Vitamin D is a group of fat-soluble secosteroids responsible for intestinal absorption of calcium and phosphate. In humans, the most important related compounds of vitamin D are vitamin D2 and vitamin D3.[1] Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are unique as they constitute what we know as vitamin D and can be ingested from the diet and/or supplements.[1][2][3] The body can also synthesize vitamin D (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. (Cats and dogs cannot synthesize vitamin D efficiently and must receive it in their diet.) 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 their 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.[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.
Measures of serum levels 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.
In the liver vitamin D is converted to calcidiol, which is also known as calcifediol (INN), 25-hydroxycholecalciferol, or 25-hydroxyvitamin D—abbreviated 25(OH)D; and which is the specific vitamin D metabolite that is measured in serum to determine a person's vitamin D status.[5][6] Part of the calcidiol is converted by the kidneys to calcitriol, the biologically active form of vitamin D.[7] 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. 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.[8]
Beyond its use to prevent osteomalacia or rickets, the evidence for other health effects of vitamin D supplementation in the general population is inconsistent.[9][10] The best evidence of benefit is for bone health[11] and a decrease in mortality in elderly women.[12]
History of study [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.[13][14][15] 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."[16] 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.[17] 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.[18] The informal academic collaboration between the team members Robert Benedict Bourdillon, Otto Rosenheim (mentioned above), Harold King (mentioned above) and Kenneth Callow was very productive and led to the isolation and characterization of vitamin D.[19] 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.[20]
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.[21] 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.[22]
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.[5][6] Part of the calcidiol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D.[7] 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.[7][23]
Effects [edit]
Mortality [edit]
Low blood levels of vitamin D are associated with increased mortality,[24] and giving supplementary vitamin D3 to elderly women in institutional care seems to decrease the risk of death.[12] Vitamin D2, alfacalcidol, and calcitriol do not appear to be effective.[12] However, both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.[25][26][27] The relationship between serum calcidiol level and all-cause mortality is parabolic,[11] Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.[11]:435
Bone health [edit]
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.[28]
In 2012, the U.S. Preventive Services Task Force issued a draft statement recommending that there is not enough evidence to indicate that healthy postmenopausal women should use supplemental doses of calcium or vitamin D to prevent fractures.[29]
Some studies have shown that supplementation with vitamin D and calcium may improve bone mineral density slightly, as well as decreasing the risk of falls and fractures in certain groups of people, specifically those older than 65 years.[28][30] This appears to apply more to people in institutions than those living independently.[31] The quality of the evidence is, however, poor.[32] And there does not appear to be a benefit to bone health from vitamin D without sufficient calcium.[33]
Cardiovascular disease [edit]
Evidence for health effects from vitamin D supplementation for cardiovascular health is poor.[9][34][35] Moderate to high doses may reduce cardiovascular disease risk but are of questionable clinical significance.[9][36]
Multiple sclerosis [edit]
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.[37][38][39] "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."[37] 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.[40][41]
Cancer [edit]
Low vitamin D levels are associated with some cancers and with worse outcomes in other cancers, but taking supplements of vitamin D does not appear to help people with prostate cancer.[42] Currently evidence is insufficient to support supplementation in those with cancer.[42] Results for a protective or harmful effect of vitamin D supplementation in other types of cancer are inconclusive.[10][43]
Pregnancy [edit]
Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia and small infants.[44] The benefit of supplements however is unclear.[44] Pregnant women who take an adequate amount of vitamin D during gestation, may experience positive immune effects.[45] Pregnant women often do not take the recommended amount of vitamin D.[45] A trial of supplementation has found 4000 IU of vitamin D3 superior to lesser amount in pregnant women for achieving specific target blood levels.[45]
Deficiency [edit]
Main article: Hypovitaminosis D
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.[46][47] However, vitamin D deficiency has become worldwide issue in the elderly and remains common in children and adults.[48][49] Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun.[50] Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases[51][52] including:
- Rickets, a childhood disease characterized by impeded growth, soft, weak, deformity of the long bones that bend and bow under their weight as they start to walk. This condition is characterized by bow legs,[52] 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[53] and in those with genetic disorders such as pseudovitamin D deficiency rickets.[54] 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.[55] In 1857, John Snow suggested that rickets, then widespread in Britain, was being caused by the adulteration of bakers' bread with alum.[56] The role of diet in the development of rickets[57][58] was determined by Edward Mellanby between 1918–1920.[59] Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.[60][61] 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.[62] 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.[63][64][65] The dietary risk factors for rickets include abstaining from animal foods.[62][66] 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.[65] 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,[67] almost two-thirds of 500 children had mild rickets in the late 1920s.[68] An increase in the proportion of animal protein[66][69] in the 20th century American diet coupled with increased consumption of milk [70][71] fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.[72] Also, in the United States and Canada, vitamin D fortified milk, infant vitamin supplements, and vitamin supplements have helped to eradicate majority of rickets for children with fat malabsorption conditions.[52]
- 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.[73] 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 approximately 10 ng/mL.[1] The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain,[74][75] There is no persuasive evidence of lower vitamin D levels in chronic pain sufferers.[76]
- Osteoporosis, osteoporosis is defined as a bone disease characterized by a decrease in bone mineral density and the appearance of small holes in bones due to loss of minerals Vitamin D inadequacy is common among patients with osteoporosis.[52][73] Vitamin D inadequacy is common among patients with osteoporosis. Vitamin D inadequacy is seen with low serum 25-hydroxyvitamin D levels of less than 20 ng/mL, however, this value can vary.[1]Osteoporosis and osteomalacia are closely associated, as both have similar symptoms for higher risk of fractures and bone loss. Supplementing with vitamin D can increase bone density and slow bone turnover in seniors. Also, supplementation for individuals with low vitamin D blood levels can significantly improve the reduction in risk of osteoporotic fractures, especially hip fractures.[49][73][77][78]
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, vitamin D supplements are not recommended for people who get enough vitamin D from their diets and from sunlight.[79]
Some research shows that dark-skinned people living in temperate climates have lower vitamin D levels.[80][81][81] 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.[82] 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.[83] A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.[84][85]
On the other hand, the uniform occurrence of low serum 25(OH)D in Indians living in India[86] and Chinese in China,[87] does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes. The leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless, saying, "I see no risk, no downside, there's only a potential benefit.[88][89] "
Toxicity [edit]
For more details on this topic, see hypervitaminosis D.
Vitamin D toxicity is rare.[49] The threshold for vitamin D toxicity has not been established, however, the UL is 4000 IU/day for ages 9–71.[11] 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;[49][90] those with certain medical conditions such as primary hyperparathyroidism[91] 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.[91][92] 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.[49][52][73] 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, FDA recommends that the dropper hold no more than 400 IU.[93] 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.[90] 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 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).[11] 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.[90] Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.[49][73] 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.[91] 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.[94]
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 μg) per day.[91] 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.[95]
Supplements [edit]
The effects of vitamin D supplementation on health are uncertain.[10] 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."[11]:5Some 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.[96] 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.[96]
Other [edit]
Vitamin D appears to have effects on immune function.[97] 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.[98]For viral infections, other implicated factors include low relative humidities produced by indoor heating and low temperatures that favor virus spread.[99] Low levels of vitamin D appear to be a risk factor for tuberculosis,[100] and historically it was used as a treatment.[101] As of 2011, it is being investigated in controlled clinical trials.[101] Vitamin D may also play a role in HIV.[102] Although there are tentative data linking low levels of vitamin D to asthma, there is inconclusive evidence to support a beneficial effect from supplementation.[103] Accordingly, supplementation is not currently recommended for treatment or prevention of asthma.[104] Also, preliminary data is inconclusive for supplemental vitamin D in promotion of human hair growth.[105]
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