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Wikipedia

Vitamin D

For other uses, see Vitamin D (disambiguation).
This article is about the family of D-“vitamins”. For individual forms, see ergocalciferol, cholecalciferol, vitamin D4, vitamin D5, and calcitriol.

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).

The major natural source of the vitamin is synthesis of cholecalciferol in the lower layers of skin epidermis through a chemical reaction that is dependent on sun exposure (specifically UVB radiation). Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements. Only a few foods, such as the flesh of fatty fish, naturally contain significant amounts of vitamin D. In the U.S. and other countries, cow's milk and plant-derived milk substitutes are fortified with vitamin D, as are many breakfast cereals. Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D. Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.

Vitamin D from the diet, or from skin synthesis, is biologically inactive. It is activated by two protein enzyme hydroxylation steps, the first in the liver and the second in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals if exposed to sufficient sunlight, it is not essential, so technically not a vitamin. Instead it can be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations.

Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status. Calcifediol is further hydroxylated by the kidneys and some of the immune system cells to form calcitriol (also known as 1,25-dihydroxycholecalciferol), the biologically active form of vitamin D. Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.

Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia). Vitamin D supplements are given to treat or to prevent osteomalacia and rickets. The evidence for other health effects of vitamin D supplementation in the general population is inconsistent. The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people, and another concluding no clear justification exists for recommending supplementation for preventing many diseases, and that further research of similar design is not needed in these areas.

Contents

Name Chemical composition Structure
Vitamin D1 Mixture of molecular compounds 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. 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, and is known collectively as calciferol.

Vitamin D2 was chemically characterized in 1931. In 1935, the chemical structure of vitamin D3 was defined and shown to result from the ultraviolet irradiation of 7-dehydrocholesterol. A chemical nomenclature for vitamin D forms was recommended in 1981 but alternative names remain in common use.

Chemically, the various forms of vitamin D are secosteroids, that is, steroids in which one of the bonds in the steroid rings is broken. The structural difference between vitamin D2 and vitamin D3 is in the side chain, which contains a double bond, between carbons 22 and 23, and a methyl group on carbon 24 in vitamin D2.

Many vitamin D analogues have been synthesized.

Calcium regulation in the human body. The role of active vitamin D (1,25-dihydroxyvitamin D, calcitriol) is shown in orange.

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. 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. 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.

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. Thus, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.

The VDR regulates 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. In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione.

Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength, mass and function, all being important factors to an athlete's performance.

Main article: Vitamin D deficiency

An estimated one billion people worldwide are either vitamin D insufficient or deficient. Vitamin D deficiency is widespread in the European population. A diet with insufficient vitamin D in conjunction with inadequate sun exposure causes vitamin D deficiency. Severe vitamin D deficiency in children causes rickets, a softening and weakening of bones, which is a rare disease in the developed world.

Vitamin D deficiency is found worldwide in the elderly and remains common in children and adults. Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases, including rickets in children and osteomalacia in adults. Low blood calcifediol (25-hydroxy-vitamin D) can result from avoiding the sun. Being deficient in vitamin D can cause intestinal absorption of dietary calcium to fall to 15%. When not deficient, an individual usually absorbs between 60 and 80%.

Bone health

Rickets

Main article: Rickets

Rickets, a childhood disease, is characterized by impeded growth and soft, weak, deformed long bones that bend and bow under their weight as children start to walk. Rickets typically appears between 3 and 18 months of age. Cases continue to be reported in North American and other Western Countries and is primarily seen in breastfed infants and those with darker skin complexions. This condition is characterized by bow legs, 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 and in those with genetic disorders such as pseudovitamin D deficiency rickets.

Maternal vitamin D deficiency may cause overt bone disease from before birth and impairment of bone quality after birth. Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.

Although rickets and osteomalacia are now rare in the UK, outbreaks have happened in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing. 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[definition needed] cereals. The dietary risk factors for rickets include abstaining from animal foods.

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 sun exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, where rickets 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.

Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are about 20% stronger than at sea level on the same latitude, almost two-thirds of 500 children had mild rickets in the late 1920s. An increase in the proportion of animal protein in the 20th century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. 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.

Osteomalacia and osteoporosis

Main articles: Osteomalacia and Osteoporosis

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. 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 10ng/mL. Although the effects of osteomalacia are thought to contribute to chronic musculoskeletal pain, there is no persuasive evidence of lower vitamin D levels in chronic pain sufferers or that supplementation alleviates chronic nonspecific musculoskeletal pain.

Osteoporosis is a condition of reduced bone mineral density with increased bone fragility and risk of bone fractures. Osteoporosis can be a long-term effect of calcium and/or vitamin D insufficiency, at least in part. This may result from inadequate calcium intake, with insufficient vitamin D contributing by reducing calcium absorption.

Skin pigmentation

Dark-skinned people living in temperate climates have been shown to have low vitamin D levels but the significance of this is not certain. Dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis. Vitamin D deficiency is common in Hispanic and African-Americans in the United States, with levels dropping significantly in the winter. This is due to the levels of melanin in the skin, as it acts as a natural protectant from sun exposure.

Supplementation with vitamin D is a reliable method for preventing or treating rickets. The effects of vitamin D supplementation on non-skeletal health are uncertain. A 2013 review did not find any effect from supplementation on the rates of non-skeletal disease, other than a tentative decrease in mortality in the elderly. Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis. Low vitamin D levels may result from disease rather than cause disease.

A United States Institute of Medicine (IOM) report states: "Outcomes related to cancer, cardiovascular disease and hypertension, and 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. 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.

Mortality, all-causes

Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly, but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable. Other forms (vitamin D2, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regard to the risk of death. High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit. Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging. The relationship between serum calcifediol concentrations and all-cause mortality is "U-shaped": mortality is elevated at high and low calcifediol levels, relative to moderate levels. Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.: 435

Bone health

In general, no good evidence supports the commonly held belief that vitamin D supplements can help prevent osteoporosis. Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed. 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. A study found that supplementation with 800 IU or more daily, in those older than 65 years was "somewhat favorable in the prevention of hip fracture and non-vertebral fracture". The effect is small or none for people living independently. Low serum vitamin D levels have been associated with falls, and low bone mineral density. Taking extra vitamin D, however, does not appear to change the risk.

Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or major breaks, particularly those engaging in contact sports. The greatest benefit with supplementation is seen in athletes who are deficient (25(OH)D serum levels <30ng/mL), or severely deficient (25(OH)D serum levels <25ng/mL). Incremental decreases in risks are observed with rising serum 25(OH)D concentrations plateauing at 50ng/mL with no additional benefits seen in levels beyond this point.

Because it found mounting evidence for a benefit to bone health, though it had not found good evidence of other benefits, the US Food and Drug Administration (FDA) has required manufacturers to declare the amount of vitamin D on nutrition facts labels, as "nutrients of public health significance", since May 2016. By a proposed deadline extension, some manufacturers had until July 1, 2021 to comply.

Cancer

Potential associations have been found between low vitamin D levels and the risk of developing several types of cancer. Meta-analyses of observational studies have found reduced risk of cancer incidence related to vitamin D intake and 25(OH)D levels, particularly for colorectal cancer, although the strength of the associations was classified as weak. While randomized controlled trials have not confirmed that vitamin D supplements reduce the risk of cancer incidence, the relative risk of cancer deaths has been found to be reduced by up to 16% in several meta-analyses.

Cardiovascular disease

Taking vitamin D supplements does not meaningfully reduce the risk of stroke, cerebrovascular disease, myocardial infarction, or ischemic heart disease. Supplementation may have no effect on blood pressure.

Immune system

Infectious diseases

In general, vitamin D functions to activate the innate and dampen the adaptive immune systems with antibacterial, antiviral and anti-inflammatory effects. Deficiency has been linked to increased risk or severity of viral infections, including HIV and COVID-19. Low levels of vitamin D appear to be a risk factor for tuberculosis, and historically it was used as a treatment.

Vitamin D supplementation in low-doses (400 to 1000 IU/day) may slightly decrease the overall risk of acute respiratory tract infections. The benefits were found in young children and adolescents (ages 1 up to 16 years) and were not confirmed with higher doses (>1000 IU per day or more). Vitamin D supplementation substantially reduces the rate of moderate or severe exacerbations of COPD in people with baseline 25(OH)D levels under 25nmol/L but not in those with less severe deficiency.

Asthma

Although tentative data link low levels of vitamin D to asthma, evidence to support a beneficial effect on asthmatics from supplementation is inconclusive. One review found that vitamin D supplementation could reduce the need for steroids used to inhibit episode frequency in people with mild to moderate asthma, and that supplementation had no effect on day-to-day asthma symptoms. In general practice, supplementation with vitamin D is not recommended for treatment or prevention of asthma.

Inflammatory bowel disease

Low levels of vitamin D are associated with two major forms of human inflammatory bowel disease (IBD): Crohn's disease and ulcerative colitis. A meta-analysis of vitamin D therapy in IBD patients with vitamin D deficiency has shown that supplementation is effective at correcting vitamin D levels and is associated with improvements in scores for clinical disease activity and biochemical markers.

Other conditions

Diabetes – A meta-analysis of eight studies found that vitamin D supplementation significantly reduced the risk of type 2 diabetes mellitus for non-obese prediabetic patients but not obese ones. A meta-analysis of 37 articles found that vitamin D supplementation significantly improved glycemic control [homeostatic model assessment-insulin resistance (HOMA-IR)], hemoglobin A1C (HbA1C), and fasting blood glucose (FBG) in individuals with type 2 diabetes mellitus. In prospective studies, high versus low level of vitamin D was respectively associated with significant decrease in risk of type 2 diabetes mellitus, combined type 2 diabetes mellitus and pre-diabetes, and pre-diabetes.

ADHD - A meta-analysis of observational studies showed that children with ADHD have lower vitamin D levels, and that there was a small association between low vitamin D levels at the time of birth and later development of ADHD. Several small randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.

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 supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate effect.

Cognition and dementia – A systematic review of clinical studies found an association between low vitamin D levels with cognitive impairment and a higher risk of developing Alzheimer's disease. However, lower vitamin D concentrations are also associated with poor nutrition and spending less time outdoors. Therefore, alternative explanations for the increase in cognitive impairment exist and hence a direct causal relationship between vitamin D levels and cognition could not be established.

Pregnancy – Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small (for gestational age) infants. Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term, the full extent of benefits for the mother or baby is unclear. Pregnant women who take an adequate amount of vitamin D during gestation may experience a lower risk of pre-eclampsia and positive immune effects. Vitamin D supplementation is also likely to reduce the risk of gestational diabetes, undersized babies and of their poor rate of growth. Pregnant women often do not take the recommended amount of vitamin D.

Weight loss – Though hypothesized that vitamin D supplementation may be an effective treatment for obesity apart from calorie restriction, one systematic review found no association of supplementation with body weight or fat mass. A 2016 meta-analysis found that circulating vitamin D status was improved by weight loss, indicating that fat mass may be inversely associated with blood levels of vitamin D.

Allowable health claims

Governmental regulatory agencies stipulate for the food and dietary supplement industries certain health claims as allowable as statements on packaging.

European Food Safety Authority

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

US Food and Drug Administration (FDA)

  • "Adequate calcium and vitamin D, as part of a well balanced diet, along with physical activity, may reduce the risk of osteoporosis."

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."

Other possible agencies with claim guidance: Japan FOSHU and Australia-New Zealand.

Recommended levels

Various institutions have proposed different recommendations for the amount of daily intake of vitamin D. These vary according to precise definition, age, pregnancy or lactation, and the extent assumptions are made regarding skin synthesis of vitamin D. Conversion: 1µg (microgram) = 40IU (international unit).

United Kingdom
Age group Intake (μg/day) Maximum intake (μg/day)
Breast-fed infants 0–12 months 8.5 - 10 25
Formula-fed infants (<500 ml/d) 10 25
Children 1 – 10 years 10 50
Children >10 and adults 10 100
United States
Age group RDA (IU/day) (μg/day)
Infants 0–6 months 400* 10
Infants 6–12 months 400* 10
1–70 years 600 15
71+ years 800 20
Pregnant/Lactating 600 15
Age group Tolerable upper intake level (IU/day) (µg/day)
Infants 0–6 months 1,000 25
Infants 6–12 months 1,500 37.5
1–3 years 2,500 62.5
4–8 years 3,000 75
9+ years 4,000 100
Pregnant/lactating 4,000 100
Canada
Age group RDA (IU) Tolerable upper intake (IU)
Infants 0–6 months 400* 1,000
Infants 7–12 months 400* 1,500
Children 1–3 years 600 2,500
Children 4–8 years 600 3,000
Children and Adults 9–70 years 600 4,000
Adults > 70 years 800 4,000
Pregnancy & Lactation 600 4,000
Australia and New Zealand
Age group Adequate Intake (μg) Upper Level of Intake (μg)
Infants 0–12 months 5* 25
Children 1–18 years 5* 80
Adults 19–50 years 5* 80
Adults 51–70 years 10* 80
Adults > 70 years 15* 80
European Food Safety Authority
Age group Adequate Intake (μg) Tolerable upper limit (μg)
Infants 0–12 months 10 25
Children 1–10 years 15 50
Children 11–17 years 15 100
Adults 15 100
Pregnancy & Lactation 15 100
* Adequate intake, no RDA/RDI yet established

United Kingdom

The UK National Health Service (NHS) recommends that people at risk of vitamin D deficiency, breast-fed babies, formula-fed babies taking less than 500ml/day, and children aged 6 months to 4 years, should take daily vitamin D supplements throughout the year to ensure sufficient intake. This includes people with limited skin synthesis of vitamin D, who are not often outdoors, are frail, housebound, living in a care home, or usually wearing clothes that cover up most of the skin, or with dark skin, such as having an African, African-Caribbean or south Asian background. Other people may be able to make adequate vitamin D from sunlight exposure from April to September. The NHS and Public Health England recommend that everyone, including pregnant and breastfeeding women, consider taking a daily supplement containing 10µg (400 IU) of vitamin D during autumn and winter because of inadequate sunlight for vitamin D synthesis.

United States

The dietary reference intake for vitamin D issued in 2010 by the Institute of Medicine (IoM) (renamed National Academy of Medicine in 2015), superseded previous recommendations which were expressed in terms of Adequate Intake. 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 assumes that calcium requirements are being met.: 5 The tolerable upper intake level (UL) 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.": 403 Although ULs are believed to be safe, information on the long-term effects is incomplete and these levels of intake are not recommended for long-term consumption.: 403: 433

For U.S food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin D labeling purposes, 100% of the Daily Value was 400IU (10μg), but on May 27, 2016, it was revised to 800IU (20μg) to bring it into agreement with the RDA. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers withUS$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Canada

Health Canada published recommended dietary allowances (RDA) and tolerable upper intake levels for vitamin D in 2012 based on the Institute of Medicine report.

Australia and New Zealand

Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in 2005. About a third of Australians have vitamin D deficiency.

European Union

The European Food Safety Authority (EFSA) in 2016 reviewed the current evidence, finding the relationship between serum 25(OH)D concentration and musculoskeletal health outcomes is widely variable. They considered that average requirements and population reference intakes values for vitamin D cannot be derived, and that a serum 25(OH)D concentration of 50nmol/L was a suitable target value. For all people over the age of 1, including women who are pregnant or lactating, they set an adequate intake of 15μg/day (600IU).

The EFSA reviewed safe levels of intake in 2012, setting the tolerable upper limit for adults at 100μg/day (4000IU), a similar conclusion as the IOM.

The Swedish National Food Agency recommends a daily intake of 10μg (400IU) of vitamin D3 for children and adults up to 75 years, and 20μg (800IU) for adults 75 and older.

Non-government organisations in Europe have made their own recommendations. The German Society for Nutrition recommends 20µg. The European Menopause and Andropause Society recommends postmenopausal women consume 15µg (600IU) until age 70, and 20µg (800IU) from age 71. This dose should be increased to 100µg (4,000IU) in some patients with very low vitamin D status or in case of co-morbid conditions.

Sources

Although vitamin D is present naturally in only a few foods, it is commonly added as a fortification in manufactured foods. In some countries, staple foods are artificially fortified with vitamin D.

Natural sources

  • Animal sources
    Source IU/g Irregular
    Cooked egg yolk 0.7 44IU for a 61g egg
    Beef liver, cooked, braised 0.5
    Fish liver oils, such as cod liver oil 100 450IU per teaspoon (4.5g)
    Fatty fish species
    Salmon, pink, cooked, dry heat 5.2
    Mackerel, Pacific and jack, mixed species, cooked, dry heat 4.6
    Tuna, canned in oil 2.7
    Sardines, canned in oil, drained 1.9
  • Fungal sources
    Source μg/g IU/g
    Cladonia arbuscula (lichen), thalli, dry vitamin D3 0.67–2.04 27–82
    vitamin D2 0.22–0.55 8.8–22
    Agaricus bisporus (common mushroom): D2 + D3
    Portobello Raw 0.003 0.1
    Exposed to ultraviolet light 0.11 4.46
    Crimini Raw 0.001 0.03
    Exposed to ultraviolet light 0.32 12.8

In general, vitamin D3 is found in animal source foods, particularly fish, meat, offal, egg and dairy. Vitamin D2 is found in fungi and is produced by ultraviolet irradiation of ergosterol. The vitamin D2 content in mushrooms and Cladina arbuscula, a lichen, increase with exposure to ultraviolet light, and is emulated by industrial ultraviolet lamps for fortification. The United States Department of Agriculture reports D2 and D3 content combined in one value.

Food fortification

Manufactured foods fortified with vitamin D include some fruit juices and fruit juice drinks, meal replacement energy bars, soy protein-based beverages, certain cheese and cheese products, flour products, infant formulas, many breakfast cereals, and milk.

In 2016 in the United States, the Food and Drug Administration (FDA) amended food additive regulations for milk fortification, stating that vitamin D3 levels not exceed 42IU vitamin D per 100g (400IU per US quart) of dairy milk, 84IU of vitamin D2 per 100g (800IU per quart) of plant milks, and 89IU per 100g (800IU per quart) in plant-based yogurts or in soy beverage products. Plant milks are defined as beverages made from soy, almond, rice, among other plant sources intended as alternatives to dairy milk.

While some studies have found that vitamin D3 raises 25(OH)D blood levels faster and remains active in the body longer, others contend that vitamin D2 sources are equally bioavailable and effective as D3 for raising and sustaining 25(OH)D.

Food preparation

Vitamin D content in typical foods is reduced variably by cooking. Boiled, fried and baked foods retained 69–89% of original vitamin D.

Global vitamin D serum levels among adults (nmol/L).
> 75
50-74
25-49

Recommendations on recommended 25(OH)D serum levels vary across authorities, and vary based on factors like age. US labs generally report 25(OH)D levels in ng/mL. Other countries often use nmol/L. Oneng/mL is approximately equal to 2.5nmol/L.

A 2014 review concluded that the most advantageous serum levels for 25(OH)D for all outcomes appeared to be close to 30ng/mL (75nmol/L). The optimal vitamin D levels are still controversial and another review concluded that ranges from 30 to 40ng/mL (75 to 100nmol/L) were to be recommended for athletes. Part of the controversy is because numerous studies have found differences in serum levels of 25(OH)D between ethnic groups; studies point to genetic as well as environmental reasons behind these variations. Supplementation to achieve these standard levels could cause harmful vascular calcification.

A 2012 meta-analysis showed that the risk of cardiovascular diseases increases when blood levels of vitamin D are lowest in a range of 8 to 24ng/mL (20 to 60nmol/L), although results among the studies analyzed were inconsistent.

In 2011 an IOM committee concluded a serum 25(OH)D level of 20ng/mL (50nmol/L) is needed 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 the specified levels of intake achieve the desired serum 25(OH)D levels in almost all persons. No contributions to serum 25(OH)D level are assumed from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight. The Institute found serum 25(OH)D concentrations above 30ng/mL (75nmol/L) are "not consistently associated with increased benefit". Serum 25(OH)D levels above 50ng/mL (125nmol/L) may be cause for concern. However, some people with serum 25(OH)D between 30 and 50ng/mL (75nmol/L-125nmol/L) will also have inadequate vitamin D.

Further information: hypervitaminosis D

Vitamin D toxicity is rare. It is caused by supplementing with high doses of vitamin D rather than sunlight. The threshold for vitamin D toxicity has not been established; however, according to some research, the tolerable upper intake level (UL) is 4,000 IU/day for ages 9–71 (100µg/day), while other research concludes that, in healthy adults, sustained intake of more than 50,000IU/day (1250μg) can produce overt toxicity after several months and can increase serum 25-hydroxyvitamin D levels to 150ng/mL and greater. Those with certain medical conditions, such as primary hyperparathyroidism, 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.

Idiopathic infantile hypercalcemia is caused by a mutation of the CYP24A1 gene, leading to a reduction in the degradation of vitamin D. Infants suffering from such a mutation have an increased sensitivity to vitamin D and in case of additional intake a risk of hypercalcaemia. The disorder can continue into adulthood.

A review published in 2015 noted that adverse effects have been reported only at 25(OH)D serum concentrations above 200nmol/L.

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 ≥40,000IU (1,000μg) per day.

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 (1IU is the biological equivalent of 25ng cholecalciferol/ergocalciferol). In addition, for products intended for infants, the FDA recommends the dropper hold no more than 400IU. For infants (birth to 12 months), the tolerable upper limit (maximum amount that can be tolerated without harm) is set at 25μg/day (1,000IU). One thousand micrograms per day in infants has produced toxicity within one month. After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010[update], has increased the tolerable upper limit (UL) to 2,500IU per day for ages 1–3 years, 3,000IU per day for ages 4–8 years and 4,000IU per day for ages 9–71+ years (including pregnant or lactating women).

Calcitriol itself is auto-regulated in a negative feedback cycle, and is also affected by parathyroid hormone, fibroblast growth factor 23, cytokines, calcium, and phosphate.

Effect of excess

Vitamin D overdose causes hypercalcemia, which is a strong indication of vitamin D toxicity – this can be 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.

The main symptoms of vitamin D overdose are hypercalcemia including anorexia, nausea, and vomiting. These may be followed by polyuria, polydipsia, weakness, insomnia, nervousness, pruritus and ultimately kidney failure. Furthermore, proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop. Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.

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. The concentrations of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D produced is degraded.

Synthesis of vitamin D in nature is dependent on the presence of UV radiation and subsequent activation in the liver and in the kidneys. Many animals synthesize vitamin D3 from 7-dehydrocholesterol, and many fungi synthesize vitamin D2 from ergosterol.

Interactive pathway

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Click on genes, proteins and metabolites below to link to respective articles.

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|alt=Vitamin D Synthesis Pathway (view / edit)]]
Vitamin D Synthesis Pathway (view / edit)
  1. The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Photochemistry

The photochemistry of vitamin D biosynthesis in animal and fungi
Thermal isomerization of previtaminD3 to vitamin D3

The transformation that converts 7-dehydrocholesterol to vitamin D3 occurs in two steps. First, 7-dehydrocholesterol is photolyzed by ultraviolet light in a 6-electron conrotatory ring-opening electrocyclic reaction; the product is previtaminD3. Second, previtaminD3 spontaneously isomerizes to vitaminD3 (cholecalciferol) in an antarafacial sigmatropic [1,7] hydride shift. At room temperature, the transformation of previtaminD3 to vitamin D3 in an organic solvent takes about 12 days to complete. The conversion of previtaminD3 to vitamin D3 in the skin is about 10 times faster than in an organic solvent.

The conversion from ergosterol to vitamin D2 follows a similar procedure, forming previtaminD2 by photolysis, which isomerizes to vitamin D2 (ergocalciferol). The transformation of previtaminD2 to vitamin D2 in methanol has a rate comparable to that of previtaminD3. The process is faster in white button mushrooms.: fig. 3

Synthesis in the skin

In the epidermal strata of the skin, vitamin D production is greatest in the stratum basale (colored red in the illustration) and stratum spinosum (colored light brown).

Vitamin D3 is produced photochemically from 7-dehydrocholesterol in the skin of most vertebrate animals, including humans. The precursor of vitamin D3, 7-dehydrocholesterol is produced in relatively large quantities. 7-Dehydrocholesterol reacts with UVB light at wavelengths of 290–315 nm. 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). Exposure to light through windows is insufficient because glass almost completely blocks UVB light.

Adequate amounts of vitamin D can be produced with moderate sun exposure to the face, arms and legs (for those with the least melanin), averaging 5–30 minutes twice per week, or approximately 25% of the time for minimal sunburn. The darker the skin, and the weaker the sunlight, the more minutes of exposure are needed. Vitamin-D overdose is impossible from UV exposure: the skin reaches an equilibrium where the vitamin degrades as fast as it is created.

The skin consists of two primary layers: the inner layer called the dermis, and the outer, thinner epidermis. Vitamin D is produced in the keratinocytes of two innermost strata of the epidermis, the stratum basale and stratum spinosum, which also are able to produce calcitriol and express the VDR.

Evolution

Vitamin D can be synthesized only by a photochemical process. Phytoplankton in the ocean (such as coccolithophore and Emiliania huxleyi) have been photosynthesizing vitamin D for more than 500million years. Primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D.

Land vertebrates required another source of vitamin D other than plants for their calcified skeletons. They had to either ingest it or be exposed to sunlight to photosynthesize it in their skin. Land vertebrates have been photosynthesizing vitamin D for more than 350million years.

In birds and fur-bearing mammals, fur or feathers block UV rays from reaching the skin. Instead, vitamin D is created from oily secretions of the skin deposited onto the feathers or fur, and is obtained orally during grooming. However, some animals, such as the naked mole-rat, are naturally cholecalciferol-deficient, as serum 25-OH vitamin D levels are undetectable. Dogs and cats are practically incapable of vitamin D synthesis due to high activity of 7-dehydrocholesterol reductase, but they do get them from prey animals.

Industrial synthesis

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification. The 7-dehydrocholesterol is a natural substance in fish organs, especially the liver, 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.

Metabolic activation

Liver hydroxylation of cholecalciferol to calcifediol
Kidney hydroxylation of calcifediol to calcitriol

Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcifediol. Circulating calcifediol may then be converted into calcitriol, the biologically active form of vitamin D, in the kidneys.

Whether it is made in the skin or ingested, vitamin D is hydroxylated in the liver at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcifediol or 25(OH)D). This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase, the product of the CYP2R1 human gene, and expressed by hepatocytes. Once made, the product is released into the plasma, where it is bound to an α-globulin carrier protein named the vitamin D-binding protein.

Calcifediol 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 (1,25-dihydroxycholecalciferol, 1,25(OH)2D). The conversion of calcifediol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene. The activity of CYP27B1 is increased by parathyroid hormone, and also by low calcium or phosphate.

Following the final converting step in the kidney, calcitriol is released into the circulation. By binding to vitamin D-binding protein, calcitriol is transported throughout the body, including to the classical target organs of intestine, kidney and bone. Calcitriol is the most potent natural ligand of the vitamin D receptor, which mediates most of the physiological actions of vitamin D.

In addition to the kidneys, calcitriol is also synthesized by certain other cells including monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, modulating body defenses against microbial invaders by stimulating the innate immune system.

Inactivation

The activity of calcifediol and calcitriol can be reduced by hydroxylation at position 24 by vitamin D3 24-hydroxylase, forming secalciferol and calcitetrol, respectively.

Difference between substrates

VitaminD2 (ergocalciferol) and vitaminD3 (cholecalciferol) share a similar mechanism of action as outlined above. Metabolites produced by vitamin D2 are sometimes named with an er- or ergo prefix to differentiate them from the D3-based counterparts.

  • Metabolites produced from vitaminD2 tend to bind less well to the vitamin D-binding protein. It is disputed whether this difference leads to a shorter half life (see § Food fortification).
  • VitaminD3 can alternatively be hydroxylated to calcifediol by sterol 27-hydroxylase (CYP27A1), but vitaminD2 cannot.
  • Ergocalciferol can be directly hydroxylated at position 24 by CYP27A1. This hydroxylation also leads to a greater degree of inactivation: the activity of calcitriol decreases to 60% of original after 24-hydroxylation, whereas ercalcitriol undergoes a 10-fold decrease in activity on conversion to ercalcitetrol.

Intracellular mechanisms

Calcitriol enters the target cell and binds to the vitamin D receptor in the cytoplasm. This activated receptor enters the nucleus and binds to vitamin D response elements (VDRE) which are specific DNA sequences on genes. Transcription of these genes is stimulated and produces greater levels of the proteins which mediate the effects of vitamin D.

Further information: Vitamin § History

American researchers Elmer McCollum and Marguerite Davis in 1914 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. 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. It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.

In 1925, 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: "Light equals vitamin D." 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. 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 the 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. 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. At this time, the policy of the Medical Research Council was not to patent discoveries, believing the results of medical research should be open to everybody. In the 1930s, Windaus clarified further the chemical structure of vitamin D.

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. After irradiating rodent food, Steenbock discovered the rodents were cured of rickets. A vitamin D deficiency is a known cause of rickets. UsingUS$300 of his own money, Steenbock patented his invention. His irradiation technique was used for foodstuffs, most notably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.

In 1969, after studying nuclear fragments of intestinal cells, a specific binding protein for vitamin D called the vitamin D receptor was identified by Mark Haussler and Tony Norman. 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 calcifediol. Calcifediol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D. 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. The vitamin D metabolites, calcifediol and calcitriol, were identified by competing teams led by Michael F. Holick in the laboratory of Hector DeLuca and by Tony Norman and colleagues.

There is conflicting evidence about the benefits of interventions with vitamin D, one view purporting an intake of 4,000–12,000IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80ng/mL, while another view is that serum concentrations above 50ng/mL are not plausible.

The United States National Institutes of Health Office of Dietary Supplements established a Vitamin D Initiative in 2014 to track current research and provide education to consumers. In their 2020 update it was recognized that a growing body of research suggests that vitamin D might play some role in the prevention and treatment of types 1 and 2 diabetes, glucose intolerance, hypertension, multiple sclerosis, and other medical conditions. However, it was concluded that the available evidence was either inadequate or too contradictory to confirm the effectiveness of vitamin D on those conditions, save for the more positive findings on bone health.

Some preliminary studies link low vitamin D levels with disease later in life. One meta-analysis found a decrease in mortality in elderly people. Another meta-analysis covering over 350,000 people concluded that vitamin D supplementation in unselected community-dwelling individuals does not reduce skeletal (total fracture) or non-skeletal outcomes (myocardial infarction, ischemic heart disease, stroke, cerebrovascular disease, cancer) by more than 15%, and that further research trials with similar design are unlikely to change these conclusions. A 2019 meta-analysis found that a small increase in risk of stroke when calcium supplements were added to vitamin D. Evidence as of 2013 is insufficient to determine whether vitamin D affects the risk of cancer.

COVID-19

Vitamin D deficiency has been shown to potentially increase the risk of severe respiratory infections. This has led to investigations of the role of vitamin D deficiency and the potential for use of vitamin D supplements during the COVID-19 pandemic.

Several systematic reviews and meta-analyses of multiple studies have described the associations of vitamin D deficiency with adverse outcomes in COVID-19. One found that while deficiency was not associated with a higher probability of becoming infected with COVID-19, there were significant associations between vitamin D deficiency or insufficiency with more severe disease, including increases in hospitalization and mortality rates by about 80%. Two other meta-analyses of around 40 studies have shown that the risk of infection was higher in those with vitamin D deficiency. The vitamin D deficient group had about a two-fold risk of disease with greater severity, and on some analyses, a significant association with higher rates of mortality. Another, reviewing 31 studies, reported that patients with COVID-19 tend to have lower 25(OH)D levels than healthy subjects but stated that the trend for associations with health outcomes was limited by the low quality of the studies and by the possibility of reverse causality mechanisms.

In July 2020, the US National Institutes of Health found insufficient evidence to recommend for or against using vitamin D supplementation to prevent or treat COVID-19. The UK National Institute for Health and Care Excellence (NICE) does not recommend to offer a vitamin D supplement to people solely to prevent or treat COVID‑19. Both organizations included recommendations to continue the previous established recommendations on vitamin D supplementation for other reasons, such as bone and muscle health, as applicable. Both organizations noted that more people may require supplementation due to lower amounts of sun exposure during the pandemic.

The major complication of COVID-19 is acute respiratory distress syndrome (ARDS), which may be aggravated by vitamin D deficiency, an association that is not specific to coronavirus infections.

A number of trials in different countries are underway or have been published, looking at the use of vitamin D, and its metabolites such as calcifediol, in the prevention and treatment of SARS-CoV-2 infections. A meta-analysis of three studies on the effect of oral vitamin D or calcifediol supplementation indicated a lower intensive care unit (ICU) admission rate (odds ratio: 0.36) compared to those without supplementation, but without a change in mortality. A Cochrane review, also of three studies, found the evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 to be very uncertain. They found there was substantial clinical and methodological heterogeneity in the three studies that were included, mainly because of different supplementation strategies, vitamin D formulations (one using calcifediol), pre-treatment status and reported outcomes. Another meta-analysis stated that the use of high doses of vitamin D in COVID-19 patients is not based on solid evidence although calcifediol supplementation may have a protective effect on ICU admissions.

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  • "Vitamin D". Drug Information Portal. U.S. National Library of Medicine.
  • "Ergocalciferol". Drug Information Portal. U.S. National Library of Medicine.
  • "Cholecalciferol". Drug Information Portal. U.S. National Library of Medicine.
  • "Vitamin D4". Drug Information Portal. U.S. National Library of Medicine.
  • "Vitamin D5". Drug Information Portal. U.S. National Library of Medicine.

Vitamin D
Vitamin D Language Watch Edit For other uses see Vitamin D disambiguation This article is about the family of D vitamins For individual forms see ergocalciferol cholecalciferol vitamin D4 vitamin D5 and calcitriol Vitamin D is a group of fat soluble secosteroids responsible for increasing intestinal absorption of calcium magnesium and phosphate and many other biological effects 1 2 In humans the most important compounds in this group are vitamin D3 also known as cholecalciferol and vitamin D2 ergocalciferol 1 2 3 Vitamin DDrug classCholecalciferol D3 Class identifiersSynonymsCalciferolsUseRickets osteoporosis vitamin D deficiencyATC codeA11CCBiological targetvitamin D receptorClinical dataDrugs comMedFacts Natural ProductsExternal linksMeSHD014807In Wikidata The major natural source of the vitamin is synthesis of cholecalciferol in the lower layers of skin epidermis through a chemical reaction that is dependent on sun exposure specifically UVB radiation 4 5 Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements 6 2 Only a few foods such as the flesh of fatty fish naturally contain significant amounts of vitamin D 1 7 In the U S and other countries cow s milk and plant derived milk substitutes are fortified with vitamin D as are many breakfast cereals Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D 1 Dietary recommendations typically assume that all of a person s vitamin D is taken by mouth as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk 1 Vitamin D from the diet or from skin synthesis is biologically inactive It is activated by two protein enzyme hydroxylation steps the first in the liver and the second in the kidneys 3 As vitamin D can be synthesized in adequate amounts by most mammals if exposed to sufficient sunlight it is not essential so technically not a vitamin 2 Instead it can be considered a hormone with activation of the vitamin D pro hormone resulting in the active form calcitriol which then produces effects via a nuclear receptor in multiple locations 2 Cholecalciferol is converted in the liver to calcifediol 25 hydroxycholecalciferol ergocalciferol is converted to 25 hydroxyergocalciferol These two vitamin D metabolites called 25 hydroxyvitamin D or 25 OH D are measured in serum to determine a person s vitamin D status 8 9 Calcifediol is further hydroxylated by the kidneys and some of the immune system cells to form calcitriol also known as 1 25 dihydroxycholecalciferol the biologically active form of vitamin D 10 11 Calcitriol circulates as a hormone in the blood having a major role regulating the concentration of calcium and phosphate and promoting the healthy growth and remodeling of bone Calcitriol also has other effects including some on cell growth neuromuscular and immune functions and reduction of inflammation 1 Vitamin D has a significant role in calcium homeostasis and metabolism Its discovery was due to effort to find the dietary substance lacking in children with rickets the childhood form of osteomalacia 12 Vitamin D supplements are given to treat or to prevent osteomalacia and rickets The evidence for other health effects of vitamin D supplementation in the general population is inconsistent 1 The effect of vitamin D supplementation on mortality is not clear with one meta analysis finding a small decrease in mortality in elderly people 13 and another concluding no clear justification exists for recommending supplementation for preventing many diseases and that further research of similar design is not needed in these areas 14 Contents 1 Types 2 Biology 3 Deficiency 3 1 Bone health 3 1 1 Rickets 3 1 2 Osteomalacia and osteoporosis 3 2 Skin pigmentation 4 Use of supplements 4 1 Mortality all causes 4 2 Bone health 4 3 Cancer 4 4 Cardiovascular disease 4 5 Immune system 4 5 1 Infectious diseases 4 5 2 Asthma 4 5 3 Inflammatory bowel disease 4 6 Other conditions 4 7 Allowable health claims 5 Dietary intake 5 1 Recommended levels 5 1 1 United Kingdom 5 1 2 United States 5 1 3 Canada 5 1 4 Australia and New Zealand 5 1 5 European Union 5 2 Sources 5 2 1 Natural sources 5 2 2 Food fortification 5 3 Food preparation 6 Recommended serum levels 7 Excess 7 1 Effect of excess 8 Biosynthesis 8 1 Interactive pathway 8 2 Photochemistry 8 3 Synthesis in the skin 8 4 Evolution 8 5 Industrial synthesis 9 Mechanism of action 9 1 Metabolic activation 9 2 Inactivation 9 3 Difference between substrates 9 4 Intracellular mechanisms 10 History 11 Research 11 1 COVID 19 12 References 13 Further reading 14 External linksTypes EditName Chemical composition StructureVitamin D1 Mixture of molecular compounds of ergocalciferol with lumisterol 1 1Vitamin 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 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 and is known collectively as calciferol 15 Vitamin D2 was chemically characterized in 1931 In 1935 the chemical structure of vitamin D3 was defined and shown to result from the ultraviolet irradiation of 7 dehydrocholesterol A chemical nomenclature for vitamin D forms was recommended in 1981 16 but alternative names remain in common use 3 Chemically the various forms of vitamin D are secosteroids that is steroids in which one of the bonds in the steroid rings is broken 17 The structural difference between vitamin D2 and vitamin D3 is in the side chain which contains a double bond between carbons 22 and 23 and a methyl group on carbon 24 in vitamin D2 3 Many vitamin D analogues have been synthesized 3 Biology Edit Calcium regulation in the human body 18 The role of active vitamin D 1 25 dihydroxyvitamin D calcitriol is shown in orange 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 17 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 19 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 20 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 21 Thus vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption 21 The VDR regulates 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 22 In vitro vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells and affects the synthesis of neurotrophic factors nitric oxide synthase and glutathione 23 Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength mass and function all being important factors to an athlete s performance 24 Deficiency EditMain article Vitamin D deficiency An estimated one billion people worldwide are either vitamin D insufficient or deficient 24 Vitamin D deficiency is widespread in the European population 25 A diet with insufficient vitamin D in conjunction with inadequate sun exposure causes vitamin D deficiency Severe vitamin D deficiency in children causes rickets a softening and weakening of bones which is a rare disease in the developed world 26 Vitamin D deficiency is found worldwide in the elderly and remains common in children and adults 27 28 29 Deficiency results in impaired bone mineralization and bone damage which leads to bone softening diseases 30 including rickets in children and osteomalacia in adults Low blood calcifediol 25 hydroxy vitamin D can result from avoiding the sun 31 Being deficient in vitamin D can cause intestinal absorption of dietary calcium to fall to 15 20 When not deficient an individual usually absorbs between 60 and 80 20 Bone health Edit Rickets Edit Main article Rickets Rickets a childhood disease is characterized by impeded growth and soft weak deformed long bones that bend and bow under their weight as children start to walk Rickets typically appears between 3 and 18 months of age 32 Cases continue to be reported in North American and other Western Countries and is primarily seen in breastfed infants and those with darker skin complexions 32 This condition is characterized by bow legs 30 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 33 and in those with genetic disorders such as pseudovitamin D deficiency rickets 34 Maternal vitamin D deficiency may cause overt bone disease from before birth and impairment of bone quality after birth 35 36 Nutritional rickets exists in countries with intense year round sunlight such as Nigeria and can occur without vitamin D deficiency 37 38 Although rickets and osteomalacia are now rare in the UK outbreaks have happened in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing 39 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 definition needed cereals 40 41 42 The dietary risk factors for rickets include abstaining from animal foods 39 43 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 sun exposure In sunny countries such as Nigeria South Africa and Bangladesh where rickets 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 42 Rickets was formerly a major public health problem among the US population in Denver where ultraviolet rays are about 20 stronger than at sea level on the same latitude 44 almost two thirds of 500 children had mild rickets in the late 1920s 45 An increase in the proportion of animal protein 43 46 in the 20th century American diet coupled with increased consumption of milk 47 48 fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases 20 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 30 Osteomalacia and osteoporosis Edit Main articles Osteomalacia and Osteoporosis 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 49 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 50 Although the effects of osteomalacia are thought to contribute to chronic musculoskeletal pain there is no persuasive evidence of lower vitamin D levels in chronic pain sufferers 51 or that supplementation alleviates chronic nonspecific musculoskeletal pain 52 Osteoporosis is a condition of reduced bone mineral density with increased bone fragility and risk of bone fractures Osteoporosis can be a long term effect of calcium and or vitamin D insufficiency at least in part This may result from inadequate calcium intake with insufficient vitamin D contributing by reducing calcium absorption 1 Skin pigmentation Edit Dark skinned people living in temperate climates have been shown to have low vitamin D levels but the significance of this is not certain 53 54 55 Dark skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis 56 Vitamin D deficiency is common in Hispanic and African Americans in the United States with levels dropping significantly in the winter 57 This is due to the levels of melanin in the skin as it acts as a natural protectant from sun exposure 57 Use of supplements EditSupplementation with vitamin D is a reliable method for preventing or treating rickets The effects of vitamin D supplementation on non skeletal health are uncertain 58 59 A 2013 review did not find any effect from supplementation on the rates of non skeletal disease other than a tentative decrease in mortality in the elderly 60 Vitamin D supplements do not alter the outcomes for myocardial infarction stroke or cerebrovascular disease cancer bone fractures or knee osteoarthritis 14 61 Low vitamin D levels may result from disease rather than cause disease 60 A United States Institute of Medicine IOM report states Outcomes related to cancer cardiovascular disease and hypertension and 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 62 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 63 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 63 Mortality all causes Edit Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly 13 60 but the effect has not been deemed pronounced or certain enough to make taking supplements recommendable 14 Other forms vitamin D2 alfacalcidol and calcitriol do not appear to have any beneficial effects with regard to the risk of death 13 High blood levels appear to be associated with a lower risk of death but it is unclear if supplementation can result in this benefit 64 Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging 65 66 67 The relationship between serum calcifediol concentrations and all cause mortality is U shaped mortality is elevated at high and low calcifediol levels relative to moderate levels 62 Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population 62 435 Bone health Edit In general no good evidence supports the commonly held belief that vitamin D supplements can help prevent osteoporosis 14 Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed 68 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 69 A study found that supplementation with 800 IU or more daily in those older than 65 years was somewhat favorable in the prevention of hip fracture and non vertebral fracture 70 The effect is small or none for people living independently 71 72 Low serum vitamin D levels have been associated with falls and low bone mineral density 73 Taking extra vitamin D however does not appear to change the risk 74 Athletes who are vitamin D deficient are at an increased risk of stress fractures and or major breaks particularly those engaging in contact sports The greatest benefit with supplementation is seen in athletes who are deficient 25 OH D serum levels lt 30 ng mL or severely deficient 25 OH D serum levels lt 25 ng mL Incremental decreases in risks are observed with rising serum 25 OH D concentrations plateauing at 50 ng mL with no additional benefits seen in levels beyond this point 75 Because it found mounting evidence for a benefit to bone health though it had not found good evidence of other benefits the US Food and Drug Administration FDA has required manufacturers to declare the amount of vitamin D on nutrition facts labels as nutrients of public health significance since May 2016 By a proposed deadline extension some manufacturers had until July 1 2021 to comply 76 Cancer Edit Potential associations have been found between low vitamin D levels and the risk of developing several types of cancer 77 78 79 Meta analyses of observational studies have found reduced risk of cancer incidence related to vitamin D intake and 25 OH D levels particularly for colorectal cancer although the strength of the associations was classified as weak 79 80 81 While randomized controlled trials have not confirmed that vitamin D supplements reduce the risk of cancer incidence the relative risk of cancer deaths has been found to be reduced by up to 16 in several meta analyses 82 81 Cardiovascular disease Edit Taking vitamin D supplements does not meaningfully reduce the risk of stroke cerebrovascular disease myocardial infarction or ischemic heart disease 14 83 Supplementation may have no effect on blood pressure 84 Immune system Edit Infectious diseases Edit In general vitamin D functions to activate the innate and dampen the adaptive immune systems with antibacterial antiviral and anti inflammatory effects 85 86 Deficiency has been linked to increased risk or severity of viral infections including HIV 87 88 and COVID 19 89 Low levels of vitamin D appear to be a risk factor for tuberculosis 90 and historically it was used as a treatment 91 Vitamin D supplementation in low doses 400 to 1000 IU day may slightly decrease the overall risk of acute respiratory tract infections 92 The benefits were found in young children and adolescents ages 1 up to 16 years and were not confirmed with higher doses gt 1000 IU per day or more 92 Vitamin D supplementation substantially reduces the rate of moderate or severe exacerbations of COPD in people with baseline 25 OH D levels under 25nmol L but not in those with less severe deficiency 93 Asthma Edit Although tentative data link low levels of vitamin D to asthma evidence to support a beneficial effect on asthmatics from supplementation is inconclusive 94 One review found that vitamin D supplementation could reduce the need for steroids used to inhibit episode frequency in people with mild to moderate asthma and that supplementation had no effect on day to day asthma symptoms 95 In general practice supplementation with vitamin D is not recommended for treatment or prevention of asthma 96 Inflammatory bowel disease Edit Low levels of vitamin D are associated with two major forms of human inflammatory bowel disease IBD Crohn s disease and ulcerative colitis 97 A meta analysis of vitamin D therapy in IBD patients with vitamin D deficiency has shown that supplementation is effective at correcting vitamin D levels and is associated with improvements in scores for clinical disease activity and biochemical markers 98 Other conditions Edit Diabetes A meta analysis of eight studies found that vitamin D supplementation significantly reduced the risk of type 2 diabetes mellitus for non obese prediabetic patients but not obese ones 99 A meta analysis of 37 articles found that vitamin D supplementation significantly improved glycemic control homeostatic model assessment insulin resistance HOMA IR hemoglobin A1C HbA1C and fasting blood glucose FBG in individuals with type 2 diabetes mellitus 100 In prospective studies high versus low level of vitamin D was respectively associated with significant decrease in risk of type 2 diabetes mellitus combined type 2 diabetes mellitus and pre diabetes and pre diabetes 101 ADHD A meta analysis of observational studies showed that children with ADHD have lower vitamin D levels and that there was a small association between low vitamin D levels at the time of birth and later development of ADHD 102 Several small randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity 103 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 supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate effect 104 Cognition and dementia A systematic review of clinical studies found an association between low vitamin D levels with cognitive impairment and a higher risk of developing Alzheimer s disease However lower vitamin D concentrations are also associated with poor nutrition and spending less time outdoors Therefore alternative explanations for the increase in cognitive impairment exist and hence a direct causal relationship between vitamin D levels and cognition could not be established 105 Pregnancy Low levels of vitamin D in pregnancy are associated with gestational diabetes pre eclampsia and small for gestational age infants 106 Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term 107 the full extent of benefits for the mother or baby is unclear 106 107 108 Pregnant women who take an adequate amount of vitamin D during gestation may experience a lower risk of pre eclampsia 109 and positive immune effects 110 Vitamin D supplementation is also likely to reduce the risk of gestational diabetes undersized babies 109 and of their poor rate of growth 111 Pregnant women often do not take the recommended amount of vitamin D 110 Weight loss Though hypothesized that vitamin D supplementation may be an effective treatment for obesity apart from calorie restriction one systematic review found no association of supplementation with body weight or fat mass 112 A 2016 meta analysis found that circulating vitamin D status was improved by weight loss indicating that fat mass may be inversely associated with blood levels of vitamin D 113 Allowable health claims Edit Governmental regulatory agencies stipulate for the food and dietary supplement industries certain health claims as allowable as statements on packaging European Food Safety Authority normal function of the immune system 114 normal inflammatory response 114 normal muscle function 114 reduced risk of falling in people over age 60 115 US Food and Drug Administration FDA Adequate calcium and vitamin D as part of a well balanced diet along with physical activity may reduce the risk of osteoporosis 116 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 117 Other possible agencies with claim guidance Japan FOSHU 118 and Australia New Zealand 119 Dietary intake EditRecommended levels Edit Various institutions have proposed different recommendations for the amount of daily intake of vitamin D These vary according to precise definition age pregnancy or lactation and the extent assumptions are made regarding skin synthesis of vitamin D 120 62 121 122 123 Conversion 1 µg microgram 40 IU international unit 120 United KingdomAge group Intake mg day Maximum intake mg day 120 Breast fed infants 0 12 months 8 5 10 25Formula fed infants lt 500 ml d 10 25Children 1 10 years 10 50Children gt 10 and adults 10 100United StatesAge group RDA IU day mg day 62 Infants 0 6 months 400 10Infants 6 12 months 400 101 70 years 600 1571 years 800 20Pregnant Lactating 600 15Age group Tolerable upper intake level IU day µg day Infants 0 6 months 1 000 25Infants 6 12 months 1 500 37 51 3 years 2 500 62 54 8 years 3 000 759 years 4 000 100Pregnant lactating 4 000 100 62 CanadaAge group RDA IU Tolerable upper intake IU 121 Infants 0 6 months 400 1 000Infants 7 12 months 400 1 500Children 1 3 years 600 2 500Children 4 8 years 600 3 000Children and Adults 9 70 years 600 4 000Adults gt 70 years 800 4 000Pregnancy amp Lactation 600 4 000Australia and New ZealandAge group Adequate Intake mg Upper Level of Intake mg 122 Infants 0 12 months 5 25Children 1 18 years 5 80Adults 19 50 years 5 80Adults 51 70 years 10 80Adults gt 70 years 15 80European Food Safety AuthorityAge group Adequate Intake mg 123 Tolerable upper limit mg 124 Infants 0 12 months 10 25Children 1 10 years 15 50Children 11 17 years 15 100Adults 15 100Pregnancy amp Lactation 15 100 Adequate intake no RDA RDI yet establishedUnited Kingdom Edit The UK National Health Service NHS recommends that people at risk of vitamin D deficiency breast fed babies formula fed babies taking less than 500ml day and children aged 6 months to 4 years should take daily vitamin D supplements throughout the year to ensure sufficient intake 120 This includes people with limited skin synthesis of vitamin D who are not often outdoors are frail housebound living in a care home or usually wearing clothes that cover up most of the skin or with dark skin such as having an African African Caribbean or south Asian background Other people may be able to make adequate vitamin D from sunlight exposure from April to September The NHS and Public Health England recommend that everyone including pregnant and breastfeeding women consider taking a daily supplement containing 10 µg 400 IU of vitamin D during autumn and winter because of inadequate sunlight for vitamin D synthesis 125 United States Edit The dietary reference intake for vitamin D issued in 2010 by the Institute of Medicine IoM renamed National Academy of Medicine in 2015 superseded previous recommendations which were expressed in terms of Adequate Intake 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 assumes that calcium requirements are being met 62 5 The tolerable upper intake level UL 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 62 403 Although ULs are believed to be safe information on the long term effects is incomplete and these levels of intake are not recommended for long term consumption 62 403 433 For U S food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value DV For vitamin D labeling purposes 100 of the Daily Value was 400 IU 10 mg but on May 27 2016 it was revised to 800 IU 20 mg to bring it into agreement with the RDA 126 127 Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US 10 million or more in annual food sales and by 1 January 2021 for manufacturers with lower volume food sales 76 128 A table of the old and new adult daily values is provided at Reference Daily Intake Canada Edit Health Canada published recommended dietary allowances RDA and tolerable upper intake levels for vitamin D in 2012 121 based on the Institute of Medicine report 62 Australia and New Zealand Edit Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in 2005 122 About a third of Australians have vitamin D deficiency 129 European Union Edit The European Food Safety Authority EFSA in 2016 123 reviewed the current evidence finding the relationship between serum 25 OH D concentration and musculoskeletal health outcomes is widely variable They considered that average requirements and population reference intakes values for vitamin D cannot be derived and that a serum 25 OH D concentration of 50 nmol L was a suitable target value For all people over the age of 1 including women who are pregnant or lactating they set an adequate intake of 15 mg day 600 IU 123 The EFSA reviewed safe levels of intake in 2012 124 setting the tolerable upper limit for adults at 100 mg day 4000 IU a similar conclusion as the IOM The Swedish National Food Agency recommends a daily intake of 10 mg 400 IU of vitamin D3 for children and adults up to 75 years and 20 mg 800 IU for adults 75 and older 130 Non government organisations in Europe have made their own recommendations The German Society for Nutrition recommends 20 µg 131 The European Menopause and Andropause Society recommends postmenopausal women consume 15 µg 600 IU until age 70 and 20 µg 800 IU from age 71 This dose should be increased to 100 µg 4 000 IU in some patients with very low vitamin D status or in case of co morbid conditions 132 Sources Edit Although vitamin D is present naturally in only a few foods 1 it is commonly added as a fortification in manufactured foods In some countries staple foods are artificially fortified with vitamin D 133 Natural sources Edit Animal sourcesSource 134 IU g IrregularCooked egg yolk 0 7 44 IU for a 61g eggBeef liver cooked braised 0 5Fish liver oils such as cod liver oil 100 450 IU per teaspoon 4 5 g Fatty fish speciesSalmon pink cooked dry heat 5 2Mackerel Pacific and jack mixed species cooked dry heat 4 6Tuna canned in oil 2 7Sardines canned in oil drained 1 9 Fungal sourcesSource mg g IU gCladonia arbuscula lichen thalli dry 135 vitamin D3 0 67 2 04 27 82vitamin D2 0 22 0 55 8 8 22Agaricus bisporus common mushroom D2 D3Portobello Raw 0 003 0 1Exposed to ultraviolet light 0 11 4 46Crimini Raw 0 001 0 03Exposed to ultraviolet light 0 32 12 8 See also Ergocalciferol Biosynthesis In general vitamin D3 is found in animal source foods particularly fish meat offal egg and dairy 136 Vitamin D2 is found in fungi and is produced by ultraviolet irradiation of ergosterol 137 The vitamin D2 content in mushrooms and Cladina arbuscula a lichen increase with exposure to ultraviolet light 135 138 and is emulated by industrial ultraviolet lamps for fortification 137 The United States Department of Agriculture reports D2 and D3 content combined in one value Food fortification Edit Manufactured foods fortified with vitamin D include some fruit juices and fruit juice drinks meal replacement energy bars soy protein based beverages certain cheese and cheese products flour products infant formulas many breakfast cereals and milk 139 140 In 2016 in the United States the Food and Drug Administration FDA amended food additive regulations for milk fortification 141 stating that vitamin D3 levels not exceed 42 IU vitamin D per 100 g 400 IU per US quart of dairy milk 84 IU of vitamin D2 per 100 g 800 IU per quart of plant milks and 89 IU per 100 g 800 IU per quart in plant based yogurts or in soy beverage products 142 143 144 Plant milks are defined as beverages made from soy almond rice among other plant sources intended as alternatives to dairy milk 145 146 While some studies have found that vitamin D3 raises 25 OH D blood levels faster and remains active in the body longer 147 148 others contend that vitamin D2 sources are equally bioavailable and effective as D3 for raising and sustaining 25 OH D 137 149 150 Food preparation Edit Vitamin D content in typical foods is reduced variably by cooking Boiled fried and baked foods retained 69 89 of original vitamin D 151 Recommended serum levels EditSee also Reference ranges for blood tests Vitamins and Hypervitaminosis D Ethnic differences Global vitamin D serum levels among adults nmol L 152 153 gt 75 50 74 25 49 Recommendations on recommended 25 OH D serum levels vary across authorities and vary based on factors like age 1 US labs generally report 25 OH D levels in ng mL 154 Other countries often use nmol L 154 One ng mL is approximately equal to 2 5 nmol L 155 A 2014 review concluded that the most advantageous serum levels for 25 OH D for all outcomes appeared to be close to 30 ng mL 75 nmol L 156 The optimal vitamin D levels are still controversial and another review concluded that ranges from 30 to 40 ng mL 75 to 100 nmol L were to be recommended for athletes 157 Part of the controversy is because numerous studies have found differences in serum levels of 25 OH D between ethnic groups studies point to genetic as well as environmental reasons behind these variations 158 Supplementation to achieve these standard levels could cause harmful vascular calcification 55 A 2012 meta analysis showed that the risk of cardiovascular diseases increases when blood levels of vitamin D are lowest in a range of 8 to 24 ng mL 20 to 60 nmol L although results among the studies analyzed were inconsistent 159 In 2011 an IOM committee concluded a serum 25 OH D level of 20 ng mL 50 nmol L is needed 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 the specified levels of intake achieve the desired serum 25 OH D levels in almost all persons No contributions to serum 25 OH D level are assumed from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight The Institute found serum 25 OH D concentrations above 30 ng mL 75 nmol L are not consistently associated with increased benefit Serum 25 OH D levels above 50 ng mL 125 nmol L may be cause for concern However some people with serum 25 OH D between 30 and 50 ng mL 75 nmol L 125 nmol L will also have inadequate vitamin D 62 Excess EditFurther information hypervitaminosis D Vitamin D toxicity is rare 29 It is caused by supplementing with high doses of vitamin D rather than sunlight The threshold for vitamin D toxicity has not been established however according to some research the tolerable upper intake level UL is 4 000 IU day for ages 9 71 160 100 µg day while other research concludes that in healthy adults sustained intake of more than 50 000 IU day 1250 mg can produce overt toxicity after several months and can increase serum 25 hydroxyvitamin D levels to 150 ng mL and greater 29 161 Those with certain medical conditions such as primary hyperparathyroidism 162 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 162 163 Idiopathic infantile hypercalcemia is caused by a mutation of the CYP24A1 gene leading to a reduction in the degradation of vitamin D Infants suffering from such a mutation have an increased sensitivity to vitamin D and in case of additional intake a risk of hypercalcaemia 164 165 The disorder can continue into adulthood 166 A review published in 2015 noted that adverse effects have been reported only at 25 OH D serum concentrations above 200 nmol L 157 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 mg per day 162 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 1 IU is the biological equivalent of 25 ng cholecalciferol ergocalciferol In addition for products intended for infants the FDA recommends the dropper hold no more than 400 IU 167 For infants birth to 12 months the tolerable upper limit maximum amount that can be tolerated without harm is set at 25 mg day 1 000 IU One thousand micrograms per day in infants has produced toxicity within one month 161 After being commissioned by the Canadian and American governments the Institute of Medicine IOM as of 30 November 2010 update 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 160 Calcitriol itself is auto regulated in a negative feedback cycle and is also affected by parathyroid hormone fibroblast growth factor 23 cytokines calcium and phosphate 168 Effect of excess Edit Vitamin D overdose causes hypercalcemia which is a strong indication of vitamin D toxicity this can be 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 29 30 49 The main symptoms of vitamin D overdose are hypercalcemia including anorexia nausea and vomiting These may be followed by polyuria polydipsia weakness insomnia nervousness pruritus and ultimately kidney failure Furthermore proteinuria urinary casts azotemia and metastatic calcification especially in the kidneys may develop 161 Other symptoms of vitamin D toxicity include mental retardation in young children abnormal bone growth and formation diarrhea irritability weight loss and severe depression 29 49 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 The concentrations of vitamin D precursors produced in the skin reach an equilibrium and any further vitamin D produced is degraded 162 Biosynthesis EditSynthesis of vitamin D in nature is dependent on the presence of UV radiation and subsequent activation in the liver and in the kidneys Many animals synthesize vitamin D3 from 7 dehydrocholesterol and many fungi synthesize vitamin D2 from ergosterol 169 137 Interactive pathway Edit Click on icon in lower right corner to open Click on genes proteins and metabolites below to link to respective articles 1 File alt Vitamin D Synthesis Pathway view edit Vitamin D Synthesis Pathway view edit The interactive pathway map can be edited at WikiPathways VitaminDSynthesis WP1531 Photochemistry Edit The photochemistry of vitamin D biosynthesis in animal and fungi Thermal isomerization of previtamin D3 to vitamin D3 The transformation that converts 7 dehydrocholesterol to vitamin D3 occurs in two steps 170 171 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 in an organic solvent takes about 12 days to complete The conversion of previtamin D3 to vitamin D3 in the skin is about 10 times faster than in an organic solvent 172 The conversion from ergosterol to vitamin D2 follows a similar procedure forming previtamin D2 by photolysis which isomerizes to vitamin D2 ergocalciferol 173 The transformation of previtamin D2 to vitamin D2 in methanol has a rate comparable to that of previtamin D3 The process is faster in white button mushrooms 137 fig 3 Synthesis in the skin Edit In the epidermal strata of the skin vitamin D production is greatest in the stratum basale colored red in the illustration and stratum spinosum colored light brown Vitamin D3 is produced photochemically from 7 dehydrocholesterol in the skin of most vertebrate animals including humans 174 The precursor of vitamin D3 7 dehydrocholesterol is produced in relatively large quantities 7 Dehydrocholesterol reacts with UVB light at wavelengths of 290 315 nm 175 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 Exposure to light through windows is insufficient because glass almost completely blocks UVB light 176 Adequate amounts of vitamin D can be produced with moderate sun exposure to the face arms and legs for those with the least melanin averaging 5 30 minutes twice per week or approximately 25 of the time for minimal sunburn The darker the skin and the weaker the sunlight the more minutes of exposure are needed Vitamin D overdose is impossible from UV exposure the skin reaches an equilibrium where the vitamin degrades as fast as it is created 29 177 The skin consists of two primary layers the inner layer called the dermis and the outer thinner epidermis Vitamin D is produced in the keratinocytes of two innermost strata of the epidermis the stratum basale and stratum spinosum which also are able to produce calcitriol and express the VDR 178 Evolution Edit Vitamin D can be synthesized only by a photochemical process Phytoplankton in the ocean such as coccolithophore and Emiliania huxleyi have been photosynthesizing vitamin D for more than 500 million years Primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D Land vertebrates required another source of vitamin D other than plants for their calcified skeletons They had to either ingest it or be exposed to sunlight to photosynthesize it in their skin 169 172 Land vertebrates have been photosynthesizing vitamin D for more than 350 million years 179 In birds and fur bearing mammals fur or feathers block UV rays from reaching the skin Instead vitamin D is created from oily secretions of the skin deposited onto the feathers or fur and is obtained orally during grooming 180 However some animals such as the naked mole rat are naturally cholecalciferol deficient as serum 25 OH vitamin D levels are undetectable 181 Dogs and cats are practically incapable of vitamin D synthesis due to high activity of 7 dehydrocholesterol reductase but they do get them from prey animals 182 Industrial synthesis Edit Vitamin D3 cholecalciferol is produced industrially by exposing 7 dehydrocholesterol to UVB light followed by purification 183 The 7 dehydrocholesterol is a natural substance in fish organs especially the liver 184 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 183 137 Mechanism of action EditMetabolic activation Edit Liver hydroxylation of cholecalciferol to calcifediol Kidney hydroxylation of calcifediol to calcitriol Vitamin D is carried in the bloodstream to the liver where it is converted into the prohormone calcifediol Circulating calcifediol may then be converted into calcitriol the biologically active form of vitamin D in the kidneys 185 Whether it is made in the skin or ingested vitamin D is hydroxylated in the liver at position 25 upper right of the molecule to form 25 hydroxycholecalciferol calcifediol or 25 OH D 3 This reaction is catalyzed by the microsomal enzyme vitamin D 25 hydroxylase the product of the CYP2R1 human gene and expressed by hepatocytes 186 Once made the product is released into the plasma where it is bound to an a globulin carrier protein named the vitamin D binding protein 187 Calcifediol is transported to the proximal tubules of the kidneys where it is hydroxylated at the 1 a position lower right of the molecule to form calcitriol 1 25 dihydroxycholecalciferol 1 25 OH 2D The conversion of calcifediol to calcitriol is catalyzed by the enzyme 25 hydroxyvitamin D3 1 alpha hydroxylase which is the product of the CYP27B1 human gene The activity of CYP27B1 is increased by parathyroid hormone and also by low calcium or phosphate 2 185 Following the final converting step in the kidney calcitriol is released into the circulation By binding to vitamin D binding protein calcitriol is transported throughout the body including to the classical target organs of intestine kidney and bone 17 Calcitriol is the most potent natural ligand of the vitamin D receptor which mediates most of the physiological actions of vitamin D 2 185 In addition to the kidneys calcitriol is also synthesized by certain other cells including monocyte macrophages in the immune system When synthesized by monocyte macrophages calcitriol acts locally as a cytokine modulating body defenses against microbial invaders by stimulating the innate immune system 185 Inactivation Edit The activity of calcifediol and calcitriol can be reduced by hydroxylation at position 24 by vitamin D3 24 hydroxylase forming secalciferol and calcitetrol respectively 3 Difference between substrates Edit Vitamin D2 ergocalciferol and vitamin D3 cholecalciferol share a similar mechanism of action as outlined above 3 Metabolites produced by vitamin D2 are sometimes named with an er or ergo prefix to differentiate them from the D3 based counterparts 16 Metabolites produced from vitamin D2 tend to bind less well to the vitamin D binding protein 3 It is disputed whether this difference leads to a shorter half life see Food fortification Vitamin D3 can alternatively be hydroxylated to calcifediol by sterol 27 hydroxylase CYP27A1 but vitamin D2 cannot 3 Ergocalciferol can be directly hydroxylated at position 24 by CYP27A1 3 This hydroxylation also leads to a greater degree of inactivation the activity of calcitriol decreases to 60 of original after 24 hydroxylation 188 whereas ercalcitriol undergoes a 10 fold decrease in activity on conversion to ercalcitetrol 189 Intracellular mechanisms Edit See also Vitamin D receptor and Calcitriol Calcitriol enters the target cell and binds to the vitamin D receptor in the cytoplasm This activated receptor enters the nucleus and binds to vitamin D response elements VDRE which are specific DNA sequences on genes Transcription of these genes is stimulated and produces greater levels of the proteins which mediate the effects of vitamin D 3 History EditFurther information Vitamin History American researchers Elmer McCollum and Marguerite Davis in 1914 12 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 12 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 190 191 It was not initially realized that unlike other vitamins vitamin D can be synthesised by humans through exposure to UV light In 1925 12 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 Light equals vitamin D 192 Adolf Windaus at the University of Gottingen in Germany received the Nobel Prize in Chemistry in 1928 for his work on the constitution of sterols and their connection with vitamins 193 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 the 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 194 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 195 At this time the policy of the Medical Research Council was not to patent discoveries believing the results of medical research should be open to everybody In the 1930s Windaus clarified further the chemical structure of vitamin D 196 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 197 After irradiating rodent food Steenbock discovered the rodents were cured of rickets A vitamin D deficiency is a known cause of rickets Using US 300 of his own money Steenbock patented his invention His irradiation technique was used for foodstuffs most notably for milk By the expiration of his patent in 1945 rickets had been all but eliminated in the US 198 In 1969 after studying nuclear fragments of intestinal cells a specific binding protein for vitamin D called the vitamin D receptor was identified by Mark Haussler and Tony Norman 199 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 calcifediol Calcifediol is then converted by the kidneys to calcitriol the biologically active form of vitamin D 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 The vitamin D metabolites calcifediol and calcitriol were identified by competing teams led by Michael F Holick in the laboratory of Hector DeLuca and by Tony Norman and colleagues 10 11 200 Research EditThere is conflicting evidence about the benefits of interventions with vitamin D 201 one view purporting 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 202 while another view is that serum concentrations above 50 ng mL are not plausible 57 202 The United States National Institutes of Health Office of Dietary Supplements established a Vitamin D Initiative in 2014 to track current research and provide education to consumers 203 In their 2020 update it was recognized that a growing body of research suggests that vitamin D might play some role in the prevention and treatment of types 1 and 2 diabetes glucose intolerance hypertension multiple sclerosis and other medical conditions However it was concluded that the available evidence was either inadequate or too contradictory to confirm the effectiveness of vitamin D on those conditions save for the more positive findings on bone health 1 Some preliminary studies link low vitamin D levels with disease later in life 204 One meta analysis found a decrease in mortality in elderly people 13 Another meta analysis covering over 350 000 people concluded that vitamin D supplementation in unselected community dwelling individuals does not reduce skeletal total fracture or non skeletal outcomes myocardial infarction ischemic heart disease stroke cerebrovascular disease cancer by more than 15 and that further research trials with similar design are unlikely to change these conclusions 14 A 2019 meta analysis found that a small increase in risk of stroke when calcium supplements were added to vitamin D 205 Evidence as of 2013 is insufficient to determine whether vitamin D affects the risk of cancer 206 COVID 19 Edit See also COVID 19 drug repurposing research vitamins Vitamin D deficiency has been shown to potentially increase the risk of severe respiratory infections 207 This has led to investigations of the role of vitamin D deficiency and the potential for use of vitamin D supplements during the COVID 19 pandemic Several systematic reviews and meta analyses of multiple studies have described the associations of vitamin D deficiency with adverse outcomes in COVID 19 208 209 210 One found that while deficiency was not associated with a higher probability of becoming infected with COVID 19 there were significant associations between vitamin D deficiency or insufficiency with more severe disease including increases in hospitalization and mortality rates by about 80 210 Two other meta analyses of around 40 studies have shown that the risk of infection was higher in those with vitamin D deficiency 208 209 The vitamin D deficient group had about a two fold risk of disease with greater severity and on some analyses a significant association with higher rates of mortality 208 209 Another reviewing 31 studies reported that patients with COVID 19 tend to have lower 25 OH D levels than healthy subjects but stated that the trend for associations with health outcomes was limited by the low quality of the studies and by the possibility of reverse causality mechanisms 211 In July 2020 the US National Institutes of Health found insufficient evidence to recommend for or against using vitamin D supplementation to prevent or treat COVID 19 212 The UK National Institute for Health and Care Excellence NICE does not recommend to offer a vitamin D supplement to people solely to prevent or treat COVID 19 213 214 Both organizations included recommendations to continue the previous established recommendations on vitamin D supplementation for other reasons such as bone and muscle health as applicable Both organizations noted that more people may require supplementation due to lower amounts of sun exposure during the pandemic 212 213 The major complication of COVID 19 is acute respiratory distress syndrome ARDS which may be aggravated by vitamin D deficiency 215 an association that is not specific to coronavirus infections 215 A number of trials in different countries are underway or have been published looking at the use of vitamin D and its metabolites such as calcifediol in the prevention and treatment of SARS CoV 2 infections 215 216 A meta analysis of three studies on the effect of oral vitamin D or calcifediol supplementation indicated a lower intensive care unit ICU admission rate odds ratio 0 36 compared to those without supplementation but without a change in mortality 217 A Cochrane review also of three studies found the evidence for the effectiveness of vitamin D supplementation for the treatment of COVID 19 to be very uncertain 218 They found there was substantial clinical and methodological heterogeneity in the three studies that were included mainly because of different supplementation strategies vitamin D formulations one using calcifediol pre treatment status and reported outcomes 218 Another meta analysis stated that the use of high doses of vitamin D in COVID 19 patients is not based on solid evidence although calcifediol supplementation may have a protective effect on ICU admissions 211 References Edit a b c d e f g h i j k Office of Dietary Supplements Vitamin D ods od nih gov October 9 2020 Retrieved October 31 2020 a b c d e f g Norman AW August 2008 From vitamin D to hormone D fundamentals of the vitamin D endocrine system essential for good health The American Journal of 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Jakobsen J Knuthsen P April 2014 Stability of vitamin D in foodstuffs during cooking Food Chemistry 148 170 5 doi 10 1016 j foodchem 2013 10 043 PMID 24262542 Wahl DA Cooper C Ebeling PR Eggersdorfer M Hilger J Hoffmann K et al August 29 2012 A global representation of vitamin D status in healthy populations PDF Archives of Osteoporosis 7 1 2 155 72 doi 10 1007 s11657 012 0093 0 hdl 11343 220606 PMID 23225293 S2CID 207300035 Wahl DA Cooper C Ebeling PR Eggersdorfer M Hilger J Hoffmann K et al February 1 2013 A global representation of vitamin D status in healthy populations reply to comment by Saadi Archives of Osteoporosis 8 1 2 122 doi 10 1007 s11657 013 0122 7 PMID 23371520 S2CID 5929230 a b 25 OH D levels in ng mL health harvard edu December 19 2016 nmol converter endmemo Bischoff Ferrari HA 2014 Optimal serum 25 hydroxyvitamin D levels for multiple health outcomes Sunlight Vitamin D and Skin Cancer Advances in Experimental Medicine and Biology Review 810 pp 500 25 doi 10 1007 978 0 387 77574 6 5 ISBN 978 0 387 77573 9 PMID 25207384 a b Dahlquist DT Dieter BP Koehle MS 2015 Plausible ergogenic effects of vitamin D on athletic performance and recovery Journal of the International Society of Sports Nutrition Review 12 33 doi 10 1186 s12970 015 0093 8 PMC 4539891 PMID 26288575 Engelman CD Fingerlin TE Langefeld CD Hicks PJ Rich SS Wagenknecht LE et al September 2008 Genetic and environmental determinants of 25 hydroxyvitamin D and 1 25 dihydroxyvitamin D levels in Hispanic and African Americans The Journal of Clinical Endocrinology and Metabolism 93 9 3381 8 doi 10 1210 jc 2007 2702 PMC 2567851 PMID 18593774 Wang L Song Y Manson JE Pilz S Marz W Michaelsson K et al November 2012 Circulating 25 hydroxy vitamin D and risk of cardiovascular disease a meta analysis of prospective studies Circulation Cardiovascular Quality and Outcomes 5 6 819 29 doi 10 1161 CIRCOUTCOMES 112 967604 PMC 3510675 PMID 23149428 a b Ross AC Manson JE Abrams SA Aloia JF Brannon PM Clinton SK et al January 2011 The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine what clinicians need to know The Journal of Clinical Endocrinology and Metabolism 96 1 53 8 doi 10 1210 jc 2010 2704 PMC 3046611 PMID 21118827 a b c Vitamin D at Merck Manual of Diagnosis and Therapy Professional Edition a b c d Vieth R May 1999 Vitamin D supplementation 25 hydroxyvitamin D concentrations and safety PDF The American Journal of Clinical Nutrition 69 5 842 56 doi 10 1093 ajcn 69 5 842 PMID 10232622 Tolerable Upper Intake Limits for Vitamins And Minerals PDF European Food Safety Authority December 2006 ISBN 978 92 9199 014 6 Schlingmann KP Kaufmann M Weber S Irwin A Goos C John U et al August 2011 Mutations in CYP24A1 and idiopathic infantile hypercalcemia The New England Journal of Medicine 365 5 410 21 doi 10 1056 NEJMoa1103864 PMID 21675912 De Paolis E Scaglione GL De Bonis M Minucci A Capoluongo E October 2019 CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia from genotype to phenotype Clinical Chemistry and Laboratory Medicine 57 11 1650 1667 doi 10 1515 cclm 2018 1208 PMID 31188746 Tebben PJ Singh RJ Kumar R October 2016 Vitamin D Mediated Hypercalcemia Mechanisms Diagnosis and Treatment Endocrine Reviews 37 5 521 547 doi 10 1210 er 2016 1070 PMC 5045493 PMID 27588937 FDA Cautions on Accurate Vitamin D Supplementation for Infants Press release Food and Drug Administration FDA June 15 2010 Archived from the original on January 12 2017 This article incorporates text from this source which is in the public domain Olmos Ortiz A Avila E Durand Carbajal M Diaz L January 2015 Regulation of calcitriol biosynthesis and activity focus on gestational vitamin D deficiency and adverse pregnancy outcomes Nutrients 7 1 443 80 doi 10 3390 nu7010443 PMC 4303849 PMID 25584965 a b Holick MF 1992 Evolutionary biology and pathology of vitamin D Journal of Nutritional Science and Vitaminology Spec No 79 83 doi 10 3177 jnsv 38 Special 79 PMID 1297827 Holick MF April 1987 Photosynthesis of vitamin D in the skin effect of environmental and life style variables Federation Proceedings 46 5 1876 82 PMID 3030826 Deluca HF January 2014 History of the discovery of vitamin D and its active metabolites BoneKEy Reports 3 479 doi 10 1038 bonekey 2013 213 PMC 3899558 PMID 24466410 a b Holick MF March 2004 Vitamin D importance in the prevention of cancers type 1 diabetes heart disease and osteoporosis The American Journal of Clinical Nutrition 79 3 362 71 doi 10 1093 ajcn 79 3 362 PMID 14985208 Eyley SC Williams DH 1975 Photolytic production of vitamin D The preparative value of a photo sensitiser Journal of the Chemical Society Chemical Communications 20 858a doi 10 1039 C3975000858A Crissey SD Ange KD Jacobsen KL Slifka KA Bowen PE Stacewicz Sapuntzakis M et al January 2003 Serum concentrations of lipids vitamin d metabolites retinol retinyl esters tocopherols and selected carotenoids in twelve captive wild felid species at four zoos The Journal of Nutrition 133 1 160 6 doi 10 1093 jn 133 1 160 PMID 12514284 Holick MF 2018 Chapter 4 Photobiology of Vitamin D In Feldman D Pike JW Bouillon R Giovannucci E Goltzman D Hewison M eds Vitamin D Volume 1 Biochemistry Physiology and Diagnostics 4th ed London UK Academic Press ISBN 978 0 12 809965 0 Holick MF 2020 Sunlight UV Radiation Vitamin D and Skin Cancer How Much Sunlight Do We Need Advances in Experimental Medicine and Biology 1268 19 36 doi 10 1007 978 3 030 46227 7 2 ISBN 978 3 030 46226 0 PMID 32918212 S2CID 221636019 108 references Holick MF February 2002 Vitamin D the underappreciated D lightful hormone that is important for skeletal and cellular health Current Opinion in Endocrinology Diabetes and Obesity 9 1 87 98 doi 10 1097 00060793 200202000 00011 S2CID 87725403 Bikle DD March 2010 Vitamin D and the skin Journal of Bone and Mineral Metabolism 28 2 117 30 doi 10 1007 s00774 009 0153 8 PMID 20107849 S2CID 6072459 Holick MF April 1 2010 The Vitamin D Solution A 3 Step Strategy to Cure Our Most Common Health Problems Penguin Publishing Group ISBN 978 1 101 22293 5 Agarwal SC Stout SD June 28 2011 Bone Loss and Osteoporosis An Anthropological Perspective Springer Science amp Business Media ISBN 978 1 4419 8891 1 Archived PDF from the original on January 29 2006 The high 25 OH D concentrations and relatively high vitamin D requirements of apes and monkeys are understandable in light of their biology their body surface area relative to mass is generally greater than for humans and they are inveterate groomers consuming by mouth the vitamin D generated from the oils secreted by skin into fur Although much of the vitamin D produced within human skin is absorbed directly birds and furbearing animals acquire most of their vitamin D orally as they groom themselves Bicknell and Prescott 1946 Carpenter and Zhao 1999 Vitamin D is generated from the oily secretions of skin into fur The oral consumption of UV exposed dermal excretion is the way many animals acquire the nutrient vitamin D Although Fraser 1983 has argued that dermal absorption of vitamin D may be more natural what we know from animals indicates that oral consumption is equally physiological Since vitamin D can be extracted from UV exposed human sweat and skin secretions Bicknell and Prescott 1946 it is also reasonable to think that early humans obtained some of their vitamin D by mouth as well by licking the skin Yahav S Buffenstein R January 1993 Cholecalciferol supplementation alters gut function and improves digestibility in an underground inhabitant the naked mole rat Heterocephalus glaber when fed on a carrot diet The British Journal of Nutrition 69 1 233 41 doi 10 1079 BJN19930025 PMID 8384476 Zafalon Rafael V A Risolia Larissa W Pedrinelli Vivian Vendramini Thiago H A Rodrigues Roberta B A Amaral Andressa R Kogika Marcia M Brunetto Marcio A January 2020 Vitamin D metabolism in dogs and cats and its relation to diseases not associated with bone metabolism Journal of Animal Physiology and Animal Nutrition 104 1 322 342 doi 10 1111 jpn 13259 PMID 31803981 a b Holick MF November 2005 The vitamin D epidemic and its health consequences PDF The Journal of Nutrition 135 11 2739S 48S doi 10 1093 jn 135 11 2739S PMID 16251641 Vitamin D3 is produced commercially by extracting 7 dehydrocholesterol from wool fat followed by UVB irradiation and purification Vitamin D2 is commercially made by irradiating and then purifying the ergosterol extracted from yeast Takeuchi A Okano T Sayamoto M Sawamura S Kobayashi T Motosugi M Yamakawa T February 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 doi 10 3177 jnsv 32 13 PMID 3012050 a b c d Adams JS Hewison M February 2010 Update in vitamin D The Journal of Clinical Endocrinology and Metabolism 95 2 471 8 doi 10 1210 jc 2009 1773 PMC 2840860 PMID 20133466 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 Proceedings of the National Academy of Sciences of the United States of America 101 20 7711 5 Bibcode 2004PNAS 101 7711C doi 10 1073 pnas 0402490101 PMC 419671 PMID 15128933 Laing CJ Cooke NE 2004 Section I Ch 8 Vitamin D Binding Protein In Feldman D Glorieux FH Pike JW eds Vitamin D 1 2 ed Academic Press pp 117 134 ISBN 978 0122526879 Holick MF Kleiner Bossaller A Schnoes HK Kasten PM Boyle IT DeLuca HF October 1973 1 24 25 Trihydroxyvitamin D3 A metabolite of vitamin D3 effective on intestine The Journal of Biological Chemistry 248 19 6691 6 doi 10 1016 S0021 9258 19 43408 X PMID 4355503 Horst RL Reinhardt TA Ramberg CF Koszewski NJ Napoli JL July 1986 24 Hydroxylation of 1 25 dihydroxyergocalciferol An unambiguous deactivation process The Journal of Biological Chemistry 261 20 9250 6 doi 10 1016 S0021 9258 18 67647 1 PMID 3013880 Carere S July 25 2007 Age old children s disease back in force Toronto Star Archived from the original on May 17 2008 Retrieved August 24 2010 McClean FC Budy AM January 28 1964 Vitamin A Vitamin D Cartilage Bones and Teeth Vitamins and Hormones 21 Academic Press pp 51 52 ISBN 978 0 12 709821 0 History of Vitamin D University of California at Riverside 2011 Archived from the original on October 16 2017 Retrieved May 9 2014 Adolf Windaus Biography Nobelprize org March 25 2010 Retrieved March 25 2010 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 Askew FA Bourdillon RB Bruce HM Callow RK St L Philpot J Webster TA 1932 Crystalline Vitamin D Proceedings of the Royal Society of London Series B Containing Papers of a Biological Character 109 764 488 506 doi 10 1098 rspb 1932 0008 JSTOR 81571 Hirsch AL 2011 Industrial aspects of vitamin D In Feldman DJ Pike JW Adams JS eds Vitamin D Academic Press p 73 ISBN 978 0 12 387035 3 Ziedonis AA Mowery DC Nelson RR Bhaven NS 2004 Ivory tower and industrial innovation university industry technology transfer before and after the Bayh Dole Act in the United States Stanford Business Books pp 39 40 ISBN 978 0 8047 4920 6 Marshall J September 2010 Elbridge a Stuart Founder of Carnation Company Kessinger Publishing ISBN 978 1 164 49678 6 Haussler MR Norman AW January 1969 Chromosomal receptor for a vitamin D metabolite Proceedings of the National Academy of Sciences of the United States of America 62 1 155 62 Bibcode 1969PNAS 62 155H doi 10 1073 pnas 62 1 155 PMC 285968 PMID 5253652 Holick MF DeLuca HF Avioli LV January 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 Dankers W Colin EM van Hamburg JP Lubberts E 2016 Vitamin D in Autoimmunity Molecular Mechanisms and Therapeutic Potential Frontiers in Immunology 7 697 doi 10 3389 fimmu 2016 00697 PMC 5247472 PMID 28163705 a b Heaney RP Holick MF March 2011 Why the IOM recommendations for vitamin D are deficient Journal of Bone and Mineral Research 26 3 455 7 doi 10 1002 jbmr 328 PMID 21337617 S2CID 41510449 ODS Vitamin D Initiative Office of Dietary Supplements US National Institutes of Health 2014 Pyrzak B Witkowska Sedek E Krajewska M Demkow U Kucharska AM 2015 Metabolic and immunological consequences of vitamin D deficiency in obese children Body Metabolism and Exercise Advances in Experimental Medicine and Biology 840 pp 13 9 doi 10 1007 5584 2014 81 ISBN 978 3 319 10249 8 PMID 25315624 Khan SU Khan MU Riaz H Valavoor S Zhao D Vaughan L et al August 2019 Effects of Nutritional Supplements and Dietary Interventions on Cardiovascular Outcomes An Umbrella Review and Evidence Map Annals of Internal Medicine 171 3 190 198 doi 10 7326 m19 0341 PMC 7261374 PMID 31284304 Vitamin D and cancer prevention National Cancer Institute US National Institutes of Health October 21 2013 Martineau AR Jolliffe DA Hooper RL Greenberg L Aloia JF Bergman P et al February 2017 Vitamin D supplementation to prevent acute respiratory tract infections systematic review and meta analysis of individual participant data BMJ 356 i6583 doi 10 1136 bmj i6583 PMC 5310969 PMID 28202713 a b c Kazemi A Mohammadi V Aghababaee SK Golzarand M Clark CC Babajafari S March 2021 Association of Vitamin D Status with SARS CoV 2 Infection or COVID 19 Severity A Systematic Review and Meta analysis Advances in Nutrition doi 10 1093 advances nmab012 PMC 7989595 PMID 33751020 a b c Petrelli F Luciani A Perego G Dognini G Colombelli PL Ghidini A March 2021 Therapeutic and prognostic role of vitamin D for COVID 19 infection A systematic review and meta analysis of 43 observational studies The Journal of Steroid Biochemistry and Molecular Biology 211 105883 doi 10 1016 j jsbmb 2021 105883 PMC 7997262 PMID 33775818 a b Damascena AD Azevedo LM Oliveira TA Santana JD Pereira M August 2021 Addendum to vitamin D deficiency aggravates COVID 19 systematic review and meta analysis Critical Reviews in Food Science and Nutrition 1 6 doi 10 1080 10408398 2021 1951652 PMID 34384300 S2CID 236997712 a b Bassatne A Basbous M Chakhtoura M Zein OE Rahme M Fuleihan GE March 2021 The link between COVID 19 and Vitamin D VIVID a systematic review and meta analysis Metabolism Systematic review 119 154753 doi 10 1016 j metabol 2021 154753 PMC 7989070 PMID 33774074 a b Vitamin D Coronavirus Disease 2019 COVID 19 Treatment Guidelines National Institutes of Health NIH July 17 2020 Retrieved February 22 2021 This article incorporates text from this source which is in the public domain a b COVID 19 rapid guideline vitamin D PDF Technical report National Institute for Health and Care Excellence NICE December 2020 ISBN 978 1 4731 3942 8 NG187 Retrieved February 22 2021 Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID 19 PDF Report National Institute for Health and Care Excellence NICE December 2020 a b c Quesada Gomez JM Entrenas Castillo M Bouillon R September 2020 Vitamin D receptor stimulation to reduce acute respiratory distress syndrome ARDS in patients with coronavirus SARS CoV 2 infections Revised Ms SBMB 2020 166 The Journal of Steroid Biochemistry and Molecular Biology 202 105719 doi 10 1016 j jsbmb 2020 105719 PMC 7289092 PMID 32535032 International clinical trials assessing vitamin D in people with COVID 19 ClinicalTrials gov US National Library of Medicine May 2020 Retrieved June 11 2021 Shah K Saxena D Mavalankar D January 2021 Vitamin D supplementation COVID 19 amp Disease Severity A meta analysis QJM Monthly Journal of the Association of Physicians 114 3 175 181 doi 10 1093 qjmed hcab009 PMC 7928587 PMID 33486522 a b Stroehlein JK Wallqvist J Iannizzi C Mikolajewska A Metzendorf MI Benstoem C et al May 2021 Vitamin D supplementation for the treatment of COVID 19 a living systematic review The Cochrane Database of Systematic Reviews 2021 5 CD015043 doi 10 1002 14651858 CD015043 PMC 8406457 PMID 34029377 S2CID 235202971 Further reading EditNIH Vitamin D Fact Sheet for Health Professionals from the U S National Institutes of HealthExternal links Edit Vitamin D Drug Information Portal U S National Library of Medicine Ergocalciferol Drug Information Portal U S National Library of Medicine Cholecalciferol Drug Information Portal U S National Library of Medicine Vitamin D4 Drug Information Portal U S National Library of Medicine Vitamin D5 Drug Information Portal U S National Library of Medicine Retrieved from https en wikipedia org w index php title Vitamin D amp oldid 1054012058, wikipedia, wiki, book,

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