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Vitamin D
Part 1: Are We Getting Enough?
Yadhu N. Singh, PhD

Professor of Pharmacology

College of Pharmacy

South Dakota State University

Brookings, South Dakota

U.S. Pharm. 2004;10:66-72.

While vitamin D is considered to be a vital nutrient, its precise role in optimal health and general well-being has so far not been fully appreciated nor thoroughly investigated. It is unique, both in terms of its physiology and because humans rely on both endogenous skin production and exogenous dietary sources to meet biological requirements. Vitamin D is converted in the liver into calcidiol (25-hydroxyvitamin D), which in turn is transformed in the kidneys into calcitriol (1,25-hydroxyvitamin D). Calcitriol is the major active form of vitamin D, and it is secreted into the blood to help regulate calcium (Ca) in the body in conjunction with some other systems including the parathyroid hormone. This is the main endocrine function of vitamin D.1,2 Because of its mode of action, vitamin D is sometimes considered to be a pro-hormone, rather than a vitamin.

Many tissues and organs other than the kidneys turn calcidiol into calcitriol to help regulate gene expression locally, this being the newly discovered autocrine (inside the cell) and paracrine (surrounding the cell) functions of the vitamin. These autocrine and paracrine functions are impaired in vitamin D~deficient subjects.1,2 The use of calcitriol by many tissues as an autocrine or paracrine hormone may help explain its role in human development. A plethora of recent research indicates there are many health benefits of vitamin D in numerous diseases, e.g., autoimmune illnesses, cardiovascular diseases, diabetes, at least 13 different types of cancer, and, perhaps, some mental illnesses.

Widespread incidence of Rickettsia, arising from vitamin D deficiency, was not observed in Europe until the beginning of the Industrial Revolution. Children who lived in the sunless, narrow alleyways developed severe growth retardation, widening of the ends of the long bones, and bowing and bending of the legs, all clinical symptoms of severe rickets.2 In addition, young women affected by rickets often had a deformed pelvis and had difficulty with childbirth, and as a result cesarean births were widely employed. Although the link between the lack of sunlight and the high incidence of rickets had been suggested as early as 1822, it wasn't until after the First World War that ultraviolet (UV) radiation from a mercury arc lamp was shown to result in alleviation of the disorder.3 Weston Price, a Canadian-born dentist, observed that the diet of isolated so-called "primitive" peoples contained at least 10 times the amount of fat-soluble vitamins as the standard American diet of his day.4 He concluded that the plentiful presence of vitamins A and D in the diet, along with Ca, phosphorus, and other minerals, conferred good protection against tooth decay and resistance to disease in nonindustrialized communities. These and other similar observations led to the subsequent fortification of milk and some other food products with vitamin D. More recently, vitamin D supplements have become a popular and convenient means to correct any deficit arising from insufficient dietary intake or lack of adequate exposure to sunlight.

There is growing evidence that there is a resurgence of vitamin D deficiency in otherwise healthy individuals in all age-groups in the United States, Europe, and elsewhere, especially in certain ethnic groups and in particular geographic regions.5 In American blacks, the problem is considered to be pandemic. At a conference on vitamin D in October 2003, sponsored by the National Institutes of Health (NIH), Michael Holick, one of the best-known vitamin D experts in the nation, confirmed that blacks make five to 10 times less vitamin D in their skin per minute of sun exposure than white people due to higher melanin pigmentation, while the CDC announced that 10 times more blacks than white persons were vitamin deficient.6 According to leading vitamin D researchers, the clinical inadequacy of vitamin D in the general population appears to be having a profoundly negative and widespread effect on the health and well-being of a great many individuals.

In the opinion of many vitamin D and Ca researchers, recent findings provide overwhelming evidence that the guidelines for optimal vitamin D intake as established by the Food and Nutrition Board (FNB) of the American Institute of Medicine7 are grossly inadequate. Ten years ago, the NIH Consensus Conference on optimal Ca intake emphasized the need for higher Ca intake.8 This effectively underscored the finding in the "Healthy People 2010" project from the Department of Health and Human Services that low Ca intake was one of only two nutrient deficiencies in the U.S. of sufficient prevalence to warrant a national effort.9 This is significant, given the metabolic interdependence of vitamin D and Ca.

The growing evidence of the widespread vitamin D deficiency and the apparent failure of the FNB to expeditiously address the situation has prompted several organizations, including the Vitamin D Council (www.cholecalciferol-council.com), and several eminent researchers to urge the federal government to seriously and promptly evaluate the relevant literature on vitamin D and to institute the necessary course of action.10 Eminent scientists who are writing and speaking out about the problem of vitamin deficiency include Hector DeLuca, William Grant, Robert Heaney, Michael Holick, Bruce Hollis, Anthony Norman, and Reinhold Vieth. None of them are members of the Vitamin D Council, although their affiliation and contact information are listed at the council's Web site.

This article provides a comprehensive review of the vitamin's sources, chemistry and biochemistry, role in health and disease, toxicity and safety, plus possible strategies for dealing with deficiency.

Sources of Vitamin D
Vitamin D required by the body can be obtained from diet or may be formed by the skin after exposure to UV light (TABLE 1). Maximum daily production of vitamin D in the skin is reached in less than 30 minutes of UV irradiation. UV light is composed of three bands or wavelength ranges, A, B, and C. UV-A, containing the longest wavelength radiation, is primarily responsible for darkening of the skin pigments and hence is known as "tanning" rays. It is less energetic than UV-B, so it will not result in a burn unless the skin is photosensitive or excessive exposure occurs. UV-B is the primary cause of sunburn (erythema) and is sometimes called "burning rays." UV-C is the most energetic, as it is composed of the shortest wavelength of the three. Thus it will burn the skin rapidly in extremely small doses but, fortunately, it is almost completely absorbed by the ozone layer. The thinning or partial loss of the ozone layer at the poles, especially in the southern hemisphere, and the increase in the incidence of skin cancer in Australia, Chile, and Argentina may be related to the reduced filtering of UV-C rays before sunlight enters the atmosphere.

It is UV-B which is primarily responsible for the production of vitamin D in the skin. The vitamin so produced requires time to show up maximally in the blood. Cholesterol-containing body oils are critical for the absorption process, and the body needs about 30 to 60 minutes for these vitamin-containing oils to be fully absorbed. Thus it is advisable to delay showering or bathing for at least one hour after exposure. Skin oils with vitamin D can also be removed by chlorine in swimming pools.11

Normally, between 90% and 95% of most human requirement for vitamin D comes from exposure to the sun,1 and the intensity of UV-B light reaching the skin has a dramatic effect on the production of vitamin D. Furthermore, greater skin pigmentation can cause up to a 50-fold reduction, while application of a sunscreen with sun protection factor (SPF) of only 8 reduces the UV-B penetration into the epidermis by as much as 97%.12 While UV-A is present throughout the day, UV-B is available in adequate quantities only between about 10 am and 3 pm during summer in both northern and southern hemispheres, the hours that we are told to avoid exposure to the sun.13 With progression of winter and an increase in the zenith angle of the sun, more and more of the UV-B photons are absorbed by the ozone layer in the stratosphere. At the height of winter in the temperate regions of the world very few of the UV-B rays reach the earth's surface. That is the reason why during winter very little vitamin D is produced in the skin at latitudes above 35°N and below 35°S. At higher altitudes, UV-B intensity is also greater than at lower altitudes. Thus, time of day, season of the year, weather conditions, latitude, and altitude all significantly affect the cutaneous production of the vitamin. A simple meter is now available to determine UV-B levels at different locations.11

Currently, it is suggested that exposure of hands, arms, and face to the sun should occur for 10 to 20 minutes, three times a week. However, this will provide only 200 to 400 IU of vitamin D each time or an average of 100 to 200 IU per day during the summer and much less during the winter. To achieve maximum levels of vitamin D, 80% to 90% of the body needs exposure to the midday sun. About 100 to 200 IU are produced for each 5% of body surface exposed, and we need a minimum of about 4,000 IU.14 Light skinned people need at least 10 to 20 minutes of exposure, while dark skinned people need 90 to 120 minutes to produce the same amount of the vitamin.7 Cultural traditions and practices may also have a significant impact. For instance, even in sunny countries, such as those in the Middle East, traditional attire, especially for most women and girls, covers well over 95% of the body, leading to drastically insufficient UV-B irradiation of the skin. Generally, vitamin D status is more troublesome in elderly persons in comparison with young adults.15,16 This is due mainly to the elderly's often modest outdoor activities and the marked decrease in the aging human skin's capacity to produce vitamin D, probably because of a decline in cutaneous levels of the vitamin D precursor, 7-dehydrocholesterol. A very low vitamin D status has also been observed in institutionalized patients.

Unless regularly exposed to UV-B~rich radiation, an individual is unlikely to obtain adequate amounts of vitamin D from the sun. Historically, the balance of one's daily requirements were met by dietary intake, but the foods selected were vitamin D~rich as they were naturally produced and exposed to sunlight. Many modern farming methods and the sunlight-poor latitudes are reducing the opportunity for adequate formation of vitamin D in poultry, farm-raised fish, pigs, cattle, vegetables, fruits, etc. Examples of some common dietary sources of vitamin D, together with their vitamin D content, are given in TABLE 1. Modern diets may also not provide sufficient amounts of the vitamin because of the trend to low-fat foods, which have a low capacity to absorb and deliver vitamin D. We are often advised to consume egg white and the flesh of fish and animals and to avoid the vitamin D~rich egg yolk, skin, organ meats, and fat because of their role in cardiovascular, cancer, and other disorders, although this may be partially compensated by vitamin D~fortified foods like milk. Because vegetarian diets are especially poor in vitamin D, there is an absolute need for UV-B light or supplementation.11

Active Forms of Vitamin D
On exposure to sunlight, UV-B photons are absorbed by 7-dehydrocholesterol in the epidermal and dermal layers of the skin. This leads to the splitting of the B ring of steroid nucleus and formation of vitamin D3 (cholecalciferol/(FIGURE 1). Vitamin D from food is mainly in the vitamin D2 (ergocalciferol) form. Both are then transported to the liver where they are converted to 25-hydroxyvitamin D3 [25(OH)D] or calcidiol by the action of the hepatic enzyme 25-hydroxy-lase (25-OHase) (FIGURE 2).

As there is no significant storage of calcidiol in the liver, it is promptly released into the blood, where it circulates with a biological half-life of approximately 12 to 20 hours.15 On reaching the kidneys, and some other organs like skin, prostate, colon, and breast, calcidiol is converted by 1a-hydroxylase (1a-OHase) into 1a-25 hydroxyvitamin D3 [1,25(OH)D] or calcitriol. Some other analogs of 1,25(OH)D are also formed, but calcidiol is by far the most potent vitamin D metabolite.

Stages of Vitamin Status
The level of circulating calcidiol closely reflects the dietary intake of vitamin D plus the amount of sunlight to which the skin is exposed. It is generally agreed that, because of its chemical stability, the calcidiol level in the serum is the best indicator to define vitamin D status, which is classified thus (in nmol/L) in decreasing order of severity: deficiency (0~12.5), insufficiency (12.5~50), hypovitaminosis (50~100), and sufficiency (100~250), with hypervitaminosis D toxicity considered to be greater than 250.7 However, defined cut-off values between stages would appear to be arbitrary and related risk factors would also need to be factored in. While calcidiol levels below 12.5 nmol/L result in bone diseases such as rickets in infants and osteomalacia in adults, levels up to 25 nmol/L can lead to these two disorders on chronic deficiency. Cases of vitamin insufficiency can lead to such functional alterations as hyperparathyroidism, in which parathyroid hormone level can be lowered by high oral doses of vitamin D.17

Physiological Roles
Up to about 25 years ago, the principal function of vitamin D was believed to be in the regulation of Ca and consequently on maintaining good bone health. However, vitamin D will also enhance the uptake of toxic metals like lead, cadmium, aluminum, and strontium if Ca, magnesium, and phosphorus are not pres-ent in adequate amounts.18 Thus vitamin D supplementation should not be suggested unless Ca intake is sufficient or supplemented at the same time.

Recent research indicates that vitamin D, in the calcitriol form, may also be involved in the physiological functions of many other organs and tissues. The vitamin D receptor for calcitriol was originally identified in the cell nuclei of the skin, small intestine, osteoblasts, and kidney cells, but subsequently its existence has been shown in over 30 sites in the body and the number is rapidly increasing (TABLE 2). The widespread distribution of vitamin D receptors in the body has led many researchers to postulate that the vitamin may play a significant role in physiological functions that are mediated at these locations.2,15 It has been ascertained, for instance, that vitamin D is a more effective antioxidant than vitamin E in reducing lipid peroxidation and free radical formation.19,20 To comment on this article, contact editor~uspharmacist.com.


First of Two Articles. Next: Chronic Diseases Associated with Low Vitamin D Status

(References will appear at the end of Part 2.)


Vol. No: 29:10 Posted: 10/15/04
October 2005

http://www.uspharmacist.com/index.a...page=8_1396.htm
Vitamin D
Part II: Low Status and Chronic Diseases
Yadhu N. Singh, PhD
Professor of Pharmacology
College of Pharmacy
South Dakota State University, Brookings, SD

US Pharm. 2004;12:39-49.

The influence of vitamin D on numerous physiological processes is best illustrated by the intimate association between low vitamin D status and various chronic diseases. (The first part of this article, on the need for vitamin D, appeared in the October issue of U.S. Pharmacist.) Selected pathophysiological disorders which are claimed in various publications, many of which are referenced in this article, to be linked to vitamin D deficiency or insufficiency, are listed in TABLE 1. The evidence for some of these claims, derived from representative studies, is discussed below in some detail.

Rheumatoid arthritis: In a recent publication, the Iowa Women's Health Study followed almost 30,000 women over 11 years, during which time 152 of the women developed rheumatoid arthritis (RA). The researchers found that women whose diets were highest in vitamin D had the lowest incidence of RA. In particular, women whose intake of the vitamin was less than 200 IU each day were 33% more likely to develop RA than those who got more.21

Multiple sclerosis: The incidence of multiple sclerosis (MS) is low in the tropics and increases with distance from the equator. It has been suggested that reduced amount of sunlight at higher latitudes, especially during the winter months, is too low to produce adequate amounts of vitamin D. The possible protective effect of dietary vitamin D on the risk of MS was tested in two separate Nurses' Health studies (NHS I: 92,253 subjects followed from 1980 to 2000, and NHS II: 95,310 subjects from 1991 to 2001).22 The data showed a 40% reduction in risk of MS among women who used supplemental vitamin D, compared to women who did not use the supplement. Limitations of the study include the fact that the effect of different amounts of exposure to sunlight was not assessed nor was the blood level of the vitamin measured. However, a study among U.S. veterans found that the average annual hours of sunshine and the average December daily solar radiation at place of birth were strongly and inversely correlated with MS incidence.13 Similar results were obtained in Australia23 and among immigrants to Israel.24

Musculoskeletal disorders: Vitamin D deficiency causes mineralization defects in the growing and adult skeletons, resulting in rickets and osteomalacia, respectively, due to the marked suppression in intestinal Ca absorption and impairment of Ca balance. Osteomalacia is associated not only with mineralization defect of the skeleton but also with isolated or global bone pain, muscle weakness, and muscle pain, which are symptoms that often go undiagnosed or misdiagnosed as some type of collagen vascular disease, such as fibromyalgia. It is now generally agreed that an insufficient vitamin D status also contributes significantly to osteoporosis in the elderly.25 Low calcidiol levels are associated with low Ca absorption rates, hyperparathyroidism, and increased bone turnover leading to bone loss.26,27 In elderly subjects, low circulating calcidiol levels are accompanied by a reduced bone mineral density in the proximal femur.26 Recent studies have also demonstrated that even in female adolescents, insufficient calcidiol levels are associated with low forearm bone mineral density.28

In clinical trials, increase in bone mineral density with vitamin D supplementation was inconclusive, although higher amounts consistently gave a positive effect.15 A large, long-term, randomized controlled trial showed that combined supplements of vitamin D (20 mcg/day) and Ca (1,200 mg/day) were capable of preventing nonvertebral fractures in healthy ambulatory subjects.29 In addition, the bone density of the proximal femur increased 2.7% in the treatment group but decreased 4.6% in the placebo group. However, it is conceivable that the antifracture effect of Ca and vitamin D is not due to their effect on bone mineral density alone. An increase in calcidiol levels may very well improve neuromuscular coordination, as measured by body sway, and may thus decrease the risk of falling and falling-related fractures.15 In a recent study in a residential care facility in Australia, it was found that calcidiol remained independently associated with time to first fall and was reduced by 20% on doubling of the serum calcidiol level.30

Recent evidence indicates that age-related changes in vitamin D concentrations may play a role not only in bone health but also in the loss of muscle mass and muscle strength, also called sarcopenia.31,32 A study just published shows that in both active and inactive ambulatory U.S. men and women over the age of 60, higher concentrations of calcidiol were associated with better musculoskeletal function in the lower extremities. It was found that, for optimal lower extremity function, much improvement occurred at calcidiol concentrations >= 40 nmol/L, with maximum improvement being evident at about 125 nmol/L.33 As almost 80% of the total U.S. population has vitamin D blood levels lower than 50 nmol/L (www.cholecaciferol-council.com), the findings raise the possibility that muscles of most Americans may benefit from increased levels of vitamin D.

Cardiovascular diseases: Essential hypertension is associated with disturbances in systemic and cellular Ca metabolism and low calcidiol levels. African-Americans, in particular, have a significantly higher prevalence of diastolic hypertension and lower calcidiol serum levels compared with white Americans.34 Short-term daily supplementation with vitamin D significantly reduced diastolic blood pressure, while both systolic and diastolic blood pressure were reduced in mildly hypertensive subjects after six weeks of UV-B exposure.14

Physical activity and an increased intake of unsaturated fatty acids are frequently recommended in the prevention and treatment of cardiovascular diseases. Physical activity is associated with higher circulating levels of calcidiol and calcitriol compared with a sedentary lifestyle.35 Thus the beneficial effect of physical activity may at least in part be due to improved vitamin D status.

Among the many important risk factors for atherosclerosis development, such as hyperlipoproteinemia, altered glucose tolerance, increase in blood coagulation factors, blood viscosity, and leukocyte counts,36 is recently identified C-reactive protein (CRP), which is an important indicator of inflammatory reactions. There is strong evidence that atherosclerosis is a low-grade systemic inflammatory disease.37 Low vitamin D status and elevated CRP levels have been linked to increased cardiovascular morbidity, which could be alleviated by vitamin D supplementation or UV exposure, even in critically ill patients. Even a low dose (500 IU/d) lowered CRP by more than 25% in one small group of such patients.38

Diabetes mellitus: The dependence of normal insulin secretion in pancreatic ß-cells on vitamin D has been known for many decades. Studies show that low vitamin D activity can result in both increased insulin resistance and reduced insulin secretion. In addition, there was a fourfold to fivefold higher prevalence of type 2 diabetes in dark-skinned Asian immigrants in comparison to British Caucasians in London, indicating that low vitamin status may contribute to diabetes pathogenesis.39 In a Norwegian study, it was found that daily intake of cod liver oil, which is extremely high in vitamin D content, during pregnancy can reduce the risk of diabetes in the offspring,40 while in Finland regular vitamin D supplementation of 50 mcg/d during infancy in the 1960s was associated with a marked reduction in the risk of type 1 diabetes 30 years later in comparison with unsupplemented infants.41

It should be mentioned that diabetes mellitus, hypertension, and cardiovascular diseases are associated with obesity. Obese individuals, as a group, have low plasma concentrations of calcidiol.42,43 While the reason for this is unknown, a number of possible causes have been mentioned, including lifestyle-dependent reduced exposure to UV light, reduced vitamin D ingestion, and negative feedback control by calcitriol on hepatic formation of calcidiol. Researchers recently evaluated the possibility that the deficiency may be due to vitamin D uptake and storage in adipose tissue.44 In agreement with previous studies, they found that, on UV-B irradiation or an oral challenge with vitamin D, the blood level of vitamin D in obese patients was more than 50% lower than in nonobese counterparts. They concluded that obesity-associated vitamin D insufficiency is likely due to the decreased bioavailability of vitamin D and metabolites from cutaneous and dietary sources because of their deposition in body fat compartments.

Cancer: Since most human cancers develop over long periods of time, it becomes difficult to perform reliable intervention studies on the association between vitamin D and cancer risks. However, there is sufficient evidence to conclude that enhanced sunlight exposure is associated with lower incidence of at least a dozen different cancers, in particular, colon, breast, prostate, ovary, uterus, bladder, esophagus, stomach, and rectal cancer.45 The strongest evidence for a protective role for vitamin D in colon or colorectal cancer rests on inverse associations between vitamin D intake and incidence of these cancers. A nested case-control study based on serum drawn from a cohort of 26,620 individuals reported that serum concentrations of calcidiol in the range of 65 to 100 nmol/L were associated with large reductions in the incidence of colo-rectal cancer compared with lower calcidiol levels.46

The NHANES I epidemiological study using several measures of sunlight exposure and dietary vitamin D intake indicates substantially reduced risk of breast cancer. The risk reduction was highest for women who lived in U.S. regions of high solar radiation and little or no reduction was found for women who lived in regions of low solar radiation.47 The data are in keeping with experimental results suggesting that high amounts of vitamin D and dietary Ca decrease susceptibility to chemically induced breast cancer.48

Prostate cancer is the most commonly diagnosed and the second most fatal cancer in American men. The inverse correlation between the mortality rate from prostate cancer and exposure to UV radiation in the U.S. population indicates that one precipitating factor for prostate cancer might be vitamin D deficiency.49 The biochemical evidence to support a role for vitamin D in prostate cancer includes the following: the abundant presence in prostate cells of vitamin D receptors, which show a special affinity for calcitriol, the active form of vitamin D; the antiproliferative, apoptotic, and prodifferentiation activities of calcitriol and its analogs in prostate cells50,51; and the presence in prostate cells of the enzyme 1�-OHase, which converts calcidiol to calcitriol.52 The hypothesis of a vitamin D dependency for prostate cancer has recently been confirmed by a large, nested, case-control study.53 In this 13-year follow-up study of about 19,000 middle-aged Finnish men, prostate cancer risk was highest among the group of younger men (ages 40 to 51 years) who had low serum calcidiol levels. Low calcidiol levels, however, appeared not to increase prostate cancer risk in older men (> 51 years). According to the authors, the data indicate that vitamin D has a protective role against prostate cancer only before the andropause, when serum androgen levels are higher. Furthermore, the lowest calcidiol concentrations in the younger men were associated with more aggressive prostate cancer.

UV radiation and skin cancer: Skin cancer is the most common cancer in the U.S., with about 1.3 million new cases diagnosed every year. It accounts for nearly 8,000 deaths annually, which represents about 2% of all cancer deaths.54 There are three major types of skin cancer: basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Although they have the lowest incidence, melanomas account for nearly 80% of all skin cancer deaths (see www.cancer.gov). Mortality from melanoma increased dramatically after the 1970s but has declined slightly in the late 1990s, possibly reflecting increased prevention and/or early detection practices. Since the late 1940s, the medical profession has stressed to the public the role of sunlight, especially of UV radiation, in the etiology of skin cancer, and provided certain loose guidelines to follow in reducing the harmful rays of the sun, namely, to stay out of the sun between 10 am to 3 pm if at all possible, but if it does become necessary to go outside, then to use a sunscreen of SPF 15 or higher; to always cover up exposed skin; to make sure to never burn; and to take extra care with children. Despite the known risks of UV exposure and attempts by health care professionals to educate the public, sunbathing and indoor tanning have remained tenaciously popular. Today, excessive UV exposure is recognized as the major cause of the approximately 1.3 million new cases of skin cancer diagnosed in the U.S. each year.

Risks versus benefits of UV radiation: The mounting scientific evidence that insufficient exposure to sunlight and subsequent deficiency of vitamin D and loss of its health benefits are prompting widespread comment, both in the scientific and professional literature and in the media.55-57 To quote one of the sources, "Government advice to 'cover up, keep in the shade … and use factor 15 plus sunscreen' is based on outdated information, mistaken interpretation of evidence and guesswork. It ignores evidence showing that insufficient vitamin D is closely associated with, and almost certainly is a cause of, dozens of chronic diseases including 16 different types of cancers, several nervous system diseases including schizophrenia and multiple sclerosis, diabetes, raised blood pressure, polycystic ovary disease, menstrual problems, infertility, infections and dental decay."54

It is also the contention of many vitamin D and Ca experts that mortality from low vitamin D is far greater than from UV-induced skin cancer. According to Grant, over 20,000 Americans die prematurely annually from insufficient vitamin D synthesized via UV-B alone, compared to only about 8,000 from skin cancer.58

Safety and Toxicity
To date, there are no credible reports of vitamin D toxicity in healthy adults after intensive sunlight exposure.15 In general, vitamin D in the skin reaches a plateau after only 15 to 60 minutes of UV-B exposure. After that, vitamin D~inactive substances such as lumisterol and tachysterol are produced, which are not absorbed into the systemic circulation. Thus, the maximum calcidiol level corresponding to an intensive UV-B exposure is considered by some as an upper limit (UL) of safety (~ 200 nmol/L) for the vitamin.15

In reviews of over 30 well-documented studies, it was found that calcidiol levels in all cases of vitamin D intoxication were well above 200 nmol/L.59-61 Levels up to 1,000 nmol/L were observed. In all cases, toxicity was the result of an excessive oral intake of vitamin D2 or vitamin D3, which then underwent hepatic 25-hydroxylation leading to high circulating calcidiol levels and, hence, hypercalcemia. Hypercalcemia, the major adverse effect of vitamin D intoxication, results primarily from intestinal Ca hyperabsorption and, to a lesser degree, from Ca release from bone62 mediated by calcidiol and/or calcitriol, although which of the two is the main signaling molecule causing vitamin D toxicity remains a point of contention.61

A tolerable upper intake level or no observed adverse effect level (NOAEL), as defined by FNB, is especially difficult for vitamin D. The concentration referred to must be that for circulating calcidiol because of the uncertain amount of the environmental component (dietary or solar). Another factor is that some individuals show hypersensitivity to vitamin D, which most commonly manifests itself as hyperparathyroidism. FNB has defined a NOAEL of 25 mcg (100 IU) vitamin D/day for infants and 50 (200 IU) mcg/day for children older than 1 year and for adults.7

The rationale for the threshold of 25 mcg/day in infants is not well founded, as most documented cases of intoxication occurred in children when circulating calcidiol could not be measured. Furthermore, recent observations suggest that an oral vitamin D intake of up to 100 mcg (400 IU)/day is safe in the adult population. No changes in serum and urinary Ca levels were obtained. The largest calcidiol level after administration of 100 mcg vitamin D/day was 140 nmol/L, which was in the range also seen during intensive UV-B exposure.63

Dealing With Insufficiency
While there is a possibility of vitamin D insufficiency, even deficiency, in the whole population during winter, it is the elderly and institutionalized persons who are at greatest risk throughout the year. Decreased availability of vitamin D may be dealt with by prevention and/or treatment. However, because vitamin D may be derived from two separate sources, from sunlight or diet, the strategy to be employed may need to be individualized for different subjects and changing circumstances. Accurate estimates of vitamin D intakes in the U.S. are not available, in part because the vitamin D composition of fortified foods is highly variable and not properly surveyed and exposure to sunlight is not uniform.

Available modes of prevention and/or treatment are threefold: dermal vitamin D application, enhanced exposure to UV-B light, and increased oral vitamin D intake.15 Dermal application of a vitamin D ointment over several weeks, as with estrogens, might prove to be one way to remedy the insufficiency. However, there are no reported clinical trials to indicate that this measure is effective.

Greater exposure to sunlight during winter may not prove to be effective due to the lack of adequate UV-B radiation. Moreover, there are serious concerns of skin cancer and photoageing of the skin on prolonged sunlight exposure that might be necessary to access enough UV-B rays. While use of artificial UV light is a possibility, the available devices, like tanning beds and sunlamps, are unacceptable as a means of getting the daily dose of vitamin D because they provide high levels of UV-A and very little of UV-B. Sunlamps which provide a natural balance of the two rays are available (e.g., from Sperti Sunlamps, www.sperti.com). When UV rays from fluorescent lamps were provided to the institutionalized and the elderly, the results were inconsistent, and complications such as skin burns, keratoconjunctivitis, and cataracts were observed.63 However, adverse effects associated with sun exposure may be avoided by frequent sunbathing in low-level radiation for short periods of time and without sunscreen to maximize the benefits. Adequate UV-B exposure and vitamin D production can be achieved in less time than it takes to cause skin redness, burning, tanning, and skin cancer~causing effects of UV radiation.

Daily oral intake of vitamin D may be an easy and effective way to maintain an adequate physiological status of the vitamin. However, the sun-mediated synthesis of vitamin D in the skin is profoundly affected by a wide range of factors, including degree of skin pigmentation, latitude, time of day, season of the year, weather conditions, and the amount of body surface that is covered with clothing or sunscreen. Thus it becomes difficult to estimate an average daily intake to subsidize the solar component. Furthermore, only a few foods contain significant amounts of vitamin D (TABLE 1). After vitamin D was recognized as being critically important for prevention of rickets, the U.S., Canada, and many other countries instituted a policy of fortifying some foods with the vitamin. Milk was chosen as the principal dietary component to be fortified, and others, like breakfast cereals, margarine, and bread, were subsequently included. However, surveys in the 1990s found that up to 70% of milk sampled in the U.S. and Canada contained less vitamin D than the prevailing labeling standards of 8 to 12 mcg (320~480 IU)/quart. Proprietary infant formulas must also contain vitamin D in the amount of 10 mcg (400 IU)/liter. However, these products have also been found to have wide variability in their vitamin D content.7

According to one source, the Recommended Daily Allowance for vitamin D is 5 to 10 mcg (200~400 IU)/day and arises from the fact that this amount will prevent rickets in children.61 The FNB, on the other hand, has made recommendations for Adequate Intake for different age-groups: 4.5 mcg (180 IU)/day for children and young adults up to age 18 years; 5.0 mcg (200 IU)/day for 19- to 50-year-olds; 10 mcg (400 IU)/day for 51- to 70-year-olds; and 10 to 20 mcg (400~800 IU)/day for persons older than 70 years.7

A UL of safety has been set at 2,000 IU of vitamin D from all sources. However, vitamin D experts almost unanimously agree that this value is too low.10,11,61,62 Vieth suggests that critical toxicity may occur at doses 10 times larger than this (20,000 IU daily) and that the UL of safety should be set at 10,000 IU,62 while Heaney10 contends that humans use between 3,000 and 5,000 IU of vitamin D a day, about 10 times the FNB recommendations, and has called for upward revisions of these recommendations. However, Chesney is of the opinion that long-term supplementation does not need to be greater than 4,000 IU, especially when combined with UV-B exposure.61

Because of the difficulty in determining the overall vitamin D dietary intake, the extent of absorption from the gut, and production in the body, the Weston A. Price Foundation for Vitamin Research11 and others2,10 have suggested that the following blood levels of the vitamin, reported in terms of calcidiol, would provide a much better indication of its status in the individual: optimal values of 40 to 50 ng/mL, acceptable values of 35 to 55 ng/mL, with levels above 55 ng/mL to be considered toxic to some individuals.

Conclusion
While the major role of vitamin D is in the maintenance of Ca homeostasis, a large body of recent evidence indicates that suboptimal levels of the vitamin contribute to the development of various chronic diseases. Replenishment from various sources readily and effectively alleviates most of the disorders. However, most vitamin D experts are of the opinion that, in general, the medical profession has not fully appreciated the full role of the vitamin in the maintenance of good health.2,6,10,15 Also, since a very convenient and effective source of vitamin D is through sun-mediated synthesis in the skin, and UV radiation is instrumental in many cases of skin cancer, there has been some reluctance on the part of health care professionals to fully address the importance of UV radiation in maintaining good health. There are experts, however, who feel that the evidence for the positive clinical role of vitamin D is so compelling that the FDA should act immediately to revise upward the regulatory guideline values and institute fortification of many more items in the food chain and increase the level of the existing items. They also contend that the official policy should advocate a proper balance between utilizing the cheap and readily available benefits of appropriate exposure to the sun to access much needed vitamin D and restraint from excessive sunbathing in an effort to safeguard against increased incidence of skin cancer.

Editors' Note: The first part of this article is available on the U.S. Pharmacist Web site (www.uspharmacist.com).

To comment on this article, contact editor~uspharmacist.com.

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Vol. No: 29:12 Posted: 12/15/04


October 2005

Optimal vitamin D levels in the blood, and vitamin D supplementation required have been set at higher levels since the article was written.

The amount of cancers implicated from vitamin D deficiency has been raised to 23.

Vitamin D supplementation does not seem to be popular. Yesterday, I went to the store to get some and, while there were numerous bottles/sizes/doses of vitamins A, C, E and the Bs, it took a lot of looking for me to find the one slot where the small bottles of vitamin D were.

I thinks it's because they've scared both consumers and pharmacies with the bogeyman of vitamin D toxicity.

Vitamin D3, natural vitamin D, has proven nontoxic at doses of 20,000 IU/day over five years. People with deficiency are routinely given pills and shots containing 50,000 IU of D3.

You can get D3 of 1,000 IU at swansonvitamins.com. I requested they carry a higher dose as I got tired of gobbling 10-16 of the 400 IU gels. Oh, you can still get the 400 IU caps there.

Vitamin D is cheap, at swansonvitamins.com you can get 250 of either 400 IU gels or 1000 IU powder for 2.59 to 3.59. It's the same price for either strength.

Vitamin D supplementation is the cheapest and surest source of prevention for cancers as well as immune and hormone system disorders.

http://www.cholecalciferol-council.com/huxley.pdf

This letter was originally posted on cholecalciferol-council.com which I think is a wonderful resource for vitamin D information.