-randomized) observational study that found long term convergence of breast cancer incidence[123] The author's response provided the required data, explained their statistical usage and commented that even if the vitamin D merely delayed the appearance of cancer (which they did not believe, based on other studies), that that was still a considerable benefit.[122]

In 2007 the Canadian Cancer Society, (a national community-based organization of volunteers) recommended that all adults begin taking 1,000 IU per day (five times more than the government says they need) .[124][125] A US National Cancer Institute study analyzed data from the third national Health and Nutrition Examination Survey to examine the relationship between levels of circulating vitamin D in the blood and cancer mortality in a group of 16,818 participants aged 17 and older. It found no support for an association between 25(OH)D and total cancer mortality. However, the study did find that "[c]olorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/L or higher associated with a 72% risk reduction (95% confidence interval = 32% to 89%) compared with lower than 50 nmol/L, Ptrend = .02."[126] Unlike other studies, this one was carried out prospectively — meaning that participants were followed looking forward  — and the researchers used actual blood tests to measure the amount of vitamin D in blood, rather than trying to infer vitamin D levels from potentially inaccurate predictive models.[114][127]

Cardiovascular disease

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).[69] Cholesterol levels were found to be reduced in gardeners in the UK during the summer months.[128] Low levels of vitamin D are associated with an increase in high blood pressure and cardiovascular risk. Numerous observational studies show this link, but of two systemic reviews one found only weak evidence of benefit from supplements and the other found no evidence of a beneficial effect whatsoever.[129][130][131]

There is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles[90] into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages.[91] These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Calcifediol (25-hydroxy-vitamin D) is implicated in the etiology of atherosclerosis, especially in non-Caucasians.[83][85][132][133] Freedman et al. (2010) have found that serum vitamin D correlates in African Americans, but not in Euro-Americans, with calcified atheroscleratic plaque. "Higher levels of 25-hydroxyvitamin D seem to be positively correlated with aorta and carotid CP in African Americans but not with coronary CP. These results contradict what is observed in individuals of European descent".[85][112][113][133][134] One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL.[132] A review of vitamin D status in India 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.[135] 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 incurred by rural Indians,[136] does not raise 25(OH)D levels to the levels typically found in Europeans,[111][137][138]

Mortality

Using information from the National Health and Nutrition Examination Survey a large scale study 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.[139] However it has been pointed out that increased mortality was also found in those with higher concentrations, (above 50 ng/ml).[140] A sophisticated August 2010 study of plasma vitamin D and mortality in older men concluded that both high (>39 ng/ml) and low (<18 ng/ml)) concentrations of plasma 25(OH)D are associated with elevated risks of overall and cancer mortality compared with intermediate concentrations. These boundaries were less than suggested by the Melamed et al. study of National Health and Nutrition Examination Survey data[141] but the immunoassay used by National Health and Nutrition Examination Survey tended to overestimate vitamin D values.[142]

Overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.[143][144][145]

Complex regulatory mechanisms control metabolism, recent epidemiologic evidence suggests that there is a narrow range of vitamin D levels in which function is optimized. Levels above or below this natural homeostasis of vitamin D increase mortality.[91][146]

See also

References

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  2. ↑ Institute of Medicine (IOM). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1997) Access date: 2010-04-14 [1]
  3. ↑ 3.0 3.1 Joshi, D; Center, J; Eisman, J (2010). "Vitamin D deficiency in adults". Australian Prescriber 33 (4): 103–6. http://www.australianprescriber.com/magazine/33/4/103/6. 
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  12. ↑ 12.0 12.1 12.2 12.3 Holick MF (March 1995). "Environmental factors that influence the cutaneous production of vitamin D". The American Journal of Clinical Nutrition 61 (3 Suppl): 638S–645S. PMID 7879731. http://www.ajcn.org/cgi/reprint/61/3/638S. 
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  140. ↑ PMID 20720256 (PubMed)
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  141. ↑ Melamed ML, Michos ED, Post W, Astor B (August 2008). "25-hydroxyvitamin D levels and the risk of mortality in the general population". Archives of Internal Medicine 168 (15): 1629–37. doi:10.1001/archinte.168.15.1629. PMID 18695076. 
  142. ↑ PMID 20720256 (PubMed)
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  143. ↑ Tuohimaa P (March 2009). "Vitamin D and aging". The Journal of Steroid Biochemistry and Molecular Biology 114 (1-2): 78–84. doi:10.1016/j.jsbmb.2008.12.020. PMID 19444937. 
  144. ↑ Keisala T, Minasyan A, Lou YR, et al. (July 2009). "Premature aging in vitamin D receptor mutant mice". The Journal of Steroid Biochemistry and Molecular Biology 115 (3-5): 91–7. doi:10.1016/j.jsbmb.2009.03.007. PMID 19500727. 
  145. ↑ Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A (December 2009). "Vitamin D, nervous system and aging". Psychoneuroendocrinology 34 (Suppl 1): S278–86. doi:10.1016/j.psyneuen.2009.07.003. PMID 19660871. 
  146. ↑ PMID 20720256 (PubMed)
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Vitamins (A11)
Fat soluble
Retinol · β-Carotene · Tretinoin · α-Carotene
D

D2 (Ergosterol, Ergocalciferol)  · D3 (7-Dehydrocholesterol, Previtamin D3, Cholecalciferol, 25-hydroxycholecalciferol, Calcitriol (1,25-dihydroxycholecalciferol), Calcitroic acid)

D4 (Dihydroergocalciferol)  · D5  · D analogues (Dihydrotachysterol, Calcipotriol, Tacalcitol, Paricalcitol)
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Water soluble

B1 (Thiamine) · B2 (Riboflavin) · B3 (Niacin, Nicotinamide) · B5 (Pantothenic acid, Dexpanthenol, Pantethine) · B6 (Pyridoxine, Pyridoxal phosphate, Pyridoxamine)

B7 (Biotin) · B9 (Folic acid, Dihydrofolic acid, Folinic acid) · B12 (Cyanocobalamin, Hydroxocobalamin, Methylcobalamin, Cobamamide)  · Choline
Ascorbic acid  · Dehydroascorbic acid
Combinations
Multivitamins

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drug(A8/11/12)