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CAS Number: 67-97-0
Molecular Weight: 384.64
EC Number: 200-578-6
MDL number: MFCD00078131
APPLICATIONS
Vitamin D3 is used as an internal analytical standard for the quantitation of vitamin D3 concentration in dietary supplements, fortified foods or within a complex biological matrix using a variety of testing applications.
The active metabolite of vitamin D3 is calcitriol (1,25-dihydroxyvitamin D3) encapsulated into polymeric nanoparticles, which finds the application in vitamin D3-based chemotherapy formulation study and in vitro evaluation.
Vitamin D has multiple roles in the body. Vitamin D assists in:
-promoting healthy bones and teeth
-supporting immune, brain, and nervous system health
-regulating insulin levels and supporting diabetes management
-supporting lung function and cardiovascular health
-influencing the expression of genes involved in cancer development.
Vitamin D plays a significant role in the regulation of calcium and maintenance of phosphorus levels in the blood.
These factors are vital for maintaining healthy bones.
People need vitamin D to allow the intestines to stimulate and absorb calcium and reclaim calcium that the kidneys would otherwise excrete.
Vitamin D deficiency in children can cause rickets, which leads to a severely bowlegged appearance due to the softening of the bones.
Similarly, in adults, vitamin D deficiency manifests as osteomalacia, or softening of the bones.
Osteomalacia results in poor bone density and muscular weakness.
A vitamin D deficiency can also present as osteoporosis, for which over 53 million people in the United States either seek treatment or face an increased risk.
A 2018 research suggested that some studies had found that vitamin D had a protective effect against the influenza virus.
However, the authors also looked at other studies where vitamin D did not have this effect on flu and flu risk.
Further research is, therefore, necessary to confirm the protective effect of vitamin D on the flu.
Vitamin D deficiency has links to high blood pressure in children.
One 2018 study found a possible connection between low vitamin D levels and stiffness in the arterial walls of children.
The American Academy of Allergy Asthma and Immunology (AAAAI) suggest that evidence points to a connection between low vitamin D exposure and an increased risk of allergic sensitization.
An example of this is children who live closer to the equator and have lower rates of admission to hospital for allergies plus fewer prescriptions of epinephrine autoinjectors.
They are also less likely to have a peanut allergy.
The AAAAI also highlight an Australian study of egg intake.
Eggs are a common early source of vitamin D.
The children who started eating eggs after months were more likely to develop food allergies than children who started between 4–6 months of age.
Furthermore, vitamin D may enhance the anti-inflammatory effects of glucocorticoids.
This benefit makes it potentially useful as a supportive therapy for people with steroid resistant asthma.
A 2019 review suggests that pregnant women who are deficient in vitamin D may have a greater risk of developing preeclampsia and giving birth preterm.
Doctors also associate poor vitamin D status with gestational diabetes and bacterial vaginosis in pregnant women.
It is also important to note that in a 2013 study, researchers associated high vitamin D levels during pregnancy with an increased risk of food allergy in the child during the first 2 years of life.
The role of vitamin D in disease prevention is a popular area of research, but clear answers about the benefit of taking amounts beyond the RDA are not conclusive. Although observational studies see a strong connection with lower rates of certain diseases in populations that live in sunnier climates or have higher serum levels of vitamin D, clinical trials that give people vitamin D supplements to affect a particular disease are still inconclusive.
This may be due to different study designs, differences in the absorption rates of vitamin D in different populations, and different dosages given to participants.
DESCRIPTION
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects.
In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).
The major natural source of the vitamin D is synthesis of cholecalciferol in the lower layers of epidermis of the skin through a chemical reaction that is dependent on sun exposure (specifically UVB radiation).
Cholecalciferol and ergocalciferol can be ingested from diet and supplements.
Only a few foods, such as the flesh of fatty fish, naturally contain significant amounts of vitamin D.
In the U.S. and other countries, cow's milk and plant-derived milk substitutes are fortified with vitamin D, as are many breakfast cereals.
Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D.
Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.
Vitamin D from the diet, or from skin synthesis, is biologically inactive.
Vitamin D is activated by two protein enzyme hydroxylation steps, the first in the liver and the second in the kidneys.
As vitamin D can be synthesized in adequate amounts by most mammals if exposed to sufficient sunlight, it is not essential, so technically not a vitamin.
Instead Vitamin D can be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations.
Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol.
These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status.
Calcifediol is further hydroxylated by the kidneys and some of the immune system cells to form calcitriol (also known as 1,25-dihydroxycholecalciferol), the biologically active form of vitamin D.
Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone.
Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.
Vitamin D has a significant role in calcium homeostasis and metabolism.
Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia).
Vitamin D supplements are given to treat or to prevent osteomalacia and rickets.
The evidence for other health effects of vitamin D supplementation in vitamin D-replete individuals is inconsistent.
The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people.
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.
A human body produces vitamin D as a response to sun exposure.
A person can also boost their vitamin D intake through certain foods or supplements.
Vitamin D is essential for several reasons, including maintaining healthy bones and teeth.
Vitamin D may also protect against a range of diseases and conditions, such as type 1 diabetes.
Despite its name, vitamin D is not a vitamin, but a prohormone, or precursor of a hormone.
Vitamins are nutrients that the body cannot create, and so a person must consume them in the diet.
However, the body can produce vitamin D.
Vitamin D is both a nutrient we eat and a hormone our bodies make.
Vitamin D is a fat-soluble vitamin that has long been known to help the body absorb and retain calcium and phosphorus; both are critical for building bone.
Also, laboratory studies show that vitamin D can reduce cancer cell growth, help control infections and reduce inflammation.
Many of the body’s organs and tissues have receptors for vitamin D, which suggest important roles beyond bone health, and scientists are actively investigating other possible functions.
Few foods naturally contain vitamin D, though some foods are fortified with the vitamin.
For most people, the best way to get enough vitamin D is taking a supplement because it is hard to eat enough through food.
Vitamin D supplements are available in two forms: vitamin D2 (“ergocalciferol” or pre-vitamin D) and vitamin D3 (“cholecalciferol”).
Both are also naturally occurring forms that are produced in the presence of the sun’s ultraviolet-B (UVB) rays, hence its nickname, “the sunshine vitamin,” but D2 is produced in plants and fungi and D3 in animals, including humans.
Vitamin D production in the skin is the primary natural source of vitamin D, but many people have insufficient levels because they live in places where sunlight is limited in winter, or because they have limited sun exposure due to being inside much of the time.
Also, people with darker skin tend to have lower blood levels of vitamin D because the pigment (melanin) acts like a shade, reducing production of vitamin D (and also reducing damaging effects of sunlight on skin, including skin cancer).
Vitamin D is an essential vitamin that helps regulate calcium and phosphorus in the body.
Vitamin D also plays a role in maintaining proper bone structure.
There are different forms of vitamin D, including ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3).
Vitamin D is found in fish, eggs, and fortified milk.
Vitamin D is also made in the skin when exposed to sunlight.
During periods of sunlight, vitamin D is stored in fat and then released when sunlight is not available.
Vitamin D supplements are commonly used to treat and prevent vitamin D deficiency.
People who don't get enough sun and people who are 65 years or older are at risk for deficiency.
People also use vitamin D for weak and brittle bones, heart disease, asthma, hay fever, and many other conditions, but there's no good scientific evidence to support many of these uses.
There is also no strong evidence to support using vitamin D supplements for COVID-19.
But it is important to maintain healthy levels of vitamin D.
This can be done by taking 400-1000 IU of vitamin D daily or spending 15-30 minutes in the sun each day.
VITAMIN D PRODUCTION
When the skin is exposed to UVB radiation (from sunlight) a molecule known as 7-dehydrocholesterol (derived from cholesterol) is converted to cholecalciferol, also known as D3. Cholecalciferol travels to the liver where it is converted to 25-hydroxyvitamin D (25OHD).
The kidney then converts 25OHD to 1,25-hydroxyvitamin D (1,25OHD), also known as calcitriol, which possesses hormonal properties and regulates calcium and phosphate balance.
Cholecalciferol or D3 can be obtained directly without the need for UVB radiation either from the diet (sources oily fish, eggs and butter) or via supplementation.
Vitamin D3 supplements are generally from animal sources although vegan sources of D3 can be obtained from lichen.
Another plant based form of vitamin D, known as ergocalciferol or D2, can also be obtained from the diet (rich food sources are mushrooms, fortified soya milk and almond milk) or via supplementation.
Vitamin D2 can also be converted by the liver to 25-hydroxyvitamin D and then to 1, 25-hydroxyvitamin D by the kidneys.
The differences between D2 and D3 are discussed later.
TYPES
Several forms (vitamers) of vitamin D exist.
The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. Vitamin D without a subscript refers to either D2 or D3, or both, and is known collectively as calciferol.
Vitamin D2 was chemically characterized in 1931.
In 1935, the chemical structure of vitamin D3 was defined and shown to result from the ultraviolet irradiation of 7-dehydrocholesterol.
A chemical nomenclature for vitamin D forms was recommended in 1981 but alternative names remain in common use.
Chemically, the various forms of vitamin D are secosteroids, that is, steroids in which one of the bonds in the steroid rings is broken.
The structural difference between vitamin D2 and vitamin D3 is in the side chain, which contains a double bond, between carbons 22 and 23, and a methyl group on carbon 24 in vitamin D2.
Many vitamin D analogues have been synthesized.
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.
The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine.
The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast.
VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.
One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels.
Vitamin D deficiency can result in lower bone mineral density and an increased risk of reduced bone density (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body.
Thus, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.
The VDR regulates cell proliferation and differentiation.
Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells.
In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione.
Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength, mass and function, all being important factors to an athlete's performance.
DEFICIENCY
An estimated one billion people worldwide are either vitamin D insufficient or deficient.
Vitamin D deficiency is widespread in the European population.
A diet with insufficient vitamin D in conjunction with inadequate sun exposure causes vitamin D deficiency.
Severe vitamin D deficiency in children causes rickets, a softening and weakening of bones, which is a rare disease in the developed world.
Vitamin D deficiency is found worldwide in the elderly and remains common in children and adults.
Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases, including rickets in children and osteomalacia in adults. Low blood calcifediol (25-hydroxy-vitamin D) can result from avoiding the sun.
Being deficient in vitamin D can cause intestinal absorption of dietary calcium to fall to 15%.
When not deficient, an individual usually absorbs between 60 and 80%.
BONE HEALTH
-Rickets
Rickets, a childhood disease, is characterized by impeded growth and soft, weak, deformed long bones that bend and bow under their weight as children start to walk. Rickets typically appears between 3 and 18 months of age.
Cases continue to be reported in North American and other Western Countries and is primarily seen in breastfed infants and those with darker skin complexions.
This condition is characterized by bow legs, which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; today, it is largely found in low-income countries in Africa, Asia, or the Middle East and in those with genetic disorders such as pseudovitamin D deficiency rickets.
Maternal vitamin D deficiency may cause overt bone disease from before birth and impairment of bone quality after birth.
Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency.
Although rickets and osteomalacia are now rare in the UK, outbreaks have happened in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing.
Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish, and eggs, and low intakes of high-extraction cereals.
The dietary risk factors for rickets include abstaining from animal foods.
Vitamin D deficiency remains the main cause of rickets among young infants in most countries because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate sun exposure.
In sunny countries such as Nigeria, South Africa, and Bangladesh, where rickets occurs among older toddlers and children, it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products.
Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are about 20% stronger than at sea level on the same latitude, almost two-thirds of 500 children had mild rickets in the late 1920s.
An increase in the proportion of animal protein in the 20th century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.
Also, in the United States and Canada, vitamin D-fortified milk, infant vitamin supplements, and vitamin supplements have helped to eradicate the majority of cases of rickets for children with fat malabsorption conditions.
-Osteomalacia and osteoporosis
Osteomalacia is a disease in adults that results from vitamin D deficiency.
Characteristics of this disease are softening of the bones, leading to bending of the spine, bowing of the legs, proximal muscle weakness, bone fragility, and increased risk for fractures.
Osteomalacia reduces calcium absorption and increases calcium loss from bone, which increases the risk for bone fractures.
Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10 ng/mL.
Although the effects of osteomalacia are thought to contribute to chronic musculoskeletal pain, there is no persuasive evidence of lower vitamin D levels in chronic pain sufferers or that supplementation alleviates chronic nonspecific musculoskeletal pain.
Osteoporosis is a condition of reduced bone mineral density with increased bone fragility and risk of bone fractures.
Osteoporosis can be a long-term effect of calcium and/or vitamin D insufficiency, at least in part.
This may result from inadequate calcium intake, with insufficient vitamin D contributing by reducing calcium absorption.
-Skin pigmentation
Dark-skinned people living in temperate climates have been shown to have low vitamin D levels but the significance of this is not certain.
Dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis.
Vitamin D deficiency is common in Hispanic and African-Americans in the United States, with levels dropping significantly in the winter.
This is due to the levels of melanin in the skin, as it acts as a natural protectant from sun exposure.
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.
A 2013 review did not find any effect from supplementation on the rates of non-skeletal disease, other than a tentative decrease in mortality in the elderly.
Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis.
Low vitamin D levels may result from disease rather than cause disease.
A United States Institute of Medicine (IOM) report states: "Outcomes related to cancer, cardiovascular disease and hypertension, and diabetes and metabolic syndrome, falls and physical performance, immune functioning and autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting.": 5 Some researchers claim the IOM was too definitive in its recommendations and made a mathematical mistake when calculating the blood level of vitamin D associated with bone health.
Members of the IOM panel maintain that they used a "standard procedure for dietary recommendations" and that the report is solidly based on the data.
Research on vitamin D supplements, including large-scale clinical trials, is continuing.
-Mortality, all-causes
Vitamin D3 supplementation has been tentatively found to lead to a reduced risk of death in the elderly, but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable.
Other forms (vitamin D2, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regard to the risk of death.
High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit.
Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging.
The relationship between serum calcifediol concentrations and all-cause mortality is "U-shaped": mortality is elevated at high and low calcifediol levels, relative to moderate levels.
Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.
-Bone health
In general, no good evidence supports the commonly held belief that vitamin D supplements can help prevent osteoporosis.
Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed.
For older people with osteoporosis, taking vitamin D with calcium may help prevent hip fractures, but it also slightly increases the risk of stomach and kidney problems.
A study found that supplementation with 800 IU or more daily, in those older than 65 years was "somewhat favorable in the prevention of hip fracture and non-vertebral fracture".
The effect is small or none for people living independently.
Low serum vitamin D levels have been associated with falls, and low bone mineral density.
Taking extra vitamin D, however, does not appear to change the risk.
Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or major breaks, particularly those engaging in contact sports.
The greatest benefit with supplementation is seen in athletes who are deficient (25(OH)D serum levels <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, some manufacturers had until July 1, 2021 to comply.
-Cancer
Potential associations have been found between low vitamin D levels and the risk of developing several types of cancer.-
Meta-analyses of observational studies have found reduced risk of cancer incidence related to vitamin D intake and 25(OH)D levels, particularly for colorectal cancer, although the strength of the associations was classified as weak.-
While randomized controlled trials have not confirmed that vitamin D supplements reduce the risk of cancer incidence, the relative risk of cancer deaths has been found to be reduced by up to 16% in several meta-analyses.
-Cardiovascular disease
Taking vitamin D supplements does not meaningfully reduce the risk of stroke, cerebrovascular disease, myocardial infarction, or ischemic heart disease. Supplementation may have no effect on blood pressure.
-Immune system
-Infectious diseases
In general, vitamin D functions to activate the innate and dampen the adaptive immune systems with antibacterial, antiviral and anti-inflammatory effects.
Deficiency has been linked to increased risk or severity of viral infections, including HIV and COVID-19.
Low levels of vitamin D appear to be a risk factor for tuberculosis, and historically it was used as a treatment.
Vitamin D supplementation in low-doses (400 to 1000 IU/day) may slightly decrease the overall risk of acute respiratory tract infections.
The benefits were found in young children and adolescents (ages 1 up to 16 years) and were not confirmed with higher doses (>1000 IU per day or more).
Vitamin D supplementation substantially reduces the rate of moderate or severe exacerbations of COPD in people with baseline 25(OH)D levels under 25nmol/L but not in those with less severe deficiency.
-Asthma
Although tentative data link low levels of vitamin D to asthma, evidence to support a beneficial effect on asthmatics from supplementation is inconclusive.
One review found that vitamin D supplementation could reduce the need for steroids used to inhibit episode frequency in people with mild to moderate asthma, and that supplementation had no effect on day-to-day asthma symptoms.
In general practice, supplementation with vitamin D is not recommended for treatment or prevention of asthma.
-Inflammatory bowel disease
Low levels of vitamin D are associated with two major forms of human inflammatory bowel disease (IBD): Crohn's disease and ulcerative colitis.
A meta-analysis of vitamin D therapy in IBD patients with vitamin D deficiency has shown that supplementation is effective at correcting vitamin D levels and is associated with improvements in scores for clinical disease activity and biochemical markers.
-Other conditions
Diabetes – A meta-analysis of eight studies found that vitamin D supplementation significantly reduced the risk of type 2 diabetes mellitus for non-obese prediabetic patients but not obese ones.
A meta-analysis of 37 articles found that vitamin D supplementation significantly improved glycemic control [homeostatic model assessment-insulin resistance (HOMA-IR)], hemoglobin A1C (HbA1C), and fasting blood glucose (FBG) in individuals with type 2 diabetes mellitus.
In prospective studies, high versus low level of vitamin D was respectively associated with significant decrease in risk of type 2 diabetes mellitus, combined type 2 diabetes mellitus and pre-diabetes, and pre-diabetes.
ADHD - A meta-analysis of observational studies showed that children with ADHD have lower vitamin D levels, and that there was a small association between low vitamin D levels at the time of birth and later development of ADHD.
Several small randomized controlled trials of vitamin D supplementation indicated improved ADHD symptoms such as impulsivity and hyperactivity.
Depression – Clinical trials of vitamin D supplementation for depressive symptoms have generally been of low quality and show no overall effect, although subgroup analysis showed supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate effect.
Cognition and dementia – A systematic review of clinical studies found an association between low vitamin D levels with cognitive impairment and a higher risk of developing Alzheimer's disease.
However, lower vitamin D concentrations are also associated with poor nutrition and spending less time outdoors.
Therefore, alternative explanations for the increase in cognitive impairment exist and hence a direct causal relationship between vitamin D levels and cognition could not be established.
Schizophrenia - Trials have demonstrated lower vitamin D levels are highly prevalent in patients with schizophrenia, particularly those with acute episodes.
Pregnancy – Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small (for gestational age) infants.
Although taking vitamin D supplements during pregnancy raises blood levels of vitamin D in the mother at term,[110] the full extent of benefits for the mother or baby is unclear.
Pregnant women who take an adequate amount of vitamin D during gestation may experience a lower risk of pre-eclampsia and positive immune effects.
Vitamin D supplementation is also likely to reduce the risk of gestational diabetes, undersized babies and of their poor rate of growth.
Pregnant women often do not take the recommended amount of vitamin D.
Weight loss – Though hypothesized that vitamin D supplementation may be an effective treatment for obesity apart from calorie restriction, one systematic review found no association of supplementation with body weight or fat mass.
A 2016 meta-analysis found that circulating vitamin D status was improved by weight loss, indicating that fat mass may be inversely associated with blood levels of vitamin D.
EXCESS
Vitamin D toxicity is rare.
It is caused by supplementing with high doses of vitamin D rather than sunlight.
The threshold for vitamin D toxicity has not been established; however, according to some research, the tolerable upper intake level (UL) is 4,000 IU/day for ages 9–71 (100 μg/day), while other research concludes that, in healthy adults, sustained intake of more than 50,000 IU/day (1250 μg) can produce overt toxicity after several months and can increase serum 25-hydroxyvitamin D levels to 150 ng/mL and greater.
Those with certain medical conditions, such as primary hyperparathyroidism, are far more sensitive to vitamin D and develop hypercalcemia in response to any increase in vitamin D nutrition, while maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.
Idiopathic infantile hypercalcemia is caused by a mutation of the CYP24A1 gene, leading to a reduction in the degradation of vitamin D.
Infants suffering from such a mutation have an increased sensitivity to vitamin D and in case of additional intake a risk of hypercalcaemia.
The disorder can continue into adulthood.
A review published in 2015 noted that adverse effects have been reported only at 25(OH)D serum concentrations above 200 nmol/L.
Published cases of toxicity involving hypercalcemia in which the vitamin D dose and the 25-hydroxy-vitamin D levels are known all involve an intake of ≥40,000 IU (1,000 μg) per day.
Those who are pregnant or breastfeeding should consult a doctor before taking a vitamin D supplement.
The FDA advised manufacturers of liquid vitamin D supplements that droppers accompanying these products should be clearly and accurately marked for 400 international units (1 IU is the biological equivalent of 25 ng cholecalciferol/ergocalciferol).
In addition, for products intended for infants, the FDA recommends the dropper hold no more than 400 IU.
For infants (birth to 12 months), the tolerable upper limit (maximum amount that can be tolerated without harm) is set at 25 μg/day (1,000 IU). One thousand micrograms per day in infants has produced toxicity within one month.
After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010, has increased the tolerable upper limit (UL) to 2,500 IU per day for ages 1–3 years, 3,000 IU per day for ages 4–8 years and 4,000 IU per day for ages 9–71+ years (including pregnant or lactating women).
Calcitriol itself is auto-regulated in a negative feedback cycle, and is also affected by parathyroid hormone, fibroblast growth factor 23, cytokines, calcium, and phosphate.
Effect of excess
Vitamin D overdose causes hypercalcemia, which is a strong indication of vitamin D toxicity – this can be noted with an increase in urination and thirst.
If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs such as the kidneys, liver, and heart, resulting in pain and organ damage.
The main symptoms of vitamin D overdose are hypercalcemia including anorexia, nausea, and vomiting.
These may be followed by polyuria, polydipsia, weakness, insomnia, nervousness, pruritus and ultimately kidney failure.
Furthermore, proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop.
Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.
Vitamin D toxicity is treated by discontinuing vitamin D supplementation and restricting calcium intake.
Kidney damage may be irreversible. Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.
The concentrations of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D produced is degraded.
Toxicity
Vitamin D toxicity most often occurs from taking supplements.
The low amounts of the vitamin found in food are unlikely to reach a toxic level, and a high amount of sun exposure does not lead to toxicity because excess heat on the skin prevents D3 from forming.
It is advised to not take daily vitamin D supplements containing more than 4,000 IU unless monitored under the supervision of your doctor.
Symptoms of toxicity:
-Anorexia
-Weight loss
-Irregular heart beat
-Hardening of blood vessels and tissues due to increased blood levels of calcium, potentially leading to damage of the heart and kidneys.
HISTORY
American researchers Elmer McCollum and Marguerite Davis in 1914 discovered a substance in cod liver oil which later was called "vitamin A".
British doctor Edward Mellanby noticed dogs that were fed cod liver oil did not develop rickets and concluded vitamin A, or a closely associated factor, could prevent the disease.
In 1922, Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed.
The modified oil cured the sick dogs, so McCollum concluded the factor in cod liver oil which cured rickets was distinct from vitamin A.
He called it vitamin D because it was the fourth vitamin to be named.
It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.
In 1925, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced (now known as D3).
Alfred Fabian Hess stated: "Light equals vitamin D."
Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928 for his work on the constitution of sterols and their connection with vitamins.
In 1929, a group at NIMR in Hampstead, London, were working on the structure of vitamin D, which was still unknown, as well as the structure of steroids.
A meeting took place with J.B.S. Haldane, J.D. Bernal, and Dorothy Crowfoot to discuss possible structures, which contributed to bringing a team together.
X-ray crystallography demonstrated the sterol molecules were flat, not as proposed by the German team led by Windaus.
In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance.
The informal academic collaboration between the team members Robert Benedict Bourdillon, Otto Rosenheim, Harold King, and Kenneth Callow was very productive and led to the isolation and characterization of vitamin D.
At this time, the policy of the Medical Research Council was not to patent discoveries, believing the results of medical research should be open to everybody.
In the 1930s, Windaus clarified further the chemical structure of vitamin D.
In 1923, American biochemist Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials.
After irradiating rodent food, Steenbock discovered the rodents were cured of rickets.
A vitamin D deficiency is a known cause of rickets. Using US$300 of his own money, Steenbock patented his invention.
His irradiation technique was used for foodstuffs, most notably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.
In 1969, after studying nuclear fragments of intestinal cells, a specific binding protein for vitamin D called the vitamin D receptor was identified by Mark Haussler and Tony Norman.
In 1971–72, the further metabolism of vitamin D to active forms was discovered.
In the liver, vitamin D was found to be converted to calcifediol.
Calcifediol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D.
Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone.
The vitamin D metabolites, calcifediol and calcitriol, were identified by competing teams led by Michael F. Holick in the laboratory of Hector DeLuca and by Tony Norman and colleagues.
RESEARCH
There is conflicting evidence about the benefits of interventions with vitamin D, one view purporting an intake of 4,000–12,000 IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80 ng/mL, while another view is that serum concentrations above 50 ng/mL are not plausible.
The United States National Institutes of Health Office of Dietary Supplements established a Vitamin D Initiative in 2014 to track current research and provide education to consumers.
In their 2020 update it was recognized that a growing body of research suggests that vitamin D might play some role in the prevention and treatment of types 1 and 2 diabetes, glucose intolerance, hypertension, multiple sclerosis, and other medical conditions.
However, it was concluded that the available evidence was either inadequate or too contradictory to confirm the effectiveness of vitamin D on those conditions, save for the more positive findings on bone health.
Some preliminary studies link low vitamin D levels with disease later in life.
One meta-analysis found a decrease in mortality in elderly people.
Another meta-analysis covering over 350,000 people concluded that vitamin D supplementation in unselected community-dwelling individuals does not reduce skeletal (total fracture) or non-skeletal outcomes (myocardial infarction, ischemic heart disease, stroke, cerebrovascular disease, cancer) by more than 15%, and that further research trials with similar design are unlikely to change these conclusions.
A 2019 meta-analysis found that a small increase in risk of stroke when calcium supplements were added to vitamin D.
Evidence as of 2013 is insufficient to determine whether vitamin D affects the risk of cancer.
FOOD SOURCES
Few foods are naturally rich in vitamin D3.
The best sources are the flesh of fatty fish and fish liver oils.
Smaller amounts are found in egg yolks, cheese, and beef liver.
Certain mushrooms contain some vitamin D2; in addition some commercially sold mushrooms contain higher amounts of D2 due to intentionally being exposed to high amounts of ultraviolet light.
Many foods and supplements are fortified with vitamin D like dairy products and cereals.
-Cod liver oil
-Salmon
-Swordfish
-Tuna fish
-Orange juice fortified with vitamin D
-Dairy and plant milks fortified with vitamin D
-Sardines
-Beef liver
-Egg yolk
-Fortified cereals
SYNONYMS
Calciferol
