Vitamin DPosted 10 years ago under Health, Natural Health, Nutrition

Vitamin D refers to 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 an essential vitamin when it cannot be made 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] In the classical sense, it is rather a hormone as it is synthesized in one place but acts elsewhere in the body. 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

The effects of vitamin D supplementation on health are uncertain.[6,14] A 2013 review did not find any effect of supplementation on the rates of disease, other than a tentative decrease in mortality in the elderly.[15] Low vitamin D levels may result from disease rather than cause disease.[15]

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] 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.[16] 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.[16]

Mortality

Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly,[8,15] 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] High blood levels appear to be associated with a lower risk of death but it is unclear if supplementation can result in this benefit.17 Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.[18,19,20] 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]

Bone health

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.[21]

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.[22] Supplementation with higher doses of vitamin D, in those older than 65 years, may decrease fracture risk.[23] This appears to apply more to people in institutions than those living independently.[24]

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.[25] Beyond that, low serum vitamin D levels have been associated with falls and low bone mineral density.[26] Taking extra vitamin D; however, does not appear to change the risk.[27]

Cancer

Vitamin D supplements have been widely marketed on the internet and elsewhere for their claimed anti-cancer properties.[28]

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.[29]

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,[30] and that higher 25-hydroxy vitamin D levels at the time of diagnosis are associated with better outcomes.[31]

Cardiovascular disease

Taking vitamin D supplements does not reduce the risk of stroke, cerebrovascular disease, cardiac infarction or ischaemic heart disease by more than 15%.[9]

Depression

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.[32]

Immune system

Infectious disease

In general, vitamin D functions to activate the innate and dampen the adaptive immune systems.[33] Vitamin D deficiency has been linked to increased risk of viral infections, including HIV and influenza.[34,35,36] Low levels of vitamin D appear to be a risk factor for tuberculosis,[37] and historically it was used as a treatment.[38]

Autoimmune disease

Although there are tentative data linking low levels of vitamin D to asthma, there is inconclusive evidence to support a beneficial effect of supplementation.[39] Accordingly, supplementation is not currently recommended for treatment or prevention of asthma.[40]

Vitamin D hypovitaminosis may be a risk factor for multiple sclerosis,[41] but there is no evidence vitamin D has any clinically significant benefit as a treatment.[42]

Pregnancy

Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small infants.[43] The benefit of supplements, however, is unclear.[43] Pregnant women who take an adequate amount of vitamin D during gestation may experience positive immune effects.[44] Pregnant women often do not take the recommended amount of vitamin D.[44] 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.[44]

Deficiency

Main article: Hypovitaminosis D

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.[45,46] However, vitamin D deficiency has become a worldwide issue in the elderly and remains common in children and adults.[47,48] Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun.[49] Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases[50,51] including:

Rickets

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,[51] 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[52] and in those with genetic disorders such as pseudovitamin D deficiency rickets.[53]

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.[54] In 1857, John Snow suggested that rickets, then widespread in Britain, was being caused by the adulteration of bakers’ bread with alum.[55] The role of diet in the development of rickets[56,57] was determined by Edward Mellanby between 1918–1920.[58] Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.[59,60]

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.[61] Having darker skin and reduced exposure to the 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.[62,63,64]

The dietary risk factors for rickets include abstaining from animal foods.[61,65] 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.[64]

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,[66] almost two-thirds of 500 children had mild rickets in the late 1920s.[67] An increase in the proportion of animal protein[65,68] in the 20th-century American diet coupled with increased consumption of milk[69,70] fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.[71] 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.[51]

Osteomalacia

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.[72] 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,[73,74] There is no persuasive evidence of lower vitamin D levels in chronic pain sufferers.[75]

Influence of skin pigmentation

Some research shows that dark-skinned people living in temperate climates have lower vitamin D levels.[76,77] 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.[78] 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.[79] A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.[80,81]

On the other hand, the uniform occurrence of low serum 25(OH)D in Indians living in India[82] and Chinese in China,[83] 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.”[84,85]

Excess

For more details on this topic, see hypervitaminosis D.

Vitamin D toxicity is rare.[48] 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;[48,86] those with certain medical conditions, such as primary hyperparathyroidism,[87] 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.[87,88]

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.[48,51,72] 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 holds no more than 400 IU.

In addition, for products intended for infants, the FDA recommends that the dropper holds no more than 400 IU.[89] 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.[86] 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.[86] Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.[48,72] 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.[87] 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.[90]

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.[87] 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.[91]

Biosynthesis

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.[1,3,48]

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.[95] The biological fate for producing 25(OH)D from vitamin D2 is expected to be the same as for 25(OH)D3,[96] although some controversy exists over whether or not D2 can fully substitute for vitamin D3 in the human diet.[97,98]

Photochemistry

The transformation that converts 7-dehydrocholesterol to Vitamin D3 (cholecalciferol) occurs in two steps.[99,100] 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.[101]

Evolution

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.[102]

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.[101]

Synthesis in the skin

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.[103] 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.[104] 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.[105,106]

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.[90]

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.[107] 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.[108]

Sunscreen

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.[109]

Metabolic activation

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.[94] 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.[111]

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,[112] which is produced by hepatocytes. Once made, the product is released into the plasma, where it is bound to α-globulin, vitamin D binding protein.[113]

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

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.[94] 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.[114] 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.[71]

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.[115] 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.[116]

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.[117] 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.[118]

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).[119,120]

Discovery

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.[121,122,123] It was not initially realized that, unlike other vitamins, vitamin D can be synthesized 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 stated that “light equals vitamin D.”[124] 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.[125] 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.[126] 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.[127] 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.[128]

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.[129] 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.[130]

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.[11,131] 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.[12,132]

Recommendations

Dietary reference intakes

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.[133]

(Conversion : 1 µg = 40 IU and 0.025 µg = 1 IU)[134]

European Union

The recommended daily amount for vitamin D in the European Union is 5 µg.[138]

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 the case of co-morbid conditions.[139]

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 gets enough vitamin D from good diets and from sunlight.[140]

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 and is intended for the North American population and assumes that calcium requirements are being met.[7]

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[141] 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.[96,141]

According to the European Food Safety Authority, the Tolerable Upper Intake Levels[142] are:

• 0–12 months: 25 µg/day (1,000 IU)
• 1–10 years: 50 µg/day (2,000 IU)
• 11–17 years: 100 µg/day (4,000 IU)
• 17+: 100 µg/day (4,000 IU)
• Pregnant/lactating women: 100 µg/day (4,000 IU)

Serum 25-hydroxyvitamin D

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.[143]

Allowable health claims

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)[144]

• Normal function of the immune system
• Normal inflammatory response
• Normal muscle function
• Reduced risk of falling in people over age 60[145]

US Food and Drug Administration (FDA)

• May reduce the risk of osteoporosis[146]

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[147]

Other possible agencies with claim guidance: Japan FOSHU[148] and Australia-New Zealand.[149]

Dietary sources

Vitamin D is found in few dietary sources.[1,3,48,51] Sunlight exposure is the primary source of vitamin D for the majority of people, other than supplements.[2]

Vitamin D2

Fungus, from USDA nutrient database (per 100 g):[150] Low values in mushrooms for vitamin D below indicate incidental exposure to sunlight which activates the synthesis of vitamin D2. When fresh mushrooms or dried powders are purposely exposed to artificial sunlight by use of an industrial ultraviolet lamp, vitamin D levels can be controlled at much higher levels.[151,152]

• Mushrooms, portabella, exposed to ultraviolet light, raw: Vitamin D2: 11.2 μg (446 IU)
• Mushrooms, portabella, exposed to ultraviolet light, grilled: Vitamin D2: 13.1 μg (524 IU)
• Mushrooms, shiitake, dried: Vitamin D2: 3.9 μg (154 IU)
• Mushrooms, shiitake, raw: Vitamin D2: 0.4 μg (18 IU)
• Mushrooms, portabella, raw: Vitamin D2: 0.3 μg (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.[153]

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.[154] Vitamin D2 from UV-irradiated yeast baked into bread or mushrooms is bioavailable and increases blood levels of 25(OH)D.[155,152]

By visual assessment or using a chromometer, no significant discoloration of irradiated mushrooms, as measured by the degree of “whiteness”, was observed.[156] 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 or 2700 IU if exposed to just 5 minutes of UV light after being harvested.[151]

Plants

Alfalfa (Medicago sativa subsp. sativa), shoot: 4.8 μg (192 IU) vitamin D2, 0.1 μg (4 IU) vitamin D3 (per 100 g).[157]

Vitamin D3

In some countries, staple foods are artificially fortified with vitamin D.[158]

• Vegan sources
• Lichen
• Cladina arbuscula specimens grown under different natural conditions: The contents of vitamin D3 range from 0.67 to 2.04 μg g⁻¹ dry matter in the thalli of C. arbuscula specimens grown under different natural conditions.[159]
• Animal sources
• Fish liver oils, such as cod liver oil, 1 Tablespoon (15 ml) provides 1,360 IU (90.6 IU/ml)
• Fatty fish species, such as:
• Catfish (wild), 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, 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, 235 IU (2.35 IU/g)
• Eel, cooked, 100 g, 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, provides 15 IU (0.15 IU/g)

Industrial production

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.[160] The 7-dehydrocholesterol is a natural substance in fish organs, especially the liver,[161] or in wool grease (lanolin) from sheep. Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.[160]

References

1. Holick MF (March 2006). “High prevalence of vitamin D inadequacy and implications for health”. Mayo Clin. Proc. 81 (3): 353–73. doi:10.4065/81.3.353. PMID 16529140.

3. Norman AW (August 2008). “From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health”. Am. J. Clin. Nutr. 88 (2): 491S–499S. PMID 18689389.

5. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM (Mar 2010). “Vitamin D and Cardiometabolic Outcomes: A Systematic Review”. Annals of internal medicine 152 (5): 307–14. doi:10.7326/0003-4819-152-5-201003020-00009. PMC 3211092. PMID 20194237.

7. Ross AC, Taylor CL, Yaktine AL Del Valle HB (2011). Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C: National Academies Press. ISBN 0-309-16394-3.

9. Bolland MJ, Grey A, Gamble GD, Reid IR (January 2014). “The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis”. Lancet Diabetes Endocrinol (Meta-analysis). doi:10.1016/S2213-8587(13)70212-2.

11. Hollis BW (January 1996). “Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it”. Calcif. Tissue Int. 58 (1): 4–5. doi:10.1007/BF02509538. PMID 8825231.

13. “Dietary Supplement Fact Sheet: Vitamin D”. Office of Dietary Supplements (ODS). National Institutes of Health (NIH). Retrieved 2010-04-11. Jump up

15. Autier P, Boniol M, Pizot C, Mullie P (December 2013). “Vitamin D status and ill health: a systematic review”. The Lancet Diabetes & Endocrinology. doi:10.1016/S2213-8587(13)70165-7.

17. Schottker, B.; Jorde, R.; Peasey, A.; Thorand, B.; Jansen, E. H. J. M.; Groot, L. d.; Streppel, M.; Gardiner, J.; Ordonez-Mena, J. M.; Perna, L.; Wilsgaard, T.; Rathmann, W.; Feskens, E.; Kampman, E.; Siganos, G.; Njolstad, I.; Mathiesen, E. B.; Kubinova, R.; Paj k, A.; Topor-Madry, R.; Tamosiunas, A.; Hughes, M.; Kee, F.; Bobak, M.; Trichopoulou, A.; Boffetta, P.; Brenner, H. (17 June 2014). “Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States”. BMJ 348 (jun17 16): g3656–g3656. doi:10.1136/bmj.g3656.

19. Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A (2009). “Vitamin D, nervous system and aging”. Psychoneuroendocrinology 34: S278–86. doi:10.1016/j.psyneuen.2009.07.003. PMID 19660871.

21. Reid IR, Bolland MJ, Grey A (Jan 11, 2014). “Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis.”. Lancet 383 (9912): 146–55. doi:10.1016/s0140-6736(13)61647-5. PMID 24119980.

23. Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA, Meyer HE, Pfeifer M, Sanders KM, Stähelin HB, Theiler R, Dawson-Hughes B (July 2012). “A pooled analysis of vitamin D dose requirements for fracture prevention”. N. Engl. J. Med. 367 (1): 40–9. doi:10.1056/NEJMoa1109617. PMID 22762317.

25. Winzenberg T, Powell S, Shaw KA, Jones G (2011). “Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis”. BMJ 342: c7254. doi:10.1136/bmj.c7254. PMC 3026600. PMID 21266418.

27. Bolland MJ, Grey A, Gamble GD, Reid IR (2014). “Vitamin D supplementation and falls: a trial sequential meta-analysis”. Lancet Diabetes Endocrinol 2 (7): 573–80. doi:10.1016/S2213-8587(14)70068-3. PMID 24768505.

29. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C (Jan 10, 2014). “Vitamin D supplementation for prevention of mortality in adults.”. The Cochrane database of systematic reviews 1: CD007470. doi:10.1002/14651858.cd007470.pub3. PMID 24414552.

31. Li M, Chen P, Li J, Chu R, Xie D, Wang H (2014). “Review: the impacts of circulating 25-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and meta-analysis”. J Clin Endocrinol Metab. Online first. doi:10.1210/jc.2013-4320. PMID 24780061.

33. Hewison M (2011). “Vitamin D and innate and adaptive immunity”. Vitam. Horm. Vitamins & Hormones 86: 23–62. doi:10.1016/B978-0-12-386960-9.00002-2. ISBN 9780123869609. PMID 21419266.

35. Spector SA (Feb 2011). “Vitamin D and HIV: letting the sun shine in”. Topics in antiviral medicine 19 (1): 6–10. PMID 21852710.

37. Nnoaham KE, Clarke A (Feb 2008). “Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis”. International Journal of Epidemiology 37 (1): 113–9. doi:10.1093/ije/dym247. PMID 18245055.

39. Hart PH (2012). “Vitamin D supplementation, moderate sun exposure, and control of immune diseases”. Discovery Medicine 13 (73): 397–404. PMID 22742645.

41. Pierrot-Deseilligny C, Souberbielle JC (Jul 2010). “Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis?”. Brain : a journal of neurology 133 (Pt 7): 1869–88. doi:10.1093/brain/awq147. PMID 20584945.

43. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM (2013). “Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies”. BMJ 346: f1169. doi:10.1136/bmj.f1169. PMID 23533188.

45. “Rickets”. National Health Service. Last reviewed 08/03/2012. Retrieved 2012-07-09.

47. Eriksen EF, Glerup H (2002). “Vitamin D deficiency and aging: implications for general health and osteoporosis”. Biogerontology 3 (1–2): 73–7. doi:10.1023/A:1015263514765. PMID 12014847.

49. Schoenmakers I, Goldberg GR, Prentice A (2008). “Abundant sunshine and vitamin D deficiency”. British Journal of Nutrition 99 (6): 1171–3. doi:10.1017/S0007114508898662. PMC 2758994. PMID 18234141.

51. Brown JE (2008). Nutrition through the life cycle. Belmont, CA: Thomson/Wadsworth. ISBN 0-495-11637-8.

53. Zargar AH, Mithal A, Wani AI, Laway BA, Masoodi SR, Bashir MI, Ganie MA (June 2000). “Pseudovitamin D deficiency rickets—a report from the Indian subcontinent”. Postgraduate Medical Journal 76 (896): 369–72. doi:10.1136/pmj.76.896.369. PMC 1741602. PMID 10824056.

55. Dunnigan M (2003). “Commentary: John Snow and alum-induced rickets from adulterated London bread: an overlooked contribution to metabolic bone disease”. International Journal of Epidemiology 32 (3): 340–1. doi:10.1093/ije/dyg160. PMID 12777415.

57. Ford JA, Colhoun EM, McIntosh WB, Dunnigan MG (1972). “Biochemical Response of Late Rickets and Osteomalacia to a Chupatty-free Diet”. British Medical Journal 3 (5824): 446–7. doi:10.1136/bmj.3.5824.446. PMC 1786011. PMID 5069221.

59. Oramasionwu GE, Thacher TD, Pam SD, Pettifor JM, Abrams SA (2008). “Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children”. The British journal of nutrition 100 (2): 387–92. doi:10.1017/S0007114507901233. PMID 18197991.

61. Dunnigan MG, Henderson JB (1997). “An epidemiological model of privational rickets and osteomalacia”. The Proceedings of the Nutrition Society 56 (3): 939–56. doi:10.1079/PNS19970100. PMID 9483661.

63. Clements MR (1989). “The problem of rickets in UK Asians”. Journal of Human Nutrition and Dietetics 2 (2): 105. doi:10.1111/j.1365-277X.1989.tb00015.x.

65. Dunnigan MG, Henderson JB, Hole DJ, Barbara Mawer E, Berry JL (2007). “Meat consumption reduces the risk of nutritional rickets and osteomalacia”. British Journal of Nutrition 94 (6): 983–91. doi:10.1079/BJN20051558. PMID 16351777.

67. Weick MT (1967). “A history of rickets in the United States”. The American Journal of Clinical Nutrition 20 (11): 1234–41. PMID 4862158.

69. DuPuis EM (2002). Nature’s Perfect Food: How Milk Became America’s Drink. ISBN 978-0-8147-1938-1.

71. Holick MF (2004). “Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease”. The American Journal of Clinical Nutrition 80 (6 Suppl): 1678S–88S. PMID 15585788.

73. Holick MF (2003). “Vitamin D: A millenium perspective”. Journal of Cellular Biochemistry 88 (2): 296–307. doi:10.1002/jcb.10338. PMID 12520530.

75. Straube S, Andrew Moore R, Derry S, McQuay HJ (2009). “Vitamin D and chronic pain”. Pain 141 (1–2): 10–3. doi:10.1016/j.pain.2008.11.010. PMID 19084336

76. Azmina Govindji RD (1 July 2010). “When it’s sunny, top up your vitamin D”. TheIsmaili.org. Retrieved 2010-07-01.

78. Signorello LB, Williams SM, Zheng W, Smith JR, Long J, Cai Q, Hargreaves MK, Hollis BW, Blot WJ (2010). “Blood vitamin D levels in relation to genetic estimation of African ancestry”. Cancer Epidemiology, Biomarkers & Prevention 19 (9): 2325–31. doi:10.1158/1055-9965.EPI-10-0482. PMC 2938736. PMID 20647395.

80. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Järvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppönen E, Spector TD (2010). “Common genetic determinants of vitamin D insufficiency: a genome-wide association study”. Lancet 376 (9736): 180–8. doi:10.1016/S0140-6736(10)60588-0. PMC 3086761. PMID 20541252.

82. Harinarayan CV, Joshi SR (2009). “Vitamin D status in India—its implications and remedial measures”. The Journal of the Association of Physicians of India 57: 40–8. PMID 19753759.

84. CBC “Dark-skinned immigrants urged to take vitamin D”. February 16, 2010. CBC News.

86. Vitamin D at Merck Manual of Diagnosis and Therapy Professional Edition

88. Tolerable Upper Intake Limits for Vitamins And Minerals (PDF). European Food Safety Authority. December 2006. ISBN 92-9199-014-0.

90. Holick MF (March 1995). “Environmental factors that influence the cutaneous production of vitamin D” (PDF). The American Journal of Clinical Nutrition 61 (3 Suppl): 638S–645S. PMID 7879731.

92. Dorland’s Illustrated Medical Dictionary, under Vitamin (Table of Vitamins)

94. About Vitamin D Including Sections: History, Nutrition, Chemistry, Biochemistry, and Diseases. University of California Riverside

96. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM (2011). “Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab 96 (7): 1911–30. doi:10.1210/jc.2011-0385. PMID 21646368.

98. Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD (March 2008). “Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D”. J. Clin. Endocrinol. Metab. 93 (3): 677–81. doi:10.1210/jc.2007-2308. PMC 2266966. PMID 18089691.

100. Deluca HF (January 2014). “History of the discovery of vitamin D and its active metabolites”. Bonekey Rep 3: 479. doi:10.1038/bonekey.2013.213. PMID 24466410.

102. Holick MF (2011). The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. New York: Plume. p. 27. ISBN 0-452-29688-9.

104. Hume EM, Lucas NS, Smith HH (1927). “On the Absorption of vitamin D from the Skin”. Biochemical Journal 21 (2): 362–367. PMC 1251921. PMID 16743844.

106. Bolton J. “UV FAQs”. Info. International Ultraviolet Association.

108. Stout SD, Agarwal SC (2003). Bone loss and osteoporosis: an anthropological perspective. New York: Kluwer Academic/Plenum Publishers. ISBN 0-306-47767-X.

110. Walter F., PhD. Boron (2003). “The Parathyroid Glands and Vitamin F”. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1094. ISBN 978-1-4160-2328-9.

112. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (May 2004). “Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase”. Proc Natl Acad Sci U S A 101 (20): 7711–7715. Bibcode:2004PNAS..101.7711C. doi:10.1073/pnas.0402490101. PMC 419671. PMID 15128933.

114. Bouillon R, Van Cromphaut S, Carmeliet G (2003). “Intestinal calcium absorption: Molecular vitamin D mediated mechanisms”. Journal of Cellular Biochemistry 88 (2): 332–9. doi:10.1002/jcb.10360. PMID 12520535.

116. American Academy of Periodontology 2010 In-Service Exam, question A-27

118. Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK (February 1996). “Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells”. Molecular Brain Research 36 (1): 193–6. doi:10.1016/0169-328X(95)00314-I. PMID 9011759.

120. “Hedgehog signaling and Vitamin D”. Medscape.com. 2009-12-18. Retrieved 2010-03-25.

122. Elena Conis (2006-07-24). “Fortified foods took out rickets”. Los Angeles Times. Retrieved 2010-08-24.

124. “History of Vitamin D”. University of California at Riverside. 2011. Retrieved 9 May 2014.

126. Rosenheim O, King H (1932). “The Ring-system of sterols and bile acids. Part II”. J. Chem. Technol. Biotechnol. 51 (47): 954–7. doi:10.1002/jctb.5000514702.

128. Hirsch AL (2011). “Industrial aspects of vitamin D”. In Feldman DJ, Pike JW, Adams JS. Vitamin D. London; Waltham, MA: Academic Press. p. 73. ISBN 978-0-12-387035-3.

130. Marshall J (2005). Elbridge A. Stuart Founder of the Carnation Company. Kessinger Publishing. p. 235. ISBN 978-1-4179-8883-9.

132. Holick MF, DeLuca HF, Avioli LV (1972). “Isolation and identification of 25-hydroxycholecalciferol from human plasma”. Archives of Internal Medicine 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID 4332591.

134. “Dietary Reference Intakes Tables Health Canada, 2005”. Retrieved 21 July 2011.

136. “Nutrient reference values for Australia and New Zealand” (PDF). National Health and Medical Research Council. 2005-09-09. Retrieved 2010-12-11.

138. “Vitamins: what they do and where to find them (EUFIC)”. European Food Information Council. 10-12-2010. Retrieved 2010-12-11. “Vitamin D”

140. “Vitamins and minerals – Vitamin D”. NHS Choices. 26 November 2012.

142. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) (2012). “Scientific Opinion on the Tolerable Upper Intake Level of vitamin D”. EFSA Journal 10 (7): 2813. doi:10.2903/j.efsa.2012.2813.

144. European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) (2010). “Scientific opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (EC) No 1924/2006”. EFSA Journal 8 (2): 1468–85. doi:10.2903/j.efsa.2010.1468.

146. “Guidance for Industry: Food Labeling: Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis”. US Food and Drug Administration. 2009-05-01.

148. “Regulatory Systems of Health Claims in Japan”. Japan Consumer Affairs Agency, Food Labelling Division. 2011-06-01.

150. “USDA nutrient database”. National Nutrient Database for Standard Reference. U.S. Agricultural Research Service, Nutrient Data Laboratory. “use the keyword ‘portabella’ and then click submit”

152. Keegan RJ, Lu Z, Bogusz JM, Williams JE, Holick MF (2013). “Photobiology of vitamin D in mushrooms and its bioavailability in humans”. Dermato-Endocrinology 5 (1): 165–76. doi:10.4161/derm.23321. PMC 3897585. PMID 24494050.

154. Urbain P, Singler F, Ihorst G, Biesalski HK, Bertz H (August 2011). “Bioavailability of vitamin D₂ from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: a randomized controlled trial”. Eur J Clin Nutr 65 (8): 965–71. doi:10.1038/ejcn.2011.53. PMID 21540874.

156. Koyyalamudi SR, Jeong SC, Song CH, Cho KY, Pang G (2009). “Vitamin D2 formation and bioavailability from Agaricus bisporus button mushrooms treated with ultraviolet irradiation”. J Agric Food Chem 57 (8): 3351–5. doi:10.1021/jf803908q. PMID 19281276.

158. DRI, Dietary reference intakes: for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, D.C: National Academy Press. 1997. p. 250. ISBN 0-309-06350-7.

160. Holick MF (2005). “The Vitamin D Epidemic and its Health Consequences”. Journal of Nutrition 135 (11): 2739S–48S. PMID 16251641.

161. Takeuchi A, Okano T, Sayamoto M, Sawamura S, Kobayashi T, Motosugi M, Yamakawa T (1986). “Tissue distribution of 7-dehydrocholesterol, vitamin D3 and 25-hydroxyvitamin D3 in several species of fishes”. Journal of nutritional science and vitaminology 32 (1): 13–22. PMID 3012050