Vitamin D

Vitamin D (also known as calciferol) is a hormone precursor that contributes to the maintenance of normal levels of calcium and phosphorus in the blood. Vitamin D is not a true vitamin since human skin can create vitamin D in some circumstance; it may be better described as a conditional vitamin.

Overview

Vitamin D plays an important role in the maintenance of an intact and strong skeleton. Its primary task seems today to be to regulate the amount of calcium and phosphorus in the blood by ensuring correct intake from intestines and secretion. However, other related tasks are still under investigation

Several studies show that vitamin D also regulates the growth of skin cells. Psoriasis gives shell-like skin as a result of uncontrolled cell growth. A synthetic vitamin D analogue called calcipotriene is used in the treatment of this disease.

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. However, vitamin D should not be excluded from the diet, especially for people who do not receive sufficient exposure to UVB sunlight.

• 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), precursor of calcidiol, which is the precursor of calcitriol
• Vitamin D₄: 22,23-dihydroergocalciferol
• Vitamin D₅: sitocalciferol (made from 7-dehydrositosterol)

Vitamin D₃, also known as cholecalciferol, is a form of vitamin D that is made by the human body. It is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light with wavelengths 290 to 315 nm. This can be found in sunlight when the sun is high enough above the horizon for UVB to penetrate the atmosphere and is responsible for the production of cholecalciferol. Up to 20,000 IU can be made in the skin only 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 the rat, D₂ is more effective as a vitamin than D₃, and in the squirrel monkey and the chick, D₃ is more effective. In humans, D₃ is more effective than D₂ at increasing 25-hydroxyvitamin D, the circulating reservoir of the vitamin D hormone.

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, foods such as milk may be 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 only way to determine vitamin D deficiency; levels should be between 40 and 60 ng/mL (100 to 150 nMol/L) for optimal health.

The most active form of the vitamin is calcitriol (1,25 dihydroxy vitamin D₃), a potent 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 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.

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

What is it: vitamin, steroid or secosteroid?

Strictly speaking, vitamin D is not a true vitamin, because it can be manufactured by the body. For historical reasons, however, it is generally called a vitamin. The use of the term "vitamin" leads consumers to believe they require it in their diet and that it is 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.

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, rather than a vitamin, 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 most accurately viewed as a secosteroid with a high degree of steroidal activity. This indicates the need for further investigation of whether vitamin D supplementation is generally beneficial.

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.

• Shiitake mushrooms, one of a few natural sources of vegan and kosher vitamin D (vitamin D2),
• Fish liver oils, such as cod liver oil, 1 Tbs. (15 ml), 1,360 IU (340% Daily value)
• Fatty fish, such as:
  • Salmon, cooked, 3.5 oz, 360 IU (90% DV)
  • 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 is commonly measured in micrograms (mcg). However, International Units (IU) is the unit of measurement for vitamin D that appears on food labels.

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.

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.
• Osteoporosis: a condition characterized by fragile 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.

However, recent research 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 There is increasing evidence for similar vitamin D hypersensitivity and dysregulation in a wide variety of autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease. Waterhouse et al 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.

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 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.

Dark-skinned people living at higher latitudes may require extra vitamin D because their high level of skin pigmentation generally retards the absorption of UV rays. This does not pose a problem in tropical areas, where the amount of sunshine is so high 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 prove detrimental to the 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 (conversely, light-skinned people are disadvantaged in the tropics, as they are more susceptible than dark-skinned people to intense sunlight and resultant problems such as sunburn, and so forth).

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.

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, 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. However, since even a few minutes of unprotected ultraviolet exposure a day increases the risk of skin cancer and causes photoaging of the skin, many dermatologists recommend supplementation of vitamin D and daily sunscreen use.

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). Despite a widespread recognition that current official advice to the public about vitamin D is out of date, the process for revising recommendations like the RDA has stopped, apparently for budgetary reasons. Vitamin D dietary guidelines are among the next in line for reassessment by the Food and Nutrition Board in North America.

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. Long-term intake of these doses would be toxic in normal human beings.

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.

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. In rodents, the hypercalcaemia effect of vitamin D leads to a highly effective rat poison.

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 in cod-liver oil — not the vitamin D.

Other research disputes the view that high vitamin D intake is so 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, new research indicates vitamin D supplementation is inadvisable due to vitamin D hypersensitivity and dysregulation.

In cancer prevention and recovery

Recent research suggests that cancer patients who have their surgery or 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.

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. Cancer experts, however, say that much further research is needed to provide concrete proof about vitamin D's ability to prevent cancer.

David Feldman's group at Stanford University has elucidated some of the ways that vitamin D, naproxen, and soy prevent and may serve as a therapy for prostate cancer.

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. This can lead to vitamin D dysregulation/hypersensitivity, which can lead to hypervitaminosis D, hypercalcemia and other symptoms. This is recognized as occurring in sarcoidosis and other diseases.

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. In this situation, supplementation with vitamin D may lead to an even greater elevation of an already elevated level of the 1,25D hormone. Marshall showed that elevated levels of 1,25D are able to cause dysfunction of alpha 2 thyroid receptors and glucocorticoid receptors, thus interfering with endocrine function and the adaptive immune response.

Some of the newest research on vitamin D emphasizes its role in combating viruses and bacteria, including tiny L-form bacteria, named after the Lister Institute where they were first described by Kleinberger-Nobel in 1934. L-forms lack a cell wall and can hide inside cells, including immune cells, like macrophages. There is increasing evidence for this in diseases like systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, sarcoidosis and multiple sclerosis.

Molecular modeling research indicates that when 25D is high enough, it actually displaces 1,25D bound to the vitamin D receptor (VDR). This may block innate immunity and bacterial killing, thus suppressing the reaction associated with bacterial killing, called the Jarisch-Herxheimer Reaction. This anti inflammatory effect may explain why some studies find that vitamin D gives the appearance of being helpful in the short term. However, if bacteria are the underlying cause of the disease, this suppression of the inflammatory innate immune response may allow bacteria to increase and cause harm occurring over several decades. This immunosuppressive effect of vitamin D, as well as other effects, are similar to the effect of steroid drugs and, in fact, it is questionable whether vitamin D should continue to be regarded as a vitamin.