Vitamin D: importância na prevenção de cancros, diabetes, doenças do coração, e osteoporose – Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis

Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis1,2,3,4,5

  1. 1.    Michael F Holick

+ Author Affiliations

  1. 1.     1From the Vitamin D, Skin, and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston

Next Section Abstract 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 D3 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.

     Vitamin D


     25-hydroxyvitamin D


     bone health


Previous SectionNext Section INTRODUCTION Once our sun ignited, it began to emit enormous amounts of energy. This energy bombarded all of its satellite planets. The third planet from the Sun (ie, Earth) had a huge ocean and a small land mass. In the bubbling, organically rich tide pools, life began to evolve and became dependent on solar energy for its very existence. Early in evolution, organisms captured the sun’s energy in the form of carbohydrates through the process of photosynthesis. As organisms evolved, they continued to make a wide variety of complex macromolecules, not only for the purpose of replication but also to sustain life’s functions. The life forms took advantage of their ocean environment and became dependent on calcium for signal transduction and metabolic functions. In addition, calcium became an important component for organisms that developed exoskeletons. The use of calcium for structural scaffolding became critically important in the evolution of ocean-dwelling vertebrates. The plentiful calcium in the oceans provided the ideal element to incorporate into a collagen-based matrix that gave rise to the structurally rigid vertebrate skeleton. The development of the vertebrate endoskeleton not only provided an opportunity for organisms to grow in size but also gave organisms the opportunity to venture onto land. As vertebrate organisms left their ocean environment for a land-based existence, they needed to develop an efficient method of utilizing the calcium that was absorbed into plants from the calcium-rich soil environment. Remarkably, it was the sun’s energy that was called on to promote the photosynthesis of vitamin D3 in the skin of vertebrates that was responsible for enhancing the efficiency of intestinal calcium absorption (1). Little is known about when vitamin D made its appearance on Earth and what its function was. However, it is known that some of the earliest phytoplankton and diatom life forms, including Emiliania huxlei, which has existed in the oceans for > 750 million years and which has used calcium for its structural support (it is a coccolithophore), produced ergosterol (provitamin D2). When exposed to simulated sunlight, the ergosterol in E huxlei was converted to previtamin D2 (which rapidly isomerized to vitamin D2; 2). Skeletonema menzelii, a diatom that also contained ergosterol, converted it to previtamin D2. Little is known about the biologic function of ergosterol, previtamin D2, and vitamin D2 in nonvertebrate species. It has been suggested that ergosterol and its photoproducts are an ideal sunscreening system because of their high absorption of ultraviolet radiation (1). Ergosterol, previtamin D2, vitamin D2, and their photoproducts efficiently absorb the ultraviolet radiation that is damaging to DNA, RNA, and protein—ie, 230-330 nm. Thus, before the ozone layer (which now efficiently absorbs all ultraviolet radiation < 290 nm) evolved, the ergosterol-vitamin D2 system may have played a critical role in protecting organisms from the high-energy ultraviolet radiation that could have damaged their ultraviolet-sensitive proteins, RNA, and DNA. It is also possible that, if ergosterol existed in the plasma membrane of early life forms, it altered the membrane’s permeability for calcium when it was converted to the structurally less rigid vitamin D2 (1, 2). Previous SectionNext Section PHOTOSYNTHESIS OF PREVITAMIN D Ergosterol is a plant and fungal sterol. Animals synthesize cholesterol. The immediate precursor in the cholesterol biosynthetic pathway is 7-dehydrocholesterol (provitamin D3). 7-Dehydrocholesterol is produced in relatively large quantities in the skin of many vertebrate animals, including humans. The few exceptions are some bat species, mole rats, cats, and dogs (35). During exposure to sunlight, the 7-dehydrocholesterol in the epidermal and dermal cells absorbs ultraviolet B (UVB) radiation with wavelengths of 290-315 nm. The absorption of this radiation results in a rearrangement of the 5,7-diene in the B-ring that causes a break in the B-ring to form the 9,10-secosterol, previtamin D3. Previtamin D3 is thermodynamically unstable, and it rearranges its double bonds to form the more thermodynamically stable vitamin D3 structure (Figure 1).

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 1. F1MH Schematic representation of cutaneous production of vita-min D and its metabolism and regulation of calcium homeostasis and cellular growth. During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin absorbs solar ultraviolet B (UVB) radiation and is converted to previtamin D3 (preD3). Once formed, preD3 undergoes thermally induced transformation to vitamin D3. Further exposure to sunlight converts preD3 and vitamin D3 to biologically inert photoproducts. Vitamin D coming from the diet or from the skin enters the circulation and is metabolized in the liver by vitamin D-25-hydroxylase (25-OHase) to 25-hydroxyvitamin D3 [25(OH)D3]. 25(OH)D3 reenters the circulation and is converted in the kidney by 25-hydroxyvitamin D3-1α-hydroxylase (1-OHase) to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. A variety of factors, including serum phosphorus (Pi) and parathyroid hormone (PTH), regulate the renal production of 1,25(OH)2D. 1,25(OH)2D regulates calcium metabolism through its interaction with its major target tissues, the bone, and the intestine. 1,25(OH)2D3 also induces its own destruction by enhancing the expression of 25-hydroxyvitamin D-24-hydroxylase (24-OHase). 25(OH)D is metabolized in other tissues for the purpose of regulation of cellular growth. VDR, vitamin D receptor. Velluz et al (6) were the first to identify previtamin D3 and to show the transformation of previtamin D3 to vitamin D3. At room temperature, this process took ≈12 d to complete (7). Although this transformation was remarkable, it would have been impractical for cold-blooded vertebrates to produce an amount of vitamin D3 in their skin that was adequate to sustain their calcium-needy skeletons. Previtamin D3 exists in 2 conformeric forms. Once 7-dehydrocholesterol undergoes its exocyclic ring opening, it converts to the 5, 6-cis, cis (cZc) conformer. However, this conformer is extremely unstable because of the steric interference of the C-19 methyl group, and it immediately rotates into the more stable 5, 6-trans,cis (tZc) previtamin D3. However, only the cZc conformer can convert to vitamin D3. To overcome this impediment, the 7-dehydrocholesterol was incorporated into the lipid bilayer of the plasma membrane. This resulted in the sandwiching of 7-dehydrocholesterol between the polar head group and the long-chain fatty acids. Thus, during exposure to sunlight, the 7-dehydrocholesterol immediately converted to cZc previtamin D3, which could not rotate into the favored tZc conformer, and that resulted in the rapid conversion of previtamin D3 to vitamin D3. This probably explains why the conversion of previtamin D3 to vitamin D3 in the skin is 10 times faster than that in an organic solvent (7). Previous SectionNext Section FACTORS THAT ALTER PHOTOSYNTHESIS OF PREVITAMIN D3 During exposure to sunlight, 7-dehydrocholesterol is converted to previtamin D3, which in turn is isomerized by a thermally induced process to vitamin D3. Once formed, vitamin D3, which is structurally incompatible with being sandwiched between the hydrophobic fatty acid chains of the plasma membrane, is ejected into the extracellular space. It is then drawn into the dermal capillary bed by the vitamin D-binding protein, which has a small but effective affinity for it (8). It is remarkable that lifeguards and sun worshippers have never suffered from vitamin D intoxication due to excessive exposure to the sun (9). The reason for this is that previtamin D3 and vitamin D3 efficiently absorb sunlight and are converted to a multitude of other photoproducts, including lumisterol, tachysterol, suprasterols, and toxisterols (1, 2, 9; Figure 1). Thus, because of this unique solar regulation, the skin can never generate quantities of vitamin D3 excessive enough to cause vitamin D3 intoxication (9). Because the production of previtamin D3 in the skin is directly related to the number of UVB photons that are absorbed by 7-dehydrocholesterol, any process that either decreases the number of UVB photons entering the epidermis or decreases the amount of 7-dehydrocholesterol in the skin will result in a significant reduction in or the complete elimination of vitamin D3 production in the skin. A heightened awareness of the role that excessive exposure to sunlight plays in increasing the risk of nonmelanoma skin cancer and wrinkles led to the widespread use of topical sunscreens. Sunscreens efficiently absorb UVB radiation and thus markedly diminish the total number of UVB photons that reach the 7-dehydrocholesterol in the skin’s cells. When used properly (ie, 2 mg/cm2 or 35 mL—ie, 1 oz—on the whole body one time), a sunscreen with an sun protection factor of 8 reduces cutaneous production of previtamin D3 by > 95% (10, 11). The proper use of a sunscreen with a sun protection factor of 15 reduces the capacity > 99%. The facts that most sunscreen users apply as little as 18% and no more than 35-50% of the recommended amount of sunscreen, and they do tan indicate that they are making sufficient amounts of vitamin D3 in their skin. The fact that they tan is a reflection of the fact that UVB penetrates the epidermis to stimulate the melanocytes and make vitamin D3. Melanin is a natural sunscreen that evolved to protect humans from blistering solar radiation as they evolved in equatorial regions of the world. This skin pigment is an extremely effective sunscreen with absorption properties from the ultraviolet C (200-280 nm) into the visible range (> 700 nm), and it competes quite well with 7-dehydrocholesterol for UVB photons. Thus, people of color who have greater amounts of melanin in their epidermis than do whites are less efficient in producing vitamin D3 than are whites (11, 12). A person with skin type 5/6 (dark skin, never develops a sunburn) requires 10-50 times the exposure to sunlight to produce the same amount of vitamin D3 in their skin as does a white person with skin type 2 or 3 (12). The stratospheric ozone layer is efficient in absorbing all solar radiation below 290 nm. However, the ozone layer also can absorb UVB radiation above 290 nm that is responsible for producing previtamin D3 in the skin. The ultraviolet radiation that can be absorbed by 7-dehydrocholesterol has energies down to 315 nm. Thus, when the angle of the sunlight (zenith angle) reaching the Earth’s surface is very oblique (ie, early morning, late afternoon, and winter), sunlight must pass through more ozone, which efficiently absorbs the previtamin D3-producing UVB photons, and thus very few, if any, reach the earth’s surface. Because the zenith angle is dependent on time of day, season of the year, and latitude, those factors have a dramatic effect on the cutaneous production of vitamin D3 (13, 14). Below ≈35°, the zenith angle is more direct, and therefore previtamin D3 synthesis can occur in the skin year-round. However, above 35° latitude, the angle of the sun is so oblique during the winter months that most, if not all, of the UVB photons below 315 nm are absorbed by the ozone layer, thereby either reducing or completely preventing the production of previtamin D3 in the skin. For example, residents of Boston (42 °N), Edmonton, Canada (52 °N), and Bergen, Norway (61 °N) cannot produce sufficient quantities of vitamin D3 in their skin for 4, 5, and 6 mo, respectively. We have conducted studies around the globe that provide guidelines for when, where, and at what time of day vitamin D3 can be produced in the skin (14; Figure 2).


View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 2. Influence of season, time of day, and latitude on the synthesis of previtamin D3 in the northern (A and C: Boston, ○; Edmonton, □; Bergen, ▴) and southern (B: Buenos Aires, ○; Johannesburg, □; Cape Town, ▴; Ushuala, ▿; D: Buenos Aires, •; Johannesburg, □; Cape Town, ▵; Ushuala, ▾) hemispheres. The hour indicated in C and D is the end of the 1-h exposure time in July and January, respectively. Adapted with permission (14). Previous SectionNext Section SOURCES OF VITAMIN D Very few foods naturally contain vitamin D. Cod liver oil and oily fish such as salmon, mackerel, and sardines are good sources. Eating oily fish at least 3-4 times/wk will help satisfy the requirement for adequate intake. Some foods such as milk (100 IU/8 oz), orange juice (100 IU/8 oz), and some cereals and breads are fortified with vitamin D (11, 12, 15). The vitamin D content in milk is often less than the label proclaims it to be, and thus the contribution of vitamin D from the diet is highly variable. To satisfy the body’s requirement for vitamin D, most humans obtain it from casual exposure to sunlight. During the spring, summer, and fall, enough vitamin D3 is produced in the skin to be stored in the body fat, and it can be mobilized during winter months when little, if any, vitamin D3 is produced in the skin. The skin has a large capacity to produce vitamin D3. Blood concentrations of vitamin D3 were compared in healthy young and middle-aged adults who were exposed to simulated sunlight that was equivalent to being on a sunny beach and obtaining enough sun to cause a slight pinkness to the skin (1 minimal erythemal dose) and who took an oral dose of vitamin D2. The exposure was equivalent to an oral dose of ≈20 000 IU vitamin D2 (9; Figure 3). Although aging decreases the amount of 7-dehydrocholesterol produced in the skin by as much as 75% by the age of 70 y (16, 17), the skin has such a large capacity to make vitamin D3 that even elderly exposed to sunlight can achieve increased blood concentrations of vitamin D3 and 25(OH)D (1719).

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 3. F3MH Serum vitamin D concentrations after a whole-body exposure to 1 minimal erythemal dose (MED) of simulated sunlight in a tanning bed and after a single oral dose of either 10 000 or 25 000 IU vitamin D2. UV, ultraviolet. Reproduced with permission (9). Previous SectionNext Section CAUSES AND CONSEQUENCES OF VITAMIN D DEFICIENCY It is estimated that 10 million households in the United States have a reptile as a pet. In their natural environment, reptiles are often exposed to sunlight. They are vertebrates, and, like humans, they require a source of calcium and vitamin D. Iguanas are at particular risk of severe vitamin D deficiency because they are herbivores that, as pets, often are fed a steady diet of lettuce and because they are housed in glass enclosures with a light source that is devoid of UVB transmission. Lettuce contains very little calcium and no vitamin D, and thus iguanas and other vertebrates who do not receive an adequate amount of calcium and vitamin D develop the metabolic bone diseases osteoporosis and osteomalacia that result in fractures and ultimately death. Most reptile owners are aware of the need not only to provide their precious pets with a commercial source of calcium supplementation, but also to provide them with a light that emits UVB radiation similar to sunlight so that the animals can produce vitamin D3 in their skin. Humans are no different. They need an adequate source of calcium and vitamin D. Without vitamin D, the small intestine absorbs no more than 10-15% of dietary calcium. In a person with vitamin D sufficiency, the small intestine absorbs, on average, 30% of dietary calcium; during growth, lactation, and pregnancy, the efficiency increases to 80%. Vitamin D deficiency during bone development and growth causes the bone-deforming disease rickets. In adults bone growth stops and bone remodeling continues. Vitamin D deficiency in adults causes secondary hyperparathyroidism that can precipitate and exacerbate osteoporosis (2, 9, 11). The secondary hyperparathyroidism associated with vitamin D deficiency often maintains the serum calcium concentration within the normal range, but it causes a loss of phosphorus in the urine. This loss results in inadequate serum calcium × phosphorus to promote mineralization of the osteoid in the bone, which in turn results in osteomalacia, ie, nonmineralization of the collagen matrix. Because the nonmineralized matrix cannot provide structural support, the risk of fracture is greater. How common is vitamin D deficiency? Surprisingly, it has made a resurgence in neonates and young children, in part because of the campaign to encourage all women to provide all of their infants’ nutrition through breastfeeding. Because there is very little, if any, vitamin D in human milk, infants, especially infants of women of color, are at high risk of developing vitaminD deficiency and rickets if they are not given a vitamin D supplement (20, 21). The elderly are at risk for vitamin D deficiency because of poor dietary vitamin D intake and decreased exposure to sunlight. We observed that 30%, 42%, and 84% of free-living white, Hispanic, and black elderly were vitamin D deficient [25(OH)D < 50 nmol/L] at the end of August in Boston (9). It has always been assumed that young and middle-aged adults are not at risk of vitamin D deficiency because of their outdoor activities and dietary intake. However, it was recently recognized that 42% of African American women aged 15-49 y throughout the United States were vitamin D deficient [25(OH)D < 40 nmol/L] at the end of the winter (22). Hard-working young and middle-aged adults who very seldom spend any time outdoors or always wear sun protection outdoors are also at high risk of vitamin D deficiency. We observed that 32% of healthy adults 18-29 y of age were vitamin D deficient [25(OH)D < 50 nmol/L] at the end of the winter in Boston (23). Obesity is often associated with vitamin D deficiency (24). It is now recognized that, whether vitamin D is ingested in the diet or obtained from exposure to sunlight, it is efficiently deposited in the large body fat stores and is not bioavailable (25; Figure 4). This is probably the reason that obese persons are chronically vitamin D deficient.

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 4. F4MH A: Mean (± SEM) serum vitamin D3 concentrations before (▪) and 24 h after (□) whole-body irradiation (27 mJ/cm2) with ultraviolet B radiation. The response of the obese subjects was attenuated when compared with that of the control group. There was a significant time-by-group interaction, P = 0.003. *Significantly different from preradiation values (P < 0.05). B: Mean (± SEM) serum vitamin D2 concentrations in the control (•) and obese (○) groups before and 25 h after oral intake of vitamin D2 (50 000 IU, or 1.25 mg). *Significant time and group effects by ANOVA (P < 0.05) but no significant time-by-group interaction. The difference in peak concentrations between obese and nonobese control subjects was not significant. Reproduced with permission (25). Vitamin D deficiency often goes undiagnosed or, worse, is misdiagnosed (9, 2629). There are 3 reasons for this. First, it is believed that either exposure to sunlight or dietary intake of vitamin D is adequate, and, therefore, that Americans and Europeans are not at risk of vitamin D deficiency. Second, physicians who perform routine blood work-ups often obtain a blood calcium value. If they find it to be normal, they assume that the patient is vitamin D sufficient, which is not correct. Third, many physicians erroneously order an analysis for the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], to determine the vitamin D status of a patient. Unfortunately, 1,25(OH)2D not only is not a measure of vitamin D status, but its measurement also can mislead the physician into thinking that the patient is vitamin D sufficient. The reason for this is that, as a person becomes vitamin D-deficient, there is an increase in the concentration of parathyroid hormone (PTH), which increases the renal production of 1,25(OH)2D, the circulating concentrations of which often become normal or even elevated (9). The vitamin D metabolite that should be measured to determine vitamin D status is 25(OH)D, which is the major circulating form of vitamin D, circulating at 1000 times the concentration of 1,25(OH)2D and having a half-life of ≈2 wk (2, 9, 11). As a person becomes vitamin D-deficient, there is a decrease in the efficiency of intestinal calcium absorption. The ionized calcium concentrations begin to drop; this decrease is immediately recognized by the calcium sensor in the parathyroid glands, which increases the production of PTH (30). PTH compensates for the decrease in intestinal calcium absorption by increasing the mobilization of calcium stores from the skeleton and by increasing tubular reabsorption of calcium in the kidney (31, 32). Previous SectionNext Section NONSKELETAL CONSEQUENCES OF VITAMIN D DEFICIENCY It has long been recognized that people who live at higher latitudes face an increased risk of many chronic diseases, including common cancers (3339), multiple sclerosis (39, 40), and hypertension (41). As early as 1941, Apperly (37) observed that people living at higher latitudes, eg, Massachusetts and New Hampshire, had a higher risk of dying of the most common cancers than did people living in the South, eg, Georgia and South Carolina. In 1979, Rostand (41) reported that people living at higher latitudes in both the United States and Europe were at higher risk of hypertension. In the late 1980s and early 1990s, several investigators reported increased risks of dying of colon, prostate, and breast cancer in people living at higher latitudes in both the United States and Europe (3335). Grant (42) reported that ≥25% of the deaths due to breast cancer in women in Europe could be attributed to the women’s lack of UVB from exposure to sunlight. Both men and women are at higher risk of dying of cancer if they have minimum exposure to sunlight (38; Figure 5 A and B). In a retrospective study, Ahonen et al (44) reported that men on average begin to develop prostate cancer by the age of 52 y, whereas men exposed to more sunlight throughout their lives did not begin developing prostate cancer until 3-5 y later.

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 5. F5MH A: Premature mortality due to cancer in white females, as determined on the basis of the July 1992 DNA-weighted ultraviolet B (UV-B) radiation by use of a total ozone mapping spectrometer. B: Premature mortality due to cancer in white males in the United States from 1970 through 1994, as determined on the basis of the July 1992 DNA-weighted UV-B radiation. Reproduced by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc (43). Copyright (2002) American Cancer Society. Previous SectionNext Section VITAMIN D METABOLISM AND NONCALCEMIC FUNCTIONS It has been known for > 30 y that vitamin D3 made in the skin or coming from the diet requires 2 obligate hydroxylations, first in the liver and then in the kidney, to create the active form of vitamin D, 1,25(OH)2D (Figure 1). 1,25(OH)2D interacts with its nuclear receptor in the intestine, bone, and kidney to regulate calcium and bone metabolism (9, 31, 45). Most tissues and cells in the body, including heart, stomach, pancreas, brain, skin, gonads, and activated T and B lymphocytes, have nuclear receptors for 1,25(OH)2D, called vitamin D receptors (4648). Thus, it is not at all surprising that 1,25(OH)2D has a multitude of biologic effects that are noncalcemic in nature (9, 31, 45). One of the most intriguing important and unappreciated biologic functions of 1,25(OH)2D is its ability to down-regulate hyperproliferative cell growth (9, 31, 49). Normal and cancer cells that have a vitamin D receptor often respond to 1,25(OH)2D by decreasing their proliferation and enhancing their maturation. This was the rationale for using 1,25(OH)2D3 and its analogs to treat the common hyperproliferative skin disorder psoriasis (50, 51). Vitamin D receptors are present in activated T and B lymphocytes and in activated macrophages. The most common autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, have all been successfully prevented in models using mice that were prone to these diseases if they received 1,25(OH)2D3 early in life (45, 5255). When nonobese diabetic mice, who typically develop type 1 diabetes, received 1,25(OH)2D3 throughout their life, their risk of developing type 1 diabetes was reduced by 80% (52, 55). This is in good agreement with the recent observation by Hypponen et al (56) that children receiving 2000 IU vitamin D from age 1 y on decreased their risk of getting type 1 diabetes by 80%. Krause et al (57) reported that hypertensive patients exposed to UVB radiation for 3 mo had a > 180% increase in circulating concentrations of 25(OH)D and a 6 mm Hg decrease in their diastolic and systolic blood pressures, results similar to those expected if the patients had received a blood pressure medication (Figure 6). A similar group of patients who were exposed to ultraviolet A radiation and whose circulating concentrations of 25(OH)D did not increase continued to be hypertensive throughout the 3-mo study. The exact mechanism by which UVB radiation returned the blood pressure to normal [presumably due to increased blood concentrations of 25(OH)D] in these hypertensive adults is not well understood, but the observation by Li et al (58) sheds some light on the question. They observed in a mouse model that 1,25(OH)2D is effective in down-regulating renin and angiotensin and thereby decreasing blood pressure.

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 6. F6MH Effect of ultraviolet B (UVB) and ultraviolet A (UVA) radiation from a tanning bed on ambulatory daytime and nighttime blood pressure in hypertensive adults before and after exposure to tanning bed radiation 3 times/wk for 3 mo. The daytime and nighttime blood pressures after UVB tanning bed radiation were significantly (P < 0.01) different from those before irradiation. The mean is indicated by the thick line. Reproduced with permission from Elsevier (57). Previous SectionNext Section THE CANCER-VITAMIN D CONNECTION Because an increased risk of vitamin D deficiency is one of the well-documented effects of living at higher latitudes on human health, it was reasonable to suggest that both living at higher latitudes and an increased risk of common diseases were associated with a decrease in the synthesis of vitamin D3 in the skin. It was intuitively obvious to many, on the basis of new information about vitamin D metabolism and action, that increased exposure to sunlight at lower latitudes would increase blood concentrations of 25(OH)D3, which could be activated in the kidney to 1,25(OH)2D3. Because 1,25(OH)2D3 is extremely potent in inhibiting cancer cell growth, this all seemed to make sense. Unfortunately, it was also well known that the renal production of 1,25(OH)2D was tightly regulated by PTH, calcium, and phosphorus (31). Indeed, neither increased exposure to sunlight nor increased oral intake of vitamin D raised blood concentrations of 1,25(OH)2D (5961). Thus, the question remained: how was it that increased exposure to sunlight was related, presumably by increasing the production of vitamin D3 in the skin, to a decreased risk of many common cancers and other chronic diseases? It had always been assumed that the kidney was the sole source for the body’s production of 1,25(OH)2D. This was based on many observations in animals and in humans whereby, in the absence of any renal function, there were little if any circulating concentrations of 1,25(OH)2D. It had been reported that the placenta, epidermal cells, and bone cells could produce 1,25(OH)2D, but the physiologic relevance of these observations was not well understood (62, 63). In 1985, Schwartz et al (64) reported that cultured prostate cancer cells expressed the enzymatic machinery to convert 25(OH)D to 1,25(OH)2D (Figure 7). Since that observation, it has been shown that a wide variety of normal tissues as well as various cancer cells, including colon cancer, breast cancer, and lung cancer, all have the ability to make 1,25(OH)2D (6567).

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 7. F7MH Measurement of 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase) activity in prostate cells that were either normal (▪), benign but hypertrophied (□), or cancerous (▧). The activity was measured by incubating the cells with [3H]25-hydroxyvitamin D3 and measuring the percentage of conversion to [3H]1,25-dihydroxyvitamin D3 after 24 h. Thus, it is reasonable to conclude that increased exposure to sunlight or increased intake of vitamin D leads to higher circulating concentrations (> 80 nmol/L) of 25(OH)D. 25(OH)D acts as a substrate for the 25-hydroxyvitamin D-1-hydroxylase in various tissues, including colon, breast, and lung. These tissues can produce 1,25(OH)2D, which acts in an autocrine fashion to regulate cell growth and decrease proliferative activity (Figure 8). It can also induce apoptosis when called on. Thus, 1,25(OH)2D3 can effectively manipulate cell growth and maintain it in a normal proliferative state under most circumstances. Once it accomplishes this, it induces the 25-hydroxyvitamin D-24-hydroyxlase, which hydroxylates the 1,25(OH)2D in the side chain on carbons 23 and 24, and this results in cleavage between carbons 23 and 24 that forms the water-soluble, biologically inert calcitroic acid (31, 68; Figure 1). This is the likely explanation for why patients with renal failure develop a 1,25(OH)2D deficiency that results in secondary hyperparathyroidism and renal osteodystrophy.

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 8. F8MH Schematic representation of the multitude of other potential physiologic actions of vitamin D with respect to cardiovascular health, cancer prevention, regulation of immune function, and decreased risk of autoimmune diseases. 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D. Previous SectionNext Section CONCLUSIONS The Institute of Medicine reported in 1997 that the recommended vitamin D intake was inadequate for adults over the age of 50 y (69). They recommended that the adequate intake for children and adults up to the age of 50 be 200 IU vitamin D/d. However, adults aged 50-70 y and ≥ 70 y required 400 and 600 IU vitamin D/d, respectively. As noted in Heaney’s McCollum Award presentation (70) and as indicated in a considerable number of published reports, including that of Heaney et al (71), the new recommendations are totally inadequate, especially if a person has no exposure to sunlight. Without exposure to sunlight, a minimum of 1000 IU vitamin D/d is required. We gave healthy young and middle-aged adults 1000 IU vitamin D/d in orange juice from March through May. Their 25(OH)D concentrations increased by 150%, and what is considered to be a healthy 25(OH)D concentration, ie, 78-100 nmol/L (30-40 ng/mL), was maintained. Those adults receiving orange juice not fortified with vitamin D increased their blood concentration of 25(OH)D by 45%. This was due to their casual exposure to sunlight in the spring (15; Figure 9).

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 9. F9M H Mean (± SEM) weekly 25-hydroxyvitamin D [25(OH)D] concentrations in healthy adults ingesting orange juice fortified with vitamin D (1000 IU · 8 oz−1 · d−1, •) or unfortified orange juice (▪). *P ≤ 0.01. Reproduced with permission (15). The easiest method of correcting vitamin D deficiency is to give the patient one pill that contains 50 000 IU vitamin D once a week for 8 wk (71). This will usually increase the 25(OH)D concentration to > 50 nmol/L (20 ng/mL; Figure 10). If not, the vitamin D “tank” may still not be full, and another 8-wk course of therapy usually corrects the vitamin D deficiency (67; Figure 10). One should suspect a fat-malabsorption problem or poor compliance if the 25(OH)D concentration does not increase by > 25% after these treatments. Exposure to sunlight or a tanning bed will correct vitamin D deficiency in patients with severe intestinal fat- malabsorption syndrome (72).

View larger version:

    In this page

    In a new window

    Download as PowerPoint Slide

FIGURE 10. F10MH A: Serum concentrations of 25-hydroxyvitamin D [25(OH)D; ▵] and parathyroid hormone (PTH; •) before and after therapy with 50 000 IU vitamin D2 and calcium supplementation once a week for 8 wk. *P < 0.05. B: Serum concentrations of PTH in patients who had 25(OH)D concentrations between 10 and 25 ng/mL and who were stratified in increments of 5 ng/mL before (•) and after (▵) receiving 50 000 IU vitamin D2 and calcium supplementation for 8 wk. *P < 0.05, **P < 0.01. Reproduced with permission (71). Why should we care about vitamin D deficiency? It is insidious and has both short- and long-term consequences. Infants and young children who are vitamin D deficient may be imprinted for the rest of their lives with increased risks of type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and many common cancers (Figure 8). Adults are at increased risk of common cancers and cardiovascular disease. Recently, it has been reported that young adults with vitamin D deficiency were at greater risk of congestive heart failure than were their vitamin D-sufficient counterparts (73, 74). Therefore, to maximize health and reduce the risk of common diseases, it is reasonable to pay attention to the 25(OH)D concentration. Just as the blood concentration of cholesterol is often measured on an annual basis, so too should the blood concentration of 25(OH)D be measured. Indeed, vigilance in maintaining a healthy 25(OH)D concentration may have more important health ramifications than a simple lowering of a blood cholesterol concentration to prevent coronary artery disease. A minimum concentration of 25(OH)D should be 50 nmol/L, and, for maximum bone health and prevention of many chronic diseases, the 25(OH)D concentration should be 78-100 nmol/L. The simplest way to obtain vitamin D is from moderate exposure to sunlight. I recommend that exposure of hands, face and arms, or arms and legs to sunlight for a period equal to 25% of the time that it would take to cause a light pinkness to the skin (1 minimum erythemal dose) is sufficient not only to satisfy the body’s requirement, but also to make sufficient amounts of vitamin D to store in the body for use on rainy days and during times when sun exposure is inadequate to produce enough vitamin D in the skin. I have provided guidelines for the amount of sun exposure needed by people of all skin types to achieve their vitamin D requirement without significantly increasing the risk of skin damage and skin cancer (9, 39). Increasing the intakes of foods fortified with vitamin D, including milk, orange juice, cereals, and oily fish, is a reasonable approach to satisfying the body’s requirement. Taking > 1 multivitamin is counterproductive, because too much vitamin A would be ingested, and that increases the risk of birth defects and osteoporosis. Alternatively, one multivitamin containing 400 IU vitamin D and a vitamin D supplement containing either 400 or 1000 IU vitamin D is appropriate. Previous SectionNext Section Footnotes 2 Presented at the American Society for Clinical Nutrition 43rd Annual Meeting, April 12, 2003, San Diego. 3 Presentation of the Robert H Herman Memorial Award in Clinical Nutrition supported by Mrs Yaye Herman. 4 Supported by NIH grants M01RR0053 and AR36963. 5 Address reprint requests to MF Holick, Boston University School of Medicine, 715 Albany Street, M-1013, Boston, MA 02118-2394. E-mail: Robert H Herman Memorial Award in Clinical Nutrition Lecture, 2003 Received June 23, 2003. Accepted September 12, 2003. Previous Section F11 REFERENCES

Holick MF. Phylogenetic and evolutionary aspects of vitamin D from phytoplankton to humans. In: Pang PKT, Schreibman MP, editors. Vertebrate endocrinology: fundamentals and biomedical implications. Vol 3. Orlando: Academic Press, 1989:7-43.

Holick MF. Vitamin D. A millenium perspective. J Cell Biochem 2003;88:296-307. CrossRefMedline

Morris JG, Earle KE. Vitamin D and calcium requirements of kittens. Vet Clin Nutr 1996;3:93.

  1. Pitcher T, Pettifor JM, Buffenstein R. The effect of dietary calcium content and oral vitamin D3 supplementation on mineral homeostasis in a subterranean mole-rat Cryptomys damarensis. Bone Miner 1994;27:145-57.


How KL, Hazewinkel HAW, Mol JA. Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D. Gen Comp Endocrinol 1994;96:12-8. CrossRefMedline

Velluz L, Amiard G, Petit A. Le precalciferol—ses relations d’equilibre avec le calciferol. [Precalciferol and its relationship of equilibrium with calciferol.] Bull Soc Chim Fr 1949;16:501-8(in French).

Holick MF, Tian XQ, Allen M. Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals. Proc Natl Acad Sci U S A 1995;92:3124-6. Abstract/FREE Full Text

Haddad JG, Matsuoka LY, Hollis BW, Hu YZ, Wortsman J. Human plasma transport of vitamin D after its endogenous synthesis. J Clin Invest 1993;91:2552-5. Medline

Holick MF. Vitamin D. The underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocrinol Diabetes 2002;9:87-98.

Matsuoka LY, Ide L, Wortsman J, MacLaughlin J, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab 1987;64:1165-8. Abstract/FREE Full Text

Holick MF. McCollum Award Lecture, 1994: vitamin D—-new horizons for the 21st century. Am J Clin Nutr 1994;60:619-30. Abstract/FREE Full Text

Clemens TL, Henderson SL, Adams JS, Holick MF. Increased skin pigment reduces the capacity of skin to synthesis vitamin D3. Lancet 1982;1:74-6. CrossRefMedline

Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988;67:373-8. Abstract/FREE Full Text

Lu Z, Chen TC, Kline L, et al. Photosynthesis of previtamin D3 in cities around the world. In: Holick MF, Kligman A, eds. Biologic effects of light. Symposium proceedings, October 13-15, 1991. Berlin: Walter De Gruyter & Company, 1992:48-51.

Tangpricha V, Koutkia P, Rieke SM, Chen TC, Perez AA, Holick MF. Fortification of orange juice with vitamin D: a novel approach to enhance vitamin D nutritional health. Am J Clin Nutr 2003;77:1478-83. Abstract/FREE Full Text

MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985;76:1536-8. Medline

Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet 1989;1:1104-5.

  1. Reid IR, Gallagher DJA, Bosworth J. Prophylaxis against vitamin D deficiency in the elderly by regular sunlight exposure. Age Aging 1985;15:35-40.


Chuck A, Todd J, Diffey B. Subliminal ultraviolet-B irradiation for the prevention of vitamin D deficiency in the elderly: a feasibility study. Photochem Photoimmunol Photomed 2001;17:168-71.

Specker B, Tsang RC, Hollis BW. Effect of race and diet on human-milk vitamin D and 25-hydroxyvitamin D. Am J Dis Child 1985;139:1134-7. CrossRefMedline

Kreiter SR, Schwartz RP, Kirkman HN, Charlton PA, Calikoglu AS, Davenport M. Nutritional rickets in African American breast-fed infants. J Pediatr 2000;137:2-6.

  1. Nesby-O’Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health Kreiter SR, Schwartz RP, Kirkman HN, Charlton PA, Calikoglu AS, Davenport M. Nutritional rickets in African American breast-fed infants. J Pediatr 2000;137:2-6.

Nesby-O’Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002;76:187-92. Abstract/FREE Full Text

Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002;112:659-62. CrossRefMedline

Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest 1985;76:370-3. Medline

Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:690-3. Abstract/FREE Full Text

Holick MF. Sunlight and vitamin D: both good for cardiovascular health. J Gen Intern Med 2002;17:733-5. CrossRefMedline

  1. Holick MF. Sunlight “D”ilemma: risk of skin cancer or bone disease and muscle weakness. Lancet 2001;357:4-6.


  1. Glerup H, Mikkelsen K, Poulsen L, et al. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. J Intern Med 2000;247:260-8.


Glerup H, Middelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of ostemalacia bone involvement. Calcif Tissue Int 2000;66:419-24. CrossRefMedline

Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995;333:234-40. CrossRefMedline

Holick MF. Vitamin D: photobiology, metabolism, mechanism of action, and clinical applications. In: Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research, 2003:129-37.

Juppner H, Kronenberg HM. Parathyroid hormone. In: Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research, 2003:117-24.

Garland CF, Garland FC, Shaw EK, Comstock GW, Helsing KJ, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989;1:1176-8. Medline

  1. Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 1990;19:614-2.


Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and pre-diagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 2000;11:847-52. CrossRefMedline

  1. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 1992;70:2861-9.


Apperly FL. The relation of solar radiation to cancer mortality in North America. Cancer Res 1941;1:191-5.

Grant WB. An estimate of premature cancer mortality in the U. S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002;94:1867-75. CrossRefMedline

Holick MF, Jenkins M. The UV advantage. New York: iBooks, Inc (in press).

Hernán MA, Olek MJ, Ascherio A. Geographic variation of MS incidence in two prospective studies of US women. Neurology 1999;51:1711-8.

Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension 1979;30:150-6.

Grant WB. An ecologic study of the role of solar UV-B radiation in reducing the risk of cancer using cancer mortality data, dietary supply data and latitude for European countries. In: Holick MF, editor. Biologic effects of light 2001 (proceedings of a symposium, Boston, MA). Boston: Kluwer Academic Publishing, 2002:267-6.

Grant WB. An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer 2002;94:272-81. CrossRefMedline

Bodiwala D, Luscombe CJ, Liu S, Saxby M, French M, Jones PW. Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight. Cancer Lett 2003;192:145-9. CrossRefMedline

DeLuca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-85. Abstract/FREE Full Text

Stumpf WE, Sar M, Reid FA, et al. Target cells for 1, 25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 1979;206:1188-90. Abstract/FREE Full Text

  1. Manolagas SC, Provvedini DM, Tsoukas CD. Interactions of 1, 25-dihydroxyvitamin D3 and the immune system. Mol Cell Endocrinol 1985;43:113-22.


Mathieu C, Adorini L. The coming of age of 1, 25-dihydroxyvitamin D3 analogs as immunomodulatory agents. Trends Mol Med 2002;8:174-9. CrossRefMedline

Feldman D, Zhao XY, Krishnan AV. Vitamin D and prostate cancer. Endocrinology 2000;141:5-9. FREE Full Text

Holick MF. Clinical efficacy of 1, 25-dihydroxyvitamin D3 and its analogues in the treatment of psoriasis. Retinoids 1998;14:12-7.

Kragballe K, Beck HI, Sogaard H. Improvement of psoriasis by a topical vitamin D3 analogue (MC903) in a double-blind study. Br J Dermatol 1988;119:223-30. CrossRefMedline

Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1α, 25-dihydroxyvitamin D3 analog enhances regulatory t-cells and arrests autoimmune diabetes in NOD mice. Diabetes 2002;51:1367-74. Abstract/FREE Full Text

  1. Cantorna MT, Hayes CE, DeLuca HF. 1, 25-Dihydroxyholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J Nutr 1998;128:68-72.

Abstract/FREE Full Text

  1. Cantorna MT, Hayes CE, DeLuca HF. 1, 25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A 1996;93:7861-4.

Abstract/FREE Full Text

Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R. Prevention of autoimmune diabetes in NOD mice by 1, 25 dihydroxyvitamin D3. Diabetologia 1994;37:552-8. Medline

Hypponen E, Laara E, Jarvelin M-R, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-3. CrossRefMedline

Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998;352:709-10. Medline

Li Y, Kong J, Wei M, Chen ZF, Liu S, Cao LP. 1, 25-dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-38. CrossRefMedline

Adams JA, Clemens TL, Parrish JA, Holick MF. Vitamin D synthesis and metabolism after ultraviolet radiation of normal and vitamin D deficient subjects. N Engl J Med 1981;306:722-5.

  1. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol responses to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-10.

Abstract/FREE Full Text

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842-56. Abstract/FREE Full Text

Weisman Y, Harell A, Edelstein S, et al. 1, 25-dihydroxyvitamin D3 and 24, 25-dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta. Nature 1979;281:317-9. CrossRefMedline

Bikle DD, Nemanic MK, Gee E, Elias P. 1, 25-Dihydroxyvitamin D3 production by human keratinocytes: kinetics and regulation. J Clin Invest 1986;78:557-66. Medline

Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF. Human prostate cells synthesize 1, 25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 1998;7:391-5. Abstract/FREE Full Text

Tangpricha V, Flanagan JN, Whitlatch LW, et al. 25-hydroxyvitamin D-1α-hydroxylase in normal and malignant colon tissue. Lancet 2001;357:1673-4. CrossRefMedline

  1. Cross HS, Bareis P, Hofer H, Bischof MG, Bajna E, Kriwanek S. 25-Hydroxyvitamin D3-1α-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Steroids 2001;66:287-92.


Mawer EB, Hayes ME, Heys SE, et al. Constitutive synthesis of 1, 25-dihydroxyvitamin D3 by a human small cell lung cell line. J Clin Endocrinol Metab 1994;79:554-60. Abstract

Harnden D, Kumar R, Holick MF, DeLuca HF. Side chain metabolism of 25-hydroxy-[26, 27-14C] vitamin D3 and 1, 25-dihydroxy-[26, 27-14C] vitamin D3 in vivo. Science 1976;193:493-4. Abstract/FREE Full Text

Holick MF. Vitamin D. In: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: Institute of Medicine. National Academy Press, 1997:250-87.

Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr 2003;78:912-9. Abstract/FREE Full Text

Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003;22:142-6. Abstract/FREE Full Text

Koutkia P, Lu Z, Chen TC, Holick MF. Treatment of vitamin D deficiency due to Crohn’s disease with tanning bed ultraviolet B radiation. Gastroenterology 2001;121:1485-8. CrossRefMedline

Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Körfer R, Stehle P. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol 2003;41:105-12. Abstract/FREE Full Text

Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351:805-6. Medline

Articles citing this article
     Serum Concentrations of 1,25-Dihydroxyvitamin D2 and 1,25-Dihydroxyvitamin D3 in Response to Vitamin D2 and Vitamin D3 Supplementation J. Clin. Endocrinol. Metab. 2013 98: 3 973-979
     Chromatin acetylation at transcription start sites and vitamin D receptor binding regions relates to effects of 1{alpha},25-dihydroxyvitamin D3 and histone deacetylase inhibitors on gene expression Nucleic Acids Res 2013 41: 1 110-124
     Recruitment and Results of a Pilot Trial of Vitamin D Supplementation in the General Population of Australia J. Clin. Endocrinol. Metab. 2012 97: 12 4473-4480
     Atorvastatin Reduces Malondialdehyde Concentrations in Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab. 2012 97: 11 3951-3955
     Relationship of Vitamin D Deficiency to Clinical Outcomes in Critically Ill Patients JPEN J Parenter Enteral Nutr 2012 36: 6 713-720
     Circulating 25-Hydroxyvitamin D3 in Pregnancy and Infant Neuropsychological Development Pediatrics 2012 130: 4 e913-e920
     Serum Vitamin D and Risk of Bladder Cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial Cancer Epidemiol. Biomarkers Prev. 2012 21: 7 1222-1225
     The Nonskeletal Effects of Vitamin D: An Endocrine Society Scientific Statement Endocr Rev 2012 33: 3 456-492
     Vitamin D Status among 4-Month-Old Infants in New England: A Prospective Cohort Study J Hum Lact 2012 28: 2 159-166
     Maternal Vitamin D Status: Effect on Milk Vitamin D Content and Vitamin D Status of Breastfeeding Infants Adv Nutr 2012 3: 3 353-361
     Human skin pigmentation, migration and disease susceptibility Phil Trans R Soc B 2012 367: 1590 785-792
     Efficacy and safety of a short
     Efficacy and safety of a short course of very-high-dose cholecalciferol in hemodialysis Am J Clin Nutr 2012 95: 2 522-528
     Association of Genetic Variants of the Vitamin D Receptor (VDR) with Cutaneous Squamous Cell Carcinomas (SCC) and Basal Cell Carcinomas (BCC): A Pilot Study in a German Population Anticancer Res 2012 32: 1 327-333
     Recommended summer sunlight exposure amounts fail to produce sufficient vitamin D status in UK adults of South Asian origin Am J Clin Nutr 2011 94: 5 1219-1224
     A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis Neurology 2011 77: 17 1611-1618
     Food Insecurity and Nutrition Transition Combine to Affect Nutrient Intakes in Canadian Arctic Communities J. Nutr. 2011 141: 9 1746-1753
     Is Vitamin D Deficiency Associated With Heart Failure? A Review of Current Evidence J CARDIOVASC PHARMACOL THER 2011 16: 3-4 354-363
     APOE {varepsilon}4 is associated with higher vitamin D levels in targeted replacement mice and humans FASEB J. 2011 25: 9 3262-3270
     Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab. 2011 96: 7 1911-1930
     Prospective Study of UV Exposure and Cancer Incidence Among Swedish Women Cancer Epidemiol. Biomarkers Prev. 2011 20: 7 1358-1367
     Active Vitamin D and Acute Respiratory Infections in Dialysis Patients CJASN 2011 6: 6 1361-1367
     Evaluation of Ergocalciferol or Cholecalciferol Dosing, 1,600 IU Daily or 50,000 IU Monthly in Older Adults J. Clin. Endocrinol. Metab. 2011 96: 4 981-988
     Serum 25-Hydroxyvitamin D and Risks of Colon and Rectal Cancer in Finnish Men Am J Epidemiol 2011 173: 5 499-508
     Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer Therapeutic Advances in Gastroenterology 2011 4: 1 49-62
     Daily Supplementation with 25 {micro}g Cholecalciferol Does Not Increase Calcium Absorption or Skeletal Retention in Adolescent Girls with Low Serum 25-Hydroxyvitamin D J. Nutr. 2010 140: 12 2139-2144
     Serum Vitamin D and Risk of Bladder Cancer Cancer Res. 2010 70: 22 9218-9223
     Nutritional Metabolic Bone Disease in Juvenile Veiled Chameleons (Chamaeleo calyptratus) and Its Prevention J. Nutr. 2010 140: 11 1923-1931
     Relationship Between Vitamin D Levels and Depressive Symptoms in Older Residents From a National Survey Population Psychosom. Med. 2010 72: 7 608-612
     Update in Pediatrics: Focus on Fat-Soluble Vitamins Nutr Clin Pract 2010 25: 4 340-346
     Circulating 25-Hydroxyvitamin D and Risk of Pancreatic Cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers Am J Epidemiol 2010 172: 1 81-93
     Fortification of orange juice with vitamin D2 or vitamin D3 is as effective as an oral supplement in maintaining vitamin D status in adults Am J Clin Nutr 2010 91: 6 1621-1626
     Colloquium Paper: Human skin pigmentation as an adaptation to UV radiation Proc. Natl. Acad. Sci. USA 2010 107: Supplement_2 8962-8968
     Cholecalciferol Supplementation in Hemodialysis Patients: Effects on Mineral Metabolism, Inflammation, and Cardiac Dimension Parameters CJASN 2010 5: 5 905-911
     Vitamin D Supplement Consumption Is Required to Achieve a Minimal Target 25-Hydroxyvitamin D Concentration of >=75 nmol/L in Older People J. Nutr. 2010 140: 3 551-556
     Vitamin D and the Immune System The Journal of Rheumatology 2010 37: 3 491-495
     A rare haplotype of the vitamin D receptor gene is protective against diabetic nephropathy Nephrol Dial Transplant 2010 25: 2 497-503
     Association of low serum 25-hydroxyvitamin D levels and high arterial blood pressure in the elderly Nephrol Dial Transplant 2010 25: 2 503-509
     Serum Vitamin D and Breast Density in Breast Cancer Survivors Cancer Epidemiol. Biomarkers Prev. 2010 19: 2 412-417
     Urgent action needed to improve vitamin D status among older people in England! Age Ageing 2010 39: 1 62-68
     Vitamin D Needs of Preterm Infants Neoreviews 2009 10: 12 e590-e599
     Predicting ambient ultraviolet from routine meteorological data; its potential use as an instrumental variable for vitamin D status in pregnancy in a longitudinal birth cohort in the UK Int J Epidemiol 2009 38: 6 1681-1688
     Serum 25-Hydroxyvitamin D Levels Among US Children Aged 1 to 11 Years: Do Children Need More Vitamin D? Pediatrics 2009 124: 5 1404-1410
     Effect of Vitamin D Deficiency and Replacement on Endothelial Function in Asymptomatic Subjects J. Clin. Endocrinol. Metab. 2009 94: 10 4023-4030
     Vitamin D: Bone Health and Beyond AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2009 3: 5 386-393
     Heritability and Environmental Factors Affecting Vitamin D Status in Rural Chinese Adolescent Twins J. Clin. Endocrinol. Metab. 2009 94: 9 3273-3281
     The Dependency of Vitamin D Status on Body Mass Index, Gender, Age and Season Anticancer Res 2009 29: 9 3713-3720
     Up-Regulation of Transporters and Enzymes by the Vitamin D Receptor Ligands, 1{alpha},25-Dihydroxyvitamin D3 and Vitamin D Analogs, in the Caco-2 Cell Monolayer J. Pharmacol. Exp. Ther. 2009 330: 2 389-402
     Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men J. Neurol. Neurosurg. Psychiatry 2009 80: 7 722-729
     Metabolism of Vitamin D2 to 17,20,24-Trihydroxyvitamin
     Metabolism of Vitamin D2 to 17,20,24-Trihydroxyvitamin D2 by Cytochrome P450scc (CYP11A1) Drug Metab. Dispos. 2009 37: 4 761-767
     Vitamin D supplementation during Antarctic winter Am J Clin Nutr 2009 89: 4 1092-1098
     Vitamin D Deficiency in Older Men J. Clin. Endocrinol. Metab. 2009 94: 4 1214-1222
     Supplements of 20 {micro}g/d Cholecalciferol Optimized Serum 25-Hydroxyvitamin D Concentrations in 80% of Premenopausal Women in Winter J. Nutr. 2009 139: 3 540-546
     25-Hydroxyvitamin D3, arterial calcifications and cardiovascular risk markers in haemodialysis patients Nephrol Dial Transplant 2009 24: 2 611-618
     Association of oral calcitriol with improved survival in non-dialysed and dialysed patients with CKD Nephrol Dial Transplant 2009 24: 2 341-344
     A Comparison of Vitamin D Levels in Nondiabetic and Diabetic Patient Populations J. Am. Podiatr. Med. Assoc. 2009 99: 1 35-41
     Vitamin D Status and Its Relationship to Body Fat, Final Height, and Peak Bone Mass in Young Women J. Clin. Endocrinol. Metab. 2009 94: 1 67-73
     Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: systematic review Am J Clin Nutr 2008 88: 6 1528-1534
     Vitamin D Supplementation during Lactation to Support Infant and Mother J. Am. Coll. Nutr. 2008 27: 6 690-701
     Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents Pediatrics 2008 122: 5 1142-1152
     Vitamin D and Prevention of Colorectal Adenoma: A Meta-analysis Cancer Epidemiol. Biomarkers Prev. 2008 17: 11 2958-2969
     Vitamin D Deficiency in Children and Its Management: Review of Current Knowledge and Recommendations Pediatrics 2008 122: 2 398-417
     Higher Prevalence of Vitamin D Deficiency Is Associated with Immigrant Background among Children and Adolescents in Germany J. Nutr. 2008 138: 8 1482-1490
     Vitamin D insufficiency in a multiethnic cohort of breast cancer survivors Am J Clin Nutr 2008 88: 1 133-139
     Sun safety: what are the health messages? Perspectives in Public Health 2008 128: 4 164-169
     Serum Metabolite Profiles and Target Tissue Gene Expression Define the Effect of Cholecalciferol Intake on Calcium Metabolism in Rats and Mice J. Nutr. 2008 138: 6 1114-1120
     Use (or misuse) of vitamin D treatment in CKD and dialysis patients: A recent meta-analysis on vitamin D compounds in chronic kidney disease [1] and an editorial comment [2] accompanying this meta-analysis have already been published. We believe that these papers deserve some comments in the interest of the NDT readership Nephrol Dial Transplant 2008 23: 6 1786-1789
     From the Cover: Addressing the health benefits and risks, involving vitamin D or skin cancer, of increased sun exposure Proc. Natl. Acad. Sci. USA 2008 105: 2 668-673
     Association between 25-hydroxyvitamin D deficiency and cardiovascular disease in type 2 diabetic patients with mild kidney dysfunction Nephrol Dial Transplant 2008 23: 1 269-274
     A New Paradigm for the Treatment of Secondary Hyperparathyroidism Clin Kidney J 2008 1: suppl_1 i24-i28
     Dose response to vitamin D supplementation among postmenopausal African American women Am J Clin Nutr 2007 86: 6 1657-1662
     Vitamin D Levels in Men in a Single Primary Care Practice Near Boston Am J Mens Health 2007 1: 4 262-268
     Response to Teriparatide in Patients with Baseline 25-Hydroxyvitamin D Insufficiency or Sufficiency J. Clin. Endocrinol. Metab. 2007 92: 12 4630-4636
     Associations of diet, supplement use, and ultraviolet B radiation exposure with vitamin D status in Swedish women during winter Am J Clin Nutr 2007 86: 5 1399-1404
     Prepregnancy Obesity Predicts Poor Vitamin D Status in Mothers and Their Neonates J. Nutr. 2007 137: 11 2437-2442
     The Effects of Vitamin D Deficiency and Insufficiency on the Endocrine and Paracrine Systems Biol Res Nurs 2007 9: 2 117-129
     Mother-child vitamin D deficiency: an international perspective Arch. Dis. Child. 2007 92: 9 737-740
     Vitamin D status and parathyroid hormone in obese children before and after weight loss Eur J Endocrinol 2007 157: 2 225-232
     A Nested Case Control Study of Plasma 25-Hydroxyvitamin D Concentrations and Risk of Colorectal Cancer JNCI J Natl Cancer Inst 2007 99: 14 1120-1129
     Risk factors for low serum 25-hydroxyvitamin D concentrations in otherwise healthy children and adolescents Am J Clin Nutr 2007 86: 1 150-158
     Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women Am J Clin Nutr 2007 85: 6 1565-1571
     Vitamin D and Its Role in Cancer and Immunity: A Prescription for Sunlight Nutr Clin Pract 2007 22: 3 305-322
     Vitamin D and Rehabilitation: Improving Functional Outcomes Nutr Clin Pract 2007 22: 3 297-304
     Synchronized Seasonal Variations of Mammographic Breast Density and Plasma 25-Hydroxyvitamin D Cancer Epidemiol. Biomarkers Prev. 2007 16: 5 929-933
     Plasma 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D and Risk of Incident Ovarian Cancer Cancer Epidemiol. Biomarkers Prev. 2007 16: 4 783-788
     Lactating Women Restricting Milk Are Low on Select Nutrients J. Am. Coll. Nutr. 2007 26: 2 149-155
     Association Between Vitamin D Status and Physical Performance: The InCHIANTI Study J Gerontol A Biol Sci Med Sci 2007 62: 4 440-446
     Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age Am J Clin Nutr 2007 85: 3 788-795
     Sun Exposure and Non-Hodgkin Lymphoma Cancer Epidemiol. Biomarkers Prev. 2007 16: 3 396-400

« Previous | Next Article »Table of Contents

This Article

  1. 1.     Am J Clin Nutr March 2004 vol. 79 no. 3 362-371
  2. Abstract
  3. » Full Text
  4. Full Text (PDF)
  5. A correction has been published
  6. Purchase Article
  7. Add to Custom Publication
  1. Email this article to a colleague
  2. Alert me when this article is cited
  3. Alert me if a correction is posted
  4. Article Usage Statistics
  5. Similar articles in this journal
  6. No Web of Science related articles
  7. Similar articles in PubMed
  8. Download to citation manager
  9. Reprints and Permissions

1.View citing article information 2.Citing articles via Web of Science (560) 3.Citing articles via Google Scholar

1.Articles by Holick, M. F. 2.Search for related content

1.PubMed citation 2.Articles by Holick, M. F.

1.Articles by Holick, M. F.

1.No related web pages Navigate This Article

  1. Top
  2. Abstract
  12. Footnotes

This Article

  1. 1.     Am J Clin Nutr March 2004 vol. 79 no. 3 362-371
  2. Abstract
  3. 2.    » Full Text
  4. 3.    Full Text (PDF)
  5. 4.    A correction has been published

Navigate This Article

  1. Top
  2. Abstract
  12. Footnotes

Current Issue

  1. March 2013, 97 (3)
  2. Alert me to new issues of Am J Clin Nutr

About AJCN Information for Authors Manuscript Submission Editorial Board Reprints Permissions Advertising Feedback Advances in Nutrition The Journal of Nutrition Nutrition Notes The American Journal of Clinical Nutrition® r ————-

Uma resposta

  1. […] Claiming That Obesity Improves Life SpanDewhurst’s Textbook of Obstetrics And GynaecologyVitamin D: importância na prevenção de cancros, diabetes, doenças do coração, e os… var analyticsFileTypes = ['']; var analyticsEventTracking = 'enabled'; var _gaq = _gaq || []; […]

Deixe um comentário

Preencha os seus dados abaixo ou clique em um ícone para log in:

Logotipo do

Você está comentando utilizando sua conta Sair / Alterar )

Imagem do Twitter

Você está comentando utilizando sua conta Twitter. Sair / Alterar )

Foto do Facebook

Você está comentando utilizando sua conta Facebook. Sair / Alterar )

Foto do Google+

Você está comentando utilizando sua conta Google+. Sair / Alterar )

Conectando a %s

%d blogueiros gostam disto: