Vitamin D
Drug class
Cholecalciferol (D3)
Use	Rickets, osteoporosis, vitamin D deficiency
Biological target	vitamin D receptor
ATC code	A11CC
External links
MeSH	D014807
AHFS/Drugs.com	MedFacts Natural Products

Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique because it can be ingested as cholecalciferol (vitamin D₃) or ergocalciferol (vitamin D₂) and because the body can also synthesize it (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 all mammals from sunlight. An organic chemical compound (or related set of compounds) is only scientifically called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. However, as with other compounds commonly called vitamins, vitamin D was discovered in an effort to find the dietary substance that was lacking in a disease, namely, rickets, the childhood form of osteomalacia.^[1] 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.

Measures of serum levels (from a vitamin D₃ blood test) reflect endogenous synthesis from exposure to sunlight as well as intake from the diet, and it is believed that synthesis may contribute generally to the maintenance of adequate serum concentrations. The evidence indicates that the synthesis of vitamin D from sun exposure works in a 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 Intakes for vitamin D assume that no synthesis occurs and that all of a person's vitamin D is from their diet, although that will rarely occur in practice.

Vitamin D is converted to calcidiol in the liver. Part of the calcidiol is converted by the kidneys to calcitriol, the biologically active form of vitamin D. This 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. Calcidiol is also converted to calcitriol outside of the kidneys for other purposes, such as the proliferation, differentiation and apoptosis of cells; calcitriol also affects neuromuscular function and inflammation.^[2]

Beyond its use to prevent osteomalacia or rickets, the evidence for other health effects of vitamin D supplementation in the general population is inconsistent.^[3][4] The best evidence of benefit is for bone health^[5] and a decrease in mortality in elderly women.^[6]

Health effects of supplements[link]

The effects of vitamin D supplementation on health are uncertain.^[4] 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."^[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.^[7] 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.^[7]

Mortality[link]

Low blood levels of vitamin D are associated with increased mortality,^[8] and giving supplementary vitamin D₃ to elderly women in institutional care seems to decrease the risk of death.^[6] Vitamin D₂, alfacalcidol, and calcitriol do not appear to be effective.^[6] However, both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.^[9][10][11] The relationship between between serum 25OHD level and all-cause mortality is U-shaped,^[12] Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population,^[12] which means that mortality is higher both at higher and at lower levels of vitamin D.

Bone health[link]

As mentioned above, vitamin D deficiency causes osteomalacia (called rickets when it occurs in children). Beyond that, low serum vitamin D levels have been associated with falls, and low bone mineral density.^[13] Supplementation with vitamin D and calcium improves bone mineral density slightly, as well as decreases the risk of falls and fractures in certain groups of people.^[13] This appears to apply more to people in institutions than those living independently.^[14] The quality of the evidence is, however, poor.^[15]

Cardiovascular disease[link]

Evidence for health effects from vitamin D supplementation for cardiovascular health is poor.^[3][16][17] Moderate to high doses may reduce cardiovascular disease risk but are of questionable clinical significance.^[3][18]

Multiple sclerosis[link]

Low levels of vitamin D are associated with multiple sclerosis. Supplementation with vitamin D may have a protective effect but there are uncertainties and unanswered questions.^[19][20][21] "The reasons why vitamin D deficiency is thought to be a risk factor for MS are as follows: (1) MS frequency increases with increasing latitude, which is strongly inversely correlated with duration and intensity of UVB from sunlight and vitamin D concentrations; (2) prevalence of MS is lower than expected at high latitudes in populations with high consumption of vitamin-D-rich fatty fish; and (3) MS risk seems to decrease with migration from high to low latitudes."^[19] A clinical trial sponsored by Charite University in Berlin, Germany was begun in 2011, with the goal of examining the efficacy, safety and tolerability of vitamin D3 in the treatment of Multiple Sclerosis.^[22][23]

Cancer[link]

Low vitamin D levels are associated with some cancers and with worse outcomes in other cancers, but taking supplements does not appear to help people with prostate cancer. Currently evidence is insufficient to support supplementation in those with cancer.^[24] Results for a protective or harmful effect of vitamin D supplementation in other types of cancer are inconclusive.^[4][25]

Other[link]

Vitamin D appears to have effects on immune function.^[26] It has been postulated to play a role in influenza with lack of vitamin D synthesis during the winter as one explanation for high rates of influenza infection during the winter.^[27] For viral infections, other implicated factors include low relative humidities produced by indoor heating and cold temperatures that favor virus spread.^[28] Low levels of vitamin D appear to be a risk factor for tuberculosis,^[29] and historically it was used as a treatment.^[30] As of 2011, it is being investigated in controlled clinical trials.^[30] Vitamin D may also play a role in HIV.^[31] Although there are tentative data linking low levels of vitamin D to asthma, there is inconclusive evidence to support a beneficial effect from supplementation.^{[citation needed]} Accordingly, supplementation is not currently recommended for treatment or prevention of asthma.^[32] Also, preliminary data do not support a role for supplemental vitamin D in promotion of human hair growth.^[33]

Deficiency[link]

A diet deficient in vitamin D causes osteomalacia (called rickets when it occurs in children), which is a softening of the bones. In the developed world, this is a rare disease.^[34][35]

Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun.^[36] Deficiency results in impaired bone mineralization and leads to bone-softening diseases^[37] including:

• Rickets, a childhood disease characterized by impeded growth and deformity of the long bones, 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^[38] and in those with genetic disorders such as pseudovitamin D deficiency rickets.^[39] 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.^[40] In 1857, John Snow suggested that rickets, then widespread in Britain, was being caused by the adulteration of bakers' bread with alum.^[41] The role of diet in the development of rickets^[42][43] was determined by Edward Mellanby between 1918–1920.^[44] Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.^[45][46] 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.^[47] 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.^[48][49][50] The dietary risk factors for rickets include abstaining from animal foods.^[47][51] 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.^[50] 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,^[52] almost two-thirds of 500 children had mild rickets in the late 1920s.^[53] An increase in the proportion of animal protein^[51][54] in the 20th century American diet coupled with increased consumption of milk ^[55][56] fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.^[57]
• Osteomalacia, a bone-thinning disorder that occurs exclusively in adults, is characterized by proximal muscle weakness and bone fragility. The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain,^[58][59] there is no persuasive evidence of lower vitamin D status in chronic pain sufferers.^[60]

The Director General of Research and Development and Chief Scientific Adviser for the UK Department of Health and NHS said that children aged six months to five years should be given vitamin D supplements, particularly during the winter. However, people who get enough vitamin D from their diets and from sunlight are not recommended for vitamin D supplements.^[61]

Some research shows that dark-skinned people living in temperate climates have lower vitamin D levels.^[62][63][63] 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.^[64] 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.^[65] A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.^[66][67]

On the other hand, the uniform occurrence of low serum 25(OH)D in Indians living in India^[68] and Chinese in China,^[69] 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.^[70][71]"

Toxicity[link]

In healthy adults, sustained intake of more than 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months;^[72] those with certain medical conditions such as primary hyperparathyroidism^[73] 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.^[73][74] 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). One thousand micrograms (40,000 IU) per day in infants has produced toxicity within one month.^[72] After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010 (2010 -11-30)^[update], has increased the tolerable upper limit (UL) to 2500 IU per day for ages 1–3 years, 3000 IU per day for ages 4–8 years and 4000 IU per day for ages 9–71+ years (including pregnant or lactating women).^[75] 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.^[72] 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.^[73] 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.^[76][76]

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 (1000 mcg) per day.^[73] 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.^[77]

Forms[link]

Name	Chemical composition	Structure
Vitamin D1	molecular compound of ergocalciferol with lumisterol, 1:1
Vitamin D2	ergocalciferol (made from ergosterol)
Vitamin D3	cholecalciferol (made from 7-dehydrocholesterol in the skin).
Vitamin D4	22-dihydroergocalciferol
Vitamin D5	sitocalciferol (made from 7-dehydrositosterol)

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.^[78] Vitamin D₂ was chemically characterized in 1932. In 1936, the chemical structure of vitamin D₃ was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.^[79]

Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.^[80] 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 D₃ (cholecalciferol) is produced by ultraviolet irradiation (UV) of its precursor 7-dehydrocholesterol. 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 D₂ is a derivative of ergosterol, a membrane sterol named for the ergot fungus, which is produced by some organisms 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. However, like all forms of vitamin D, it cannot be produced without UV irradiation. D₂ is not produced by land plants or vertebrates, because they lack the precursor ergosterol.^[81] The biological fate for producing 25(OH)D from vitamin D₂ is expected to be the same as for 25(OH)D₃,^[82] although some controversy exists over whether or not D₂ can fully substitute for vitamin D₃ in the human diet.^{[83] [84]}

Evolution[link]

The photosynthesis of vitamin D evolved over an estimated 750 million years ago; the phytoplankton coccolithophore Emiliania huxleyi 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 an estimated 350 million years ago.^{[citation needed]}

Vitamin D can be synthesized only via a photochemical process, so 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.^[85]

Production in the skin[link]

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 is made in the skin when 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.^[86] These wavelengths are present in sunlight when the UV index is greater than three, 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). At a UV index greater than three, 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. Latitude does not consistently predict the average serum 25(OH)D level of a population. The assumption that vitamin D levels in the population follow a latitude gradient is especially questionable in view of surveys which have shown that UVB penetrating to the earth's surface over 24 hours during the summer months in northern Canada equals or exceeds UVB penetration at the equator. Accordingly, there is sufficient opportunity during the spring, summer, and fall months at high latitude for humans to form and store vitamin D₃.^[87] 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.^[76]

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.

Cholecalciferol (D₃) is produced photochemically in the skin from 7-dehydrocholesterol; 7-dehydrocholesterol is produced in relatively large quantities^{[clarification needed]} in the skin of most vertebrate animals, including humans.^[88] The naked mole rat appears to be naturally cholecalciferol deficient, as serum 25-OH vitamin D levels are undetectable.^[89] 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.^[90]

Interactive metabolism and pathway map[link]

Click on genes, proteins and metabolites below to link to respective articles. ^[91]

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Vitamin D Synthesis Pathway edit

Sunscreen[link]

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 (Matsuoka et al., 1987).^[92]

Mechanism of action[link]

Calcium regulation in the human body.^[93] The role of vitamin D is shown in orange.

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.^[94] 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.^[80]

Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.^[80] 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.^[95]

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.^[57]

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.^[96]

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.^[97]

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).^[98][99]

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.^[100] Thus, although it may initially appear paradoxical, vitamin D is critical for proper bone formation despite its role as a potent stimulator of bone resorption.^[101]

Recommendations[link]

Dietary reference intakes[link]

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.^[102]

(Conversion : 1 µg = 40 IU and 0.025 µg = 1 IU.^[103])

Australia and New Zealand[link]

Australia and New Zealand have established average intakes for vitamin D, as follows:^[104] Children 5.0 μg /day Adults 19–50 yr 5.0 μg/day, 51–70 yr 10.0 μg/day, >70 yr 15.0 μg/day

Canada[link]

According to Health Canada^[105] the recommended dietary allowances (RDA) for vitamin D are:

Note*: Adequate Intake rather than Recommended Dietary Allowance.

European Union[link]

The recommended daily amount for vitamin D in the European Union is 5 µg.^[106]

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.^[107]

United States[link]

According to the United States Institute of Medicine,^[5] the recommended dietary allowances of vitamin D are:

• 1–70 years of age: 600 IU/day (15 μg/day)
• 71+ years of age: 800 IU/day (20 μg/day)
• Pregnant/lactating: 600 IU/day (15 μg/day)

Upper intake levels[link]

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 .^[108]" 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 ^[109]:

• 0–6 months of age: 1,000 IU
• 6–12 months of age: 1,500 IU
• 1–3 years of age: 2,500 IU
• 4–8 years of age: 3,000 IU
• 9–71+ years of age: 4,000 IU
• Pregnant/lactating: 4,000 IU ^[5]

Comment[link]

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.^[5]

One school of thought contends that human physiology is fine tuned to an intake of 4000–12,000 IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80 ng/mL^[110] 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.^[111][110]

Serum 25-hydroxyvitamin D[link]

An (U.S.) Institute of Medicine committee concluded that a serum 25-hydroxyvitamin D level of 20 ng/mL 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.^[112]

The Institute found that serum 25-hydroxyvitamin D concentrations above 30 ng/mL are "not consistently associated with increased benefit". Serum 25-hydroxyvitamin D levels above 50 ng/mL may be cause for concern.^[112]

Allowable health claims[link]

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)^[113]

• normal function of the immune system
• normal inflammatory response
• normal muscle function
• reduced risk of falling in people over age 60^[114]

US Food and Drug Administration (FDA)

• may reduce the risk of osteoporosis^[115]

Health Canada

• adequate calcium and regular exercise may help to achieve strong bones in children and adolescents and may reduce the risk of osteoporosis in older adults. An adequate intake of vitamin D is also necessary^[116]

Other possible agencies with claim guidance: Japan FOSHU^[117] and Australia-New Zealand.^[118]

Dietary sources[link]

[edit] Vitamin D₂

• Plantae
  • Alfalfa (Medicago sativa subsp. sativa), shoot: 4.8 mcg (192 IU) vitamin D₂, 0.1 mcg (4 IU) vitamin D₃^{[119][citation needed]}

• Fungus, from USDA nutrient database^[120]:
  • Mushrooms, portabella, exposed to ultraviolet light, raw: Vitamin D₂: 11.2 mcg (446 IU)
  • Mushrooms, portabella, exposed to ultraviolet light, grilled: Vitamin D₂: 13.1 mcg (524 IU)
  • Mushrooms, shiitake, dried: Vitamin D₂: 3.9 mcg (154 IU)
  • Mushrooms, shiitake, raw: Vitamin D₂: 0.4 mcg (18 IU)
  • Mushrooms, portabella, raw: Vitamin D₂: 0.3 mcg (10 IU)
  • Mushroom powder, any species, illuminated with sunlight or artificial ultraviolet light sources

Vitamin D₂, or ergocalciferol found in fungi, is synthesized from viosterol, which in turn is activated when ultraviolet light stimulates ergosterol.^[121]

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 to a vitamin D₂ supplement.^[122] Vitamin D₂ from UV-irradiated yeast baked into bread is bioavailable.^[123] By visual assessment or using a chromometer, no significant discoloration of irradiated mushrooms, as measured by the degree of "whiteness", was observed.^[124] 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,^[125] or 2700 IU if exposed to just 5 minutes of UV light after being harvested.^[126]

[edit] Vitamin D₃

In some countries, staple foods are artificially fortified with vitamin D.^[127] Dietary sources of vitamin D include:^[2]

• Fatty fish species, such as:
  • Catfish, 85 g (3 oz) provides 425 IU (5 IU/g)
  • Salmon, cooked, 100 g (3.5 oz) provides 360 IU (3.6 IU/g)
  • Mackerel, cooked, 100 g (3.5 oz), 345 IU (3.45 IU/g)
  • Sardines, canned in oil, drained, 50 g (1.75 oz), 250 IU (5 IU/g)
  • Tuna, canned in oil, 100 g (3.5 oz), 235 IU (2.35 IU/g)
  • Eel, cooked, 100 g (3.5 oz), 200 IU (2.00 IU/g)
• A whole egg provides 20 IU if egg weighs 60 g (0.333 IU/g)
• Beef liver, cooked, 100 g (3.5 oz), provides 15 IU (0.15 IU/g)
• Fish liver oils, such as cod liver oil, 1 Tbs. (15 ml) provides 1360 IU (90.6 IU/ml)

History[link]

American researchers Elmer McCollum and Marguerite Davis in 1913 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 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 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.^{[128][129][130]} It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.

In 1923, 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."^[131] 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.^[132] In the 1930s he clarified further the chemical structure of vitamin D.^[133]

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.^[134] 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.^[135]

Industrial production[link]

Vitamin D₃ (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.^[136] 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.^[136]

Synthesis[link]

In the skin, 7-dehydrocholesterol, a derivative of cholesterol, is photolyzed by ultraviolet light in a 6-electron conrotatory electrocyclic reaction. The product is previtamin D3.
Previtamin D3 spontaneously isomerizes to vitamin D 3 (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.[85]
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,[137] 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.[138]
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).

References[link]

Further reading[link]

• Ross, A.C/Taylor, C.L./Yaktine, A.L./Valle, H.B.D. (editors, 2011) Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press. ISBN 978-0-309-16394-1
• Rubin, A.L. (2011). Vitamin D for Dummies. Wiley Publishing. ISBN 978-0-470-89175-9
• Dietary Supplement Fact Sheet: Vitamin D from the U.S. National Institutes of Health
• Disagreement among experts about the correct vitamin D dose. (Nature News, July 6, 2011)

A major contributor to this article appears to have a close connection with its subject. It may require cleanup to comply with Wikipedia's content policies, particularly neutral point of view. Please discuss further on the talk page. (September 2009)

John Jacob Cannell, M.D. (born June 21, 1948, Washington, D.C.) is an American activist, most notably taking a stand on the Vitamin D deficiency epidemic. In the past, he contributed to such areas of public debate as Black Lung legislation, and the problems with educational testing. In recent years, Dr. Cannell has taken an active role in educating the public about the health benefits of Vitamin D. He is the founder of the Vitamin D Council.