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Overview
Vitamin D plays an important role in the maintenance of an intact and strong skeleton. The role traditionally attributed to the vitamin D system is to regulate the amount of calcium and phosphorus in the blood by ensuring correct intake from intestines and secretion. However, vitamin D has been implicated in a growing list of functions related to human biology.
Vitamin D is passively produced in skin exposed to ultraviolet B radiation. The cholesterol precursor, 7-dehydrocholesterol, is unstable to UVB light, and the B-ring of the steroid structure breaks open to produce the seco-steroid, vitamin D3, more formally known as cholecalciferol. Diet is usually a minor secondary source of vitamin D, but foods such as oily fish and eggs contain only very small amounts. It is almost impossible to obtain sufficient amounts of vitamin D from diet alone, without sunlight exposure.•
The human body produces its own vitamin D in the skin - this is done by activating some chemicals in the body. This process is dependent on ultraviolet radiation from sunlight. Diet is a secondary source of vitamin D, but foods such as oily fish and eggs contain only very small amounts. It is almost impossible to obtain sufficient amounts of vitamin D from diet alone, without sunlight exposure or supplementation.
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Forms
Vitamin D4: 22,23-dihydroergocalciferol
Vitamin D3, also known as cholecalciferol, is the form of vitamin D that is natural to all animal life, including human. It is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light with wavelengths 290 to 315 nm. This light is present in sunlight when the sun at sea level is more than 45 degrees above the horizon (when your shadow is no longer than you are tall, or when the UV index is more than 3). Typically, 10,000 IU (in the more modern units of nutritional science, this equals 250 micrograms) can be made in the skin only after one minimal erythemal dose of exposure, or until the skin just begins to turn pink. An equilibrium is achieved in the skin whereby longer exposure to UVB simply degrades the product as fast as it is generated.
Vitamin D2 is derived by irradiating fungi to produce ergocalciferol. Ergocalciferol does not naturally occur in the human body unless it is added by supplementation. In most mammals including humans, D3 is more effective than D2 at increasing 25-hydroxyvitamin D, the circulating reservoir of the vitamin D hormone. In the rat, D2 is more effective as a vitamin than D3, and in the squirrel monkey and the chick, D3 is more effective
In certain parts of the world, particularly at higher latitudes, total vitamin D input from skin is usually not sufficient, especially in the winter. To help minimize risk of low serum 25-hydroxyvitamin D concentrations (the measure of vitamin D nutrition status), foods such as milk are often fortified with vitamin D2 or vitamin D3, typically giving 100 IU per glass.
Cholecalciferol is transported to the liver where it is hydroxylated to calcidiol or 25-hydroxy-vitamin D, the form of the vitamin that the body stores. A blood calcidiol level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D remains a contentious point for debate among medical scientists. One recent consensus concludes that for optimal prevention of osteoporotic fracture the concentration should be higher than 30 ng/mL (US units), which is equal to 75 nmol/L (System International units).
The most active form of the vitamin is calcitriol (1,25 dihydroxy vitamin D3). This is both a potent hormone produced by the kidney and released into the circulation, and it is a paracrine/autocrine signalling molecule produced by many tissues for local regulation of cellular biology, but not released into the circulation. Calcitriol is synthesized from calcidiol in the kidneys to perform its endocrine function of maintaining the calcium economy. Calcitriol binds to a transcription factor which then regulates gene expression of transport proteins like TRPV6 and calbindin that are involved in calcium absorption in the intestine. The general result is the maintenance of calcium and phosphorus levels in the bone and blood with the assistance of parathyroid hormone and calcitonin.
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Biochemistry
Biochemically, the various forms of vitamin D, including calcidiol (25D) and calcitriol (1,25D) are secosteroids. Secosteroids are very similar in structure to steroids except that two of the ring carbon atoms (C9 and 10) of the typical four steroid rings are not fused in secosteroids, whereas in steroids they are fused. This structual similarity suggests that vitamin D can bind to some of the same receptors to which steroids bind. And in fact, molecular modeling calculations confirm that vitamin D has a high affinity for several steroid receptors, including glucocorticoid and thyroid receptors.
In May 2006, Professor Ronald M. Evans, a Fellow of the Salk Institute, delivered a continuing medical education seminar to FDA's Center for Drug Evaluation and Research. In response to a question of what the impact on public health policy should be, given that "vitamin D" is actually a secosteroid, he indicated that he would not supplement with "vitamin D" in the food chain. This position is also supported by new evidence that vitamin D supplementation is harmful in many chronic autoimmune diseases (see section on "In Chronic Disease" below), and not just those previously identified (sarcoidosis, granulomatous malignancy such as lymphoma, oat-cell lung cancer, or when cancer has spread to the bone).
Thus, based on its activity, vitamin D is accurately viewed as a secosteroid with a high degree of steroidal activity. The use of the term "vitamin" leads consumers to believe that products containing it are generally safe. Alternatively, seeing vitamin D as a steroid or secosteroid implies a powerful role, as found with steroid hormones and drugs, and calls for a closer examination of the implications of its supplementation.
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In food
Fortified foods are the major dietary sources of vitamin D. Prior to the fortification of milk products with vitamin D in the 1930s, rickets, commonly caused by vitamin D deficiency, was a major public health problem. In the United States milk is fortified with 10 micrograms (400 IU) of vitamin D per quart, and rickets is now uncommon there.
One cup of vitamin D fortified milk supplies about one-fourth of the official estimated adequate intake of vitamin for adults older than age 50 years. Although milk is often fortified with vitamin D, dairy products made from milk (cheese, yogurt, ice cream, and so forth) are generally not. Only a few foods naturally contain significant amounts of vitamin D, including:
Mackerel, cooked, 3.5 oz, 345 IU (90% DV)
Sardines, canned in oil, drained, 1.75 oz, 250 IU (70% DV)
Tuna, canned in oil, 3 oz, 200 IU (50% DV)
Eel, cooked, 3.5 oz, 200 IU
One whole egg, 20 IU (6% DV)
Vitamin D dose is officially measured in micrograms (mcg). However, International Units (IU) is the unit of measurement for vitamin D that appears on food labels, in North America.
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Nutrition
The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) for a 25-year old male for vitamin D is 5 micrograms/day (200 units/day). This rises to 15 micrograms/day (600 units/day) at age 70.
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Diseases caused by deficiency
Vitamin D deficiency is known to cause several bone diseases, due to insufficient calcium or phosphate in the bones:
Rickets: a childhood disease characterized by failure of growth and deformity of long bones.
Osteomalacia: a bone-thinning disorder in adults that is characterised by proximal muscle weakness and bone fragility. Osteomalacia can only occur in a mature skeleton.
Pioneering work in isolating vitamin D and determining its role in rickets was done by Edward Mellanby in 1918–1920. The 1928 Nobel Prize was awarded to Adolf Windaus, who discovered the steroid, 7-dehydrocholesterol, the precursor of vitamin D. Vitamin D deficiency has been said to be endemic in dark-skinned races living in high latitudes (see below).
Vitamin D malnutrition may possibly be linked to chronic diseases such as cancer (breast, ovarian, colon, prostate, lung and skin and probably a dozen more types), chronic pain, weakness, chronic fatigue, autoimmune diseases like multiple sclerosis and Type 1 diabetes, high blood pressure, mental illnesses (depression, seasonal affective disorder and possibly schizophrenia) heart disease, rheumatoid arthritis, psoriasis, tuberculosis, periodontal disease and inflammatory bowel disease.•• indicates that in many chronic diseases where vitamin D levels (25 hydroxyvitamin D) appear to be low, vitamin D supplementation can actually cause long term harm. For example, supplementation with vitamin D is potentially hazardous for those with sarcoidosis and other diseases involving vitamin D hypersensitivity and dysregulation. including rheumatoid arthritis• reports vitamin D may appear to be low in these conditions, but only because it is being energetically converted to its active hormonal form (1,25 dihydroxyvitamin D) by disease processes.
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Groups at greater risk
Older people (age 50 and over) have a higher risk of developing vitamin D deficiency. The ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 is decreased in older people. The kidneys, which help convert calcidiol to its active form, sometimes do not work as well when people age. Therefore, many older people may need vitamin D supplementation.
Newborn infants who are exclusively breastfed require vitamin D supplements. Breast milk does not contain significant levels of the vitamin, and although infants could receive this vitamin from sunlight, parents are usually advised to avoid exposing babies to open sunshine. The Canadian and American Pediatric Associations advise vitamin D supplementation from birth onwards, with 200 IU/day (5 mcg/d) in the south up to 800 IU/day in the north.[ Infant formula is generally fortified with vitamin D, so this requirement only applies to breastfed infants. Liquid "drops" of vitamin D for infants usually include vitamin A or other vitamins, and are available in pharmacies. These products are either detergent-solublized water based preparations (given at 0.5-1 mL/day). Vitamin D as a single infant nutrient is also available in an oil that is given as one drop/day ( "Baby Ddrops" in North America, or "Vigantol oil" in Europe). ]
Dark-skinned people living at higher latitudes may require extra vitamin D because melanin acts like a sun-block, prolonging the time required to generate vitamin D. This does not pose a problem at latitudes below about 30 degrees, where the sunshine is so high in the sky all year that enough vitamin D is produced despite the dark skin color. At higher latitudes, however, the decreased angle of the sun's rays, reduced daylight hours in winter, and protective clothing worn to guard against cold weather diminish absorption of sunlight and the production of vitamin D. Light-skinned people at higher latitudes also face these problems, but the lower amount of pigmentation in their skin allows more sunlight to be absorbed, thereby reducing the risk of vitamin D deficiency.
Those who avoid or are not exposed to summer midday sunshine may also require vitamin D supplements. In particular, recent studies have shown Australians and New Zealanders are vitamin D deficient
There is also evidence that obese people have lower levels of the circulating form of vitamin D, probably because it is deposited in body fat compartments and is less bioavailable, so obese people whose vitamin D production and intake is marginal or inadequate are at higher risk of deficiency.
Adults taking vitamin D in vitamin pills containing 5 micrograms (200 IU) per day are not protected against vitamin D deficiency — even though 200 IU/day is the adequate intake officially recommended up to age 50 years. Currently, the general public is advised that the safety of vitamin D intake cannot be assured beyond 50 micrograms/day (2000 IU/day). Patients with chronic liver disease or intestinal malabsorption may require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily). 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 patients with primary hyperparathyroidism) or who suffer with hypoparathyroidism.
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Oral overdose
The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) for a 25-year old male for vitamin D is 50 micrograms/day. This is equivalent to 2000 IU/day.
Vitamin D in the human body has a large volume of distribution and a long half-life. In any case all common foods and correctly-formulated vitamin pills contain such small amounts that for overdose could ever occur under normal circumstances and normal doses.•
Indeed, Stoss therapy involves taking a dose over a thousand times the daily RDA once every few months, and even then often fails to normalise vitamin D3 levels in the body. However, oral overdose has been recorded due to manufacturing and industrial accidents and leads to hypercalcaemia and atherosclerosis and ultimately death.
The exact long-term safe dose is not entirely known, but intakes of up to 2000 IU (10x the RDA) are believed to be safe, and some researchers believe that 10,000 IU does not lead to long term overdose. It seems that there are chemical processes that destroy excess vitamin D, even when taken orally, although these processes have not been identified (in experiments blood levels of vitamin D do not continue to increase over many months at these doses as presumably would be needed for toxicity to occur.)
Note that although normal food and pill vitamin D concentration levels are too low to be toxic, cod-liver oil, if taken in multiples of the normal dose, could reach poisonous levels because of the high vitamin A content of cod-liver oil.
Other research disputes the view that high vitamin D intake is benign. In one study, hypercalciuria and bone loss occurred at levels of 25D above approximately 50 ng/ml.• Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/ml.• In many chronic diseases, research indicates vitamin D supplementation is inadvisable.
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In cancer prevention and recovery
Research suggests that cancer patients who have their surgery or treatment in the summer — and therefore get more vitamin D — have a better chance of surviving than those who undergo treatment in the winter when they are exposed to less sunlight.•
In 2005, U.S. scientists released a study, published in the American Journal of Public Health, which seems to demonstrate a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from their meta-analysis of 63 published reports, the scientists claimed that an additional intake of 1,000 international units (IU) — or 25 micrograms — of the vitamin daily could lower an individual's cancer risk by 50% in colon cancer, and by 30% in breast and ovarian cancer•. These are cross-sectional data, and thus the evidence is circumstantial. Clinical trial research is needed to provide concrete proof about vitamin D's ability to prevent cancer. However, because cancer-prevention clinical trials will likely take decades.
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In chronic disease
There is increasing recognition that Th1 immune inflammation, occurring in rheumatic diseases can result in excessive numbers of activated macrophages converting 25-hydroxyvitamin D (25D) to its active 1,25 dihydroxyvitamin D (1,25D) hormonal form.[Fauci, A.S. et al. (1998). Harrison’s Principles of Internal Medicine. New York: McGraw Hill.]
Serum vitamin D, measured by the precursor, 25D, may appear to be deficient in chronic diseases in which vitamin D dysregulation occurs, because it is being depleted due to excessive conversion into the active 1,25D form by macrophages.
Research on vitamin D[Mattman, L.H. (2000). Cell Wall Deficient Forms: Stealth Pathogens. Third Edition. Boca Raton, FL: CRC Press.]
Molecular modeling research
The success of a new antibacterial protocol[Autoimmunity Research Foundation] that includes lowering of vitamin D levels, supports the importance of vitamin D dysregulation in many chronic diseases.
This new research on vitamin D's effects and the role of vitamin D dysregulation may require reinterpretation of much past research supporting vitamin D supplementation in the prevention and treatment of many chronic diseases.
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Synthesis mechanism (form 3)
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