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Vitamin D 2000 IU Linus Pauling - July 2011

Summary followed by details

Adrian Gombart, Ph.D., Associate Professor of Biochemistry and Biophysics, LPI Principal Investigator

from Research Newsletter of Spring 2011 - attached at bottom of this page

The Institute of Medicine (IOM) released new dietary reference intakes (DRIs) for calcium and vitamin D on November 30, 2010. The IOM concluded that vitamin D plays a key role in bone health and that current evidence does not support other health benefits from vitamin D supplementation, although the IOM called for additional research targeted at other health outcomes to continue. The changes in the recommended dietary allowance (RDA) for vitamin D were based solely on bone health. The IOM raised the RDA in children (1-18 years) and adults (19-70 years) from 200 IU to 600 IU per day and raised the tolerable upper intake level (UL) for adults from 2,000 IU to 4,000 IU per day. For the elderly (>70 years), the RDA was increased to 800 IU per day. The majority of vitamin D experts were disappointed by these conservative increases, but they should be considered steps in the right direction.

The IOM also made another very important change. After reviewing the published literature, they concluded that the serum level of vitamin D sufficient for bone health is above 20 ng/ml rather than 30-32 ng/ml, a value that has been used extensively by physicians. During the press conference, they said that it was warranted by the available scientific evidence even though it had not been one of their tasks. By lowering the sufficient level, they, in effect, reduced the number of people that would be considered to have inadequate serum levels of vitamin D. This change will likely cause significant confusion for both physicians and their patients, but it should be noted that it is only relevant to bone health and may not be optimal for other health benefits that have been attributed to vitamin D.

While the new RDA may bring many people into the new sufficient range, a cut-off of 20 ng/ml is controversial in the vitamin D research community because it does not consider other areas of health that the IOM has concluded are not supported by the currently published data.

The IOM is very conservative and based their decisions on a lack of randomized controlled trials (RCTs) that demonstrate a clear benefit from taking vitamin D supplements beyond bone health, but there is overwhelming evidence that supports biological plausibility for a role of vitamin D in numerous other health outcomes. For example, most non-bone cells have receptors for vitamin D, and we know that the function of immune cells is affected by vitamin D. The IOM narrowly focused on RCTs as the "gold standard"—an almost impossible hurdle to clear when applied to micronutrients. For example, subjects in the placebo group in an RCT will still have some of the micronutrient under evaluation in their bodies—unlike an RCT testing drugs; otherwise, they would get deficiency diseases. While anecdotal reports or single studies seem to be good enough for the IOM to determine the UL, multiple RCTs demonstrating similar outcomes are required for the RDA. Clearly, this is a double standard. DRIs need to take into account the totality of evidence, not just RCTs.

LPI continues to recommend a daily intake of 2,000 IU of vitamin D. This is well below the UL of 4,000 IU set by the IOM and should ensure that individuals, particularly in areas of the world where sun exposure is limited for extended periods of the year, get enough vitamin D. Also, to adjust for individual differences and ensure adequate body vitamin D status, LPI recommends aiming for a serum 25-hydroxyvitamin D level of at least 80 nmol/l (32 ng/ml). You can find this information and the recommendations for infants and children in the LPI Micronutrient Information Center section on vitamin D http ://lpi.oregonstate. edu/infocenter/vitamins/vitaminD
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Appears to be unaware of the need for vitamin D by

The obese - which store vitamin D in the fat

People with health problems who consume more

People who had recent surgery/trauma

People with health problems who do not get as much into the blood

See also Vitamin D Life

IoM and Endocine recommendations graph

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Vitamin D is a fat-soluble vitamin that is essentialfor maintaining normal calcium metabolism (1).Vitamin D3 (cholecalciferol) can be synthesized by humansin the skin upon exposure to ultraviolet-B (UVB) radiation fromsunlight, or it can be obtained from the diet. Plants synthesizeergosterol, which is converted to vitamin D2(ergocalciferol) by ultraviolet light (2).When exposure to UVB radiation is insufficient for the synthesisof adequate amounts of vitamin D3 in the skin, adequateintake of vitamin D from the diet is essential for health.

Function

Activation of Vitamin D

Vitamin D itself is biologically inactive, and it mustbe metabolized to its biologically active forms. After it is consumedin the diet or synthesized in the epidermis of skin, vitamin D entersthe circulation and is transported to the liver. In the liver,vitamin D is hydroxylatedto form 25-hydroxyvitamin D (calcidiol; 25-hydroxyvitamin D, themajor circulating form of vitamin D. Increased exposure to sunlightor increased dietary intake of vitamin D increases serumlevels of 25-hydroxyvitamin D, making the serum 25-hydroxyvitamin Dconcentration a useful indicator of vitamin D nutritional status. Inthe kidney, the 25-hydroxyvitamin D3-1-hydroxylase enzymecatalyzes a second hydroxylation of 25-hydroxyvitamin D, resulting inthe formation of 1,25-dihydroxyvitamin D (calcitriol,1alpha,25-dihydroxyvitamin D]—the most potent form of vitaminD. Most of the physiological effects of vitamin D in the body arerelated to the activity of 1,25-dihydroxyvitamin D (2).The various forms of vitamin D are illustrated in the figure.

Mechanisms of Action

Most if not all actions of vitamin D are mediated through anuclear transcriptionfactor known as the vitamin D receptor (VDR) (3).Upon entering the nucleus of a cell, 1,25-dihydroxyvitamin Dassociates with the VDR and promotes its association with theretinoic acid X receptor (RXR). In the presence of1,25-dihydroxyvitamin D the VDR/RXR complex binds small sequences ofDNAknown as vitamin D response elements (VDREs) and initiates a cascadeof molecular interactions that modulate the transcriptionof specific genes.More than 50 genes in tissues throughout the body are known to beregulated by 1,25-dihydroxyvitamin D (4).

Calcium Balance

Maintenance of serum calcium levels within a narrow range is vitalfor normal functioning of the nervous system, as well as for bonegrowth and maintenance of bone density. Vitamin D is essential forthe efficient utilization of calcium by the body (1).The parathyroidglands sense serumcalcium levels and secrete parathyroid hormone (PTH) if calciumlevels drop too low (diagram).Elevations in PTH increase the activity of the 25-hydroxyvitaminD3-1-hydroxylase enzymein the kidney, resulting in increased production of1,25-dihydroxyvitamin D. Increasing 1,25-dihydroxyvitamin Dproduction results in changes in geneexpression that normalize serum calcium by (1) increasing theintestinal absorption of dietary calcium, (2) increasing thereabsorption of calcium filtered by the kidneys, and (3) mobilizingcalcium from bone when there is insufficient dietary calcium tomaintain normal serum calcium levels. Parathyroid hormone and1,25-dihydroxyvitamin D are required for these latter two effects(5).

Cell Differentiation

Cells that are dividing rapidly are said to beproliferating. Differentiation results in the specialization of cellsfor specific functions. In general, differentiation of cells leads toa decrease in proliferation. While cellular proliferation isessential for growth and wound healing, uncontrolled proliferation ofcells with certain mutationsmay lead to diseases like cancer. The active form of vitamin D,1,25-dihydroxyvitamin D, inhibits proliferation and stimulates thedifferentiation of cells (1).

Immunity

Vitamin D in the form of 1,25-dihydroxyvitamin D is apotent immune system modulator. The vitamin D receptor (VDR) isexpressed by most cells of the immune system, including T cells andantigen-presenting cells, such as dendritic cells and macrophages(6).Under some circumstances, macrophages also produce the25-hydroxyvitamin D3-1-hydroxylase enzyme that converts25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (7).There is considerable scientific evidence that 1,25-dihydroxyvitaminD has a variety of effects on immune system function, which mayenhance innate immunity and inhibit the development of autoimmunity(8).

Insulin Secretion

The VDR is expressed by insulin-secretingcells of the pancreas,and the results of animal studies suggest that 1,25-dihydroxyvitaminD plays a role in insulin secretion under conditions of increasedinsulin demand (9).Limited data in humans suggest that insufficient vitamin D levels mayhave an adverse effect on insulin secretion and glucosetolerance in type 2 diabetes(noninsulin-dependent diabetes mellitus; NIDDM) (10-12).

Blood Pressure Regulation

The renin-angiotensin system plays an important role inthe regulation of blood pressure (13).Renin is an enzymethat catalyzesthe cleavage (splitting) of a small peptide(Angiotensin I) from a larger protein (angiotensinogen) produced inthe liver. Angiotensin converting enzyme (ACE) catalyzes the cleavageof angiotensin I to form angiotensin II, a peptide that can increaseblood pressure by inducing the constriction of small arteries and byincreasing sodium and water retention. The rate of angiotensin IIsynthesis is dependent on renin (14).Research in mice lacking the geneencoding the VDR indicates that 1,25-dihydroxyvitamin D decreases theexpressionof the gene encoding renin through its interaction with the VDR (15).Since inappropriate activation of the renin-angiotensin system isthought to play a role in some forms of human hypertension,adequate vitamin D levels may be important for decreasing the risk ofhigh blood pressure.

Deficiency

In vitamin D deficiency, calcium absorption cannot beincreased enough to satisfy the body’s calcium needs (2).Consequently, PTH production by the parathyroidglands is increased and calcium is mobilized from the skeleton tomaintain normal serum calcium levels—a condition known assecondary hyperparathyroidism.Although it has long been known that severe vitamin D deficiency hasserious consequences for bone health, recent research suggests thatless obvious states of vitamin D deficiency are common and increasethe risk of osteoporosis and other health problems (16,17).

Severe Vitamin D Deficiency

Rickets

In infants and children, severe vitamin D deficiencyresults in the failure of bone to mineralize. Rapidly growing bonesare most severely affected by rickets. The growth plates of bonescontinue 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 fontanels (soft spots)in the skull, and the rib cage may become deformed due to the pullingaction of the diaphragm. In severe cases, low serum calcium levels(hypocalcemia) may cause seizures. Although fortificationof foods has led to complacency regarding vitamin D deficiency,nutritional rickets is still being reported in cities throughout theworld (18,19).

Osteomalacia

Although adult bones are no longer growing, they are ina constant state of turnover, or "remodeling."In adults with severe vitamin D deficiency, the collagenousbone matrix is preserved but bone mineral is progressively lost,resulting in bone pain and osteomalacia (soft bones).

Muscle Weakness and Pain

Vitamin D deficiency causes muscle weakness and pain inchildren and adults. Muscle pain and weakness were a prominentsymptoms of vitamin D deficiency in a study of Arab and Danish Moslemwomen living in Denmark (20).In a cross-sectionalstudy of 150 consecutive patients referred to a clinic inMinnesota for the evaluation of persistent, nonspecificmusculoskeletal pain, 93% had serum 25-hydroxyvitamin D levelsindicative of vitamin D deficiency (21).A randomizedcontrolled trial found that supplementation of elderly women with800 IU/day of vitamin D and 1,200 mg/day of calcium for three monthsincreased muscle strength and decreased the risk of falling by almost50% compared to supplementation with calcium alone (22).More recently, a randomized controlled trial in 124 nursing homeresidents (average age, 89 years) found that those taking 800 IU/dayof supplemental vitamin D had a 72% lower fall rate than those takinga placebo (23).

Risk Factors for Vitamin D Deficiency

  • Exclusively breast-fed infants: Infants who are exclusively breast-fed and do not receive vitamin D supplementation are at high risk of vitamin D deficiency, particularly if they have dark skin and/or receive little sun exposure (19). Human milk generally provides 25 IU of vitamin D per liter, which is not enough for an infant if it is the sole source of vitamin D. Older infants and toddlers exclusively fed milk substitutes and weaning foods that are not vitamin D fortified are also at risk of vitamin D deficiency (18). The American Academy of Pediatrics recommends that all breast-fed and partially breast-fed infants be given a vitamin D supplement of 400 IU/day (19).

  • Dark skin: People with dark-colored skin synthesize less vitamin D on exposure to sunlight than those with light-colored skin (1). The risk of vitamin D deficiency is particularly high in dark-skinned people who live far from the equator. One U.S. study reported that 42% of African American women between 15 and 49 years of age were vitamin D deficient compared to 4% of White women (24).

  • Aging: The elderly have reduced capacity to synthesize vitamin D in skin when exposed to UVB radiation, and the elderly are more likely to stay indoors or use sunscreen, which blocks vitamin D synthesis. Institutionalized adults who are not supplemented with vitamin D are at extremely high risk of vitamin D deficiency (25, 26).

  • Covering all exposed skin or using sunscreen whenever outside: Osteomalacia has been documented in women who cover all of their skin whenever they are outside for religious or cultural reasons (27, 28). The application of sunscreen with an SPF factor of 8 reduces production of vitamin D by 95% (1).

  • Fat malabsorption syndromes: Cystic fibrosis and cholestatic liver disease impair the absorption of dietary vitamin D (29).

  • Inflammatory bowel disease: People with inflammatory bowel disease like Crohn’s disease appear to be at increased risk of vitamin D deficiency, especially those who have had small bowel resections (30).

  • Obesity: Obesity increases the risk of vitamin D deficiency (31). Once vitamin D is synthesized in the skin or ingested, it is deposited in body fat stores, making it less bioavailable to people with large stores of body fat.

Assessing Vitamin D Nutritional Status

Growing awareness that vitamin D insufficiency hasserious health consequences beyond rickets and osteomalaciahighlights the need for accurate assessment of vitamin D nutritionalstatus. Although there is general agreement that serum25-hydroxyvitamin D level is the best indicator of vitamin Ddeficiency and sufficiency, the cutoff values have not been clearlydefined (18).While laboratory reference ranges for serum 25-hydroxyvitamin Dlevels are often based on average values from populations of healthyindividuals, recent research suggests that health-based cutoff valuesaimed at preventing secondary hyperparathyroidismand bone loss should be considerably higher. In general, serum25-hydroxyvitamin D values less than 20-25 nmol/L (8-10 ng/mL)indicate severe deficiency associated with rickets and osteomalacia(16,18).Although 50 nmol/L (20 ng/mL) has been suggested as the low end ofthe normal range (32),more recent research suggests that PTH levels (33,34) and calcium absorption (35)are not optimized until serum 25-hydroxyvitamin D levels reachapproximately 80 nmol/L (32 ng/mL). Thus, at least one vitamin Dexpert has argued that serum 25-hydroxyvitamin D values less than 80nmol/L should be considered deficient (17),while another suggests that a healthy serum 25-hydroxyvitamin D valueis between 75 nmol/L and 125 nmol/L (30 ng/mL and 50 ng/mL) (36).With this latter cutoff value for insufficiency (i.e., 75 nmol/L or30 ng/mL), it is estimated that one billion people in the world arecurrently vitamin D deficient (37).Data from supplementation studies indicate that vitamin D intakes ofat least 800-1,000 IU/day are required by adults living in temperatelatitudes to achieve serum 25-hydroxyvitamin D levels of at least 80nmol/L (38,39).

The Recommended Dietary Allowance(RDA)

In 2010, the Food and Nutrition Board (FNB) of theInstitute of Medicine set a Recommended Dietary Allowance (RDA)based on the amount of vitamin D needed for bone health. While therecommended intake was increased from the adequate intake level (AI)set in 1997, some experts feel that this level is still too low toresult in sufficient 25-hydroxyvitamin D levels (40-43).The RDA for vitamin D is listed in the table below by life stage andgender.

Recommended Dietary Allowance (RDA) for Vitamin D
Set by the Institute of Medicine

Life Stage 

Age 

Males
mcg/day (IU/day)

Females
mcg/day (IU/day)

Infants 

0-6 months 

10 mcg (400 IU) (AI

10 mcg (400 IU) (AI) 

Infants 

6-12 months 

10 mcg (400 IU) (AI) 

10 mcg (400 IU) (AI) 

Children 

1-3 years 

15 mcg (600 IU) 

15 mcg (600 IU) 

Children

4-8 years 

15 mcg (600 IU) 

15 mcg (600 IU) 

Children 

9-13 years 

15 mcg (600 IU) 

15 mcg (600 IU) 

Adolescents 

14-18 years 

15 mcg (600 IU) 

15 mcg (600 IU) 

Adults 

19-50 years 

15 mcg (600 IU) 

15 mcg (600 IU) 

Adults 

51-70 years

15 mcg (600 IU) 

15 mcg (600 IU) 

Adults

71 years and older

20 mcg (800 IU) 

20 mcg (800 IU) 

Pregnancy 

all ages 

15 mcg (600 IU) 

Breast-feeding 

all ages 

15 mcg (600 IU) 

 

DiseasePrevention

Osteoporosis

Although osteoporosisis a multifactorial disease, vitamin D insufficiency can be animportant contributing factor. A multinational (18 differentcountries with latitudes ranging from 64 degrees north to 38 degreessouth) survey of more than 2,600 postmenopausal women withosteoporosis revealed that 64% of subjects had 25-hydroxyvitamin Dlevels lower than 75 nmol/L (30 ng/mL) (44).Without sufficient vitamin D from sun exposure or dietary intake,intestinal calcium absorption cannot be maximized. This causes PTHsecretion by the parathyroidglands; elevated PTH results in increased bone resorption,which may lead to osteoporotic fracture (45).A prospectivecohort study that followed more than 72,000 postmenopausal womenin the U.S. for 18 years found that those who consumed at least 600IU/day of vitamin D from diet and supplements had a 37% lower risk ofosteoporotic hip fracture than women who consumed less than 140IU/day of vitamin D (46).The results of most clinical trials suggest that vitamin Dsupplementation can slow bone density losses or decrease the risk ofosteoporotic fracture in men and women who are unlikely to be gettingenough vitamin D. However, recent analyses indicate that there is athreshold of vitamin D intake that is necessary to observe reductionsin fracture risk. For instance, a recent meta-analysis of randomizedcontrolled trials in older adults found that supplementation with 700to 800 IU vitamin D daily had a 26% and 23% lower risk of hipfracture and nonvertebral fracture, respectively. In contrast,supplementation with 400 IU of vitamin D daily did not decrease riskof either hip or nonvertebral fracture (47).Additionally, recent results from the Women's Health Initiative trialin 36,282 postmenopausal women showed that daily supplementation with400 IU of vitamin D3, in combination with 1,000 mgcalcium, did not significantly reduce risk of hip fracture comparedto a placebo (48).Bischoff-Ferrari et al. suggest that daily intakes of greater than700 IU of vitamin D may be necessary to optimize serum concentrationsof 25-hydroxyvitamin D and thus reduce fracture risk (40).

Support for such a threshold effect of vitamin D onbone health also comes from previous studies. One study in 247postmenopausal U.S. women reported that supplementation with 500mg/day of calcium and either 100 IU/day or 700 IU/day of vitamin D3for two years slowed bone density losses at the hip only in the grouptaking 700 IU/day (49).Another study found that daily supplementation of elderly men andwomen with 500 mg/day of calcium and 700 IU/day of vitamin D3for three years reduced bone density losses at the hip and spine andalso reduced the frequency of nonvertebral fractures (50).A subsequent analysis of this cohort revealed that when the calciumand vitamin D3 supplements were discontinued, the bonedensity benefits were lost within two years (51).Another study found that oral supplementation with 800 IU/day ofvitamin D3 and 1,200 mg/day of calcium for three yearsdecreased the incidence of hip fracture in elderly French women (52).Further, oral supplementation of elderly adults in the UK with100,000 IU of vitamin D3 once every four months(equivalent to about 800 IU/day) for five years reduced the risk ofosteoporotic fracture by 33% compared to placebo (53).However, oral supplementation with 400 IU/day of vitamin D3for more than three years did not affect the incidence of fracture ina study of elderly Dutch men and women (54).All of these studies indicate that at least 700 IU of vitamin D3daily may be required to observe a beneficial effect on fractureincidence.

However, the Randomised Evaluation of Calcium Or vitamin D(RECORD) trial reported that oral supplemental vitamin D3(800 IU/day) alone, or in combination with calcium (1,000 mg/day),did not prevent the occurrence of osteoporotic fractures in elderlyadults who had already experienced a low-trauma, osteoporoticfracture (55).A lack of an effect could be possibly due to a low compliance in thisstudy or the fact that vitamin D supplementation did not raise serum25-hydroxyvitamin D levels to a level that would protect againstfractures (40).

To date, clinical trials have generally found that vitamin D2(ergocalciferol) is not effective at preventing fractures (56).Overall, the current evidence suggests that vitamin D3supplements of at least 800 IU/day may be helpful in reducing boneloss and fracture rates in the elderly. In order for vitamin Dsupplementation to be effective in preserving bone health, adequatedietary calcium (1,000 to 1,200 mg/day) should also be consumed (seethe article on Calcium).

Cancer

Two characteristics of cancer cells are lack ofdifferentiation (specialization) and rapid growth or proliferation.Many malignanttumors 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-dihydroxyvitaminD and its analogs,have been found to induce cell differentiation and/or inhibitproliferation of a number of cancerous and noncancerous cell typesmaintained in cell culture (57).Results of some, but not all, human epidemiological studies suggestthat vitamin D may protect against various cancers. However, it isimportant to note that epidemiological studies cannot prove suchassociations.

Colorectal Cancer

The geographic distribution of colon cancer mortalityresembles the historical geographic distribution of rickets (58),providing circumstantial evidence that decreased sunlight exposureand diminished vitamin D nutritional status may be related to anincreased risk of colon cancer. However, prospectivecohort studies have not generally found total vitamin D intake tobe associated with significant reductions in risk of colorectalcancer when other risk factors are taken into account (59-62).However, some more recent studies have reported that higher vitamin Dintakes and serum 25-hydroxyvitamin D levels are associated withreductions in colorectal cancer risk. One five-year study of morethan 120,000 people found that men with the highest vitamin D intakeshad a risk of colorectal cancer that was 29% lower than men with thelowest vitamin D intakes (63).Vitamin D intake in this study was not significantly associated withcolorectal cancer risk in women. Moreover, serum 25-hydroxyvitamin Dlevel, which reflects vitamin D intake and vitamin D synthesis, wasinversely associated with the risk of potentially precancerouscolorectal polyps (64)and indices of colonic epithelial cell proliferation (65),two biomarkersfor colon cancer risk. More recently, a case-control analysis fromthe Nurses' Health Study cohort reported that plasma25-hydroxyvitamin D levels were inversely associated with colorectalcancer (66).A randomized, double-blind, placebo-controlled trial in 36,282postmenopausal women participating in the Women's Health Initiativestudy found that a combination of supplemental vitamin D (400 IU/day)and calcium (1,000 mg/day) did not lower incidence of colorectalcancer (67).However, it has been suggested that the daily vitamin D dose, 400 IU,was too low to detect any effect on cancer incidence (68).In fact, a recent dose-response analysis estimated that 1,000 IU oforal vitamin D daily would lower one's risk of colorectal cancer by50% (69).

Breast Cancer

Although breast cancer mortality follows a similar geographicdistribution to that of colon cancer (58,70),direct evidence of an association between vitamin D nutritionalstatus and breast cancer risk is limited. A prospectivestudy of women who participated in the first National Health andNutrition Examination Survey (NHANES I) found that several measuresof sunlight exposure and dietary vitamin D intake were associatedwith a reduced risk of breast cancer 20 years later (71).More recently, a 16-year study of more than 88,000 women found thathigher intakes of vitamin D were associated with significantly lowerbreast cancer risk in premenopausal women but not postmenopausalwomen (72).Garland et al. conducted a pooled, dose-response analysis of twocase-control studies in which women with breast cancer hadsignificantly lower plasma 25-hydroxyvitamin D levels compared tocontrols (73,74). These authors reported that women with a 25-hydroxyvitamin Dlevel of 52 ng/ml (130 nmol/L) experienced a 50% lower risk ofdeveloping breast cancer compared to women with 25-hydroxyvitamin Dlevels lower than 13 ng/mL (32.5 nmol/L) (75).The authors state that to obtain a 25-hydroxyvitamin D level of 52ng/mL, around 4,000 IU of vitamin D3 would need to beconsumed daily, or 2,000 IU of vitamin D3 daily plus verymoderate sun exposure (75).The current tolerable upper limit of intake (UL)for adults, set by the Food and Nutrition Board of the Institute ofMedicine, is 4,000 IU/day (see Safety).

Prostate Cancer

Epidemiologicalstudies show correlations between risk factors for prostatecancer and conditions that can result in decreased vitamin D levels(57).Increased age is associated with an increased risk of prostatecancer, as well as with decreased sun exposure and decreased capacityto synthesize vitamin D. The incidence of prostate cancer is higherin African American men than in white American men, and the highmelanin content of dark skin is known to reduce the efficiency ofvitamin D synthesis. Geographically, mortality from prostate canceris inversely associated with the availability of sunlight. Findingsthat prostate cells in culture can synthesize the 25-hydroxyvitaminD3-1-hydroxylase enzymeand that, unlike the renal enzyme, its synthesis is not influenced byPTH or calcium levels also provide support for the idea thatincreasing 25-hydroxyvitamin D levels may be useful in preventingprostate cancer (76).In contrast, prospective studies have not generally found significantrelationships between serum 25-hydroxyvitamin D levels and subsequentrisk of developing prostate cancer (77-80).Although a prospective study of Finnish men found that low serum25-hydroxyvitamin D levels were associated with earlier and moreaggressive prostate cancer development (81),another prospective study of men from Finland, Norway and Swedenfound a U-shaped relationship between serum 25-hydroxyvitamin Dlevels and prostate cancer risk. In that study serum25-hydroxyvitamin D concentrations of 19 nmol/L or lower and 80nmol/L or higher were associated with higher prostate cancer risk(82).Further research is needed to determine the nature of therelationship between vitamin D nutritional status and prostate cancerrisk.

Autoimmune Diseases

Insulin-dependent diabetesmellitus (IDDM; type 1 diabetes mellitus), multiplesclerosis (MS), and rheumatoidarthritis (RA) are examples of autoimmunediseases. Autoimmune diseases occur when the body mounts animmune response against its own tissue, rather than a foreignpathogen.In IDDM, insulin-producingbeta-cells of the pancreasare the target of the inappropriate immune response. In MS, thetargets are the myelin-producingcells of the central nervous system, and in RA, the targets are thecollagen-producingcells of the joints (83).Autoimmune responses are mediated by immune cells called T cells. Thebiologically active form of vitamin D, 1,25-dihydroxyvitamin D, hasbeen found to modulate T cell responses, such that the autoimmuneresponses are diminished. Epidemiologicalstudies have found that the prevalenceof IDDM, MS, and RA increases as latitude increases, suggesting thatlower exposure to UVB radiation and associated decreases inendogenous vitamin D synthesis may play a role in the pathology ofthese diseases. The results of several prospectivecohort studies also suggest that adequate vitamin D intake couldpossibly decrease the risk of autoimmune diseases. A prospectivecohort study of children born in Finland during the year 1966 andfollowed for thirty years found that those who received supplementalvitamin D during the first year of life had a significantly lowerrisk of developing IDDM, while children suspected of developingrickets (severe vitamin D deficiency) during the first year of lifehad a significantly higher risk of developing IDDM (84).Vitamin D deficiency has also been implicated in MS. A recentcase-control study in U.S. military personnel, including 257 cases ofdiagnosed MS, found that white subjects in the highest quintile ofserum 25-hydroxyvitamin D (>99.1 nmol/L) had a 62% lower risk ofdeveloping MS (85).A relationship between this indicator of vitamin D status and MS wasnot observed in blacks or Hispanics, but the power to detect such anassociation was limited by small sample sizes and overall low serum25-hydroxyvitamin D concentrations (85).In two large cohorts of U.S. women followed for at least ten years,vitamin D supplement use was associated with a significant reductionin the risk of developing MS (86).Similarly, postmenopausal women with the highest total vitamin Dintakes were at significantly lower risk of developing RA after 11years of follow-up than those with the lowest intakes (87).Thus, evidence from both animal model studies and humanepidemiological studies suggests that maintaining sufficient vitaminD levels could possibly help decrease the risk of several autoimmunediseases.

Hypertension (High BloodPressure)

The results of epidemiological and clinical studies suggest aninverse relationship between serum 1,25-dihydroxyvitamin D levels andblood pressure, which may be explained by recent findings that1,25-dihydroxyvitamin D decreases the expressionof the geneencoding renin (see Function).Data from epidemiological studies suggest that conditions thatdecrease vitamin D synthesis in the skin, such as having dark-coloredskin or living in temperate latitudes, are associated with increasedprevalenceof hypertension(88).A controlled clinical trial in 18 hypertensive men and women livingin the Netherlands found that exposure to UVB radiation three timesweekly for six weeks during the winter increased serum25-hydroxyvitamin D levels and significantly decreased 24-hourambulatory systolicand diastolicblood pressure measurements by an average of 6 mmHg (89).In randomizedcontrolled trials of vitamin D supplementation, a combination of1,600 IU/day of vitamin D and 800 mg/day of calcium for eight weekssignificantly decreased systolic blood pressure in elderly women by9% compared to calcium alone (90),but supplementation with 400 IU of vitamin D daily or a single doseof 100,000 IU of vitamin D did not significantly lower blood pressurein elderly men and women over a two-month period (91,92). At present, data from controlled clinical trials are toolimited to determine whether vitamin D supplementation will beeffective in lowering blood pressure or preventing hypertension.

Sources

Sunlight

Solar ultraviolet-B radiation (UVB; wavelengths of 290to 315 nanometers) stimulates the production of vitamin D3in the epidermis of the skin (93).Sunlight exposure can provide most people with their entire vitamin Drequirement. Children and young adults who spend a short time outsidetwo or three times a week will generally synthesize all the vitamin Dthey need to prevent deficiency. One study reported that serumvitamin D concentrations following exposure to 1 minimal erythemaldose of simulated sunlight (the amount required to cause a slightpinkness of the skin) was equivalent to ingesting approximately20,000 IU of vitamin D2 (94).People with dark-colored skin synthesize markedly less vitamin D onexposure to sunlight than those with light-colored skin (1).Additionally, the elderly have diminished capacity to synthesizevitamin D from sunlight exposure and frequently use sunscreen orprotective clothing in order to prevent skin cancer and sun damage.The application of sunscreen with an SPF factor of 8 reducesproduction of vitamin D by 95%. In latitudes around 40 degrees northor 40 degrees south (Boston is 42 degrees north), there isinsufficient UVB radiation available for vitamin D synthesis fromNovember to early March. Ten degrees farther north or south(Edmonton, Canada) the “vitamin D winter” extends frommid-October to mid-March. According to Dr. Michael Holick, as littleas 5-10 minutes of sun exposure on arms and legs or face and armsthree times weekly between 11:00 am and 2:00 pm during the spring,summer, and fall at 42 degrees latitude should provide alight-skinned individual with adequate vitamin D and allow forstorage of any excess for use during the winter with minimal risk ofskin damage (36).

Food sources

Vitamin D is found naturally in very few foods. Foodscontaining vitamin D include some fatty fish (mackerel, salmon,sardines), fish liver oils, and eggs from hens that have been fedvitamin D. In the U.S., milk and infant formula are fortified withvitamin D so that they contain 400 IU (10 mcg) per quart. However,other dairy products, such as cheese and yogurt, are not alwaysfortified with vitamin D. Some cereals and breads are also fortifiedwith vitamin D. Recently, orange juice fortified with vitamin D hasbeen made available in the U.S. Accurate estimates of average dietaryintakes of vitamin D are difficult because of the high variability ofthe vitamin D content of fortified foods (29).Vitamin D contents of some vitamin D-rich foods are listed in thetable below in both international units (IU) and micrograms (mcg).For more information on the nutrient content of specific foods,search the USDAfood composition database.

Food

Serving

Vitamin D (IU)

Vitamin D (mcg)

Pink salmon, canned

3 ounces

530

13.3

Sardines, canned

3 ounces

231

5.8

Mackerel, canned

3 ounces

213

5.3

Quaker Nutrition for Women Instant Oatmeal

1 packet

154

3.9

Cow's milk, fortified with vitamin D

8 ounces

98

2.5

Soy milk, fortified with vitamin D

8 ounces

100

2.5

Orange juice, fortified with vitamin D

8 ounces

100

2.5

Cereal, fortified

1 serving (usually 1 cup)

40-50

1.0-1.3

Egg yolk

1 large

21

0.53

 

Supplements

Most vitamin D supplements available without aprescription contain cholecalciferol (vitamin D3).Multivitamin supplements generally provide 400 IU (10 mcg) of vitaminD. Single ingredient vitamin D supplements may provide 400 to 2,000IU of vitamin D, but 400 IU is the most commonly available dose. Anumber of calcium supplements may also provide vitamin D.

Safety

Toxicity

Vitamin D toxicity (hypervitaminosis D) inducesabnormally high serumcalcium levels (hypercalcemia), which could result in bone loss,kidney stones, and calcification of organs like the heart and kidneysif untreated over a long period of time. Hypercalcemia has beenobserved following daily doses of greater than 50,000 IU of vitamin D(37).Overall, research suggests that vitamin D toxicity is very unlikelyin healthy people at intake levels lower than 10,000 IU/day (38,95,96). However, the Food and Nutrition Board of the Institute ofMedicine conservatively set a tolerable upper intake level (UL)of 4,000 IU/day (100 mcg/day) for all adults (see table below).Vitamin D toxicity has not been observed to result from sun exposure(37).Certain medical conditions can increase the risk of hypercalcemia inresponse to vitamin D, including primary hyperparathyroidism,sarcoidosis, tuberculosis, and lymphoma (38).People with these conditions may develop hypercalcemia in response toany increase in vitamin D nutrition and should thus consult aqualified health care provider regarding any increase in vitamin Dintake.

Tolerable Upper Intake Level (UL) for Vitamin D
Set by the Institute of Medicine

Age Group 

mcg/day (IU/day)

Infants 0-6 months 

25 mcg (1,000 IU)

Infants 6-12 months 

37.5 mcg (1,500 IU)

Children 1-3 years 

62.5 mcg (2,500 IU)

Children 4-8 years 

75 mcg (3,000 IU)

Children 9-13 years 

100 mcg (4,000 IU)

Adolescents 14-18 years 

100 mcg (4,000 IU)

Adults 19 years and older 

100 mcg (4,000 IU)

 

Drug interactions

The following medications increase the metabolism ofvitamin D and may decrease serum25-hydroxyvitamin D levels: phenytoin (Dilantin), fosphenytoin(Cerebyx), phenobarbital (Luminal), carbamazepine (Tegretol), andrifampin (Rimactane). The following medications should not be takenat the same time as vitamin D because they can decrease theintestinal absorption of vitamin D: cholestyramine (Questran),colestipol (Colestid), orlistat (Xenical), mineral oil, and the fatsubstitute Olestra. The oral anti-fungal medication, ketoconazole,inhibits the 25-hydroxyvitamin D3-1-hydroxylase enzyme andhas been found to reduce serum levels of 1,25-hydroxyvitamin D inhealthy men. The induction of hypercalcemia by toxic levels ofvitamin D may precipitate cardiac arrhythmiain patients on digitalis (Digoxin) (97,98).

Linus PaulingInstitute Recommendation

The Linus Pauling Institute recommends that generallyhealthy adults take 2,000 IU (50 mcg) of supplemental vitamin Ddaily. Most multivitamins contain 400 IU of vitamin D, and singleingredient vitamin D supplements are available for additionalsupplementation. Sun exposure, diet, skin color, and obesity havevariable, substantial impact on body vitamin D levels. To adjust forindividual differences and ensure adequate body vitamin D status, theLinus Pauling Institute recommends aiming for a serum25-hydroxyvitamin D level of at least 80 nmol/L (32 ng/mL). Numerousobservational studies have found that serum 25-hydroxyvitamin Dlevels of 80 nmol/L (32 ng/mL) and above are associated with reducedrisk of bone fractures, several cancers, multiple sclerosis, and type1 (insulin-dependent) diabetes.

Infants should have a daily intake of 400 to 1,000 IU(10 to 25 mcg) of vitamin D, and children and adolescents should havea daily intake of 600 to 1,000 IU (15 to 25 mcg) of vitamin D,consistent with the recommendations of The Endocrine Society (99).Given the average vitamin D content of breast milk, infant formula,and the diets of children and adolescents, supplementation may benecessary to meet these recommendations. The American Academy ofPediatrics currently suggests that all infants, children, andadolescents receive 400 IU of supplemental vitamin D daily (19).

Older adults (> 50 years)

Daily supplementation with 2,000 IU (50 mcg) of vitaminD is especially important for older adults because aging isassociated with a reduced capacity to synthesize vitamin D in theskin upon sun exposure.

References


Written in March 2004 by: Jane Higdon, Ph.D. LinusPauling Institute, Oregon State University

Updated in January 2008 by: Victoria J. Drake, Ph.D.,Linus Pauling Institute, Oregon State University

Reviewed in January 2008 by: Hector F. DeLuca, Ph.D.,Steenbock Research Professor,
Department of , University ofWisconsin-Madison

Last updated 6/22/11  Copyright 2000-2011 Linus Pauling Institute


Disclaimer

The Linus Pauling Institute Micronutrient Information Centerprovides scientific information on health aspects of micronutrientsand phytochemicals for the general public. The information is madeavailable with the understanding that the author and publisher arenot providing medical, psychological, or nutritional counselingservices on this site. The information should not be used in place ofa consultation with a competent health care or nutritionprofessional.

The information on micronutrients and phytochemicals contained onthis Web site does not cover all possible uses, actions, precautions,side effects, and interactions. It is not intended as medical advicefor individual problems. Liability for individual actions oromissions based upon the contents of this site is expresslydisclaimed.


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