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vitamin D

 
Dictionary: vitamin D
 
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n.

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.


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Sci-Tech Encyclopedia: Vitamin D
 
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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.

 
Food and Nutrition: vitamin D
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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.

 
Food and Fitness: vitamin D
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anti-rachitic factor

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.

 
Dental Dictionary: vitamin D
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n
antirachitic factor, calciferol, cholecalciferol, ergosterol, ergocalciferol

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.

 
Alternative Medicine Encyclopedia: Vitamin D
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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]

 
Britannica Concise Encyclopedia: vitamin D
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Any of a group of fat-soluble alcohols important in calcium metabolism in animals to form strong bones and teeth and prevent rickets and osteoporosis. It is formed by ultraviolet radiation (sunlight) of sterols (see steroid) present in the skin. The most important of these sterols are 7-dehydrocholesterol, formed by metabolic processes in animals, and ergosterol, present in vegetable oils. The action of sunlight on the skin converts these two compounds, respectively, to cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Vitamin D is added to margarine, milk, and cereals for the benefit of those who may not get enough sunlight in winter. As little as 5 micrograms each day appear adequate for children. Because the body cannot excrete it, prolonged high intake can cause a toxic reaction including fatigue, nausea, and abnormal calcium accumulation.

For more information on vitamin D, visit Britannica.com.

 
Sports Science and Medicine: vitamin D
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anti-rachitic factor

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.

 
Veterinary Dictionary: vitamin D
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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.

  • v. D2 — ergocalciferol.
  • v. D3 — cholecalciferol.
 
Wikipedia: Vitamin D
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Cholecalciferol (D3)

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. However, sunlight exposure, to avoid deficiency, carries other risks, including skin cancer; this risk is avoided with dietary absorption, either through diet or as a dietary supplement.

Contents

Forms

Name Chemical composition Structure
Vitamin D1 molecular compound of ergocalciferol with lumisterol, 1:1
Vitamin D2 ergocalciferol (made from ergosterol) Note double bond at top center.
Vitamin D3 cholecalciferol (made from 7-dehydrocholesterol in the skin).
Vitamin D4 22-dihydroergocalciferol
Vitamin D5 sitocalciferol (made from 7-dehydrositosterol

Several forms (vitamers) of vitamin D have been discovered (see table). The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. These are known collectively as calciferol.[9]

Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.[10] 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 (made from ergosterol) is produced by invertebrates, fungus and plants in reponse to UV irradiation; it is not produced by vertebrates. Little is known about the biologic function of vitamin D2 in nonvertebrate species. Because ergosterol can more efficiently absorb the ultraviolet radiation that can damage DNA, RNA and protein it has been suggested that ergosterol serves as a sunscreening system that protects organisms from damaging high energy ultraviolet radiation.[11]

Vitamin D3 is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm.[12][13] These wavelengths are present in sunlight when the UV index is greater than 3. 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 after only 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 humans, D3 is as effective as D2 in vitamin D hormone activity in circulation,[14] although others state that D3 is more effective than D2.[15] However, in some species, such as rats, vitamin D2 is more effective than D3.[16] Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.[17]

Biochemistry

Vitamin D is a prohormone, meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism. Production of vitamin D in nature always appears to require the presence of some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, from mushrooms to animals, which are not able to synthesize it except through the action of sunlight at some point in the synthetic chain. For example, fish contain vitamin D only because they ultimately exist on calories from ocean algae which synthesize vitamin D in shallow waters from the action of solar UV.

Production in the skin

The epidermal strata of the skin. Production is greatest in the stratum basale (colored red in the illustration) and stratum spinosum (colored orange).

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. 7-Dehydrocholesterol is produced in relatively large quantities in the skin of most vertebrate animals, including humans. The few exceptions are some bat species, mole rats, cats, and dogs,[11] which produce little vitamin D.[18] In most animals the highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum.[12] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is less. At room temperature the transformation of previtamin-D3 to vitamin D3 takes about 12 days to complete.[11]

Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. While 7-Dehydrocholesterol absorbs UV light at wavelengths between 270–300 nm, optimal synthesis occurs in a narrow band of UVB spectra between 295-300 nm. Peak isomerization is found at 297 nm. This narrow segment is sometimes referred to as D-UV.[13] 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.[12]

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 µg/cm² of skin) are available in the stratum spinosum and stratum basale of the skin to meet the body's vitamin D requirements,[12] and melanin content does not alter the amount of vitamin D that can be produced.[19] 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. As noted below, the amount of time an individual requires to produce a given amount of Vitamin D may also depend upon the person's distance from the equator and on the season of the year.

In some animals the presence of fur or feathers blocks the UV rays from reaching the skin. In birds and fur-bearing mammals vitamin D is generated from the oily secretions of the skin deposited onto the fur and obtained orally during grooming.[20]

Synthesis mechanism (form 3)

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.

Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a antarafacial hydride [1,7] Sigmatropic shift.

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, with renal 1α-hydroxylase being stimulated by either parathyroid hormone or hypophosphatemia. Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end).

Mechanism of action

After 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). This physiologically active form of vitamin D is known as calcitriol. Following this conversion, calcitriol is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs.[10]

The physiologically 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.[10] 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.[21]

The VDR is known to be involved in cell proliferation and differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells.[17]

Nutrition

Milk and cereal grains are often fortified with vitamin D.

Vitamin D is naturally produced by the human body when exposed to direct sunlight. 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. Extra vitamin D is also recommended for older adults and people with dark skin. Individuals having a high risk of deficiency should consume 25 μg (1000 IU) of vitamin D daily to maintain adequate blood concentrations of 25-hydroxyvitamin D.[1]

As civilization and the Industrial Revolution enabled humans to work indoors and wear more clothes when outdoors, these cultural changes reduced natural production of vitamin D and caused deficiency diseases. In many countries, such foods 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.[22] In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or a quarter of the estimated adequate intake for adults over age 50.[1] Supplementation of 100 IU (2.5 microgram) vitamin D3 raises blood calcidiol levels by 2.5 nmol/litre (1 ng/ml).[23]

Fatty fish, such as salmon, are natural sources of vitamin D.

Natural sources of vitamin D include:[1]

  • Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU (one IU equals 25 ng)
  • Fatty fish species, such as:
    • Herring, 85 g (3 ounces (oz)) provides 1383 IU
    • Catfish, 85 g (3 oz) provides 425 IU
    • Salmon, cooked, 100 g (3.5 oz]) provides 360 IU
    • Mackerel, cooked, 100 g (3.5 oz]), 345 IU
    • Sardines, canned in oil, drained, 50 g (1.75 oz), 250 IU
    • Tuna, canned in oil, 85 g (3 oz), 200 IU
    • Eel, cooked, 100 g (3.5 oz), 200 IU
  • A whole egg, provides 20 IU
  • Beef liver, cooked, 100 g (3.5 oz), provides 15 IU
  • UV-irradiated mushrooms (Vitamin D2)[24][25]

The practical reality is that on average, the U.S. diet provides 100 IU/day. One problem is that much of the fortified milk is not fortified to the required amount (Vit D Dietary Reference Intakes, pp. 256-57).

Adequate Intake has been defined as 200 IU/day for ages infant to 50, 400/day for 51-70, and 600/day over 70. The 100% Daily Value used for product labels is 400 IU. The safe upper limit is set at 2000 IU. The Institute Of Medicine is revisiting vitamin D and calcium recommendations. The report is expected Spring 2010.

Measuring nutritional status

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 is 35–55 ng/mL (or 90-140 nmol/L); with some debate among medical scientists for the slightly higher value.[23]

For instance, a later classification is:[26]

  • 0-14.9 ng/mL = Severely deficient
  • 15.0-31.9 ng/mL = Mildly deficient
  • 32.0-100.0 ng/mL = Optimal
  • >100.0 ng/mL = Toxicity possible

Deficiency

Main article: Hypovitaminosis D

Deficiency of vitamin D can result from a number of factors including: inadequate intake coupled with inadequate sunlight (UVB) exposure, disorders that limit its absorption from the gastrointestinal tract, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders and body characteristics such as skin color and body fat. Rarely deficiency can result from a number of hereditary disorders.[2] Deficiency results in impaired bone mineralization, and leads to bone softening diseases[27] including:

  • Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones. The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920.[28] In 1921 Elmer McCollum identified a substance found in certain fats that could prevent rickets. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States the fortification of milk with 10 micrograms (400 IU) of vitamin D per quart in the 1930s led to a dramatic decline in the number of rickets cases.[21]
  • Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain.[29] A number of reports thus indicate that vitamin D deficiency may be related to various types of pain,[30] but of the five small double-blind randomized controlled trials, only one found a reduction in pain after supplementation, and there is no persuasive evidence of lower vitamin D status in chronic pain sufferers compared to controls.[31]
  • Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility.

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, seasonal affective disorder [32][33], peripheral artery disease[34], cognitive impairment which includes memory loss and foggy brain,[35] and several autoimmune diseases including type 1 diabetes (see role in immunomodulation).[8][21] There is an association between low vitamin D levels and Parkinson's disease, but whether Parkinson's causes low vitamin D levels, or whether low vitamin D levels play a role in the pathogenesis of Parkinson's disease has not been established.[36]

Overdose

For more details on this topic, see hypervitaminosis D.

Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a half-life of about 20 to 29 days.[17] Ordinarily, the synthesis of bioactive vitamin D hormone is tightly regulated, and prevalent thinking is that vitamin D toxicity usually occurs only if excessive doses (prescription forms or rodenticide analogs) are taken.[37] Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 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 exact long-term safe dose of vitamin D is not known. In 1997 the U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults was set at 50 micrograms/day (2,000 IU), but this is viewed as outdated and overly restrictive. A 2007 risk assessment suggested that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit.[38] In adults, sustained intake of 2500 micrograms/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), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. Other sources indicate that the threshold for vitamin D toxicity in humans is 500 to 600 micrograms per kilogram body weight per day."[39] In rats an oral LD50 of 619 mg/kg is noted.[40] All known cases of vitamin D toxicity with hypercalcemia have involved intake of or over 1,000 micrograms/day (40,000 IU)[41].

Although normal food and pill vitamin D concentration levels are far too low to be toxic in adults, people taking multiples of the normal dose of codliver oil may reach toxic levels of vitamin A, not vitamin D, [42] if taken in an attempt to increase the levels of vitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.[41] In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004, leading to 1 death.[43]

Some symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure.[44] Gastrointestinal symptoms of vitamin D toxicity can include 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.[45] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.[46] 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]

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.[41] 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.[47] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.[41]

Role in immunomodulation

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, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects.[48]

VDR ligands have been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages.[17] Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi.[49] Vitamin D deficiency tends to increase the risk of infections, such as influenza[50] and tuberculosis[51][52][53]. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.[54]

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.[55] 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.[56]

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); central nervous systems diseases (multiple sclerosis); and in preventing organ transplant rejection.[48]

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.[57] Further research indicates that vitamin D is required to activate a histocompatibility gene (HLA-DRB1*1501) necessary for differentiating between self and foreign proteins in a subgroup of individuals genetically predisposed to MS.[58]

Role in cancer prevention and recovery

The vitamin D hormone, calcitriol, has been found to induce death of cancer cells in vitro and in vivo. The anti-cancer activity of vitamin D is thought to result from its role as a nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a wide range of cellular mechanisms central to the development of cancer.[59] These effects may be mediated through vitamin D receptors expressed in cancer cells.[17]

A search of primary and review medical literature published between 1970 and 2007 found an increasing body of research supporting the hypothesis that the active form of vitamin D has significant, protective effects against the development of cancer. Epidemiological studies show an inverse association between sun exposure, serum levels of 25(OH)D, and intakes of vitamin D and risk of developing and/or surviving cancer. In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast and ovarian cancer risks by 30%.[60][61][62] A scientific review undertaken by the National Cancer Institute found that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels of 80 nmol/L or higher associated with a 72% risk reduction. However, the same study found no link between baseline vitamin D status and overall cancer mortality.[63]

A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers.[64] Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight.[65] Another 2006 study found that taking the U.S. RDA of vitamin D (400 IU per day) cut the risk of pancreatic cancer by 43% in a sample of more than 120,000 people from two long-term health surveys.[66][67] A randomized intervention study involving 1,200 women, published in June 2007, reports that vitamin D supplementation (1,100 international units (IU)/day) resulted in a 60% reduction in cancer incidence, during a four-year clinical trial, rising to a 77% reduction for cancers diagnosed after the first year (and therefore excluding those cancers more likely to have originated prior to the vitamin D intervention).[68][69] Research has also indicated beneficial effects of high levels of calcitriol on patients with advanced prostate cancer.[70]

Low levels of vitamin D in serum have also been correlated with breast cancer disease progression and bone metastases,[71] and studies suggest that increased intake of vitamin D reduces the risk of breast cancer in premenopausal women.[72] Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an increased risk of breast cancer.[71] Impairment of the VDR-mediated gene expression is thought to alter mammary gland development or function and may predispose cells to malignant transformation. Women with homozygous FOK1 mutations in the VDR gene had an increased risk of breast cancer compared with the women who did not. FOK1 mutation has also been associated with decreasing bone mineral density which in turn may be associated with an increase in the risk of breast cancer.[73]

Role in cardiovascular disease prevention

Research indicates that vitamin D may play a role in preventing or reversing coronary disease.[74][75] Vitamin D deficiency is associated with an increase in high blood pressure and cardiovascular risk. When researchers monitored the vitamin D levels, blood pressure and other cardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years, they found that those people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels.[76] Low levels of vitamin D have also been implicated in hypertension, elevated VLDL triglycerides, and impaired insulin metabolism.[77]

A report from the National Health and Nutrition Examination Survey (NHANES) involving nearly 5,000 participants found that low levels of vitamin D were associated with an increased risk of peripheral artery disease (PAD). The incidence of PAD was 80% higher in participants with the lowest vitamin D levels (<17.8 ng/mL).[34] Cholesterol levels were found to be reduced in gardeners in the UK during the summer months.[78] Heart attacks peak in winter and decline in summer in temperate[79] but not tropical latitudes.[80]

The issue of vitamin D in heart health has not yet been settled, and exercise may account for some of the benefit attributed to vitamin D, since vitamin D levels are generally higher in physically active persons.[81] Moreover, there may be an upper limit after which cardiac benefits decline. One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL.[46] These sun-living groups results do not generalize to sun-deprived urban dwellers. Among a group with heavy sun exposure, taking supplemental vitamin D is unlikely to result in blood levels over the ideal range, while urban dwellers not taking supplemental vitamin D may fall under the levels recognized as ideal.

Role in all-cause mortality

Using information from the National Health and Nutrition Examination Survey a group of researchers concluded that having low levels of vitamin D (<17.8 ng/mL) was independently associated with an increase in all-cause mortality in the general population.[82] The study evaluated whether low serum vitamin D levels were associated all-cause mortality, cancer, and cardiovascular disease (CVD) mortality among 13,331 diverse American adults who were 20 years or older. Vitamin D levels of these participants were collected over a 6-year period (from 1988 through 1994), and individuals were passively followed for mortality through the year 2000.

Among many factors that may be responsible for vitamin D's apparent beneficial effect on all-cause mortality is its effect on telomeres and its potential effect on slowing aging. Shortening of leukocyte telomeres is a marker of aging. Leukocyte telomere length (LTL) predicts the development of aging-related disease, and length of these telomeres decreases with each cell division and with increased inflammation (more common in the elderly) Research indicates that vitamin D is a potent inhibitor of the proinflammatory response and slows the turnover of leukocytes. Higher vitamin D levels were also associated with longer leukocyte telomere length, indicating that vitamin D sufficiency may be play a role in preventing age-related diseases.[83]

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Further reading

v • d • e
Vitamins (A11)
Fat soluble
D
Water soluble
v • d • e
Endocrine system: hormones (Peptide hormones · Steroid hormones)
Endocrine
glands
Other end.
glands
Non-end.
glands
Target-derived
NGF · BDNF · NT-3

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