Vitamin D

Vitamin D

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and multiple other biological effects.[1] In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).[2]

The major natural source of the vitamin is synthesis of cholecalciferol in the lower layers of skin epidermis through a chemical reaction that is dependent on sun exposure (specifically UVB radiation).[3][4] Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements.[2][5][6] Only a few foods, such as the flesh of fatty fish, naturally contain significant amounts of vitamin D.[7][8] In the U.S. and other countries, cow's milk and plant-derived milk substitutes are fortified with vitamin D, as are many breakfast cereals. Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D.[7] Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.[7]

Vitamin D from the diet, or from skin synthesis, is biologically inactive. A protein enzyme must hydroxylate it to convert it to the active form. This is done in the liver and in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals exposed to sufficient sunlight, it is not an essential dietary factor, although not technically a vitamin.[6] Instead it could be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations.[6]

Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status.[9][10] Calcifediol is further hydroxylated by the kidneys to form calcitriol (also known as 1,25-dihydroxycholecalciferol), the biologically active form of vitamin D.[11] Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.[7]

Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia).[12] Vitamin D supplements are given to treat or to prevent osteomalacia and rickets. The evidence for other health effects of vitamin D supplementation in the general population is inconsistent.[13][14] The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people,[15] and another concluding no clear justification exists for recommending supplementation for preventing many diseases, and that further research of similar design is not needed in these areas

Several forms (vitamers) of vitamin D exist. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol; vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol.[17] Vitamin D2 was chemically characterized in 1931. In 1935, the chemical structure of vitamin D3 was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.[18]

Chemically, the various forms of vitamin D are secosteroids, i.e., steroids in which one of the bonds in the steroid rings is broken.[18] The structural difference between vitamin D2 and vitamin D3 is the side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.

Biology

The active vitamin D metabolite calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[18] The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine.[20] The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast.

VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.[1]

One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Vitamin D deficiency can result in lower bone mineral density and an increased risk of reduced bone density (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body.[21] Thus, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.[21]

The VDR regulates cell proliferation and differentiation. Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells.[22] In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione.[23]

Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength, mass and function, all being important factors to an athlete's performance.[24]

Deficiency

An estimated one billion people worldwide are either vitamin D insufficient or deficient.[24] A diet with insufficient vitamin D in conjunction with inadequate sun exposure causes vitamin D deficiency. Severe vitamin D deficiency in children causes rickets, a softening and weakening of bones, which is a rare disease in the developed world.[25] Vitamin D deficiency is found worldwide in the elderly and remains common in children and adults.[26][27][28] Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases,[29] including rickets in children and osteomalacia in adults. Low blood calcifediol (25-hydroxy-vitamin D) can result from avoiding the sun.[30] Being deficient in vitamin D can cause intestinal absorption of dietary calcium to fall to 15%.[1] When not deficient, an individual usually absorbs between 60-80%.[1]

Bone health

Rickets

Main article: Rickets

Rickets, a childhood disease, is characterized by impeded growth and soft, weak, deformed long bones that bend and bow under their weight as children start to walk. Rickets typically appears between 3 and 18 months of age.[31] Cases continue to be reported in North American and other Western Countries and is primarily seen in breastfed infants and those with darker skin complexions.[31] This condition is characterized by bow legs,[29] which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; today, it is largely found in low-income countries in Africa, Asia, or the Middle East[32] and in those with genetic disorders such as pseudovitamin D deficiency rickets.[33]

Maternal vitamin D deficiency may cause overt bone disease from before birth and impairment of bone quality after birth.[34][35] Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.[36][37]

Although rickets and osteomalacia are now rare in the UK, outbreaks have happened in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing.[38] Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish, and eggs, and low intakes of high-extraction cereals.[39][40][41] The dietary risk factors for rickets include abstaining from animal foods.[38][42]

Vitamin D deficiency remains the main cause of rickets among young infants in most countries because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate sun exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, where rickets occurs among older toddlers and children, it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products.[41]

Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are about 20% stronger than at sea level on the same latitude,[43] almost two-thirds of 500 children had mild rickets in the late 1920s.[44] An increase in the proportion of animal protein[42][45] in the 20th century American diet coupled with increased consumption of milk[46][47] fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.[1] Also, in the United States and Canada, vitamin D-fortified milk, infant vitamin supplements, and vitamin supplements have helped to eradicate the majority of cases of rickets for children with fat malabsorption conditions.[29]

Osteoporosis and osteomalacia

Osteomalacia is a disease in adults that results from vitamin D deficiency. Characteristics of this disease are softening of the bones, leading to bending of the spine, bowing of the legs, proximal muscle weakness, bone fragility, and increased risk for fractures.[48] Osteomalacia reduces calcium absorption and increases calcium loss from bone, which increases the risk for bone fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10 ng/mL.[2] Although the effects of osteomalacia are thought to contribute to chronic musculoskeletal pain,[49] there is no persuasive evidence of lower vitamin D levels in chronic pain sufferers[50] or that supplementation alleviates chronic nonspecific musculoskeletal pain.[51]

Skin pigmentation

Dark-skinned people living in temperate climates have been shown to have low vitamin D levels but the significance of this is not certain.[52][53][54] Dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis.[55] Vitamin D deficiency is common in Hispanic and African-Americans in the United States, with levels dropping significantly in the winter.[56] This is due to the levels of melanin in their skin, as it acts as a natural protectant from sun exposure.[56]

Use of supplements

Supplementation with vitamin D is a reliable method for preventing or treating rickets. The effects of vitamin D supplementation on non-skeletal health are uncertain.[14][57] A 2013 review did not find any effect from supplementation on the rates of non-skeletal disease, other than a tentative decrease in mortality in the elderly.[58] Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis.[16][59] Low vitamin D levels may result from disease rather than cause disease.[58]

A United States Institute of Medicine (IOM) report states: "Outcomes related to cancer, cardiovascular disease and hypertension, and diabetes and metabolic syndrome, falls and physical performance, immune functioning and autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting."[60]: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.[61] Members of the IOM panel maintain that they used a "standard procedure for dietary recommendations" and that the report is solidly based on the data. Research on vitamin D supplements, including large-scale clinical trials, is continuing.[61]

Mortality, all-causes

Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly,[15][58] but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable.[16] Other forms (vitamin D2, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regard to the risk of death.[15] High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit.[62] Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.[63][64][65] The relationship between serum calcifediol level and all-cause mortality is parabolic.[60] Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.[60]:435

Bone health

In general, no good evidence supports the commonly held belief that vitamin D supplements can help prevent osteoporosis.[16] Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed.[66] 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.[67] Supplementation with higher doses of vitamin D, in those older than 65 years, may decrease fracture risk.[68] The effect is small or none for people living independently.[69][70] Low serum vitamin D levels have been associated with falls, and low bone mineral density.[71] Taking extra vitamin D, however, does not appear to change the risk.[72] Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or major breaks, particularly those engaging in contact sports. The greatest benefit with supplementation is seen in athletes who are deficient (25(OH)D serum levels <30 ng/mL), or severely deficient (25(OH)D serum levels <25 ng/mL). Incremental decreases in risks are observed with rising serum 25(OH)D concentrations plateauing at 50 ng/mL with no additional benefits seen in levels beyond this point

Because it found mounting evidence for a benefit to bone health, though it had not found good evidence of other benefits, the US Food and Drug Administration (FDA) has required manufacturers to declare the amount of vitamin D on nutrition facts labels, as "nutrients of public health significance", since May 2016. By a proposed deadline extension, small manufacturers with less than $10 million in annual food sales will have to comply by January 1, 2021, while larger ones have to comply by January 1, 2020.[74] Manufacturers of single-ingredient sugars such as honey and maple syrup and certain cranberry products have until July 1, 2021, to make the changes.[74]

Cancer

Vitamin D supplements have been widely marketed for their claimed anti­cancer properties.[75] Associations have been shown in observational studies between low vitamin D levels and the risk of development of certain cancers.[76] It is unclear, however, if taking additional vitamin D in the diet or as supplements affects the risk of cancer. Reviews have described the evidence as being "inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements"[60] and "not sufficiently robust to draw conclusions".[69] One 2014 review found that supplements had no significant effect on cancer risk.[16]

Another 2014 review concluded that vitamin D3 may decrease the risk of death from cancer (one fewer death in 150 people treated over 5 years), but concerns with the quality of the data were noted.[15] Insufficient evidence exists to recommend vitamin D supplements for people with cancer, although some evidence suggests that low vitamin D may be associated with a worse outcome for some cancers,[77] and that higher 25-hydroxy vitamin D levels at the time of diagnosis are associated with better outcomes.[78]

Cardiovascular disease

Taking vitamin D supplements does not meaningfully reduce the risk of stroke, cerebrovascular disease, cardial infarction, or ischemic heart disease.[16][79] Supplementation may have no effect on blood pressure.[80]

Immune system

Infectious diseases

In general, vitamin D functions to activate the innate and dampen the adaptive immune systems.[81] Deficiency has been linked to increased risk or severity of viral infections, including HIV.[82][83] Low levels of vitamin D appear to be a risk factor for tuberculosis,[84] and historically it was used as a treatment.[85] Supplementation slightly decreases the risk of acute respiratory tract infections and the exacerbation of asthma.[86][87][88] Evidence is lacking on whether it does so in children under five years of age.[89] No clinical trials have been done to assess its effect on preventing other infections, such as malaria.

Autoimmune diseases

Although tentative data link low levels of vitamin D to asthma, evidence to support a beneficial effect on asthmatics from supplementation is inconclusive.[90] Accordingly, supplementation is not currently recommended for treatment or prevention of asthma.[91] Vitamin D and multiple sclerosis incidence have been linked, but it is not clear what the nature of any causal relationship might be.[92] Two systemic reviews concluded that the evidence for vitamin D supplementation being helpful for treating people with multiple sclerosis is inconclusive.[93][94]

Inflammatory bowel disease

Low levels of vitamin D are associated with two major forms of human Inflammatory bowel disease (IBD): Crohn's disease and ulcerative colitis.[95] However, further studies are required to determine its significance and the potential role of vitamin D axis in IBD.[95][96]

Other conditions

Diabetes -- A systematic review of 2014 concluded that the available studies show no evidence of vitamin D3 supplementation having an effect on glucose homeostasis or diabetes prevention.[97] A review article of 2016 reported that while there is increasing evidence that vitamin D deficiency may be a risk factor for diabetes, over-all evidence regarding vitamin D levels and diabetes mellitus is contradictory, requiring further studies.[98]

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.[99]

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.[100]

Pregnancy -- Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small (for gestational age) infants.[101] Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term,[102] the full extent of benefits for the mother or baby is unclear.[101][102][103] Pregnant women who take an adequate amount of vitamin D during gestation may experience a lower risk of pre-eclampsia[104] and positive immune effects.[105] Vitamin D supplementation is also likely to reduce the risk of gestational diabetes, undersized babies[104] and of their poor rate of growth.[106] Pregnant women often do not take the recommended amount of vitamin D.[105]

Weight loss -- Though hypothesized that vitamin D supplementation may be an effective treatment for obesity apart from calorie restriction, one systematic review found no association of supplementation with body weight or fat mass.[107] A 2016 meta-analysis found that circulating vitamin D status was improved by weight loss, indicating that fat mass may be inversely associated with blood levels of vitamin D.[108]

Allowable health claims

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

European Food Safety Authority

normal function of the immune system[109]

normal inflammatory response[109]

normal muscle function[109]

reduced risk of falling in people over age 60[110]

US Food and Drug Administration (FDA)

"Adequate calcium and vitamin D, as part of a well balanced diet, along with physical activity, may reduce the risk of osteoporosis."[111]

Health Canada

Adequate calcium and regular exercise may help to achieve strong bones in children and adolescents and may reduce the risk of osteoporosis in older adults. An adequate intake of vitamin D is also necessary[112]

Other possible agencies with claim guidance: Japan FOSHU[113] and Australia-New Zealand