Vitamin D is a fat-soluble vitamin that is essential for maintaining normal calcium metabolism. Vitamin D3 (cholecalciferol) can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation from sunlight, or it can be obtained from the diet. Plants synthesize vitamin D2 (ergocalciferol), which also has vitamin D activity in humans. When exposure to UVB radiation is insufficient for the synthesis of adequate amounts of vitamin D3 in the skin, adequate intake of vitamin D from the diet is essential for health.
Vitamin D itself is biologically inactive, and it must be metabolized to its biologically active forms. After it is consumed in the diet or synthesized in the skin, vitamin D enters the circulation and is transported to the liver. In the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. Increased exposure to sunlight or increased intake of vitamin D increases serum levels of 25(OH)D, making the serum 25(OH)D concentration a useful indicator of vitamin D nutritional status. In the kidney and other tissues, the 25(OH)D3-1-hydroxylase enzyme catalyzes a second hydroxylation of 25(OH)D, resulting in the formation of 1alpha,25-dihydroxyvitamin D [1,25(OH)2D] - the most potent form of vitamin D. Most of the physiological effects of vitamin D in the body are related to the activity of 1,25(OH)2D.
Maintenance of serum calcium levels within a narrow range is vital for normal functioning of the nervous system, as well as for bone growth, and maintenance of bone density. Vitamin D is essential for the efficient utilization of calcium by the body. The parathyroid glands sense serum calcium levels, and secrete parathyroid hormone (PTH) if calcium levels drop too low. Elevations in PTH increase the activity of 25(OH)D3-1-hydroxylase enzyme in the kidney, resulting in increased production of 1,25(OH)2D. Increasing 1,25(OH)2D production results in changes in gene expression that normalize serum calcium by 1) increasing the intestinal absorption of dietary calcium, 2) increasing the reabsorption of calcium filtered by the kidneys and 3) mobilizing calcium from bone when there is insufficient dietary calcium to maintain normal serum calcium levels. Parathyroid hormone and 1,25(OH)2D are required for the latter two effects.
Vitamin D in the form of 1,25(OH)2D is a potent immune system modulator. The VDR is expressed by most cells of the immune system, including T cells and antigen-presenting cells, such as dendritic cells and macrophages. Macrophages also produce the 25(OH)D3-1-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D. There is considerable scientific evidence that 1,25(OH)2D has a variety of effects on immune system function that may enhance innate immunity and inhibit the development of autoimmunity.
In vitamin D deficiency, calcium absorption cannot be increased enough to satisfy the body's calcium needs. Consequently, PTH production by the parathyroid glands is increased and calcium is mobilized from the skeleton to maintain normal serum calcium levels - a condition known as secondary hyperparathyroidism. Although it has long been known that severe vitamin D deficiency has serious consequences for bone health, recent research suggests that less obvious states of vitamin D deficiency are common and increase the risk of osteoporosis and other health problems.
In infants and children, severe vitamin D deficiency results in the failure of bone to mineralize. Rapidly growing bones are most severely affected by rickets. The growth plates of bones continue to enlarge, but in the absence of adequate mineralization, weight-bearing limbs (arms and legs) become bowed. In infants, rickets may result in delayed closure of the fontanelles (soft spots) in the skull, and the rib cage may become deformed due to the pulling action of the diaphragm. In severe cases, low serum calcium levels (hypocalcemia) may cause seizures. Although fortification of foods has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported in cities throughout the world.
Although adult bones are no longer growing, they are in a constant state of turnover. In adults with severe vitamin D deficiency, the collagenous bone matrix is preserved but bone mineral is progressively lost, resulting in bone pain and osteomalacia (soft bones).
Vitamin D deficiency causes muscle weakness and pain in children and adults. Muscle pain and weakness was a prominent symptom of vitamin D deficiency in a study of Arab and Danish Muslim women living in Denmark. In a cross-sectional study of 150 consecutive patients referred to a clinic in Minnesota for the evaluation of persistent, nonspecific musculoskeletal pain, 93% had serum 25(OH)D levels indicative of vitamin D deficiency. A randomized controlled trial found that supplementation of elderly women with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three months increased muscle strength and decreased the risk of falling by almost 50% compared to supplementation with calcium alone.
Although osteoporosis is a multifactorial disease, vitamin D insufficiency can be an important contributing factor. Without sufficient vitamin D, calcium absorption cannot be maximized and the resulting elevation in PTH secretion by the parathyroid glands results in increased bone resorption, which may lead to osteoporotic fracture. A prospective cohort study that followed more than 72,000 postmenopausal women in the U.S. for 18 years found that those who consumed at least 600 IU/day of vitamin D from diet and supplements had a risk of osteoporotic hip fracture that was 37% lower than women who consumed less than 140 IU/day. The results of most clinical trials suggest that vitamin D supplementation can slow bone density losses or decrease the risk of osteoporotic fracture in men and women who are unlikely to be getting enough vitamin D.
Supplementation of postmenopausal women in the U.S. with 500 mg/day of calcium and either 100 IU/day or 700 IU/day of vitamin D for two years slowed bone density losses at the hip only in the group taking 700 IU/day. Daily supplementation of elderly men and women with 500 mg/day of calcium and 700 IU/day of vitamin D for three years reduced bone density losses at the hip and spine and reduced the frequency of nonvertebral fractures. When the calcium and vitamin D supplements were discontinued, the bone density benefits were lost within 2 years. In Denmark, supplementation of elderly women with 400 IU/day of vitamin D for two years increased bone density at the hip.
An annual injection of 150,000-300,000 IU of vitamin D2 (ergocalciferol) for four years decreased the incidence of fracture in elderly Finnish women (44), and oral supplementation with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three years decreased the incidence of hip fracture in elderly French women. Oral supplementation of elderly adults in the U.K. with 100,000 IU of vitamin D once every four months (equivalent to about 800 IU/day) for five years reduced the risk of osteoporotic fracture by 33% compared to placebo. However, oral supplementation with 400 IU/day of vitamin D for more than 3 years did not affect the incidence of fracture in a study of elderly Dutch men and women. Overall, the evidence to date suggests that vitamin D supplements of about 800 IU/day may be helpful in reducing bone loss and fracture rates in the elderly. In order for vitamin D supplementation to be effective in preserving bone health, adequate calcium (1,000 to 1,200 mg/day) should also be consumed.
Two characteristics of cancer cells are their lack of differentiation (specialization) and their rapid growth or proliferation. Many malignant tumors have been found to contain vitamin D receptors (VDR), including breast, lung, skin (melanoma), colon, and bone. Biologically active forms of vitamin D, such as 1,25(OH)2D and its analogs, have been found to induce cell differentiation and/or inhibit proliferation of a number of cancerous and noncancerous cell types maintained in cell culture.
The geographic distribution of colon cancer is similar to the historic geographic distribution of rickets, providing circumstantial evidence that decreased sunlight exposure and diminished vitamin D nutritional status may be related to an increased risk of colon cancer. However, prospective cohort studies have not generally found total vitamin D intake to be associated with significant reductions in colorectal cancer when other risk factors are taken into account. One five-year study of more than 120,000 people found that men with the highest vitamin D intakes had a risk of colorectal cancer that was 29% lower than men with the lowest vitamin D intakes. Vitamin D intake was not significantly associated with colorectal cancer risk in women. Serum 25(OH)D level, which reflects vitamin D intake and vitamin D synthesis, was inversely associated with the risk of potentially precancerous colorectal polyps and indices of colonic epithelial cell proliferation, which are considered biomarkers for colon cancer risk.
Although breast cancer mortality follows a similar geographic distribution to that of colon cancer, direct evidence of an association between vitamin D nutritional status and breast cancer risk is limited.. A prospective study of women who participated in the first National Health and Nutrition Examination Survey (NHANES I) found that several measures of sunlight exposure and dietary vitamin D intake were associated with a reduced risk of breast cancer 20 years later. More recently, a 16-year study of more than 88,000 women found that higher intakes of vitamin D were associated with significantly lower breast cancer risk in premenopausal women but not postmenopausal women.
Epidemiological studies show correlations between risk factors for prostate cancer and conditions that can result in decreased vitamin D levels. Increased age is associated with an increased risk of prostate cancer, as well as with decreased sun exposure and decreased capacity to synthesize vitamin D. The incidence of prostate cancer is higher in African American men than in White American men, and the high melanin content of dark skin is known to reduce the efficiency of vitamin D synthesis. Geographically, mortality from prostate cancer is inversely associated with the availability of sunlight. Recent findings that prostate cells in culture can synthesize the 25(OH)D3-1-hydroxylase enzyme and that, unlike the renal enzyme, its synthesis is not influenced by PTH or calcium levels also provide support for the idea that increasing 25(OH)D levels may be useful in preventing prostate cancer. In contrast, prospective studies have not generally found significant relationships between serum 25(OH)D levels and subsequent risk of developing prostate cancer. Although a prospective study of Finnish men found that low serum 25(OH)D levels were associated with earlier and more aggressive prostate cancer development, another prospective study of men from Norway found a U-shaped relationship between serum 25(OH)D levels and prostate cancer risk. In that study serum 25(OH)D concentrations of 19 nmol/L or lower and 80 nmol/L or higher were associated with higher prostate cancer risk. Further research is needed to determine the nature of the relationship between vitamin D nutritional status and prostate cancer risk.
Insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), and rheumatoid arthritis (RA) are each examples of autoimmune disease. Autoimmune diseases occur when the body mounts an immune response to its own tissue, rather than a foreign pathogen. In IDDM, insulin producing beta-cells of the pancreas are the target of the inappropriate immune response. In MS, the targets are the myelin producing cells of the central nervous system, and in RA, the targets are the collagen producing cells of the joints. Autoimmune responses are mediated by immune cells called T cells. The biologically active form of vitamin D, 1,25(OH)2D, has been found to modulate T cell responses, such that the autoimmune responses are diminished.
The results of several prospective cohort studies also suggest that adequate vitamin D intake may decrease the risk of autoimmune diseases. A prospective cohort study of children born in Finland during the year 1966 and followed for thirty years found that those who received vitamin D supplementation in the first year of life had a significantly lower risk of developing IDDM, while children suspected of developing rickets (severe vitamin D deficiency) during the first year of life had a significantly higher risk of developing IDDM. Vitamin D supplement use was associated with a significant reduction in the risk of developing MS in two large cohorts of women followed for at least ten years. Similarly, postmenopausal women with the highest total vitamin D intakes were at significantly lower risk of developing RA after eleven years of follow up than those with the lowest intakes. Evidence from animal models and epidemiological studies suggests that maintaining sufficient vitamin D levels may help decrease the risk of several autoimmune diseases.
The results of epidemiological and clinical studies suggest an inverse relationship between serum 1,25(OH)2D levels and blood pressure, which may be explained by recent findings that 1,25(OH)2D decreases the expression of the gene encoding renin (see Function). Data from epidemiological studies suggest that conditions that decrease vitamin D synthesis in the skin, such as having dark skin and living in temperate latitudes, are associated with increased prevalence of hypertension (71). A controlled clinical trial in 18 hypertensive men and women living in the Netherlands found that exposure to UVB radiation three times weekly for six weeks during the winter increased serum 25(OH)D levels and significantly decreased 24-hour ambulatory systolic and diastolic blood pressure measurements by an average of 6 mm Hg. In randomized controlled trials of vitamin D supplementation, a combination of 1,600 IU/day of vitamin D and 800 mg/day of calcium for eight weeks significantly decreased systolic blood pressure in elderly women by 9% compared to calcium alone, but supplementation with 400 IU/day or a single dose of 100,000 IU of vitamin D did not significantly lower blood pressure in elderly men and women over the next two months. At present, data from controlled clinical trials are too limited to determine whether vitamin D supplementation will be effective in lowering blood pressure or preventing hypertension.
Taking vitamin D supplements may reduce the risk of falls in elderly people in residential care facilities, results of a study published in the Journal of the American Geriatrics Society suggest. In the study, Australian researchers examined the effect of vitamin D supplementation in 625 residents of 149 residential care facilities. The subjects were not vitamin D deficient.
The participants were randomly assigned to receive vitamin D supplements or inactive "placebo" for 2 years. All of the residents were prescribed 600 mg of calcium daily. Care staff recorded falls and fractures in diaries. At the start of the study, patient characteristics were similar in both groups.
The researchers report that vitamin D use cut the risk of falls by 27 percent to 37 percent compared with placebo. This study supports the use of vitamin D supplements in older people in residential care. The demonstrated benefits in this study on the rates of falls for individuals with marginal vitamin D levels, even without vitamin D deficiency, highlights the potential benefits of vitamin D supplementation in this population.
For maintaining calcium metabolism, intake of calcium levels above 800 milligrams daily is probably unnecessary provided that vitamin D status is adequate, according to a report in the Journal of the American Medical Association this week. Vitamin D is essential to healthy teeth and bones, and it helps the body absorb and use calcium, but the ideal intake of vitamin D has been unclear, senior author Dr. Gunnar Sigurdsson. The researchers assessed calcium intake and serum vitamin D levels with respect to optimal parathyroid hormone (PTH) levels in 944 healthy Icelandic adults. PTH is a major hormone maintaining normal serum concentrations of calcium and phosphate and is itself regulated through levels of calcium. An insufficiency of vitamin D or calcium is generally associated with an increase in PTH, but the relative importance of each nutrient to this process has not been addressed.
In their study, Sigurdsson and colleagues noticed that in the presence of low vitamin D levels, maintaining calcium intake above 800 mg/d seems to help normalize calcium metabolism, as determined by the PTH level. By contrast, in the presence of higher vitamin D levels, there appears to be no benefit for achieving calcium intake above 800 mg/d.
Our study suggests that vitamin D sufficiency may be more important than high calcium intake in maintaining desired values of serum PTH," the authors conclude. "Vitamin D may have a calcium-sparing effect and as long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. The report also indicates that vitamin D supplements are needed to achieve an adequate status for people living in northern climates.
Lack of sufficient vitamin D can increase the risk of many common and serious conditions - some cancers, type 1 diabetes, cardiovascular disease, and osteoporosis.
This vitamin is not widely available in foods. Oily fish, such as salmon, mackerel, and sardines are good sources, as well as cod liver oil. Some foods may be fortified with vitamin D; these include milk, orange juice, cereals, and breads. Easting oily fish three or four times a week will provide enough vitamin D for most people. Otherwise, the body must rely on exposure to sunlight.
The skin can produce large amounts of vitamin D3, although this ability decreases with age. The vitamin D3 produced by casual exposure to sunlight during the spring, summer, and fall, is stored in the body fat, and becomes available in the winter, when required.
Who's at risk of vitamin D deficiency? Lack of vitamin D is seen commonly in the very young and the very old. Encouraging breast feeding of infants is partially responsible for a resurgence of this deficiency, as breast milk contains very little vitamin D. Infants usually require a vitamin D supplement. The elderly are at risk, because of poor dietary intake, decreased exposure to sunlight, and reduced formation in the skin; by age 70, the amount of vitamin D3 formed in the skin decreases by as much as 75%. Race also plays a role, especially in the elderly. Deficiency was reported in white, Hispanic, and black elderly Bostonians at the end of August in 30%, 42% and 84%, respectively; presumably the differences are largely related to skin pigmentation. Obesity is another risk factor. It's thought that the vitamin D deposited in large body fat stores is not readily accessible to the rest of the body.
Consequences of vitamin D deficiency: without vitamin D, the small intestine only absorbs about 10% to 15% of dietary calcium, instead of the normal 30% in someone without a deficiency. (In fact, absorption of calcium usually increases to about 80% during growth, lactation, and pregnancy; these periods are obviously time of increased risk for deficiency, too.) Lack of vitamin D in childhood causes rickets. In adults bone growth stops and deformities can occur, and there is an attempt by the parathyroid glands to counteract this, by producing more parathormone. This hormone tries to maintain the serum calcium, but it causes loss of phosphorus in the urine instead; this results in softening of the bone (osteomalacia), and the risk of fractures is increased.
Apart from effects on bone, lack of vitamin D has been associated with an increased risk of colon, prostate, and breast cancer. This was discovered because of the increase in these tumors seen in people living at high latitudes, i.e. with fewer hours of sunshine. And it's been shown that a breakdown product of vitamin D can slow the multiplication rate of very active cell growth. This action of vitamin D has led to its successful use in treating the skin disease psoriasis, in which the skin cells multiply too quickly.
Although the way it works is not always understood, there is some evidence that vitamin D is able to reduce the chances of development of autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. An interesting finding is the reduction in blood pressure in hypertensive patients when they are exposed to ultraviolet B radiation that raises their circulating vitamin D. Exposure to ultraviolet A radiation had no effect on these patients' vitamin D levels, or their raised blood pressure.
Finally, some people are mistakenly diagnosed with fibromyalgia, when they really have a deficiency of vitamin D deficiency. Muscle weakness and bone pain, often reported in fibromyalgia patients, may be presenting symptoms of this vitamin deficiency.
What should be done to avoid vitamin D deficiency? Without exposure to sunlight, Doctor recommends a minimum of 1000 IU vitamin D daily. And they believes that the blood concentration of 25(OH)D - the actual active form of vitamin D - should be measured once a year, just as we measure cholesterol levels. Early correction of a deficiency may prevent some of the conditions outlined in the previous section.
The best way to get enough vitamin D is by moderate exposure to sunlight. Exposure of the hands, face and arms, or arms and legs to sunlight for a period of time equal to a quarter of that required to make the skin pink is quite sufficient. There's no need to increase the risk of skin damage and skin cancer by 'overdosing'. And it can't hurt to consume foods fortified with vitamin D, as well as oily fish a few times a week.
Doctors warns against taking more than one multivitamin a day, as too much vitamin A would be consumed, increasing the risk of birth defects and osteoporosis. But one daily multivitamin containing 400 IU vitamin D is quite appropriate.
1. Colli E, Rigatti P, Montorsi F, Artibani W, Petta S, Mondaini N, Scarpa R, Usai P, Olivieri L, Maggi M. A Novel Vitamin D3 Analog Arrests Prostate Growth in Patients with Benign Prostatic Hyperplasia: A Randomized Clinical Trial. Eur Urol. 2005 Nov 15.
Objective: To evaluate the effect of BXL628, a vitamin D3 analog, on prostate volume in patients with benign prostatic hyperplasia (BPH). METHODS: We conducted a phase II, double blind, randomized, placebo controlled, clinical study. Patients eligible were aged >/=50 years, had a diagnosis of BPH and a prostate volume >/=40ml. Eligible patients were randomized and given either BXL628 150mcg daily or placebo for 12 weeks. All randomized patients underwent at baseline and at the end of study pelvic MRI to measure prostatic volume, uroflowmetry (Q(max)), American Urological Association Symptom Index (AUASI), serum PSA, testosterone, dihydrotestosterone and luteizing hormone. RESULTS: A total of 119 patients were randomized: 57 patients to BXL628 and 62 to placebo.
The percentage change of prostate volume at 12 week was -2.90 in the BXL628 group vs. +4.32 in the placebo group (p-value <0.0001). The estimated difference between treatments (BXL628 minus placebo) was -7.22% (95% confidence limit -9.27 to -5.18). Considering Q(max), mean change vs. baseline was -0.30 in BXL628 vs. +1.50 in the placebo group: this finding was not statistically significant. The mean change of the AUASI total score at final visit vs. baseline was -1.77 in the BXL628 group vs. -3.45 in the placebo group (p= not significant). Conclusion: BXL628 was able to arrest prostate growth within 12 weeks in men aged >/=50 years with prostatic volume >/=40ml. Its unprecedented mechanism of action may offer a new opportunity for the treatment of BPH.
2. Morishita M, Ohtsuru A, Kumagai A, Namba H, Sato N, Hayashi T, Yamashita S. Vitamin D3 Treatment for Locally Advanced Thyroid Cancer: A Case Report. Endocr J. 2005 Oct;52(5):613-6.
There are many intricacies in the surgical treatment of locally advanced thyroid cancer, including the medical management of the remaining functional organ and any cosmetic impairments, which are sometimes very difficult to manage and eventually carry a relatively high morbidity and mortality. Here, we report on a case of a 65-year-old female with an extremely locally-advanced thyroid cancer involving both lobes of the thyroid, blood vessels, trachea and esophagus. Despite the severity of her condition, oral administration of vitamin D3 (alphacalcido) has stalled both the tumor growth and further increases of serum thyroglobulin (Tg) level, and has led to a good preservation of quality of life for the last two years. Several reports have previously demonstrated the efficacy of vitamin D3 to inhibit the proliferation of thyroid cancer cell lines in vitro, but clinical evidence has been limited so far. Therefore, this case report provides important evidence for the effectiveness of vitamin D3 therapy against advanced thyroid cancers.
3. Tokar EJ, Webber MM. Chemoprevention of Prostate Cancer by Cholecalciferol (vitamin D3): 25-hydroxylase (cyp27a1) in Human Prostate Epithelial Cells. Clin Exp Metastasis. 2005;22(3):265-73.
The 20-30 year latency period for prostate cancer provides an important opportunity to prevent the development of invasive cancer. A logical approach for chemoprevention to reduce incidence is to identify agents, such as, vitamin D, which can inhibit cell proliferation and induce differentiation, are safe, and readily available to the public at low cost. Epidemiological evidence suggests that vitamin D deficiency is associated with increased risk for prostate cancer. We examined the ability and mechanisms of action of cholecalciferol, a precursor of the most biologically active hormone calcitriol, to block or reverse premalignant changes. The immortalized, non-tumorigenic, RWPE-1 human prostate epithelial cell line, was used.
Results show that cholecalciferol, at physiological levels: (i) inhibits anchorage-dependent growth (ii) induces differentiation by increasing PSA expression and (iii) exerts its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptors (RXRs), and androgen receptor (AR). Furthermore, we discovered that human prostate epithelial cells constitutively express appreciable levels of 25-hydroxylase CYP27A1 protein, the enzyme which catalyzes the conversion of cholecalciferol to 25(OH)D(3), and that CYP27A1 is up-regulated by cholecalciferol. Recent studies show that human mitochondrial CYP27A1 can also catalyze 1alpha-hydroxylation of 25(OH)D(3) to calcitriol. The presence of 25-hydroxylase in human prostate epithelial cells has not previously been shown. Since human prostate epithelial cells have the necessary enzymes and the rare ability to locally convert cholecalciferol to the active hormone calcitriol, we propose that they are a prime target for chemoprevention of prostate cancer with cholecalciferol whose safety is well established as a supplement in vitamins and fortified foods.
4. Guilhou JJ. The Therapeutic Effects of Vitamin D3 and its Analogues in Psoriasis. Expert Opin Investig Drugs. 1998 Jan;7(1):77-84.
Psoriasis is a common skin disease which is characterised by the proliferation and abnormal differentiation of keratinocytes, coupled with complex immune disturbances. The beneficial effects of vitamin D derivatives in this disease are due to their capacity to inhibit proliferation, their ability to induce normal differentiation and their immunomodulatory properties. Since the systemic administration of these compounds is limited by their effect on calcium metabolism, topical preparations have become available in most countries. Topical calcipotriol and/or tacalcitol are now considered as first-line treatment for mild-to-moderate psoriasis and can be taken in combination with other systemic therapies in more severe cases of the disease. Novel orally active vitamin D analogues, with minimal calcitropic effercts, are, however, required for more effective treatment.
5. Moore ME, Piazza A, McCartney Y, Lynch MA. Evidence that Vitamin D3 Reverses Age-related Inflammatory Changes in the Rat Hippocampus. Biochem Soc Trans. 2005 Aug;33(Pt 4):573-7.
One of the major challenges in neuroscience is to identify the changes which accompany aging and which contribute to the well-documented age-related deterioration in cognitive function. This is a particular challenge in the light of the vast array of reported changes, which include morphological changes like synaptic and perhaps cell loss, alteration in membrane composition and the resultant changes in function of membrane proteins, modulation of the hypothalamo-pituitary axis, impaired calcium homoeostatic mechanisms, alteration in enzyme function and decreased neurotransmitter release. In the past few years, evidence suggesting that an aged brain exhibits signs of oxidative stress and inflammatory stress has been accumulating, and recent evidence using microarray analysis has added support to this view. In this paper, we provide evidence to suggest that vitamin D3 acts as an anti-inflammatory agent and reverses the age-related increase in microglial activation and the accompanying increase in IL-1beta (interleukin-1beta) concentration.
6. Holick MF. Vitamin D: Importance in the Prevention of Cancers, Type 1 Diabetes, Heart Disease, and Osteoporosis. Am J Clin Nutr. 2004 Mar;79(3):362-71.
The purpose of this review is to put into perspective the many health benefits of vitamin D and the role of vitamin D deficiency in increasing the risk of many common and serious diseases, including some common cancers, type 1 diabetes, cardiovascular disease, and osteoporosis. Numerous epidemiologic studies suggest that exposure to sunlight, which enhances the production of vitamin D(3) in the skin, is important in preventing many chronic diseases. Because very few foods naturally contain vitamin D, sunlight supplies most of our vitamin D requirement. 25-Hydroxyvitamin D [25(OH)D] is the metabolite that should be measured in the blood to determine vitamin D status.
Vitamin D deficiency is prevalent in infants who are solely breastfed and who do not receive vitamin D supplementation and in adults of all ages who have increased skin pigmentation or who always wear sun protection or limit their outdoor activities. Vitamin D deficiency is often misdiagnosed as fibromyalgia. A new dietary source of vitamin D is orange juice fortified with vitamin D. Studies in both human and animal models add strength to the hypothesis that the unrecognized epidemic of vitamin D deficiency worldwide is a contributing factor of many chronic debilitating diseases. Greater awareness of the insidious consequences of vitamin D deficiency is needed. Annual measurement of serum 25(OH)D is a reasonable approach to monitoring for vitamin D deficiency. The recommended adequate intakes for vitamin D are inadequate, and, in the absence of exposure to sunlight, a minimum of 1000 IU vitamin D/d is required to maintain a healthy concentration of 25(OH)D in the blood.
7. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of Vitamin D and Risk of Type 1 Diabetes: A Birth-cohort Study. Lancet. 2001 Nov 3;358(9292):1500-3.
Dietary vitamin D supplementation is associated with reduced risk of type 1 diabetes in animals. Our aim was to ascertain whether or not vitamin D supplementation or deficiency in infancy could affect development of type 1 diabetes. A birth-cohort study was done, in which all pregnant women (n=12055) in Oulu and Lapland, northern Finland, who were due to give birth in 1966 were enrolled. Data was collected in the first year of life about frequency and dose of vitamin D supplementation and presence of suspected rickets. Our primary outcome measure was diagnosis of type 1 diabetes by end of December, 1997. 12058 of 12231 represented live births, and 10821 (91% of those alive) children were followed-up at age 1 year. Of the 10366 children included in analyses, 81 were diagnosed with diabetes during the study.
Vitamin D supplementation was associated with a decreased frequency of type 1 diabetes when adjusted for neonatal, anthropometric, and social characteristics (rate ratio [RR] for regular vs no supplementation 0.12, 95% CI 0.03-0.51, and irregular vs no supplementation 0.16, 0.04-0.74. Children who regularly took the recommended dose of vitamin D (2000 IU daily) had a RR of 0.22 (0.05-0.89) compared with those who regularly received less than the recommended amount. Children suspected of having rickets during the first year of life had a RR of 3.0 (1.0-9.0) compared with those without such a suspicion. Dietary vitamin D supplementation is associated with reduced risk of type 1 diabetes. Ensuring adequate vitamin D supplementation for infants could help to reverse the increasing trend in the incidence of type 1 diabetes.
8. Blutt SE, Weigel NL. Vitamin D and Prostate Cancer. Proc Soc Exp Biol Med. 1999 Jun;221(2):89-98.
Classically, the actions of vitamin D have been associated with bone and mineral metabolism. More recent studies have shown that vitamin D metabolites induce differentiation and/or inhibit cell proliferation of a number of malignant and nonmalignant cell types including prostate cancer cells. Epidemiological studies show correlations between the risk factors for prostate cancer and conditions that can result in decreased vitamin D levels. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits growth of both primary cultures of human prostate cancer cells and cancer cell lines, but the mechanism by which the cells are growth-inhibited has not been clearly defined. Initial studies suggest that calcitriol alters cell cycle progression and may also initiate apoptosis. One of the disadvantages of using vitamin D in vivo is side-effects such as hypercalcemia at doses above physiological levels. Analogs of calcitriol have been developed that have comparable or more potent antiproliferative effects but are less calcemic. Further research into the mechanisms of vitamin D action in prostate and identification of suitable analogs for use in vivo may lead to its use in the treatment or prevention of prostate cancer.
9. Zittermann A. Vitamin D in Preventive Medicine: Are We Ignoring the Evidence? Br J Nutr. 2003 May;89(5):552-72.
Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer.
Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.
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