Unlike the other twelve vitamins, vitamin D is only conditionally essential - in a preindustrial society people had adequate exposure to sunlight and the vitamin was a hormone, as the primary natural source of vitamin D was 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.[2][4] In the U.S. and other countries, cow's milk and plant-based milk substitutes are fortified with vitamin D3, as are many breakfast cereals. Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, given the paucity of sunlight exposure due to urban living, cultural choices for amount of clothing worn when outdoors, and use of sunscreen because of concerns about safe levels of sunlight exposure, including risk of skin cancer.[2][5]
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.[3] 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.[8] 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 the vitamin in 1922 was due to effort to identify the dietary deficiency in children with rickets.[9] Present day, government food fortification programs in some countries and consumption of vitamin D supplements are used to prevent or treat rickets and osteomalacia. The evidence for other health benefits of vitamin D supplementation in individuals who are already vitamin D sufficient is unproven.[2][10][11][12]
Several forms (vitamers) of vitamin D exist, with the two major forms being vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol.[1] The common-use term "vitamin D" refers to both D2 and D3, which were chemically characterized, respectively, in 1931 and 1935. Vitamin D3 was shown to result from the ultraviolet irradiation of 7-dehydrocholesterol. Although a chemical nomenclature for vitamin D forms was recommended in 1981,[13] alternative names remain commonly used.[3]
Chemically, the various forms of vitamin D are secosteroids, meaning that one of the bonds in the steroid rings is broken.[14] 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.[3]
Biology
The role of active vitamin D or calcitriol (orange) in calcium metabolism in the human body.[15]
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][14] 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.[16] 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.
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.[18]
Worldwide, more than one billion people[21] - infants, children, adults and elderly[22] - can be considered vitamin D deficient, with reported percentages dependent on what measurement is used to define "deficient."[23] Deficiency is common in the Middle-East,[22] Asia,[24] Africa[25] and South America,[26] but also exists in North America and Europe[27][22][28][29] Ethnic, dark-skinned immigrant populations in North America, Europe and Australia have a higher percentage of deficiency compared to light-skinned populations that had their origins in Europe.[30][31][32]
Serum 25(OH)D concentration is used as a biomarker for vitamin D deficiency. Units of measurement are either ng/mL or nmol/L, with oneng/mL equal to 2.5nmol/L. There is not a consensus on defining vitamin D deficiency, insufficiency, sufficiency, or optimal for all aspects of health.[23] According to the US Institute of Medicine Dietary Reference Intake Committee, below 30nmol/L significantly increases the risk of vitamin D deficiency caused rickets in infants and young children, and reduces absorption of dietary calcium from the normal range of 60–80% to as low as 15%, whereas above 40nmol/L is needed to prevent osteomalacia bone loss in the elderly, and above 50nmol/L to be sufficient for all health needs.[5] Other sources have defined deficiency as less than 25nmol/L, insufficiency as 30-50nmol/L[33] and optimal as greater than 75nmol/L.[34][35] Part of the controversy is because studies have reported differences in serum levels of 25(OH)D between ethnic groups, with studies pointing to genetic as well as environmental reasons behind these variations. African-American populations have lower serum 25(OH)D than their age-matched white population, but at all ages have superior calcium absorption efficiency, a higher bone mineral density and as elderly, a lower risk of osteoporosis and fractures.[5] Supplementation in this population to achieve proposed 'standard' concentrations could in theory cause harmful vascular calcification in vitamin-sensitive populations.[36]
Using the 25(OH)D assay as a screening tool of the generally healthy population to identify and treat individuals is considered not as cost-effective as a government mandated fortification program. Instead, there is a recommendation that testing should be limited to those showing symptoms of vitamin D deficiency or who have health conditions known to cause vitamin deficiency.[29]
Causes of insufficient vitamin D synthesis in the skin are a combination of insufficient exposure to ultraviolet-B light from sunlight due to living in high latitudes (farther distance from the equator with resultant shorter daylight hours) and sunlight being blocked by air pollution,[37] urban/indoor living, long-term hospitalizations and stays in extended care facilities, cultural or religious lifestyle choices that favors sun-blocking clothing, recommendations to use sun-blocking clothing or sunscreen to reduce risk of skin cancer, and lastly, the UV-B blocking nature of dark skin.[28] Dark-skinned individuals living in temperate climates are more likely to have low vitamin D levels. This is because melanin in the skin, which hinders vitamin D synthesis, makes dark-skinned individuals less efficient at producing vitamin D.[38] In the U.S., vitamin D deficiency is particularly common among Hispanic and African-American populations.[33] Despite the higher incidence of serum concentrations described as deficient, dark-skinned individuals do not necessarily manifest 'deficiency diseases'. [36][39]
Diets of foods that naturally contain vitamin D are rarely sufficient to maintain recommended serum concentration of 25(OH)D in the absence of the contribution of skin synthesis. Governments have mandated or voluntary food fortification programs to bridge the difference in, respectively, 15 and 10 countries.[40] The United States is one of the few mandated countries. The original fortification practices, circa early 1930s, were limited to cow's milk, which had a large effect on reducing infant and child rickets. In July 2016 the US Food and Drug Administration approved the addition of vitamin D to plant milk beverages intended as milk alternatives, such as beverages made from soy, almond, coconut and oats.[41] At an individual level, people may choose to consume a multi-vitamin/mineral product or else a vitamin-D-only product.[42]
There are many disease states, medical treatments and medications that put people at risk for vitamin D deficiency. Chronic diseases that increase risk include kidney and liver failure, Crohn’s disease, inflammatory bowel disease and malabsorption syndromes such as cystic fibrosis, and hyper- or hypo-parathyroidism.[28] Obesity sequesters vitamin D in fat tissues thereby lowering serum levels,[43] but bariatric surgery to treat obesity interferes with dietary vitamin D absorption, also causing deficiency.[44] Medications include antiretrovirals, anti-seizure drugs, glucocorticoids, systemic antifungals such as ketoconazole, cholestyramine and rifampicin.[28]Organ transplant recipients receive immunosuppressive therapy that is associated with an increased risk to develop skin cancer, so they are advised to avoid sunlight exposure, and to take a vitamin D supplement.[45]
Vitamin D toxicity, or hypervitaminosis D, is the toxic state of an excess of vitamin D. It is rare, and requires the consumption of vitamin D dietary supplements.[46] 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."[5] 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.[5] 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.[47][48][49][50]
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).[5] 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."[51] The U.S. ULs in microgram (mcg or μg) and International Units (IU) for both males and females, by age, are:
0–6 months: 25 μg/d (1000 IU/d)
7–12 months: 38 μg/d (1500 IU/d)
1–3 years: 63 μg/d (2500 IU/d)
4–8 years: 75 μg/d (3000 IU/d)
9+ years: 100 μg/d (4000 IU/d)
Pregnant and lactating: 100 μg/d (4000 IU/d)
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.[52][53] 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.[54][5]
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.[42]
Special cases
People with primary hyperparathyroidism, are more sensitive to vitamin D supplementation, and as a consequence may develop hypercalcemia.[55] 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.[56] The disorder can continue into adulthood.[57]
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.[58][59] 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.[60] Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis.[11][61]
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."[5]: 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.[62] 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.[62]
Mortality, all-causes
Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly,[63][60] but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable.[11] Other forms (vitamin D2, alfacalcidol, and calcitriol) do not appear to have any beneficial effects concerning the risk of death.[63] 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] 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.[5] 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.[5]: 435
X-ray of the legs in a two year old child with rickets showing bowing of the femur and low bone density.
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.[67][68] Rickets typically appear between 3 and 18 months of age.[69] This condition can be caused by vitamin D, calcium or phosphorus deficiency.[70] 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.[citation needed] 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.[17][71][72][73] For young children with rickets, supplementation with vitamin D plus calcium was superior to the vitamin alone for bone healing.[74][75]
Calcium and Vitamin D3 are often combined, with claims for adult bone health (This label predates current U.S. Food and Drug Administration regulations on health claims.[76])
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.[77] 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.[10] 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.[78][79] The reduced rick for fractures is not seen in healthier, community-dwelling elderly.[11][80][81] Low serum vitamin D levels have been associated with falls,[82] but taking extra vitamin D does not appear to reduce that risk.[83]
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.[84]
Cancer
While serum low 25-hydroxyvitamin D status has been associated with a higher risk of cancer in observational studies,[85][86][87] the general conclusion is that there is insufficient evidence for an effect of vitamin D supplementation on the risk of cancer,[2][88][89] although there is some evidence for reduction in cancer mortality.[85][90]
In general, vitamin D functions to activate the innate and dampen the adaptive immune systems with antibacterial, antiviral and anti-inflammatory effects.[97][98] Low serum levels of vitamin D appear to be a risk factor for tuberculosis.[99] However, supplementation trials showed no benefit.[100][101] Vitamin D supplementation at low doses may slightly decrease the overall risk of acute respiratory tract infections.[102] The benefits were found in children and adolescents, and were not confirmed with higher doses.[102]
Inflammatory bowel disease
Vitamin D deficiency has been linked to the severity of inflammatory bowel disease (IBD).[103] However, whether vitamin D deficiency causes IBD or is a consequence of the disease is not clear.[104] Supplementation leads to improvements in scores for clinical inflammatory bowel disease activity and biochemical markers and[105][104] less frequent relapse of symptoms in IBD.[104]
As of September 2022[update] 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.[106] 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.[107][108] 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.[106][107]
Vitamin D deficiency and insufficiency have been associated with adverse outcomes in COVID-19.[109][110][111][112][113][114] 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,[115] but another review considered the evidence for treatment of COVID-19 to be very uncertain.[116] 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.[112]
Vitamin D supplementation does not help prevent asthma attacks or alleviate symptoms.[118]
Diabetes
A meta-analysis reported that vitamin D supplementation significantly reduced the risk of type 2 diabetes for non-obese people with prediabetes.[119] 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.[120] 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.[121] A systematic review included one clinical trial that showed vitamin D supplementation together with insulin maintained levels of fasting C-peptide after 12 months better than insulin alone.[122]
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.[123] Several small, randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.[124]
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.[125]
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.[126]
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.[127][128] Results from supplementation trials have been inconclusive.[127]
Pregnancy
Pregnant women often do not take the recommended amount of vitamin D.[129] Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small for gestational age infants.[130] 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.[130][131][132]
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.[43] Bariatric surgery as a treatment for obesity can lead to vitamin deficiencies. Long-term follow-up reported deficiencies for vitamins D, E, A, K and B12, with D the most common at 36%.[44]
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.[133][134]
Allowed health claims
Governmental regulatory agencies stipulate for the food and dietary supplement industries certain health claims as allowable as statements on packaging.
"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."[137]
Japan: Foods with Nutrient Function Claims (FNFC)
"Vitamin D is a nutrient which promotes the absorption of calcium in the gut intestine and aids in the development of bone."[138]
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][5][141][139][140][142]
Conversion: 1μg (microgram) = 40IU (international unit).[139]
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.[139] 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.[144]
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]: 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."[5]: 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.[5]: 403 : 433
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).[145][146] 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.[5][140]
Australia and New Zealand
Australia and New Zealand published nutrient reference values including guidelines for dietary vitamin D intake in 2006.[141] About a third of Australians have vitamin D deficiency.[147][148]
European Union
The European Food Safety Authority (EFSA) in 2016[142] 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).[142]
The EFSA reviewed safe levels of intake in 2012,[143] 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.[149]
Non-government organisations in Europe have made their own recommendations. The German Society for Nutrition recommends 20μg.[150] 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.[151]
Food sources
In general, vitamin D3 is found in animal source foods, particularly fish, meat, offal, egg, and dairy.[152] Vitamin D2 is found in fungi and is produced by ultraviolet irradiation of ergosterol.[153] The vitamin D2 content in mushrooms increases with exposure to ultraviolet light,[154] and is stimulated by industrial ultraviolet lamps for fortification.[153] The United States Department of Agriculture reports D2 and D3 content combined in one value.
Vitamin D content in typical foods is reduced variably by cooking. Boiled, fried and baked foods retained 69–89% of original vitamin D.[156]
Fortification
In the early 1930s, the United States and countries in northern Europe began to fortify milk with vitamin D in an effort to eradicate rickets. This, plus medical advice to expose infants to sunlight, effectively ended the high prevalence of rickets. The proven health benefit of vitamin D led to fortification to many foods, even foods as inappropriate as hot dogs and beer. In the 1950s, due to some highly publicized cases of hypercalcemia and birth defects, vitamin D fortification became regulated, and in some countries discontinued.[157] As of 2024, governments have established mandated or voluntary food fortification programs to combat deficiency in, respectively, 15 and 10 countries.[40] Depending on the country,[40] manufactured foods fortified with either vitamin D2 or D3 may include dairy milk and other dairy foods, fruit juices and fruit juice drinks, meal replacement food bars, soy protein-based beverages, wheat flour or corn meal products, infant formulas, breakfast cereals and 'plant milks',[41][158][27] the last described as beverages made from soy, almond, rice, oats and other plant sources intended as alternatives to dairy milk.[159]
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.[153][160]
Interactive pathway
Click on icon in lower right corner to open.
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
The conversion from ergosterol to vitamin D2 follows a similar procedure, forming previtaminD2 by photolysis, which isomerizes to vitamin D2 (ergocalciferol).[163] 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.[153]: 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).
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.[164] Vitamin D3 is produced photochemically from 7-dehydrocholesterol in the skin of most vertebrate animals, including humans.[165] 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.[166] 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.[167]
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.[168] Vitamin D overdose from UV exposure is impossible: the skin reaches an equilibrium where the vitamin D degrades as fast as it is created.[48]
Evolution
For at least 1.2 billion years, eukaryotes - a classification of life forms that includes single-cell species, fungi, plants and animals, but not bacteria - have been able to synthesize 7-dehydrocholesterol. When this molecule is exposed to ultraviolet-B (UV-B) light from the sun it absorbs the energy in the process of being conveted to vitamin D. The function was to prevent DNA damage, the vitamin molecule at this time being an end product without function. Present day, phytoplankton in the ocean photosynthesize vitamin D without any calcium management function. Ditto some species of algae, lichen, fungi and plants.[169][170][171] Only circa 500 million years ago, when animals began to leave the oceans for land, did the vitamin molecule take on an hormone function as a promoter of calcium regulation. This function required development of a nuclear vitamin D receptor (VDR) that binds the biologically active vitamin D metabolite 1α,25-dihydroxyvitamin (D3), plasma transport proteins and vitamin D metabolizing CYP450 enzymes regulated by calciotropic hormones. The triumvarate of receptor protein, transport and metabolizing enzymes are found only in vertebrates.[172][173][174]
The initial function evolved for control of metabolic genes supporting innate and adaptive immunity. Only later did the VDR system start to functions as an important regulator of calcium supply for a calcified skeleton in land-based vertebrates. From amphibians onward, bone management is biodynamic, with bone functioning as internal calcium reservoir under the control of osteoclasts via the combined action of parathyroid hormone and 1α,25-dihydroxyvitamin D3 Thus, the vitamin D story started as inert molecule but gained an essential role for calcium and bone homeostasis in terrestrial animals to cope with the challenge of higher gravity and calcium-poor environment.[172][173][174]
Most herbivores produce vitamin D in response to sunlight. Llamas and alpacas out of their natural high altitude intense solar radiation environments are susceptible to vitamin D deficiency at low altitudes.[175] Interestingly, domestic dogs and cats are practically incapable of vitamin D synthesis due to high activity of 7-dehydrocholesterol reductase, which converts any 7-dehydrocholesterol in the skin to cholesterol before it can be UV-B light modified, but instead get vitamin D from diet.[176]
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.[177] 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.[178] 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.[179] 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.[180] Melanin also protects against photodegradation of the vitamin folate in skin tissue, and in the eyes, preserves eye health.[177]
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.[181] 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.[174][173][177] 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.[177]
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.[182] Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast as a starting material.[182][183]
Vitamin D is carried via the blood to the liver, where it is converted into the prohormonecalcifediol. 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).[3] 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.[14] Calcitriol is the most potent natural ligand of the vitamin D receptor, which mediates most of the physiological actions of vitamin D.[1][184] 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.[184]
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).[13]
Metabolites produced from vitaminD2 tend to bind less well to the vitamin D-binding protein.[3]
VitaminD3 can alternatively be hydroxylated to calcifediol by sterol 27-hydroxylase (CYP27A1), but vitaminD2 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,[187] whereas ercalcitriol undergoes a 10-fold decrease in activity on conversion to ercalcitetrol.[188]
It is disputed whether these differences lead to a measurable drop in efficacy (see § Food fortification).
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]
Children being given cod liver oil, Cambridgeshire, England, 1944Scott’s Emulsion of Pure Cod Liver Oil Trade Card
In northern European countries, cod liver oil had a long history of folklore medical uses, including applied to the skin and taken orally as a treatment for rheumatism and gout.[191][192] There were several extraction processes. Fresh livers cut to pieces and suspended on screens over pans of boiling water would drip oil that could be skimmed off the water, yielding a pale oil with a mild fish odor and flavor. For industrial purposes such as a lubricant, cod livers were placed in barrels to rot, with the oil skimmed off over months. The resulting oil was light to dark brown, and exceedingly foul smelling and tasting. In the 1800s, cod liver oil became popular as bottled medicinal products for oral consumption - a teaspoon a day - with both pale and brown oils were used.[191] The trigger for the surge in oral use was the observation made in several European countries in the 1820s that young children fed cod liver oil did not develop rickets.[192] Thus, the concept that a food could prevent a disease predated by 100 years the identification of a substance in the food that was responsible.[192] In northen Europe and the United States, the practice of giving children cod liver oil to prevent rickets persisted well in the 1950s.[191] This overlapped with the fortification of cow's milk with vitamin D, which began in the early 1930s.[157]
Vitamin D was identified and named in 1922.[193] In 1914, American researchers Elmer McCollum and Marguerite Davis had discovered a substance in cod liver oil which later was named "vitamin A".[9]Edward Mellanby, a British researcher, observed that dogs that were fed cod liver oil did not develop rickets, and (wrongly) concluded that vitamin A 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 it was the fourth vitamin to be named.[9][194][195]
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.[9]Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928 "...for the services rendered through his research into the constitution of the sterols and their connection with the vitamins.”[196]Alfred Fabian Hess, his research associate, stated: "Light equals vitamin D."[197] In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids,[198] and soon thereafter collaborated with Kenneth Callow and others on isolation and characterization of vitamin D.[199] Windaus further clarified the chemical structure of vitamin D.[200]
In 1969, a specific binding protein for vitamin D called the vitamin D receptor was identified.[201] Shortly thereafter, the conversion of vitamin D to calcifediol and then to calcitriol, the biologically active form, was confirmed.[8] The photosynthesis of vitamin D3 in skin via previtamin D3 and its subsequent metabolism was described in 1980.[202]
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