Vitamin D

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Cholecalciferol (D₃)

Ergocalciferol (D₂). Note double bond at top center.

Calcitriol (1,25-dihydroxycholecalciferol). Active form. Note extra OH groups at upper right and lower left.

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 several organ systems.^[2]

• Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys.
• It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton.
• It inhibits parathyroid hormone secretion from the parathyroid gland.
• Vitamin D affects the immune system by promoting immunosuppression, phagocytosis, and anti-tumor activity.

[edit] Forms

Several forms of vitamin D have been described. The two major forms are vitamin D₂ or ergocalciferol, and vitamin D₃ or cholecalciferol.

• Vitamin D₁: molecular compound of ergocalciferol with lumisterol, 1:1
• Vitamin D₂: ergocalciferol or calciferol (made from ergosterol)
• Vitamin D₃: cholecalciferol (made from 7-dehydrocholesterol in the skin).
• Vitamin D₄: dihydrotachysterol
• Vitamin D₅: sitocalciferol (made from 7-dehydrositosterol)

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] 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.^[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]

[edit] Biochemistry

Vitamin D is a prohormone, that is, it has no hormone activity itself, but is converted to a molecule which does, through a tightly regulated synthesis mechanism.

[edit] 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 (less than 25μm (.001 inch)) 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.

[edit] Synthesis mechanism (form 3)

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) and stored until it is needed. 25-hydroxycholecalciferol is further hydroxylated in the kidneys to 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).

[edit] Mechanism of action

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 plasma, vitamin D binding protein (VDBP), it is transported to various target organs.^[3]

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 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 B cells.^[8]

[edit] Nutrition

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. One recent consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL (US units), which is equal to 75 nmol/L (System International units).^[1]

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 units/day).^[11] Adequate intake increases to 10 micrograms/day (400 units/day) for men and women aged 51-70 and to 15 micrograms/day (600 units/day) past the age of 70.^[1]

Milk and cereal grains are often fortified with vitamin D.

[edit] In food

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, yoghurt, 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]

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

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]

• Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU
• Fatty fish, such as:
  • Salmon, cooked, 3.5 oz provides 360 IU
  • Mackerel, cooked, 3.5 oz, 345 IU
  • Sardines, canned in oil, drained, 1.75 oz, 250 IU
  • Tuna, canned in oil, 3 oz, 200 IU
  • Eel, cooked, 3.5 oz, 200 IU
• One whole egg, 20 IU
• Shiitake mushrooms, one of a few natural sources of vegan and kosher vitamin D (in the form of ergosterol vitamin D₂)

[edit] Deficiency

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]

[edit] Diseases caused by deficiency

The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920.^[13] 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.^[13] 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^[14] including:

• Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones.
• Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterised by proximal muscle weakness and bone fragility.
• Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility.

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]

[edit] Groups at greater risk of deficiency

Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D₃ decreases. 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.

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).^[15] 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 exposure to sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes.^[15] 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.^[16] 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).

Individuals who avoid or are not exposed to midday sunshine may also require vitamin D supplements. Although a few minutes of exposure for light-skinned individuals may be all that is required, the dermatology community contends that even a few minutes of unprotected ultraviolet exposure a day increases the risk of skin cancer and causes photoaging of the skin. The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin.^[10] 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.^[17] To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use.

At higher latitudes (above 30°) during the winter months the decreased angle of the sun's rays, reduced daylight hours, and protective clothing worn to guard against cold weather, 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 latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required.^[5] 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.^[18]

[edit] Overdose

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.^[19] 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 codliver oil it is possible to reach poisonous levels of vitamin A,^[20] if taken in multiples of the normal dose in an attempt to increase the intake of vitamin D. Most cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.^[21]

Exposure to sunlight for extended periods of time does not cause Vitamin D toxicity.^[21] 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.^[22]

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] The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults is 50 micrograms/day (2000 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 μg/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.^[23]

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 at serum concentrations of 25D above 50 ng/mL in patients supplementing with up to 3600 IU/day of D₃.^[24] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.^[25]

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]

[edit] 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.^[26]

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.^[27] 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.^[28]

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.^[29] Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.^[30]

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.^[26] 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.^[31][21][32]

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.^[33]

[edit] 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. Although the anti-cancer activity of vitamin D is not fully understood, it is thought that these effects are mediated through vitamin D receptors expressed in cancer cells, and may be related it its immunomodulatory abilities. The anti-cancer activity of vitamin D observed in the laboratory has prompted some to propose that vitamin D supplementation might be beneficial in the treatment or prevention of some types of cancer.^[8]

In 2005, scientists released a study 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%.^[34] Research has also shown a beneficial effect of high levels of calcitriol on patients with advanced prostate cancer.^[35]

Research has suggested that cancer patients who have surgery or treatment in the summer — and therefore get more 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.^[36]

[edit] Notes and references

[edit] External links

• Vitamin D Fact Sheet from the National Institutes of Health
• History of Vitamin D
• The Vitamin D Council
• SUNARC-Sunlight, Nutrition And Health Research Center
• Contemporary Diagnosis and Treatment of Vitamin D-Related Disorders Professional level webcasts from the annual meeting of The American Society for Bone and Mineral Research.