Vitamin D Explained

Synonyms:Calciferols
Imageclass:skin-invert-image
Use:Rickets, osteoporosis, osteomalacia, vitamin D deficiency
Atc Prefix:A11CC
Biological Target:vitamin D receptor

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions.[1] [2] In humans, the most significant compounds within this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).[3]

The primary natural source of vitamin D is the synthesis of cholecalciferol in the lower layers of the skin’s epidermis, triggered by a photochemical reaction with ultraviolet B (UV-B) radiation from sunlight or UV-B lamps. Cholecalciferol and ergocalciferol can also be obtained through diet and supplements. Foods such as the flesh of fatty fish are good sources of vitamin D, though there are few other foods where it naturally appears in significant amounts.[4] In the U.S. and other countries, cow's milk and plant-based milk substitutes are fortified with vitamin D, as are many breakfast cereals. Mushrooms exposed to ultraviolet light also provide useful amounts of vitamin D2.[5] Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, given the variability in sunlight exposure among the population and uncertainties regarding safe levels of sunlight exposure, particularly due to the associated risk of skin cancer.

Vitamin D obtained from the diet or synthesised in the skin is biologically inactive. It becomes active by two enzymatic hydroxylation steps, the first occurring in the liver and the second in the kidneys. Since most mammals can synthesise sufficient vitamin D with adequate sunlight exposure, it is technically not essential in the diet and thus not a true vitamin. Instead, it functions as a hormone; the activation of the vitamin D pro-hormone produces calcitriol, the active form. Calcitriol then exerts its effects via the vitamin D receptor, a nuclear receptor found in various tissues throughout the body.[6]

Cholecalciferol is converted in the liver to calcifediol (also known as calcidiol or 25-hydroxycholecalciferol), while ergocalciferol is converted to ercalcidiol (25-hydroxyergocalciferol). These two vitamin D metabolites, collectively referred to as 25-hydroxyvitamin D or 25(OH)D, are measured in serum to assess a person's vitamin D status.[7] Calcifediol is further hydroxylated by the kidneys and certain immune cells to form calcitriol (1,25-dihydroxycholecalciferol), the biologically active form of vitamin D. Calcitriol circulates in the blood as a hormone, playing a major role in regulating calcium and phosphate concentrations, as well as promoting bone health and bone remodeling.

The discovery of vitamin D was due to effort to identify the dietary deficiency in children with rickets, the childhood form of osteomalacia.[8] The evidence for other health benefits of vitamin D supplementation in individuals who are already vitamin D sufficient is inconsistent. The effect of vitamin D supplementation on morbidity and mortality is also unclear, with one meta-analysis finding a small decrease in mortality in elderly people. Except for the prevention of rickets and osteomalacia in high-risk groups, any benefit of vitamin D supplements to musculoskeletal or general health may be small and in some cases, may have adverse effects on health.[9]

Types

NameChemical compositionStructure
Vitamin D1Mixture of molecular compounds of ergocalciferol with lumisterol, 1:1
Vitamin D2ergocalciferol (made from ergosterol)
Vitamin D3cholecalciferol(made from 7-dehydrocholesterol in the skin).
Vitamin D422-dihydroergocalciferol
Vitamin D5sitocalciferol(made from 7-dehydrositosterol)

Several forms (vitamers) of vitamin D exist, with the two major forms being vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol.[1] The term 'vitamin D' 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. Although a chemical nomenclature for vitamin D forms was recommended in 1981,[10] alternative names remain commonly used.

Chemically, the various forms of vitamin D are secosteroids, meaning that one of the bonds in the steroid rings is broken.[11] The structural difference between vitamin D2 and vitamin D3 lies in the side chain: vitamin D2 has a double bond between carbons 22 and 23, and a methyl group on carbon 24. Numerous vitamin D analogues have also been synthesized.

Biology

The active vitamin D metabolite, calcitriol, exerts its biological effects by binding to the vitamin D receptor (VDR), which is primarily located in the nuclei of target cells.[1] When calcitriol binds to the VDR, it enables the receptor to act as a transcription factor, modulating the gene expression of transport proteins involved in calcium absorption in the intestine, such as TRPV6 and calbindin.[12] The VDR is part of the nuclear receptor superfamily of steroid hormone receptors, which are hormone-dependent regulators of gene expression. These receptors are expressed in cells across most organs.

Activation of VDR in the intestine, bone, kidney, and parathyroid gland cells plays a crucial role in maintaining calcium and phosphorus levels in the blood, a process that is assisted by parathyroid hormone and calcitonin, thereby supporting bone health.[1] [13]

One of the most important functions of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast numbers, maintaining calcium and phosphate levels necessary for bone formation, and facilitating the proper function of parathyroid hormone to sustain serum calcium levels.[1] Vitamin D deficiency can lead to decreased bone mineral density, increasing the risk of osteoporosis and bone fractures due to its impact on mineral metabolism.Consequently, vitamin D is also important for bone remodeling, acting as a potent stimulator of bone resorption.[14]

The VDR also regulates cell proliferation and differentiation. Additionally, vitamin D influences the immune system, with VDRs being expressed in several white blood cells, including monocytes and activated T and B cells.[15] In vitro studies indicate that vitamin D increases the expression of the tyrosine hydroxylase gene in adrenal medullary cells and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione, which may control the body's response and adaption to stress.[16] VDR expression decreases with age.[1]

Deficiency

See main article: Vitamin D deficiency.

A diet insufficient in vitamin D, combined with inadequate sunlight exposure, can lead to vitamin D deficiency, which is defined as a blood 25-hydroxyvitamin D or 25(OH)D level below 12 ng/mL (30 nmol/liter). Vitamin D insufficiency is characterized by a blood 25(OH)D level between 12–20 ng/mL (30–50 nmol/liter).[2] [17] It is estimated that one billion adults worldwide are either vitamin D insufficient or deficient, including those in developed countries across Europe.[18] Severe vitamin D deficiency in children, although rare in the developed world, can cause a softening and weakening of growing bones, leading to a condition known as rickets.[19]

Vitamin D deficiency is prevalent globally, particularly among the elderly, and remains common in both children and adults.[20] [21] [22] This deficiency impairs bone mineralization and causes bone damage, leading to bone-softening diseases such as rickets in children and osteomalacia in adults.[23] Low blood calcifediol (25-hydroxyvitamin D3) levels can result from limited sun exposure.[24] When vitamin D levels are deficient, the total absorption of dietary calcium can decrease from the normal range of 60–80% to 15%.

Dark-skinned individuals living in temperate climates are more likely to have low vitamin D levels.[25] [26] [27] This is because melanin in the skin, which hinders vitamin D synthesis, makes dark-skinned individuals less efficient at producing vitamin D.[28] In the U.S., vitamin D deficiency is particularly common among Hispanic and African-American populations.[17]

Excess

Vitamin D toxicity, or hypervitaminosis D, is the toxic state of an excess of vitamin D. There is no general agreement about the intake levels at which vitamin D may cause harm. From a review of the human trial literature, "Doses below 10,000 IU/day are not usually associated with toxicity, whereas doses equal to or above 50,000 IU/day for several weeks or months are frequently associated with toxic side effects including documented hypercalcemia." The normal range for blood concentration of 25-hydroxyvitamin D in adults is 20 to 50 nanograms per milliliter (ng/mL). Blood levels necessary to cause adverse effects in adults are thought to be greater than about 150 ng/mL. An excess of vitamin D causes abnormally hypercalcaemia (high blood concentrations of calcium), which can cause overcalcification of the bones and soft tissues including arteries, heart, and kidneys. Untreated, can lead to irreversible kidney failure. Symptoms of vitamin D toxicity may include the following: increased thirst, increased urination, nausea, vomiting, diarrhea, decreased appetite, irritability, constipation, fatigue, muscle weakness, and insomnia. In almost every case, stopping the vitamin D supplementation combined with a low-calcium diet and corticosteroid drugs will allow for a full recovery within a month.[22] [23] [29]

In 2011, the U.S. National Academy of Medicine revised tolerable upper intake levels (UL) to protect against vitamin D toxicity. Before the revision the UL for ages 9+ years was 50 μg/d (2000 IU/d). Per the revision: "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."[30] The U.S. ULs in microgram (mcg or μg) and International Units (IU) for both males and females, by age, are:

As shown in the Dietary intake section, different government organizations have set different ULs for age groups, but there is accord on the adult maximum of 100 μg/d (4000 IU/d). In contrast, some non-government authors have proposed a safe upper intake level of 250 μg (10,000 IU) per day in healthy adults.[31] [32] In part, this is based on the observation that endogenous skin production with full body exposure to sunlight or use of tanning beds is comparable to taking an oral dose between 250 μg and 625 μg (10,000 IU and 25,000 IU) per day and maintaining blood concentrations on the order of 100 ng/mL.[33]

Although in the U.S. the adult UL is set at 4000 IU/day, over-the-counter products are available at 5000 and 10000 IU. The percentage of the U.S. population taking over 4000 IU/day has increased since 1999.[34]

Special cases

People with primary hyperparathyroidism, are more sensitive to vitamin D supplementation, and as a consequence may develop hypercalcemia.[35] Idiopathic infantile hypercalcemia is caused by a mutation of the CYP24A1 gene, leading to a reduction in the degradation of vitamin D. Infants who have such a mutation have an increased sensitivity to vitamin D and in case of additional intake a risk of hypercalcaemia.[36] The disorder can continue into adulthood.[37]

Health effects

Supplementation with vitamin D is a reliable method for preventing or treating rickets. On the other hand, the effects of vitamin D supplementation on non-skeletal health are uncertain.[38] [39] A 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.[40] Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis.[41]

A US 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 intake of either calcium or vitamin D, and were often conflicting."[42] 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.[43]

Mortality, all-causes

Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly,[40] 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 concerning the risk of death.[44] High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit.[45] Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.[46] [47] 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.[42] Harm from vitamin D appears to occur at a lower vitamin D level in the dark-skinned Canadian and United States populations which have been studied than in the light-skinned Canadian and United States populations that have been studied. Whether this is so with dark-skinned populations in other parts of the world is unknown.

Bone health

Rickets

See 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. Maternal vitamin D deficiency can cause fetal bone defects from before birth and impairment of bone quality after birth.[48] [49] Rickets typically appear between 3 and 18 months of age.[50] This condition can be caused by vitamin D, calcium or phosphorus deficiency.[51] Vitamin D deficiency remains the main cause of rickets among young infants in most countries because breast milk is low in vitamin D, and darker skin, social customs, and climatic conditions can contribute to inadequate sun exposure. A post-weaning Western omnivore diet characterized by high intakes of meat, fish, eggs and vitamin D fortified milk is protective, whereas low intakes of those foods and high cereal/grain intake contribute to risk.[52] [53] [54] For young children with rickets, supplementation with vitamin D plus calcium was superior to the vitamin alone for bone healing.[55]

Osteomalacia and osteoporosis

See main article: Osteomalacia and Osteoporosis. Characteristics of osteomalacia are softening of the bones, leading to bending of the spine, bone fragility, and increased risk for fractures.[1] Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10ng/mL.[56] Osteomalacia progress to osteoporosis, 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, the latter contributing by reducing calcium absorption.[2] In the absence of confirmed vitamin D deficiency there is no evidence that vitamin D supplementation without concomitant calcium slows or stops the progression of osteomalacia to osteoporosis.[57] 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.[58] [59] The reduced rick for fractures is not seen in healthier, community-dwelling elderly.[60] [61] Low serum vitamin D levels have been associated with falls,[62] but taking extra vitamin D does not appear to reduce that risk.[63]

Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or major breaks, particularly those engaging in contact sports. Incremental decreases in risk are observed with rising serum 25(OH)D concentrations plateauing at 50ng/mL with no additional benefits seen in levels beyond this point.[64]

Cancer

While serum low 25-hydroxyvitamin D status has been associated with a higher risk of cancer in observational studies,[65] [66] [67] the general conclusion is that there is insufficient evidence for an effect of vitamin D supplementation on the risk of cancer,[2] [68] [69] although there is some evidence for reduction in cancer mortality.[70]

Cardiovascular disease

Vitamin D supplementation is not associated with a reduced risk of stroke, cerebrovascular disease, myocardial infarction, or ischemic heart disease.[71] [72] [73] Supplementation does not lower blood pressure in the general population.[74] [75] [76] One meta-analysis found a small increase in risk of stroke when calcium and vitamin D supplements were taken together.[77]

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.[78] [79] Low serum levels of vitamin D appear to be a risk factor for tuberculosis.[80] However, supplementation trials showed no benefit.[81] [82] Vitamin D supplementation at low doses may slightly decrease the overall risk of acute respiratory tract infections.[83] The benefits were found in children and adolescents, and were not confirmed with higher doses.

Inflammatory bowel disease

Vitamin D deficiency has been linked to the severity of inflammatory bowel disease (IBD).[84] However, whether vitamin D deficiency causes IBD or is a consequence of the disease is not clear.[85] Supplementation leads to improvements in scores for clinical inflammatory bowel disease activity and biochemical markers and[86] less frequent relapse of symptoms in IBD.

COVID-19

the US National Institutes of Health state there is insufficient evidence to recommend for or against using vitamin D supplementation to prevent or treat COVID-19.[87] 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.[88] [89] 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.

Vitamin D deficiency and insufficiency have been associated with adverse outcomes in COVID-19.[90] [91] [92] [93] [94] [95] A review of supplement trials indicated a lower intensive care unit (ICU) admission rate compared to those without supplementation, but without a change in mortality,[96] but another review considered the evidence for treatment of COVID-19 to be very uncertain.[97] Another meta-analysis stated that the use of high doses of vitamin D in people with COVID-19 is not based on solid evidence although calcifediol supplementation may have a protective effect on ICU admissions.[93]

Other conditions

Chronic obstructive pulmonary disease

Vitamin D supplementation substantially reduced the rate of moderate or severe exacerbations of chronic obstructive pulmonary disease (COPD).[98]

Asthma

Vitamin D supplementation does not help prevent asthma attacks or alleviate symptoms.[99]

Diabetes

A meta-analysis reported that vitamin D supplementation significantly reduced the risk of type 2 diabetes for non-obese people with prediabetes.[100] Another meta-analysis reported 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.[101] In prospective studies, high versus low levels of vitamin D were respectively associated with a significant decrease in risk of type 2 diabetes, combined type 2 diabetes and prediabetes, and prediabetes.[102] A 2011 Cochrane systematic review examined one study that showed vitamin D together with insulin maintained levels of fasting C-peptide after 12 months better than insulin alone. However, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.[103]

Attention deficit hyperactivity disorder (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.[104] Several small, randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.[105]

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.[106]

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.[107]

Schizophrenia

People diagnosed with schizophrenia tend to have lower serum vitamin D concentrations compared to those without the condition. This may be a consequence of the disease rather than a cause, due, for example, to low dietary vitamin D and less time spent exposed to sunlight.[108] [109] Results from supplementation trials have been inconclusive.[108]

Pregnancy

Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small (for gestational age) infants.[110] Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term,[111] the full extent of benefits for the mother or baby is unclear.[110] [111] [112] [113] Pregnant women often do not take the recommended amount of vitamin D,[114] however, the benefits and risk of vitamin D supplementation during pregnancy have not been well studied.

Obesity

Obesity increases the risk of having low serum vitamin D. Supplementation does not lead to weight loss, but weight loss increases serum vitamin D. The theory is that fatty tissue sequesters vitamin D.[115]

Uterine fibroids

There is evidence that the pathogenesis of uterine fibroids is associated with low serum vitamin D and that supplementation reduces the size of fibroids.[116] [117]

Allowed health claims

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

Europe: European Food Safety Authority (EFSA)

US: Food and Drug Administration (FDA)

Canada: Health Canada

Japan: Foods with Nutrient Function Claims (FNFC)

Australia-New Zealand.

Dietary intake

United Kingdom
Age groupIntake (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 groupRDA (IU/day)(μg/day)
Infants 0–6 months 400* 10
Infants 6–12 months 400* 10
1–70 years 600 15
Adults > 70 years 800 20
Pregnant/Lactating 600 15
Age groupTolerable 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 groupRDA (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 groupAdequate 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 groupAdequate 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

Recommended levels

Various government 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.[2] [42] Conversion: 1μg (microgram) = 40IU (international unit).

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.[123] 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 those who are pregnant and breastfeeding, consider taking a daily supplement containing 10μg (400 IU) of vitamin D during autumn and winter because of inadequate sunlight for vitamin D synthesis.[124]

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.[42] 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."[42] 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.[42]

For US 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 in May 2016, it was revised to 800IU (20μg) to bring it into agreement with the recommended dietary allowance (RDA).[125] [126] A table of the old and new adult daily values is provided at Reference Daily Intake.

Canada

Health Canada published recommended dietary intakes (DRIs) and tolerable upper intake levels (ULs) for vitamin D based on the jointly commissioned and funded Institute of Medicine 2010 report.[42] [127]

Australia and New Zealand

Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in 2006.[128] About a third of Australians have vitamin D deficiency.[129] [130]

European Union

The European Food Safety Authority (EFSA) in 2016[131] 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 intake 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).[131]

The EFSA reviewed safe levels of intake in 2012,[132] 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.[133]

Non-government organisations in Europe have made their own recommendations. The German Society for Nutrition recommends 20μg.[134] 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.[135]

Sources

In general, vitamin D3 is found in animal source foods, particularly fish, meat, offal, egg, and dairy.[136] It is commonly added as a fortification in manufactured foods.[42] Vitamin D2 is found in fungi and is produced by ultraviolet irradiation of ergosterol.[137] The vitamin D2 content in mushrooms increases with exposure to ultraviolet light,[138] and is stimulated by industrial ultraviolet lamps for fortification.[137] The United States Department of Agriculture reports D2 and D3 content combined in one value.

Natural sources

Animal sources
Source[139] IU/g
Cooked egg yolk0.7
Beef liver, cooked, braised0.5
Fish liver oils, such as cod liver oil100
Fatty fish species
Salmon, pink, cooked, dry heat5.2
Mackerel, Pacific and jack, mixed species, cooked, dry heat4.6
Tuna, canned in oil2.7
Sardines, canned in oil, drained1.9
Fungal sources
Sourceμg/gIU/g
Agaricus bisporus (common mushroom): D2 + D3
PortobelloRaw0.0030.1
Exposed to ultraviolet light0.114.46
CriminiRaw0.0010.03
Exposed to ultraviolet light0.3212.8

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.[140] [141]

In 2016 in the United States, the Food and Drug Administration (FDA) amended food additive regulations for milk fortification,[142] 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.[143] [144] [145] Plant milks are defined as beverages made from soy, almond, rice, among other plant sources intended as alternatives to dairy milk.[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

Vitamin D content in typical foods is reduced variably by cooking. Boiled, fried and baked foods retained 6989% of original vitamin D.[151]

Recommended serum levels

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.[152] Other countries often use nmol/L.[152] Oneng/mL is approximately equal to 2.5nmol/L.[153]

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).[154] 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.[155] 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.[156] Supplementation to achieve these standard levels could cause harmful vascular calcification.[27]

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.[157]

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.[42]

Biosynthesis

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.[137] [158]

Interactive pathway

Click on icon in lower right corner to open.

Photochemistry

The transformation that converts 7-dehydrocholesterol to vitamin D3 occurs in two steps.[159] [160] 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).[161] 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.

Synthesis in the skin

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 vitamin D receptor.[162] Vitamin D3 is produced photochemically from 7-dehydrocholesterol in the skin of most vertebrate animals, including humans.[163] 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.[164] 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.[165]

For people with low skin melanin, and hence pale skin tone, adequate amounts of vitamin D can be produced with moderate sun exposure to the face, arms and legs averaging 5–30 minutes twice per week, or approximately 25% of the time that would cause minimal sunburn. The darker the skin on the Fitzpatrick scale or the weaker the sunlight, the more minutes of exposure are needed.[166] Vitamin D overdose from UV exposure is impossible: the skin reaches an equilibrium where the vitamin D degrades as fast as it is created.[22]

Evolution

Vitamin D can be synthesized only by a photochemical process. Its production from sterols would have started very early in the evolution of life around the origin of photosynthesis, possibly helping to prevent DNA damage by absorbing UVB, making vitamin D an inactive end product. The familiar vitamin D endocrine machinery containing vitamin D receptor (VDR), various CYP450 enzymes for activation and inactivation, and a vitamin D binding protein (DBP) is found in vertebrates only. Primitive marine vertebrates are thought to absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D, although the function in those without calcified cartilage is unclear.[167] Phytoplankton in the ocean (such as coccolithophore and Emiliania huxleyi) have been photosynthesizing vitamin D for more than 500million years.

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.[158] [168] Land vertebrates have been photosynthesizing vitamin D for more than 350million years.[169]

The 7-dehydrocholesterol is a natural substance in fish organs, especially the liver,[170] in some plants, fungi, algae and lichen.[171] [172] [173]

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.[174] Dogs and cats are practically incapable of vitamin D synthesis due to high activity of 7-dehydrocholesterol reductase, but get vitamin D from prey animals.[175]

Human evolution

During the long period between one and three million years ago, hominids, including ancestors of homo sapiens, underwent several evolutionary changes. A long-term climate shift toward drier conditions promoted life-changes from sedentary forest-dwelling with a primarily plant-based diet toward upright walking/running on open terrain and more meat consumption. One consequence of the shift to a culture that included more physically active hunting was a need for evaporative cooling from sweat, which to be functional, meant an evolutionary shift toward less body hair, as evaporation from sweat-wet hair would have cooled the hair but not the skin underneath.[176] A second consequence was darker skin.[177] The early humans who evolved in the regions of the globe near the equator had permanent large quantities of the skin pigment melanin in their skins, resulting in brown/black skin tones. For people with light skin tone, exposure to UV radiation induces synthesis of melanin causing the skin to darken, i.e., sun tanning. Either way, the pigment is able to provide protection by dissipating up to 99.9% of absorbed UV radiation.[178] In this way, melanin protects skin cells from UVA and UVB radiation damage that causes photoaging and the risk of malignant melanoma, a cancer of melanin cells.[179] Melanin also protects against photodegradation of the vitamin folate in skin tissue, and in the eyes, preserves eye health.

The dark-skinned humans who had evolved in Africa populated the rest of the world through migration some 50,000 to 80,000 years ago.[180] Following settlement in Asia and Europe, the selective pressure for radiation protective skin tone decreased while a need for efficient vitamin D synthesis in skin increased, resulting in low-melanin, lighter skin tones in the rest of the prehistoric world.[181] [182] However, cultural changes such as clothing, indoor living and working, UV-blocking skin products to reduce the risk of sunburn and emigration of dark-skinned people to countries far from the equator have all contributed to an increased incidence of vitamin D insufficiency and deficiency that need to be addressed by food fortification and vitamin D dietary supplements.

Industrial synthesis

Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB and UVC light, followed by purification. The 7-dehydrocholesterol is sourced as an extraction from lanolin, a waxy skin secretion in sheep's wool.[183] Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.[183]

Mechanism of action

Metabolic activation

Vitamin D is carried via the blood 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.[184]

Whether synthesized 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.[185] 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.[186]

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).[1] 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.[1] The activity of CYP27B1 is increased by parathyroid hormone, and also by low calcium or phosphate.[1] 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 intestine, kidneys, and bones. Calcitriol is the most potent natural ligand of the vitamin D receptor, which mediates most of the physiological actions of vitamin D.[1] 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.[3]

Difference between substrates

VitaminD2 (ergocalciferol) and vitaminD3 (cholecalciferol) share a similar mechanism of action as outlined above.[3] Metabolites produced by vitamin D2 are named with an er- or ergo- prefix to differentiate them from the D3-based counterparts (sometimes with a chole- prefix).[10]

It is disputed whether these differences lead to a measurable drop in efficacy (see).

Intracellular mechanisms

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.[1] Transcription of these genes is stimulated and produces greater levels of the proteins that mediate the effects of vitamin D.[3]

Some reactions of the cell to calcitriol appear to be too fast for the classical VDRE transcription pathway, leading to the discovery of various non-genomic actions of vitamin D. The membrane-bound PDIA3 likely serves as an alternate receptor in this pathway.[189] The classical VDR may still play a role.[190]

History

Vitamin D was discovered in 1922.[191] In 1914, American researchers Elmer McCollum and Marguerite Davis had discovered a substance in cod liver oil which later was named "vitamin A".[8] Edward Mellanby, a British researcher, observed that dogs that were fed cod liver oil did not develop rickets, and (wrongly) concluded that vitamin A or a closely associated factor could prevent the disease. In 1922, 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 he believed it was the fourth vitamin to be named.[8] [192] [193]

In 1925, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble substance is produced, now known as vitamin D3.[8] 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.[194] Alfred Fabian Hess, his research associate, stated: "Light equals vitamin D."[195] In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids,[196] and soon thereafter collaborated with Kenneth Callow and others on isolation and characterization of vitamin D.[197] Windaus further clarified the chemical structure of vitamin D.[198]

In 1969, a specific binding protein for vitamin D called the vitamin D receptor was identified.[199] Shortly thereafter, the conversion of vitamin D to calcifediol and then to calcitriol, the biologically active form, was confirmed.[200] The photosynthesis of vitamin D3 in skin via previtamin D3 and its subsequent metabolism was described in 1980. The fact that vitamin D can be synthesized in the skin through exposure to UV light means that technically it is not a vitamin, but rather can be considered a hormone.[201]

Notes and References

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