Vitamin D

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Vitamin D
Drug class
Cholecalciferol-3d.png
UseRickets, osteoporosis, vitamin D deficiency
Biological targetvitamin D receptor
ATC codeA11CC
External links
MeSHD014807d
AHFS/Drugs.comMedFacts Natural Products
 
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Vitamin D
Drug class
Cholecalciferol-3d.png
UseRickets, osteoporosis, vitamin D deficiency
Biological targetvitamin D receptor
ATC codeA11CC
External links
MeSHD014807d
AHFS/Drugs.comMedFacts Natural Products

Vitamin D is a group of fat-soluble secosteroids responsible for enhancing intestinal absorption of calcium, iron, magnesium, phosphate and zinc. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).[1] Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements.[1][2][3] The body can also synthesize vitamin D (specifically cholecalciferol) in the skin, from cholesterol, when sun exposure is adequate (hence its nickname, the "sunshine vitamin").

Although vitamin D is commonly called a vitamin, it is not actually an essential dietary vitamin in the strict sense, as it can be synthesized in adequate amounts by most mammals exposed to sunlight. A substance is only classified as an essential vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from its diet. In common with other compounds commonly called vitamins, vitamin D was nevertheless discovered in an effort to find the dietary substance lacking in a disease, namely rickets, the childhood form of osteomalacia.[4] Additionally, like other compounds called vitamins, in the developed world, vitamin D is added to staple foods, such as milk, to avoid disease due to deficiency.

Synthesis from exposure to sunlight, as well as intake from the diet, generally contribute to the maintenance of adequate serum concentrations. Evidence indicates the synthesis of vitamin D from sun exposure is regulated by a negative feedback loop that prevents toxicity, but, because of uncertainty about the cancer risk from sunlight, no recommendations are issued by the Institute of Medicine, USA, for the amount of sun exposure required to meet vitamin D requirements. Accordingly, the Dietary Reference Intake for vitamin D assumes no synthesis occurs and all of a person's vitamin D is from food intake, although that will rarely occur in practice. Beyond its use to prevent osteomalacia or rickets, the evidence for other health effects of vitamin D supplementation in the general population is inconsistent.[5][6] The best evidence of benefit is for bone health.[7] The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a decrease in mortality in elderly people,[8] and another concluding there is no clear justification for recommending vitamin D.[9]

In the liver, cholecalciferol (vitamin D3) is converted to calcidiol, which is also known as calcifediol (INN), 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 — abbreviated 25(OH)D3. Ergocalciferol (vitamin D2) is converted in the liver to 25-hydroxyergocalciferol, also known as 25-hydroxyvitamin D2 — abbreviated 25(OH)D2. These are the two specific vitamin D metabolites that are measured in serum to determine a person's vitamin D status.[10][11] Part of the calcidiol is converted by the kidneys to calcitriol, the biologically active form of vitamin D.[12] Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. Calcitriol also affects neuromuscular and immune function.[13]

Effects[edit]

The effects of vitamin D supplementation on health are uncertain.[6] A 2013 review did not find any effect from supplementation on the rates of disease, other than a tentative decrease in mortality in the elderly.[14] Low vitamin D levels may result from disease rather than cause disease.[14]

A United States Institute of Medicine, (IOM) report states: "Outcomes related to cancer, cardiovascular disease and hypertension, diabetes and metabolic syndrome, falls and physical performance, immune functioning and autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting."[7]:5 Some researchers claim the IOM was too definitive in its recommendations and made a mathematical mistake when calculating the blood level of vitamin D associated with bone health.[15] Members of the IOM panel maintain that they used a "standard procedure for dietary recommendations" and that the report is solidly based on the data. Research on vitamin D supplements, including large scale clinical trials, is continuing.[15]

Mortality[edit]

Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly,[14][8] but the effect has not been deemed pronounced or certain enough to make taking supplements recommendable.[9]

Other forms (Vitamin D2, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regards to the risk of death.[8] However, both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.[16][17][18] The relationship between serum calcidiol level and all-cause mortality is parabolic.[7] Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.[7]:435

Bone health[edit]

In general, there is no good evidence to support the commonly-held belief that vitamin D can help prevent osteoporosis.[9] Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed.[19]

For older people with osteoporosis, taking vitamin D with calcium may help prevent hip fractures, but it also slightly increases the risk of stomach and kidney problems.[20] Supplementation with higher doses of vitamin D, in those older than 65 years, may decrease fracture risk.[21] This appears to apply more to people in institutions than those living independently.[22]

Vitamin D deficiency causes osteomalacia (called rickets when it occurs in children). Use of vitamin D in children with normal vitamin D levels does not appear to improve bone density.[23] Beyond that, low serum vitamin D levels have been associated with falls, and low bone mineral density.[24]

Cancer[edit]

Vitamin D supplements have been widely marketed on the internet and elsewhere for their claimed anti-cancer properties.[25]

Taking vitamin D supplements has no significant effect on cancer risk.[9] Vitamin D3; however, appears to decrease the risk of death from cancer but there are concerns with the quality of the data.[26]

There is insufficient evidence to recommend that vitamin D be prescribed for people with cancer, although there is some evidence that hypovitaminosis D may be associated with a worse outcome for some cancers.[27]

Cardiovascular disease[edit]

Taking vitamin D supplements has no significant effect on the risk of stroke, cerebrovascular disease, cardial infarction or ischaemic heart disease.[9]

Depression[edit]

Clinical trials of Vitamin D supplementation for depressive symptoms have generally been of low quality and show no overall effect, although subgroup analysis showed that supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate effect.[28]

Immune system[edit]

Infectious disease[edit]

In general, vitamin D functions to activate the innate and dampen the adaptive immune systems.[29] Vitamin D deficiency has been linked to increased risk of viral infections, including HIV and influenza.[30][31][32] Low levels of vitamin D appear to be a risk factor for tuberculosis,[33] and historically it was used as a treatment.[34][34]

Autoimmune disease[edit]

Although there are tentative data linking low levels of vitamin D to asthma, there is inconclusive evidence to support a beneficial effect from supplementation.[35] Accordingly, supplementation is not currently recommended for treatment or prevention of asthma.[36]

Vitamin D hypovitaminosis may be a risk factor for multiple sclerosis,[37] but there is no evidence vitamin D has any clinically significant benefit as a treatment.[38]

Pregnancy[edit]

Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small infants.[39] The benefit of supplements, however, is unclear.[39] Pregnant women who take an adequate amount of vitamin D during gestation may experience positive immune effects.[40] Pregnant women often do not take the recommended amount of vitamin D.[40] A trial of supplementation has found 4,000 IU of vitamin D3 superior to lesser amounts in pregnant women for achieving specific target blood levels.[40]

Deficiency[edit]

A diet deficient in vitamin D in conjunction with inadequate sun exposure causes osteomalacia (or rickets when it occurs in children), which is a softening of the bones. In the developed world, this is a rare disease.[41][42] However, vitamin D deficiency has become worldwide issue in the elderly and remains common in children and adults.[43][44] Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun.[45] Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases[46][47] including:

Rickets[edit]

Rickets, a childhood disease, is characterized by impeded growth, soft, weak, deformity of the long bones that bend and bow under their weight as children start to walk. This condition is characterized by bow legs,[47] which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; today, it is largely found in low-income countries in Africa, Asia, or the Middle East[48] and in those with genetic disorders such as pseudovitamin D deficiency rickets.[49] Rickets was first described in 1650 by Francis Glisson, who said it had first appeared about 30 years previously in the counties of Dorset and Somerset.[50] In 1857, John Snow suggested that rickets, then widespread in Britain, was being caused by the adulteration of bakers' bread with alum.[51] The role of diet in the development of rickets[52][53] was determined by Edward Mellanby between 1918–1920.[54] Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.[55][56] Although rickets and osteomalacia are now rare in Britain, there have been outbreaks in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing.[57] 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.[58][59][60] The dietary risk factors for rickets include abstaining from animal foods.[57][61] Vitamin D deficiency remains the main cause of rickets among young infants in most countries, because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate UVB exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, where the disease occurs among older toddlers and children, it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products.[60] Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are approximately 20% stronger than at sea level on the same latitude,[62] almost two-thirds of 500 children had mild rickets in the late 1920s.[63] An increase in the proportion of animal protein[61][64] in the 20th century American diet coupled with increased consumption of milk[65][66] fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.[67] Also, in the United States and Canada, vitamin D fortified milk, infant vitamin supplements, and vitamin supplements have helped to eradicate the majority of cases of rickets for children with fat malabsorption conditions.[47]

Osteomalacia[edit]

Osteomalacia is a disease in adults that results from vitamin D deficiency. Characteristics of this disease are softening of the bones, leading to bending of the spine, bowing of the legs, proximal muscle weakness, bone fragility, and increased risk for fractures.[68] Osteomalacia reduces calcium absorption and increases calcium loss from bone, which increases the risk for bone fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10 ng/mL.[1] The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain,[69][70] There is no persuasive evidence of lower vitamin D levels in chronic pain sufferers.[71]

Influence of skin pigmentation[edit]

Some research shows that dark-skinned people living in temperate climates have lower vitamin D levels.[72][73][73] 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.[74] 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.[75] A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.[76][77]

On the other hand, the uniform occurrence of low serum 25(OH)D in Indians living in India[78] and Chinese in China,[79] 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."[80][81]

Excess[edit]

Vitamin D toxicity is rare.[44] The threshold for vitamin D toxicity has not been established; however, the tolerable upper intake level (UL) is 4,000 IU/day for ages 9–71.[7] Vitamin D toxicity is not caused by sunlight exposure, but can be caused by supplementing with high doses of vitamin D. In healthy adults, sustained intake of more than 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months and can increase serum 25-hydroxyvitamin D levels to 150 ng/mL and greater;[44][82] those with certain medical conditions, such as primary hyperparathyroidism,[83] are far more sensitive to vitamin D and develop hypercalcemia in response to any increase in vitamin D nutrition, while maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.[83][84]

Since hypercalcemia is a strong indication of vitamin D toxicity, this condition is noted with an increase in urination and thirst. If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs such as the kidneys, liver, and heart, resulting in pain and organ damage.[44][47][68] Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. The FDA advised manufacturers of liquid vitamin D supplements that droppers accompanying these products should be clearly and accurately marked for 400 international units (IU). In addition, for products intended for infants, the FDA recommends that the dropper hold no more than 400 IU.[85] For infants (birth to 12 months), the tolerable upper limit (maximum amount that can be tolerated without harm) is set at 25 micrograms/day (1,000 IU). One thousand micrograms (40,000 IU) per day in infants has produced toxicity within one month.[82] After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010, has increased the tolerable upper limit (UL) to 2,500 IU per day for ages 1–3 years, 3,000 IU per day for ages 4–8 years and 4,000 IU per day for ages 9–71+ years (including pregnant or lactating women).[7]

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, insomnia, nervousness, pruritus, and, ultimately, renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop.[82] Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.[44][68] 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.[83] 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.[86]

Published cases of toxicity involving hypercalcemia in which the vitamin D dose and the 25-hydroxy-vitamin D levels are known all involve an intake of ≥40,000 IU (1,000 μg) per day.[83] 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 high serum 25(OH)D by supplementation.[87]

Types[edit]

NameChemical compositionStructure
Vitamin D1molecular compound of ergocalciferol with lumisterol, 1:1
Vitamin D2ergocalciferol (made from ergosterol)Note double bond at top center.
Vitamin D3cholecalciferol (made from 7-dehydrocholesterol in the skin).Cholecalciferol.svg
Vitamin D422-dihydroergocalciferol22-Dihydroergocalciferol.png
Vitamin D5sitocalciferol (made from 7-dehydrositosterol)Vitamin D5 structure.svg

Several forms (vitamers) of vitamin D exist (see table). The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol; vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol.[88] Vitamin D2 was chemically characterized in 1931. In 1935, the chemical structure of vitamin D3 was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.[89]

Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.[90] 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.

Biosynthesis[edit]

Vitamin D3 (cholecalciferol) is produced through the action of ultraviolet irradiation (UV) on its precursor 7-dehydrocholesterol. Our skin makes vitamin D3 and supplies about 90 percent of our vitamin D.[1] This molecule occurs naturally in the skin of animals and in milk. Vitamin D3 can be made by exposure of the skin to UV, or by exposing milk directly to UV (one commercial method). Vitamin D3 is also found in oily fish and cod liver oil.[1][3][44]

Vitamin D2 is a derivative of ergosterol, a membrane sterol named for the ergot fungus, which is produced by some kinds of phytoplankton, invertebrates, yeasts, and higher fungi such as mushrooms. The vitamin ergocalciferol (D2) is produced in all of these organisms from ergosterol, in response to UV irradiation. Like all forms of vitamin D, it cannot be produced without UV irradiation. D2 is not produced by green land plants or vertebrates, because they lack the precursor ergosterol.[91] The biological fate for producing 25(OH)D from vitamin D2 is expected to be the same as for 25(OH)D3,[92] although some controversy exists over whether or not D2 can fully substitute for vitamin D3 in the human diet.[93][94]

Photochemistry[edit]

The photochemistry of Vitamin D biosynthesis in animal and fungi
Thermal isomerization of previtamin D3 to vitamin D3

The transformation that converts 7-dehydrocholesterol to Vitamin D3 (cholecalciferol) occurs in two steps. First, 7-dehydrocholesterol, is photolyzed by ultraviolet light in a 6-electron conrotatory ring-opening electrocyclic reaction. The product is previtamin D3. Second, previtamin D3 spontaneously isomerizes to vitamin D3 (cholecalciferol) in an antarafacial sigmatropic [1,7] hydride shift. At room temperature, the transformation of previtamin D3 to vitamin D3 takes about 12 days to complete.[95]

Evolution[edit]

Photosynthesis of vitamin D in the ocean by phytoplankton (such as coccolithophore and Emiliania huxleyi) has existed for more than 500 million years and continues to the present. Although primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D, land animals required another way to satisfy their vitamin D requirement for a calcified skeleton without relying on plants. Land vertebrates have been making their own vitamin D for more than 350 million years.[96]

Vitamin D can be synthesized only via a photochemical process, so land vertebrates 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.[95]

Synthesis in the skin[edit]

In 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 (cholecalciferol) is produced photochemically in the skin from 7-dehydrocholesterol. The precursor of vitamin D3, 7-Dehydrocholesterol is produced in relatively large quantities, 10,000 to 20,000 IU of vitamin D are produced in 30 minutes of whole-body exposure, in the skin of most vertebrate animals, including humans.[97] 7-dehydrocholesterol reacts with ultraviolet light of UVB type at wavelengths between 270 and 300 nm, with peak synthesis occurring between 295 and 297 nm.[98] These wavelengths are present in sunlight, as well as in the light emitted by the UV lamps in tanning beds (which produce ultraviolet primarily in the UVA spectrum, but typically produce 4% to 10% of the total UV emissions as UVB). Vitamin D3 can be made in the skin. Exposure to light through windows is insufficient because glass almost completely blocks UVB light.[99][100]

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.[86]

The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis. Thick epidermis in the soles and palms 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.

The naked mole rat appears to be naturally cholecalciferol deficient, as serum 25-OH vitamin D levels are undetectable.[101] 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 feathers or fur and is obtained orally during grooming.[102]

Sunscreen[edit]

Sunscreen absorbs ultraviolet light and prevents it from reaching the skin. It has been reported that sunscreen with a sun protection factor (SPF) of 8 based on the UVB spectrum can decrease vitamin D synthetic capacity by 95 percent, whereas sunscreen with an SPF of 15 can reduce synthetic capacity by 98 percent.[103]

Metabolic activation[edit]

Calcium regulation in the human body.[104] The role of vitamin D is shown in orange.
Liver hydroxylation of cholecalciferol to calcidiol
Kidney hydroxylation of calcidiol to calcitriol

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, in the kidneys. 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.[90] In addition to the kidneys, calcitriol is also synthesized by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders by stimulating the innate immune system.[105]

Whether it is made in the skin or ingested, cholecalciferol is hydroxylated in the liver at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcidiol or 25(OH)D). This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase,[106] which is produced by hepatocytes. Once made, the product is released into the plasma, where it is bound to an α-globulin, vitamin D binding protein.[107]

Calcidiol is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-α position (lower right of the molecule) to form calcitriol (aka 1,25-dihydroxycholecalciferol and abbreviated to 1,25(OH)2D). 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).

Biological activity[edit]

Synthesis of vitamin D

The active vitamin D metabolite calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[90] 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.[108] 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.[67]

One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Vitamin D deficiency can result in lower bone mineral density and an increased risk of reduced bone density (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body.[109] Thus, although it may initially appear paradoxical, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.[110]

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.[111] Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. It also is involved in the biosynthesis of neurotrophic factors, synthesis of nitric oxide synthase, and increased glutathione levels.[112]

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).[113][114]

Discovery[edit]

American researchers Elmer McCollum and Marguerite Davis in 1914[4] discovered a substance in cod liver oil which later was called "vitamin A". British doctor Edward Mellanby noticed dogs that were fed cod liver oil did not develop rickets and concluded vitamin A, or a closely associated factor, could prevent the disease. In 1922, Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed.[4] The modified oil cured the sick dogs, so McCollum concluded 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.[115][116][117] It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.

In 1925,[4] it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced (now known as D3). Alfred Fabian Hess showed "light equals vitamin D."[118] 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.[119] In 1929 a group at NIMR in Hampstead, London, were working on the structure of vitamin D, which was still unknown, as well as the structure of steroids. A meeting took place with J.B.S. Haldane, J.D. Bernal and Dorothy Crowfoot to discuss possible structures, which contributed to bringing a team together. X-ray crystallography demonstrated that sterol molecules were flat, not as proposed by the German team led by Windaus. In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance.[120] The informal academic collaboration between the team members Robert Benedict Bourdillon, Otto Rosenheim, Harold King and Kenneth Callow was very productive and led to the isolation and characterization of vitamin D.[121] At this time the policy of the Medical Research Council was not to patent discoveries, believing that results of medical research should be open to everybody. In the 1930s Windaus clarified further the chemical structure of vitamin D.[122]

In 1923, American biochemist Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials.[123] After irradiating rodent food, Steenbock discovered the rodents were cured of rickets. A vitamin D deficiency is a known cause of rickets. Using $300 of his own money, Steenbock patented his invention. His irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.[124]

In 1971–72, the further metabolism of vitamin D to active forms was discovered. In the liver, vitamin D was found to be converted to calcidiol.[11][125] Part of the calcidiol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D.[12] Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. Both calcidiol and calcitriol were identified by a team led by Michael F. Holick in the laboratory of Hector DeLuca.[12][126]

Recommendations[edit]

Dietary reference intakes[edit]

Different institutions propose different recommendations concerning daily amounts of the vitamin.

Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.[127]

(Conversion : 1 µg = 40 IU and 0.025 µg = 1 IU)[128]

Australia and New Zealand[edit]

About a third of Australians have vitamin D deficiency.[129] Australia and New Zealand have established guidelines for dietary vitamin D intake as follows:[130]

Age groupAdequate Intake (μg)Upper Level of Intake (μg)
Infants 0–12 months5.025.0
Children 1–18 years5.080.0
Adults 19–50 years5.080.0
Adults 51–70 years10.080.0
Adults > 70 years15.080.0

Canada[edit]

According to Health Canada[131] the recommended dietary allowances (RDA) for vitamin D are:

Age groupRDA (IU)Tolerable Upper Intake (IU)
Infants 0–6 months400*1,000
Infants 7–12 months400*1,500
Children 1–3 years6002,500
Children 4–8 years6003,000
Children and Adults 9–70 years6004,000
Adults > 70 years8004,000
Pregnancy & Lactation6004,000

Note*: Adequate Intake rather than Recommended Dietary Allowance.

European Union[edit]

The recommended daily amount for vitamin D in the European Union is 5 µg.[132]

The European Menopause and Andropause Society (EMAS) recommended 15 µg (600 IU) until age 70, and 20 µg (800 IU) in older than 71 years, in postmenopausal women. This dose should be increased up to 4,000 IU/day in some patients with very low vitamin D status or in case of co-morbid conditions.[133]

The UK National Health Service recommends that babies and young children aged six months to five years, pregnant or breastfeeding women, and sun-deprived elderly people should take daily vitamin supplements to ensure sufficient vitamin D intake; the general population get enough vitamin D from good diets and from sunlight.[134]

United States[edit]

According to the United States Institute of Medicine,[7] the recommended dietary allowances (RDA) of vitamin D are:

Age groupRDA (IU/day)
Infants 0–6 months400*
Infants 6–12 months400*
1–70 years600 (15 μg/day)
71+ years800 (20 μg/day)
Pregnant/Lactating600 (15 μg/day)
Upper intake levels[edit]

The Tolerable Upper Intake Level is defined as "the highest average daily intake of a nutrient that is likely to pose no risk of adverse health effects for nearly all persons in the general population.[7]:403 " Although tolerable upper intake levels are believed to be safe, information on the long-term effects is incomplete and these levels of intake are not recommended:[7]:403:433

Age groupTolerable Upper Intake Level
Infants 0–6 months1,000 IU/day (25 µg/day)
Infants 6–12 months1,500 IU/day (37.5 µg/day)
1–3 years2,500 IU/day (62.5 µg/day)
4–8 years3,000 IU/day (75 µg/day)
9+ years4,000 IU/day (100 µg/day)
Pregnant/Lactating4,000 IU/day[7]:5(100 µg/day)

The Dietary Reference Intake for vitamin D issued by the American (U.S.) Institute of Medicine (IOM) in 2010 superseded a previous recommendation which had Adequate Intake status. The recommendations were formed assuming the individual has no skin synthesis of vitamin D because of inadequate sun exposure. The reference intake for vitamin D refers to total intake from food, beverages and supplements, is intended for the North American population, and assumes that calcium requirements are being met.[7]:5

One school of thought contends that human physiology is fine tuned to an intake of 4,000–12,000 IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80 ng/mL[135] and that this is required for optimal health. Proponents of this view, who include some members of the panel that drafted a now superseded 1997 report on vitamin D from the Institute of Medicine, contend that the IOM's warning about serum concentrations above 50 ng/mL lacks biological plausibility. They suggest that for some people reducing the risk of preventable disease requires a higher level of vitamin D than that recommended by the IOM.[92][135]

According to the European Food Safety Authority the Tolerable Upper Intake Levels[136] are:

Serum 25-hydroxyvitamin D[edit]

US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L.

A U.S. Institute of Medicine committee concluded that a serum 25-hydroxyvitamin D level of 20 ng/mL (50 nmol/L) is desirable for bone and overall health. The Dietary Reference Intakes for vitamin D are chosen with a margin of safety and 'overshoot' the targeted serum value to ensure that the specified levels of intake achieve the desired serum 25-hydroxyvitamin D levels in almost all persons. It is assumed there are no contributions to serum 25-hydroxyvitamin D level from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight.

The Institute found that serum 25-hydroxyvitamin D concentrations above 30 ng/mL (75 nmol/L) are "not consistently associated with increased benefit". Serum 25-hydroxyvitamin D levels above 50 ng/mL (125 nmol/L) may be cause for concern.[7] However, the desired range of serum 25-hydroxyvitamin D is between 20-50 ng/mL.[7]

There is a lower risk of cardiovascular disease when vitamin D ranged from 20 to 60 nmol/L (8 to 24 ng/mL). There appears to be a "threshold effect" once 60 nmol/L (24 ng/mL) have been reached i.e., levels of vitamin D over 60 nmol/L did not show added benefit.[137]

Allowable health claims[edit]

Apart from the above discussion on health effects or scientific evidence for lowering disease risk, governmental regulatory agencies stipulate for the food industry health claims allowable as statements on packaging.

European Food Safety Authority (EFSA)[138]

US Food and Drug Administration (FDA)

Health Canada

Other possible agencies with claim guidance: Japan FOSHU[142] and Australia-New Zealand.[143]

Dietary sources[edit]

Vitamin D is found in few dietary sources.[1][3][44][47] Sunlight exposure is the primary source of vitamin D for majority of people, other than supplements.[2]

Vitamin D2[edit]

Fungus, from USDA nutrient database (per 100 g):[144]

Vitamin D2, or ergocalciferol found in fungi, is synthesized from viosterol, which in turn is activated when ultraviolet light stimulates ergosterol.[145]

Human bioavailability of vitamin D2 from vitamin D2-enhanced button mushrooms via UV-B irradiation is effective in improving vitamin D status and not different from a vitamin D2 supplement.[146] from UV-irradiated yeast baked into bread is bioavailable.[147] By visual assessment or using a chromometer, no significant discoloration of irradiated mushrooms, as measured by the degree of "whiteness", was observed.[148] Claims have been made that a normal serving (approx. 3 oz or 1/2 cup, or 60 grams) of fresh mushrooms treated with ultraviolet light have increased vitamin D content to levels up to 80 micrograms,[149] or 2700 IU if exposed to just 5 minutes of UV light after being harvested.[150]

Plants

Vitamin D3[edit]

In some countries, staple foods are artificially fortified with vitamin D.[152]

Industrial production[edit]

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.[154] The 7-dehydrocholesterol is a natural substance in wool grease (lanolin) from sheep or other woolly animals. Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.[154]

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