Vitamin D

Vitamin D is a fat-soluble steroid hormone precursor that contributes to the maintenance of normal levels of calcium and phosphorus in the bloodstream. Strictly speaking, it is not a vitamin since human skin can manufacture it, but it is referred to as one for historical reasons. It is often known as calciferol.

Forms of Vitamin D

• Vitamin D₁: molecular compound of ergocalciferol with lumisterol, 1:1
• Vitamin D₂: ergocalciferol (made from ergosterol)
• Vitamin D₃: cholecalciferol (made from 7-dehydrocholesterol)
• Vitamin D₄: 22,23-dihydroergocalciferol
• Vitamin D₅: sitocalciferol (made from 7-dehydrositosterol)

Overview

Vitamin D₃, also known as cholecalciferol, is the natural human form of vitamin D. It is made in the skin when cholesterol via 7-dehydrocholesterol reacts with ultraviolet light in the skin. Ultraviolet light (UVB, which is wavelengths 290 to 315 nm), found in sunlight when the sun is high enough above the horizon for UVB to penetrate the atmosphere, is responsible for the production of cholecalciferol. Up to 20,000 IU can be made in the skin after one minimal erythemal dose of exposure, or until the skin just begins to turn pink. 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 certain parts of the world, particularly at higher latitudes, total vitamin D input is usually not sufficient, especially in the winter, thus the recent concern about widespread vitamin D deficiency. To help prevent this possibility, foods such as milk may be fortified with vitamin D₂ or vitamin D₃, but milk only contains 100 IU per glass, 1/200 as much as is made after 15 minutes of sunbathing at solar noon in the summer. A severe deficiency of vitamin D leads to rickets in children, which is a softening of the bones owing to faulty mineralization, and a similar condition in adults, osteomalacia. Recent medical studies also associate vitamin D deficiency with everything from most forms of cancer, to heart disease, depression, diabetes, hypertension, autoimmune diseases, periodontal disease, and even obesity.

Cholecalciferol is transported to the liver where it is hydroxylated to calcidiol or 25-hydroxy-vitamin D, the storage form of the vitamin. A blood calcidiol level is the only way to determine vitamin D deficiency; levels should be between 40 and 60 ng/ml (100 to 150 nMol/L) for optimum health.

The most active form of the vitamin is calcitriol, a potent steroid hormone. 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. The outcome is the maintenance of calcium and phosphorus levels in the bone and blood with the assistance of parathyroid hormone and calcitonin.

A number of tissues throughout the human body also have the ability to make and regulate their own calcitriol, which is the autocrine, and perhaps paracrine, functions of the vitamin D steroid hormone system. It is these autocrine and paracrine functions of vitamin D which may explain vitamin D's association with a host of chronic diseases.

Diseases

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 "soft" bones
• Osteoporosis: a condition characterized by fragile bones.
• Osteomalacia: a bone-thinning disorder in adults that is similar to rickets.

Pioneering work in isolating vitamin D and determining its role in rickets was done by Edward Mellanby in 1918-1920.

Vitamin D malnutrition may also be linked to chronic diseases such as cancer (breast, ovarian, colon, prostate, lung and skin), 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.

Who may need extra vitamin D to prevent a deficiency?

Older people (greater than age 50) 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 may require vitamin D supplements. Breast milk does not contain significant levels of the vitamin, and although infants could receive this vitamin from sunlight, it is usually not recommended that small infants be exposed to sunlight in the levels required to produce a sufficient amount of vitamin D. Infant formula is generally fortified with vitamin D, so this requirement only applies to breastfed infants.

There is also evidence that obese people have lower levels of the circulating form of vitamin D, probably because it is is deposited in body fat compartments and is less bioavailable, so obese people whose vitamin D production and/or intake is marginal or inadequate are at higher risk of 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 [1], particularly after the successful "Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer. Ironically, a vitamin D deficiency may also lead to skin cancer. Still, only a few minutes of exposure (probably 6 times more in dark-skinned people) is all that is required; the production is very rapid.

Recent research suggests that adult human beings can handle up to 5,000 international units (IU) per day long-term, although the metabolic pathways have not yet been identified. Given this, and given that humans on vitamin pills of 200 IU per day become deficient if not exposed to sunlight, there is reasonably convincing evidence that the Recommended Dietary Allowance (RDA) of 200 IU (5 micrograms) may be rather too small.

Human skin production of vitamin D

Human skin exposed to sunlight can, under the right conditions, produce quantities as large as 20,000 IU in just a few minutes without any apparent toxicity. This is easily enough to avoid deficiency and builds up the body's stores.

Exposure to sunlight also destroys vitamin D, so long term exposure to sunlight cannot cause toxicity, as levels are self-adjusting.

However merely being exposed to sunlight does not automatically mean that vitamin D is produced, only the UVB in sunlight triggers vitamin D production, but UVB only reaches ground level when the sun is high in the sky. This only ever occurs a few hours around solar midday (1 pm summertime). Further, at higher latitudes, the sun is only high enough in the sky in summer. For example, in the United States, those living north of a line from San Francisco to Atlanta will not be able to produce it at all for 3 to 6 months a year.

Therefore from the end of summertime to the following spring humans run on stores which gradually deplete. By some estimates 10-20% of the population become at least mildly deficient by the end of winter, and deficiency is high even in very sunny countries like India. People who never go out in the midday sun become deficient even on supplementation at 100% of the RDA.

In addition, suntan lotion blocks production. Deficiencies are now much more common in Australia, which had a very successful 'slip slop slap' campaign, though most of the deficient people have dark skin, cover up when outdoors or are confined indoors (e.g. elderly preople or those with a disability or serious illness). Melanin screens UVB light so dark skin is much less efficient at generating vitamin D. It would therefore be expected that people with darker skin would suffer from deficiencies more frequently, especially if they live at higher latitudes or have an urban lifestyle, and there is much evidence that this is the case.

Oral overdose of vitamin D3

Overdose is extremely rare; in fact, mild deficiencies are far more common.

While the sunshine-generated quantity is self-limiting, vitamin pills were thought not to be; and this has led to widespread concern, which may well be misplaced.

In practice, the human body has enormous storage capacity for vitamin D, and in any case all common foods and correctly-formulated vitamin pills contain far too little for overdose to ever occur in 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, so overdose is very definitely possible.

Acute one-time overdose requires over 50mg (ten thousand times the RDA, 2,000,000 IU). For overdose to occur in adults, chronic doses of 1-2mg (over 200 times the RDA, 40,000 IU) over many months are normally required. Intriguingly, the RDA itself is in fact more than 100x less than the amount that may be generated in about 20 minutes of midday sunshine.

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.

Vitamin D and cancer prevention and recovery

Recent research suggests that cancer patients who have their surgery/treatment in the summer - and therefore get more vitamin D - have a much better chance of surviving the disease than those who have their treatment in the winter when they are exposed to less sunlight. [2]

In 2005, U.S. scientists released a study, published in the American Journal of Public Health, which seems to demonstrate a beneficial corelation between Vitamin D intake and prevention of cancer. Drawing from their review of 63 old studies, the scientists claimed that taking 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.[3] Cancer experts, however, say that much further research is needed to provide concrete proof about Vitamin D's ability to prevent cancer.

Vitamin D food sources

Fortified foods are the major dietary sources of vitamin D. Prior to the fortification of milk products in the 1930s, rickets 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 in the US.

One cup of vitamin D fortified milk supplies about one-fourth of the estimated daily need for this vitamin for adults. Although milk is fortified with vitamin D, dairy products made from milk (cheese, yogurt, ice cream, etc.) are generally not. Only a few foods naturally contain significant amounts of vitamin D, including:

• Fish oils, such as cod liver oil, 1 Tbs., 1,360 IU
• Fatty fish, such as:
  • Salmon, cooked, 3.5 oz, 360 IU
  • Mackerel, cooked, 3.5 oz, 345 IU
  • Sardines, canned in oil, drained, 3.5 oz, 270 IU
  • Eel, cooked, 3.5 oz, 200 IU
• One whole egg, 25 IU
• Beef liver, cooked, 3½ ounces 15 IU
• One (100% RDA) vitamin pill, 200 IU

Sources: National Institutes of Health, National Osteoporosis Society

Synthesis

Vitamin D₃

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 Previtamin D₃.

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

Vitamin D₃ (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (calcidiol) and then further hydroxylated in the kidneys to the main biologically active form 1,25-dihydroxycholecalciferol (calcitriol):

External links

• The Vitamin D Council
• Medical Encyclopedia article (note: not a public domain resource)
• Food Sources of Vitamin D.
• How much Vitamin D is too much? Half of the world seem to be deficient...
• History of Vitamin D
• National Institutes of Health Dietary Fact Sheet
• Vitamin D information and 3D molecular picture