Vitamin D

Vitamin D
Drug class

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

Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it (as vitamin D3) when sun exposure is adequate (hence its nickname, the "sunshine vitamin").

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.

When synthesized in the kidneys, calcitriol circulates as a hormone, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. Vitamin D prevents rickets in children and osteomalacia in adults, and, together with calcium, helps to protect older adults from osteoporosis. Vitamin D also affects neuromuscular function, inflammation, and influences the action of many genes that regulate the proliferation, differentiation and apoptosis of cells.[1]

The evidence for the health effects of vitamin D supplementation in the general population is inconsistent.[2][3][4] The best evidence of benefit is for bone health[5] and a decrease in mortality in elderly women.[6]

Contents

Health effects

The effects of vitamin D supplementation on health is uncertain.[2] 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

Low blood levels of vitamin D are associated with increased mortality.[8] Supplemental vitamin D3 appears to decrease all cause mortality, with the best evidence of a benefit in elderly women.[6] Vitamin D2, alfacalcidol, and calcitriol do not appear to be effective.[6] Excess or deficiency levels of vitamin D appear to cause abnormal functioning and premature aging[9][10][11] with a U-shaped risk curve between serum 25OHD level and all-cause mortality.[12] The detrimental effects appear at a lower level in people with black skin.[12]

Bone health

Low serum vitamin D levels are associated with rickets, falls, and low bone mineral density.[13] Supplementation with vitamin D and calcium improves bone mineral density slightly, as well as decreases the risk 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

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

Cancer

Low vitamin D levels are associated with some cancers. When supplementation is used to treat people with prostate cancer, however, there does not appear to be a benefit.[18] Results for a protective or harmful effect of vitamin D supplementation in other types of cancer are inconclusive.[4]

Multiple sclerosis

Vitamin D appears to have a protective effect against multiple sclerosis.[19][20][21] While the initial hypothesis was based on that fact that MS occurred at high rates in the region of the world with long periods with little sunlight further supportive evidence is now available.[19] The relationship between latitude and UVB penetration is however complicated by factors such as atmosphere height (50% higher at the equator), cloud cover (denser at the equator) and ozone layer density, and latitude does not consistently predict the average serum vitamin D level of a population. UVB penetrating to the earth's surface over 24 hours during the summer months in northern Canada (where summer days are longer) equals or exceeds UVB penetration at the equator, allowing sufficient opportunity during the spring, summer, and fall at high latitude to form and store vitamin D3. This, combined with recent computer modeling may call into question the assumption that vitamin D levels in the population follow a latitude gradient.[1] Whether vitamin D supplements during pregnancy can lessen the likelihood of the child developing MS later in life is not known.[22][23]

Infections

Vitamin D appears to have effects on immune function.[24] 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.[25] For viral infections, other implicated factors include low relative humidities produced by indoor heating and cold temperatures that favor virus spread.[26] Low levels of vitamin D appear to be a risk factor for tuberculosis[27] and historically, it was used as a treatment.[28] As of 2011 it is being investigated in controlled clinical trials.[28] Vitamin D may also play a role in HIV.[29]

Deficiency

Main article: Hypovitaminosis D

Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun.[30] Deficiency results in impaired bone mineralization, and leads to bone softening diseases[31] including:

Adequate vitamin D may also be associated with healthy hair follicle growth cycles.[55] There are also associations between low 25(OH)D levels and peripheral vascular disease,[56] certain cancers, multiple sclerosis, rheumatoid arthritis, juvenile diabetes,[51] Parkinson's and Alzheimer's disease.[57] However these associations were found in observational studies and vitamin D vitamin supplements have not been demonstrated to reduce the risks of these diseases.[58]

Research shows that dark-skinned people living in temperate climates have lower vitamin D levels.[59][60][60] 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.[61]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.[62] A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.[63][64]

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 diet and from sunlight are not recommended for vitamin D supplements.[65]

With an emphasis on recommending treatment and intake levels for patients at risk of deficiency listed below, a panel of experts issued a clinical guideline in 2011, stating that vitamin D2 and D3 sources are equivalent.[66]

Toxicity

For more details on this topic, see hypervitaminosis D.

In healthy adults, sustained intake of more than 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months;[67] those with certain medical conditions such as primary hyperparathyroidism[68] 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.[68][69] 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.[67] After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010 (2010 -11-30), 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).[70] Vitamin D overdose causes hypercalcemia, and the main symptoms of vitamin D overdose are those of hypercalcemia:anorexia, nausea, and vomiting can occur, frequently followed by polyuria, polydipsia, weakness, nervousness, pruritus, and, ultimately, renal failure.Proteinuria, urinary casts, azotemia, and metastatic calcification(especially in the kidneys) may develop.[67] 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.[68] 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.[71]According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day.[68]According to Holick, "the skin has a large capacity to produce cholecalciferol" his experiments indicate: "[W]hole-body exposure to one minimal erythemal dose [a dose that would just begin to produce sunburn in a given individual] of simulated solar ultraviolet radiation is comparable with taking an oral dose of between 250 and 625 micrograms (10,000 and 25,000 IU) vitamin D."[71]

Based on the non-observation of toxicity at daily intakes of up to 50,000 IU per day, leading to calcidiol levels of more than 600 nmol/L, and the similar effect of supplementation and whole body exposure to one erythemal dose, it is believed that 250 micrograms/day (10,000 IU) in healthy adults are safe and can thus be adopted as the tolerable upper limit.[72]

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.[68] Recommending supplementation, when those supposedly in need of it are labeled healthy, has proved contentious, and doubt exists concerning long term effects of attaining and maintaining serum 25(OH)D of at least 80 nmol/L by supplementation.[73] A Toronto study concluded, "skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D."

The uniform occurrence of low serum 25(OH)D in Indians living in India[74] and Chinese in China,[75] 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.[76][77]"

Forms

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 resulted 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, and fungi. The vitamin ergocalciferol (D2) is produced in these organisms from ergosterol in response to 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 D3,[66] although some controversy exists over whether or not D2 can fully substitute for vitamin D3 in the human diet.[82] [83]

Evolution

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.

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.[84]

Production in the skin

Vitamin D3 is made in the skin when 7-dehydrocholesterol reacts with ultraviolet light (UVB) at wavelengths between 270 and 300 nm, with peak synthesis occurring between 295 and 297 nm.[85] 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 25OHD 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.[86] 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.[71]

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 is produced photochemically in the skin from 7-dehydrocholesterol; 7-dehydrocholesterol is produced in relatively large quantities in the skin of most vertebrate animals, including humans.[87] The naked mole rat appears to be naturally cholecalciferol deficient, as serum 25-OH vitamin D levels are undetectable.[88] 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.[89]

Mechanism of action

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.[91] 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.[92]

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.[51]

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.[93]

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.[94]

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).[95][96]

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 bone loss (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body.[97]

Recommendations

Dietary reference intakes

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

(Conversion : 1 µg = 40 IU and 0.025 µg = 1 IU.[98])

Australia and New Zealand

Australia and New Zealand have established average intakes for vitamin D, as follows:[99] 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

European Union

The recommended daily amount for vitamin D in the European Union is 5 µg.[100]

Canada

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

Comment

The Dietary Reference Intake for vitamin D[101] 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.[102]

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[103] 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.[103][104]

Upper intake levels

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 .[105]" 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 [106]:

Serum 25-hydroxyvitamin D

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.[107]

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.[107]

Dietary sources

In some countries, staple foods are artificially fortified with vitamin D.[108] Dietary sources of vitamin D include:[1]

History

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.[112][113][114] 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-solublevitamin is produced (now known as D3). Alfred Fabian Hess showed "light equals vitamin D."[115] 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.[116] In the 1930s he clarified further the chemical structure of vitamin D.[117]

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.[118]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.[119]

Industrial production

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification.[120] The 7-dehydrocholesterol is a natural substance in wool grease (lanolin) from sheep or other woolly animals. Vitamin D 2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.[120]

Synthesis

In the skin, 7-dehydrocholesterol, a derivative of cholesterol, is photolyzed by ultraviolet light in a 6-electronconrotatory 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.[84]
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,[121] 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.[122]
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 formcalcitriol (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 enzyme25-hydroxyvitamin D3 1-alpha-hydroxylase, the levels of which are increased by parathyroid hormone (and additionally by low calcium or phosphate).

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Further reading

Fat soluble
D
Tocopherol (Alpha, Beta, Gamma, Delta) · Tocotrienol (Alpha, Beta, Gamma, Delta)  · Tocofersolan
Water soluble
Combinations

M: NUT

cof, enz, met

noco, nuvi, sysi/epon, met

drug(A8/11/12)