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A fat-soluble vitamin occurring in several forms, especially vitamin D2 or vitamin D3, required for normal growth of teeth and bones, and produced in general by ultraviolet irradiation of sterols found in milk, fish, and eggs.
Either of two fat-soluble sterol-like compounds, ergocalciferol (vitamin D2) and activated cholecalciferol (vitamin D3). Vitamin D2 is formed from the irradiation of ergosterol, a plant sterol. However, vitamin D3 is normally manufactured in the skin, where ultraviolet light activates the compound 7-dehydrocholesterol. Vitamins D3 and D2 are about equal in activity in all mammals except New World monkeys and birds, in which vitamin D2 is approximately one-tenth as active as vitamin D3. See also Vitamin.
Vitamin D as acquired from the diet or produced in the skin is biologically inactive. It must be metabolized by the liver to produce 25-hydroxyvitamin D3. However, this compound is also biologically inactive under physiological circumstances and must be activated by the kidney to produce the final vitamin D hormone, 1,25-dihydroxyvitamin D3. This hormonal form of vitamin D plays an essential role in stimulating intestinal absorption of calcium and phosphorus, in the mobilization of calcium from bone, and in renal reabsorption of calcium. The function of vitamin D has been expanded beyond regulating plasma calcium and phosphorus levels, and hence healing the diseases of rickets and osteomalacia. It is now known that the vitamin D hormone controls parathyroid gland growth and production of the parathyroid hormone. It is an immunomodulator. Vitamin D hormone also appears to play a role in the regulation of insulin production or secretion. Finally, it is required for female reproduction. These new sites of action of vitamin D are under intense investigation. See also Hormone.
Vitamin D is largely absent from the food supply. It is found in large amounts in fish liver oils; cod liver oil has long been known to be an important source of vitamin D. Fortified foods are the major dietary source of vitamin D, but the major overall source is the production of vitamin D in skin by exposure to sunlight or ultraviolet irradiation. In winter months at temperate latitudes, insufficient amounts of vitamin D are produced in skin, and unless it is replaced by a dietary source, danger of insufficiency exists.
A deficiency of vitamin D in growing animals results in the disease rickets. A similar disease, osteomalacia, occurs in adult animals. By far the most serious disorder of vitamin D deficiency is the low-blood calcium levels which result in convulsions known as hypocalcemic tetany. Moderate deficiency of vitamin D may contribute to osteoporosis, especially in the elderly. See also Bone; Osteoporosis.
The recommended daily requirement for vitamin D3 is 10 micrograms or 400 international units (IU). Higher requirements are reported for the elderly and for rapidly growing adolescents: 20 μg or 800 IU per day. It is possible that the average requirement is lower than 10 μg per day. The exact absolute requirement has never been determined.
Vitamin D3 is calciol or cholecalciferol; formed in the skin by the action of ultraviolet light on 7-dehydrocholesterol, and hence not strictly a vitamin. However, in northern latitudes sunlight exposure may not be adequate to meet requirements, and a dietary source may become essential. Vitamin D2 (ercalciol or ergocalciferol) is a synthetic vitamer produced by irradiation of ergosterol. The name vitamin D1 was given originally to an impure mixture and is not used now.
The metabolic function of the vitamin is to control calcium metabolism. It stimulates the absorption of dietary calcium from the intestine and calcium turnover in bone. Deficiency causes rickets in young children, osteomalacia in adults. It is not widely distributed in foods, but is found in egg yolk, butter, fatty fish, and enriched margarine. There are no reference intakes for adults in the UK or the EU; the US/Canadian RDA for adults is 5 μg, increasing to 10 and 15 μg with increasing age. The obsolete international unit of vitamin D = 25 ng calciol; 1 μg calciol = 40 iu.
A fat-soluble vitamin that enhances the absorption of calcium and phosphorus from the intestine and, with parathyroid hormone, mobilizes their deposition in bones. Vitamin D is relatively stable when exposed to heat and light. It is stored in the liver and, to a lesser extent, in the fatty tissue in the skin. Vitamin D occurs in two forms: vitamin D2 and vitamin D3. Vitamin D2 (ergocalciferol or calciferol) is obtained in the diet from foods such as oily fish, eggs, and margarine. Vitamin D3 (cholecalciferol) is the main form of the vitamin and is produced in the skin by the action of ultraviolet light on another compound, 7-dehydrocholesterol. Vitamin D deficiency causes a loss of muscle tone, restlessness, and irritability. It also causes rickets in children, and demineralization and softening of the bones (osteomalacia) in adults.
In the UK, no Dietary Reference Values are given for adults with normal sunlight exposure because the main source of vitamin D is from the action of sunlight on skin. However, for those confined indoors during the winter months, the Reference Nutrient Intake is 10 micrograms for adults (18-65 years) and 7 micrograms for children. In the USA, a daily intake of 10 micrograms throughout life is recommended. As with vitamin A, vitamin D can be toxic if large amounts are consumed over a long period of time. Calcium may be deposited in the organs and soft tissues of the body damaging, for example, the kidneys. Vitamin D supplements have been used to treat rheumatoid arthritis and they may reduce the risk of osteoporosis, but the evidence is conflicting: most studies show no benefit, and some even show an adverse effect. Nevertheless, vitamin D supplements in the elderly will prevent osteomalacia which may occur together with, or independently of, osteoporosis.
The group of lipidsoluble sterol compounds capable of preventing rickets. Of primary importance are D2, or ergosterol, from plants and D3, or cholecalciferol, from animal sources, especially fish liver oils. The latter is also formed in the skin from 7-dehydrocholesterol on exposure to ultraviolet light. Liver mitochondria further activate vitamin D to 25-(OH)-D, which in turn is metabolized to 1,25-(OH)2-D by the kidney. The dihydroxy metabolites significantly increase dietary calcium absorption and bone resorption to maintain proper blood calcium and phosphorus levels. A primary vitamin D deficiency results from inadequate exposure to sunlight and low dietary intake. Secondary deficiencies occur from abnormalities of intestinal resorption and interference with vitamin D hydroxylation. The manifestations of rickets include enamel hypoplasia, poorly calcified bones, bowed legs, and a deformed rib cage with beadlike swellings of the ribs (rachitic rosary) in infants and children and osteomalacia in adults. Vitamin D intake in excess is toxic.
Description
Vitamin D, also known as calciferol, is essential for strong teeth and bones. There are two major forms of vitamin D: D2 or ergocalciferol and D3 or cholecarciferol. Vitamin D can be synthesized by the body in the presence of sunlight, as opposed to being required in the diet. It is the only vitamin whose biologically active formula is a hormone. It is fat-soluble, and regulates the body's absorption and use of the minerals calcium and phosphorus. Vitamin D is important not only to the maintenance of proper bone density, but to the many calcium-driven neurologic and cellular functions, as well as normal growth and development. It also assists the immune system by playing a part in the production of a type of white blood cell called the monocyte. White blood cells are infection fighters. There are many chemical forms of vitamin D, which have varying amounts of biological activity.
General Use
The needed amount of vitamin D is expressed as an Adequate Intake (AI) rather than an Required Daily Amount (RDA). This is due to a difficulty in quantifying the amount of the vitamin that is produced by the body with exposure to sunlight. Instead, the AI estimates the amount needed to be eaten in order to maintain normal function. It is measured in International Units (IU) and there are 40 IU in a microgram (mcg). The AI for vitamin D in the form of cholecarciferol or ergocalciferol for everyone under 50 years of age, including pregnant and lactating women, is 200 IU. It goes up to 400 IU for people 51-70 years old, and to 600 IU for those over age 70. A slightly higher dose of vitamin D, even as little as a total of 700 IU for those over age 65, can significantly reduce age-related fractures when taken with 500 mg of calcium per day.
One of the major uses of vitamin D is to prevent and treat osteoporosis. This disease is essentially the result of depleted calcium, but calcium supplements alone will not prevent it since vitamin D is required to properly absorb and utilize calcium. Taking vitamin D without the calcium is also ineffective. Taking both together may actually increase bone density in postmenopausal women, who are most susceptible to bone loss and complications such as fractures.
Osteomalacia and rickets are also effectively prevented and treated through adequate vitamin D supplementation. Osteomalacia refers to the softening of the bones that occurs in adults that are vitamin D deficient. Rickets is the syndrome that affect deficient children, causing bowed legs, joint deformities, and poor growth and development.
Vitamin D also has a part in cancer prevention, at least for colon cancer. A deficiency increases the risk of this type of cancer, but there is no advantage to taking more than the AI level. There may also be a protective effect against breast and prostate cancer, but this is not as well established. Studies are in progress to see if it can help to treat leukemia and lymphoma. The action of at least one chemotherapeutic drug, tamoxifen, appears to be improved with small added doses of vitamin D. Tamoxifen is commonly used to treat ovarian, uterine, and breast cancers.
Many older adults are deficient in vitamin D. This can affect hearing by causing poor function of the small bones in the ear that transmit sound. If this is the cause of the hearing loss, it is possible that supplementation of vitamin D can act to reverse the situation.
Some metabolic diseases are responsive to treatment with specific doses and forms of vitamin D. These include Fanconi syndrome and familial hypophosphatemia, both of which result in low levels of phosphate. For these conditions, the vitamin is given in conjunction with a phosphate supplement to aid in absorption.
A topical form of vitamin D is available, and can be helpful in the treatment of plaque-type psoriasis. It may also be beneficial for those with vitiligo or scleroderma. This cream, in the form of calcitriol, is not thought to affect internal calcium and phosphorus levels. Oral supplements of vitamin D are not effective for psoriasis. The cream is obtainable by prescription only.
Evidence does not support the use of vitamin D to treat alcoholism, acne, arthritis, cystic fibrosis, or herpes.
Preparations
Natural Sources
Exposure to sunlight is the primary method of obtaining vitamin D. In clear summer weather, approximately ten minutes per day in the sun will produce adequate amounts, even when only the face is exposed. In the winter, it may require as much as two hours. Many people don't get that amount of winter exposure, but are able to utilize the vitamin that was stored during extra time in the sun over the summer. Sunscreen blocks the ability of the sun to produce vitamin D, but should be applied as soon as the minimum exposure requirement has passed, in order to reduce the risk of skin cancer. The chemical 7-dehydrocholesterol in the skin is converted to vitamin D3 by sunlight. Further processing by first the liver, and then the kidneys, makes D3 more biologically active. Since it is fat-soluble, extra can be stored in the liver and fatty tissues for future use. Vitamin D is naturally found in fish liver oils, butter, eggs, and fortified milk and cereals in the form of vitamin D2. Milk products are the main dietary source for most people. Other dairy products are not a good supply of vitamin D, as they are made from unfortified milk. Plant foods are also poor sources of vitamin D.
Supplemental Sources
Most oral supplements of vitamin D are in the form of ergocalciferol. It is also available in topical (calcitriol or calcipotriene), intravenous (calcitriol), or intramuscular (ergocalciferol) formulations. Products designed to be given by other than oral routes are by prescription only. As with all supplements, vitamin D should be stored in a cool, dry place, away from direct light, and out of the reach of children.
Deficiency
In adults, a mild deficiency of vitamin D may be manifested as loss of appetite and weight, difficulty sleeping, and diarrhea. A more major deficiency causes osteomalacia and muscle spasm. The bones become soft, fragile, and painful as a result of the calcium depletion. This is due to an inability to properly absorb and utilize calcium in the absence of vitamin D. In children, a severe lack of vitamin D causes rickets.
Risk Factors for Deficiency
The most likely cause of vitamin D deficiency is inadequate exposure to sunlight. This can occur with people who don't go outside much, those in areas of the world where pollution blocks ultraviolet (UV) light or where the weather prohibits spending much time outdoors. Glass filters out the rays necessary for vitamin formation, as does sunscreen. Those with dark skin may also absorb smaller amounts of the UV light necessary to effect conversion of the vitamin. In climates far to the north, the angle of the sun in winter may not allow adequate UV penetration of the atmosphere to create D3 Getting enough sun in the summer, and a good dietary source, should supply enough vitamin D to last through the winter. Vegans, or anyone who doesn't consume dairy products in combination with not getting much sun is also at higher risk, as are the elderly, who have a decreased ability to synthesize vitamin D.
Babies are usually born with about a nine-month supply of the vitamin, but breast milk is a poor source. Those born prematurely are at an increased risk for deficiency of vitamin D and calcium, and may be prone to tetany. Infants past around nine months old who are not getting vitamin D fortified milk or adequate sun exposure are at risk of deficiency.
People with certain intestinal, liver and kidney diseases may not be able to convert vitamin D3 to active forms, and may need at activated type of supplemental vitamin D.
Those taking certain medications may require supplements, including anticonvulsants, corticosteroids, or the cholesterol-lowering medications cholestyramine or colestipol. This means that people who are on medication for arthritis, asthma, allergies, autoimmune conditions, high cholesterol, epilepsy, or other seizure problems should consult with a healthcare practitioner about the advisability of taking supplemental vitamin D. As with some other vitamins, the abuse of alcohol also has a negative effect. In the case of vitamin D, the ability to absorb and store it is diminished by chronic overuse of alcohol products.
Populations with poor nutritional status may tend to be low on vitamin D, as well as other vitamins. This can be an effect of poor sun exposure, poor intake, or poor absorption. A decreased ability to absorb oral forms of vitamin D may result from cystic fibrosis or removal of portions of the digestive tract. Other groups who may need higher than average amounts of vitamin D include those who have recently had surgery, major injuries, or burns. High levels of stress and chronic wasting illnesses also tend to increase vitamin requirements.
Precautions
The body will not make too much vitamin D from overexposure to sun, but since vitamin D is stored in fat, toxicity from supplemental overdose is a possibility. Symptoms are largely those of hypercalcemia, and may include high blood pressure, headache, weakness, fatigue, heart arrhythmia, loss of appetite, nausea, vomiting, diarrhea, constipation, dizziness, irritability, seizures, kidney damage, poor growth, premature hardening of the arteries, and pain in the abdomen, muscles, and bones. If the toxicity progresses, itching and symptoms referable to renal disease may develop, such as thirst, frequent urination, proteinuria, and inability to concentrate urine. Overdoses during pregnancy may cause fetal abnormalities. Problems in the infant can include tetany, seizures, heart valve malformation, retinal damage, growth suppression, and mental retardation. Pregnant women should not exceed the AI, and all others over one year of age should not exceed a daily dose of 2000 IU. Infants should not exceed 1000 IU. These upper level doses should not be used except under the advice and supervision of a healthcare provider due to the potential for toxicity.
Individuals with hypercalcemia, sarcoidosis, or hypoparathyroidism should not use supplemental calciferol. Those with kidney disease, arteriosclerosis, or heart disease should use ergocalciferol only with extreme caution and medical guidance.
Side Effects
Minor side effects may include poor appetite, constipation, dry mouth, increased thirst, metallic taste, or fatigue. Other reactions, which should prompt a call to a healthcare provider, can include headache, nausea, vomiting, diarrhea, or confusion.
Interactions
The absorption of vitamin D is improved by calcium, choline, fats, phosphorus, and vitamins A and C. Supplements should be taken with a meal to optimize absorption.
There are a number of medications that can interfere with vitamin D levels, absorption, and metabolism. Rifampin, H2 blockers, barbiturates, heparin, isoniazid, colestipol, cholestyramine, carbamazepine, phenytoin, fosphenytoin, and phenobarbital reduce serum levels of vitamin D and increase metabolism of it. Anyone who is on medication for epilepsy or another seizure disorder should check with a healthcare provider to see whether it is advisable to take supplements of vitamin D. Overuse of mineral oil, Olestra, and stimulant laxatives may also deplete vitamin D. Osteoporosis and hypocalcemia can result from long-term use of corticosteroids. It may be necessary to take supplements of calcium and vitamin D together with this medication. The use of thiazide diuretics in conjunction with vitamin D can cause hypercalcemia in individuals with hypoparathyroidism. Concomitant use of digoxin or other cardiac glycosides with vitamin D supplements may lead to hypercalcemia and heart irregularities. The same caution should be used with herbs containing cardiac glycosides, including black hellebore, Canadian hemp, digitalis, hedge mustard, figwort, lily of the valley, motherwort, oleander, pheasant's eye, pleurisy, squill, and strophanthus.
Resources
Books
Bratman, Steven, and David Kroll. Natural Health Bible. CA Prima Publishing, 1999.
Feinstein, Alice. Prevention's Healing with Vitamins. PA: Rodale Press, 1996.
Griffith, H. Winter. Vitamins, Herbs, Minerals & Supplements: The Complete Guide. AZ: Fisher Books, 1998.
Jellin, Jeff, Forrest Batz, and Kathy Hitchens. Pharmacist's letter/Prescriber's Letter Natural Medicines Comprehensive Database. CA: Therapeutic Research Faculty, 1999.
Pressman, Alan H., and Sheila Buff. The Complete Idiot's Guide to Vitamins and Minerals. New York: Alpha Books, 1997.
[Article by: Judith Turner]
For more information on vitamin D, visit Britannica.com.
A fat-soluble vitamin containing a number of distinct chemicals that enhance the absorption of calcium and phosphorus from the intestine and, with parathyroid hormone, mobilizes their deposition in bones. Vitamin D is relatively stable when exposed to heat and light. It is stored in the liver and, to a lesser extent, in the fatty tissue in the skin. Vitamin D occurs in two forms: vitamin D2 and vitamin D3. Vitamin D2 (ergocalciferol or calciferol) is obtained in the diet from foods such as oily fish, eggs, and margarine. Vitamin D3 (cholecalciferol) is the main form of the vitamin and is produced in the skin by the action of ultraviolet light on another compound, 7-dehydrocholesterol. Vitamin D deficiency causes a loss of muscle tone, restlessness, and irritability. It also causes rickets in children, and demineralization and softening of the bones (osteomalacia) in adults. For most adults, the main source of vitamin D is from the action of sunlight on skin. As with vitamin A, vitamin D can be toxic if large amounts are consumed over a long period of time. Calcium may be deposited in the organs and soft tissues of the body forming obvious growths. Total intake should not exceed 400 IU (10 μg) per day. Vitamin D supplements have been used to treat osteoporosis and rheumatoid arthritis.
A group of closely related steroids that have antirachitic properties. They commence as provitamins in both plants and animals and are converted by exposure to ultraviolet light. In plants ergosterol is converted to vitamin D2 (the provitamin ergocalciferol) by exposure to sunlight. In animals the provitamin 7-dehydrocalciferol (formed from cholesterol) is irradiated to form vitamin D3. Pharmaceutical vitamin D is manufactured by the ultraviolet irradiation of ergosterol.
A deficiency of vitamin D, from a nutritional deficiency of vitamin D2 and a deficiency of exposure to sunlight so that little vitamin D3 is formed, is characterized by the development of rickets in young animals or osteomalacia in adults.
Poisoning due to overdosing with vitamin D causes demineralization of bones and mineralization of soft tissues. The same effect is achieved by feeding on some plants. See enzootic calcinosis.
Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).[1] The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation.
Vitamin D plays an important role in the maintenance of organ systems.[2]
Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders.[2] Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. Vitamin D deficiency may also be linked to many forms of cancer.
Several forms of vitamin D have been described. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol.
Chemically, the various forms of vitamin D are secosteroids; i.e. broken-open steroids.[3] The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.
Vitamin D2 is derived from fungal and plant sources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–290 nm.[4] These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV index is greater than 3.[5] At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin only after ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated.[1]
In most mammals, including humans, D3 is more effective than D2 at increasing the levels of vitamin D hormone in circulation; D3 is at least 3-fold, and likely closer to 10-fold, more potent than D2.[6] However, in some species, such as rats, vitamin D2 is more effective than D3.[7] Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.[8]
Vitamin D is a prohormone, that is, it has no hormone activity itself, but is converted to a hormone 1,25-D which does, through a tightly regulated synthesis mechanism.
The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.
Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum.[4] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is reduced.
Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. 7-Dehydrocholesterol absorbs UV light most effectively at wavelengths between 270–290 nm and thus the production of vitamin D3 will only occur at those wavelengths. The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum.[4]
A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin
is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum
basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 mg/cm2 of skin) are available in the stratum spinosum and
stratum basale of human skin to meet the body's vitamin D requirements,[4] and melanin content does not alter the amount of vitamin D that can be produced.[9] Thus, individuals with higher skin melanin content will simply
require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content.
| 1. Vitamin D3 is synthesized from 7-dehydrocholesterol, a derivative of cholesterol, which is then photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is pre-vitamin D3. |  |
| 2. Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a antarafacial hydride [1,7]Sigmatropic shift. |  |
| 3. Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3
or calcidiol) by the enzyme 25-hydroxylase produced by
hepatocytes, and stored until it is needed. 25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D3 or calcitriol) and 24R,25(OH)2D3. This conversion occurs in a tightly regulated fashion. Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end). |
 |
Once vitamin D is produced in the skin or consumed in food, it is converted in the liver and
kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form
of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). Following this
conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein in the
The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[3] 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 VDR 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.[10]
The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune
system, and VDR are expressed in several white blood cells including
monocytes and activated T and
Very few foods are naturally rich in vitamin D, and most vitamin D intake is in the form of fortified products including milk, soy milk and cereal grains.[1]
A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D remains a point for debate among medical scientists.
The U.S. Dietary Reference Intake for Adequate Intake (AI) of vitamin D for infants, children and men and women aged 19–50 is 5 micrograms/day (200 IU/day).[11] Adequate intake increases to 10 micrograms/day (400 IU/day) for men and women aged 51–70 and to 15 micrograms/day (600 IU/day) past the age of 70.[1]
Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet.
In some countries, foods such as milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency.[12] In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50.[1]
Fortified foods represent the major dietary sources of vitamin D, as very few foods naturally contain significant amounts of vitamin D.
Natural sources of vitamin D include:[1]
Vitamin D deficiency can result from: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders.[2] Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis.[2]
The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920.[14] In 1921 Elmer McCollum identified an anti-rachitic substance found in certain fats could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D.[14] The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid, 7-dehydrocholesterol, the precursor of vitamin D.
Vitamin D deficiency is known to cause several bone diseases[15] including:
Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases.[10]
Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia, seasonal affective disorder and several autoimmune diseases (see role in immunomodulation).[10]
Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 decreases.[16] In addition the ability of the kidneys to convert calcidiol to its active form also decreases with age, prompting the need for increased vitamin D supplementation in elderly individuals. One consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL, which is equal to 75 nmol/L.[17]
The American Pediatric Associations advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards.[1] Health Canada recommends 400IU/day (10μg/d).[18] While infant formula is generally fortified with vitamin D, breast milk does not contain significant levels of vitamin D, and parents are usually advised to avoid exposing babies to prolonged sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes.[18] Liquid "drops" of vitamin D, as a single nutrient or combined with other vitamins, are available in water based or oil-based preparations ("Baby Drops" in North America, or "Vigantol oil" in Europe). However, babies may be safely exposed to sunlight for short periods; as little as 10 minutes a day without a hat can suffice, depending on location and season. The vitamin D found in supplements and infant formula is less easily absorbed than that produced by the body naturally and carries a risk of overdose that is not present with natural exposure to sunlight.
Obese individuals may have lower levels of the circulating form of vitamin D, probably because of reduced bioavailability, and are at higher risk of deficiency. To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their parathyroid glands removed (most commonly renal dialysis patients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism.[19] Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily).
The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin.[10][20] Recent studies showed that, following the successful "Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer, an increased number of Australians and New Zealanders became vitamin D deficient.[12] Ironically, there are indications that vitamin D deficiency may lead to skin cancer.[21] To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use.
The reduced pigmentation of light-skinned individuals tends to allow more sunlight to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D deficiency.[17] However, at higher latitudes (above 30°) during the winter months, the decreased angle of the sun's rays, reduced daylight hours, protective clothing during cold weather, and fewer hours of outside activity, diminish absorption of sunlight and the production of vitamin D. Because melanin acts like a sun-block, prolonging the time required to generate vitamin D, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes. At latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required.[5] Individuals clad in full body coverings during all their outdoor activity, most notably women wearing burquas in daylight, are at risk of vitamin D deficiency. This poses a lifestyle-related health risk mostly for female residents of conservative Muslim nations in the Middle East, but also for strict adherents in other parts of the world.[22]
Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a long
half-life (about 20 to 29 days).[8] However, the synthesis of bioactive vitamin D hormone is tightly regulated and vitamin D toxicity
usually occurs only if excessive doses (prescription or megavitamin) are
taken.[23] Although normal food and pill
vitamin D concentration levels are too low to be toxic in adults, because of the high vitamin
A content in
Exposure to sunlight for extended periods of time does not cause Vitamin D toxicity.[25] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[26] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.[25]
The exact long-term safe dose of vitamin D is not entirely known, but dosages up to 60 micrograms (2,400 IU) /day in healthy adults are believed to be safe.[8], and all known cases of vitamin D toxicity with hypercalcemia involve intake of or over 1,000 micrograms (40,000 IU)/day[25]. The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults is 50 micrograms/day (2,000 IU/day). In adults, sustained intake of 2500 μg/day (100,000 IU) can produce toxicity within a few months.[2] For infants (birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU/day), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004, leading to 1 death.[27]
Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 25 to 40 ng/mL (60 to 100 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose.[2]
The symptoms of vitamin D toxicity or (hypervitaminosis D) are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Gastrointestinal symptoms of vitamin D toxicity can develop including anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop.[2] In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity.[28] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.[29]
Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.[2]
The hormonally active form of vitamin D mediates immunological effects by binding to
nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in
activated macrophages, dendritic cells,
Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns.[31] VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression.[32]
VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages.[8] Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in
macrophages triggered by bacteria, viruses, and fungi.[33] Vitamin D deficiency tends to increase the risk of infections, such as
influenza and tuberculosis. In a 1997 study,
These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection.[30] However the effects of supplementation with vitamin D, as yet, remain unclear, and supplementation may be inadvisable for individuals with sarcoidosis and other diseases involving vitamin D hypersensitivity.[35][25][36]
A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D.[37]
The vitamin D hormone, calcitriol, has been found to induce death of cancer cells
