- Vitamin D
Vitamin D is a group of fat-soluble
prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).cite web|url=http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp|title=Dietary Supplement Fact Sheet: Vitamin D|publisher=National Institutes of Health|accessdate=2007-09-10|archiveurl=http://www.webcitation.org/5Rl5u0LB5 |archivedate=2007-09-10] The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultravioletB radiation.
Vitamin D plays an important role in the maintenance of organ systems.MerckManual|01|004|k|BABBBEAE|Vitamin D]
*Vitamin D regulates the
calciumand phosphoruslevels in the bloodby promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys, which enables normal mineralization of boneand prevents hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts. [cite journal |author=van den Berg H |title=Bioavailability of vitamin D |journal=Eur J Clin Nutr |volume=51 Suppl 1 |issue= |pages=S76–9 |year=1997 |month=January |pmid=9023488 |doi= |url=] [cite journal |author=Cranney A, Horsley T, O'Donnell S, "et al" |title=Effectiveness and safety of vitamin D in relation to bone health |journal=Evid Rep Technol Assess (Full Rep) |volume= |issue=158 |pages=1–235 |year=2007 |month=August |pmid=18088161 |doi= |url=] .
*Absent vitamin K or with drugs (particularly blood thinners) which interfere with Vitamin K metabolism, Vitamin D can promote soft tissue calcification. [cite journal |author=Price PA, Faus SA, Williamson MK |title=Warfarin-induced artery calcification is accelerated by growth and vitamin D |journal=Arterioscler. Thromb. Vasc. Biol. |volume=20 |issue=2 |pages=317–27 |year=2000 |month=Feb |pmid=10669626 |doi= |url=http://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=10669626]
parathyroid hormonesecretion from the parathyroidgland.
*Vitamin D affects the
immune systemby promoting phagocytosis, anti-tumor activity, and immunomodulatory functions.
Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active
metabolites, such as liveror kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, ricketsin children and osteomalaciain adults, and possibly contributes to osteoporosis.
Vitamin D regulates the expression of genes associated with cancers and autoimmune disease by controlling the activation of the vitamin D receptor (VDR), a type 1
nuclear receptorand DNA transcription factor. [cite journal |author=Marshall TG |title=Vitamin D discovery outpaces FDA decision making |journal=Bioessays |volume=30 |issue=2 |pages=173–82 |year=2008 |month=February |pmid=18200565 |doi=10.1002/bies.20708 |url=] Research has indicated that vitamin D deficiency is linked to colon cancer and more recently, to breast cancer. [Findings presented at the American Society of Clinical Oncology's annual meeting in Chicago on 30 May 2008, as reported in the [http://www.smh.com.au/news/health/study-backs-vitamin-d-in-cancer-fight/2008/05/31/1211654373048.html Sydney Morning Herald] on 1 June 2008.] Conflicting evidence links vitamin D deficiency to other forms of cancer.
Several forms (
vitamers) of vitamin D have been discovered. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol.
*Vitamin D1: molecular compound of
ergocalciferolwith lumisterol, 1:1
ergocalciferolor calciferol(made from ergosterol)
cholecalciferol(made from 7-dehydrocholesterolin the skin).
sitocalciferol(made from 7-dehydrositosterol)
Chemically, the various forms of vitamin D are
secosteroids; i.e., broken-open steroids. [http://vitamind.ucr.edu/about.html About Vitamin D] Including Sections: History, Nutrition, Chemistry, Biochemistry, and Diseases. University of California Riverside] The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.
Vitamin D2 is derived from
fungaland plantsources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterolreacts with UVB ultraviolet lightat wavelengthsbetween 270–300 nm, with peak synthesis occurring between 295-297 nm.cite journal |author=Norman AW |title=Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system |journal=Am. J. Clin. Nutr. |volume=67 |issue=6 |pages=1108–10 |year=1998 |month=Jun |pmid=9625080 |doi= |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=9625080] cite journal |author=MacLaughlin JA, Anderson RR, Holick MF |title=Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin |journal=Science (journal) |volume=216 |issue=4549 |pages=1001–3 |year=1982 |month=May |pmid=6281884 |doi= |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6281884] These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV indexis greater than 3. [http://amateurastronomy.org/Events/EH473.html Fun with UVB] Includes calculations and measurements of UVB levels at various angles of solar rays.] At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin after only ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated.
In humans, D3 is as effective as D2 at increasing the levels of vitamin D hormone in circulation; [cite journal |author=Holick MF, Biancuzzo RM, Chen TC, "et al" |title=Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=3 |pages=677–81 |year=2008 |month=March |pmc=2266966 |pmid=18089691 |doi=10.1210/jc.2007-2308 |url=] However, in some species, such as rats, vitamin D2 is more effective than D3. [ cite journal | author=Coates, M. E. | title= Requirements of different species for vitamins Full Text-pdf| journal=Proceedings of the Nutrition Society | year=1968 | volume= 27| issue= 2| pages= 143–148 | pmid= 5755261 | url= http://docstore.ingenta.com/cgi-bin/ds_deliver/1/u/d/ISIS/33840020.1/cabi/pns/1968/00000027/00000002/art00019/89A25EAB89BAB011116525855554705D47CC65A51B.pdf?link=http://www.ingentaconnect.com/error/delivery&format=pdf | doi = 10.1079/PNS19680039 ] Both vitamin D2 and D3 are used for human nutritional supplementation, and
pharmaceuticalforms include calcitriol(1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene. [http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/vit_0265.shtml Vitamin D] The Physicians Desk Reference. 2006 Thompson Healthcare.]
Vitamin D is a prohormone, meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism. Production of vitamin D in nature always appears to require the presence of some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, from mushrooms to animals, which are not able to synthesize it except through the action of sunlight at some point in the synthetic chain. For example, fish contain vitamin D only because they ultimately exist on calories from ocean algae which synthesize vitamin D in shallow waters from the action of solar UV.
Production in the skin
The skin consists of two primary layers: the inner layer called the
dermis, composed largely of connective tissue, and the outer, thinner epidermis. The epidermis consists of five "strata"; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.
Vitamin D3 is produced photochemically in the
skinfrom 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum.cite journal |author=Norman AW |title=Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system |journal=Am. J. Clin. Nutr. |volume=67 |issue=6 |pages=1108–10 |year=1998 |month=Jun |pmid=9625080 |doi= |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=9625080] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is less.
Synthesis in the skin involves
UVB radiationwhich effectively penetrates only the epidermal layers of skin. While 7-Dehydrocholesterol absorbs UV light at wavelengths between 270–300 nm, optimal synthesis occurs in a narrow band of UVB spectra between 295-300 nm. Peak isomerization is found at 297 nm. This narrow segment is sometimes referred to as D-UV.cite journal |author=MacLaughlin JA, Anderson RR, Holick MF |title=Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin |journal=Science (journal) |volume=216 |issue=4549 |pages=1001–3 |year=1982 |month=May |pmid=6281884 |doi= |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6281884] The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum. A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 µg/cm² of skin) are available in the stratum spinosum and stratum basale of human skin to meet the body's vitamin D requirements, and melanin content does not alter the amount of vitamin D that can be produced. [cite journal |author=Matsuoka LY, Wortsman J, Haddad JG, Kolm P, Hollis BW |title=Racial pigmentation and the cutaneous synthesis of vitamin D |journal=Arch Dermatol |volume=127 |issue=4 |pages=536–8 |year=1991 |month=Apr |pmid=1848745 |doi= |url=] Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. As noted below, the amount of time an individual requires to produce a given amount of Vitamin D may also depend upon the person's distance from the equator and on the season of the year.
ynthesis mechanism (form 3)
1. Vitamin D3 is synthesized from 7-dehydrocholesterol, a derivative of cholesterol, which is then photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is "pre-vitamin D3" . 2. Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a antarafacialhydride [1,7] Sigmatropic shift. 3. Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylatedin the liverto 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylaseproduced by hepatocytes, and stored until it is needed.25-hydroxycholecalciferol is further hydroxylated in the kidneysby the enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D3 or calcitriol) and 24R,25(OH)2D3. This conversion occurs in a tightly regulated fashion.Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end).
Mechanism of action
Once vitamin D is produced in the skin or consumed in food, it is converted in the
liverand kidneyto form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). Following this conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs. [http://vitamind.ucr.edu/about.html About Vitamin D] Including Sections: History, Nutrition, Chemistry, Biochemistry, and Diseases. University of California Riverside]
The hormonally active form of vitamin D mediates its biological effects by binding to the
vitamin D receptor(VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factorthat modulates the gene expressionof transport proteins (such as TRPV6and calbindin), which are involved in calcium absorption in the intestine.
The Vitamin D receptor belongs to the
nuclear receptorsuperfamily of steroid/thyroid hormone receptors, and VDR are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calciumand phosphoruslevels in the blood(with the assistance of parathyroid hormoneand calcitonin) and to the maintenance of bonecontent.cite journal | author=Holick MF | title=Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease | journal=American Journal of Clinical Nutrition Full Text | year=2004 | pages=1678S–88S| volume=80 | issue=6 | url=http://www.ajcn.org/cgi/content/full/80/6/1678S | pmid=15585788 ]
The VDR is known to be involved in
cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells. [http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/vit_0265.shtml Vitamin D] The Physicians Desk Reference. 2006 Thompson Healthcare.]
Only fish is naturally rich in vitamin D, so much vitamin D intake in the industrialized world is from fortified products including
milk, soy milkand breakfast cereals or supplements.
A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D is 35–55 ng/mL; with some debate among medical scientists for the slightly higher value. Suplementation of 100 IU (2.5 mcg) vitamin D3 raises circulating 25(OH)D by 2.5 nmol/l (1 ng/ml). [Michael Holick, 5 May 2007, http://www.uvadvantage.org/portals/0/pres/]
The 2005 Dietary Guidelines for Americans recommend that older adults, people with dark skin, and those exposed to insufficient ultraviolet radiation (i.e., sunlight) consume extra vitamin D from vitamin D-fortified foods and/or supplements. Individuals in these high-risk groups should consume 25 μg (1000 IU) of vitamin D daily to maintain adequate blood concentrations of 25-hydroxyvitamin D, the biomarker for vitamin D status.
The Canadian Pediatric Society recommends 2,000 IU daily for pregnant and breastfeeding women. [The vitamin D miracle: Is it for real? March 8, 2008 Martin Mittelstaedt [http://www.theglobeandmail.com/servlet/story/RTGAM.20080308.wxvitamin08/BNStory/specialScienceandHealth/home/?pageRequested=2] ]
latitude, time of day, cloud cover, smog, and sunscreenaffect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet.
In some countries, foods such as
milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and breadare fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency.cite journal |author=Nowson C, Margerison C |title=Vitamin D intake and vitamin D status of Australians |url=http://www.mja.com.au/public/issues/177_03_050802/now10763_fm.html |journal=Med J Aust |volume=177 |issue=3 |pages=149–52 |year=2002 |pmid=12149085] In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50.
Fortified foods represent the major dietary sources of vitamin D, as very few foods naturally contain significant amounts of vitamin D.
Natural sources of vitamin D include:
*Fish liver oils, such as
cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU
*Fatty fish species, such as:
Herring, 85g (3 oz) provides 1383 IU
Catfish, 85g (3 oz) provides 425 IU
Salmon, cooked, 3.5 oz provides 360 IU
Mackerel, cooked, 3.5 oz, 345 IU
Sardines, canned in oil, drained, 1.75 oz, 250 IU
Tuna, canned in oil, 3 oz, 200 IU
Eel, cooked, 3.5 oz, 200 IU
*One whole egg, 20 IU
Vitamin D deficiency can result from: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active
metabolites, such as liveror kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, ricketsin children and osteomalaciain adults, and contributes to osteoporosis.
Diseases caused by deficiency
The role of diet in the development of
ricketswas determined by Edward Mellanbybetween 1918–1920.cite journal |author=Rajakumar K |title=Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective |url=http://pediatrics.aappublications.org/cgi/content/full/112/2/e132 |journal=Pediatrics |volume=112 |issue=2 |pages=e132–5 |year=2003 |pmid=12897318| doi = 10.1542/peds.112.2.e132 ] In 1921 Elmer McCollum identified an anti-rachitic substance found in certain fats could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D. The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid 7-dehydrocholesterol, the precursor of vitamin D.
Vitamin D deficiency is known to cause several bone diseases [cite journal | author=Grant WB, Holick MF | title=Benefits and requirements of vitamin D for optimal health: a review | journal=Altern Med Rev | year=2005 | pages=94–111 | volume=10 | issue=2 | pmid=15989379] including:
Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones. The earliest sign of subclinical vitamin D deficiency is Craniotabes, abnormal softening or thinning of the skull.cite journal |author=Yorifuji J, Yorifuji T, Tachibana K, "et al" |title=Craniotabes in normal newborns; the earliest sign of subclinical vitamin D deficiency |journal=J. Clin. Endocrinol. Metab. |volume= 93|issue= |pages= 1784|year=2008 |month=February |pmid=18270256 |doi=10.1210/jc.2007-2254 |url=]
Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximalmuscle weakness and bone fragility.
Osteoporosis, a condition characterized by reduced bone mineral densityand increased bone fragility.
Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per
quartsince the 1930s, leading to a dramatic decline in the number of rickets cases. Zincand Ironare often found to be poorly regulated or even deficient in Vitamin D deficiency. Vitamin D enhances the activities of Vitamin A, and Zincreduces the toxicity of Vitamin A, while Ironreduces the toxicity of Zinc.Fact|date=June 2008 These four are seen as part of the pathology of Alzheimer's, Parkinson'sand some peripheral neuropathies including Restless legs syndrome
Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure,
tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia, seasonal affective disorder, peripheral artery diseasecite journal |author=Melamed ML, Muntner P, Michos ED, "et al" |title=Serum 25-Hydroxyvitamin D Levels and the Prevalence of Peripheral Arterial Disease. Results from NHANES 2001 to 2004 |journal= Arterioscler. Thromb. Vasc. Biol.|volume= 28|issue= |pages= 1179|year=2008 |pmid=18417640 |doi=10.1161/ATVBAHA.108.165886 |url=] and several autoimmune diseases including type 1 diabetes(see role in immunomodulation). [Travera-Mendoza, Luz E. and White, John H. "Cell Defenses and the Sunshine Vitamin." "Scientific American", November 2007, p. 42.]
Groups at greater risk of deficiency
Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 decreases. [cite news | first= | last= | coauthors= | title=Low vitamin D levels linked to poor physical performance in older adults |date=April 23 2007 | publisher= | url =http://www.eurekalert.org/pub_releases/2007-04/wfub-lvd041807.php | work =EurekAlert | pages = | accessdate = 2007-04-24 | language = ] In addition the ability of the
kidneys to convert calcidiol to its active form also decreases with age, prompting the need for increased vitamin D supplementation in elderly individuals. One consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL, which is equal to 75 nmol/L.cite journal | author=Heaney RP | title=Functional indices of vitamin D status and ramifications of vitamin D deficiency Full Text| journal=Am J Clin Nutr | year=2004 | pages=1706S–9S | volume=80 | issue=6 Suppl |url=http://www.ajcn.org/cgi/content/full/80/6/1706S | pmid=15585791] One billion people in the world are currently Vitamin D deficient, if 75 nmol/L is used as cutoff value for insufficiency.cite journal |author=Holick MF |title=Vitamin D deficiency |journal=N. Engl. J. Med. |volume=357 |issue=3 |pages=266–81 |year=2007 |pmid=17634462 |doi=10.1056/NEJMra070553] [http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/ Linus Pauling Institute: Vitamin D] ]
Because inflammation leads to the increased conversion of 25D into 1,25 D and because studies typically only measure 25D to determine deficiency, it is important to differentiate symptoms caused by insufficient 25D from those conditions which themselves cause lower levels of 25D, which presents as insufficiency.
The American Pediatric Association advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards. (1 IU Vitamin D is the biological equivalent of 0.025 μg cholecalciferol/ergocalciferol). The Canadian Paediatric Society recommends that pregnant or breastfeeding women consider taking 2000 IU/day, that all babies who are exclusively breastfed receive a supplement of 400 IU/day, and that babies living above 55 degrees latitude get 800 IU/day from October to April. [http://www.cps.ca/english/media/newsreleases/2007/vitamind.htm Canadian mothers and babies don't get enough vitamin D] 2007 Canadian Paediatric Society Recommendation] Health Canada recommends 400IU/day (10μg/d). [http://www.hc-sc.gc.ca/fn-an/nutrition/child-enfant/infant-nourisson/vita_d_supp_e.html Vitamin D Supplementation for Breastfed Infants] - 2004 Health Canada Recommendation] While
infant formulais generally fortified with vitamin D, breast milkdoes not contain significant levels of vitamin D, and parents are usually advised to avoid exposing babies to prolonged sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes. Liquid "drops" of vitamin D, as a single nutrient or combined with other vitamins, are available in water based or oil-based preparations ("Baby Ddrops(R)" in North America, or "Vigantol(R) oil" in Europe). However, babies may be safely exposed to sunlight for short periods; as little as 10 minutes a day without a hat can suffice, depending on location and season. The vitamin D used for in supplements and infant formula is not distinguishable in efficacy from that produced by the body naturally. The risk of overdose is not present with natural exposure to sunlight, because the skin's capacity to produce vitamin D is self-limiting (skin production is thought to reflect the dose of vitamin D to which our evolution optimized human biology). In contrast, care should be given to limit oral intake for infants to no more than 1000 IU (25 mcg) daily, or for adults no more than 10,000 IU (250 mcg) daily. Obeseindividuals may have lower levels of the circulating form of vitamin D, probably because of reduced bioavailability, and are at higher risk of deficiency. To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their parathyroid glands removed (most commonly renal dialysispatients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism. [cite journal | author=Holick MF | title=The vitamin D epidemic and its health consequences Full Text| journal=J Nutr | year=2005 | pages=2739S–48S | volume=135 | issue=11 | url=http://jn.nutrition.org/cgi/content/full/135/11/2739S | pmid=16251641] Patients with chronic liver diseaseor intestinal malabsorptiondisorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily). The use of sunscreenwith a sun protection factor(SPF) of 8 inhibits more than 95% of vitamin D production in the skin. [cite journal |author=Sayre RM, Dowdy JC |title=Darkness at noon: sunscreens and vitamin D3 |journal=Photochem. Photobiol. |volume=83 |issue=2 |pages=459–63 |year=2007 |pmid=17115796 |doi=10.1562/2006-06-29-RC-956 |url=http://www.blackwell-synergy.com/doi/abs/10.1562/2006-06-29-RC-956 ] Recent studies showed that, following the successful " Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer, an increased number of Australians and New Zealanders became vitamin D deficient. Ironically, there are indications that vitamin D deficiency may lead to skin cancer. [cite journal | author=Grant WB | title=An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation | journal=Cancer | year=2002 | pages=1867–75 | volume=94 | issue=6 | pmid=11920550 | doi = 10.1002/cncr.10427 ] To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use.
pigmentationof light-skinned individuals tends to allow more sunlight to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D deficiency. However, at higher latitudes (above 30°) during the winter months, the decreased angle of the sun's rays, reduced daylight hours, protective clothing during cold weather, and fewer hours of outside activity, diminish absorption of sunlight and the production of vitamin D. Because melaninacts like a sun-block, prolonging the time required to generate vitamin D, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes. In June 2007, The Canadian Cancer Society began recommending that all adult Canadians consider taking 1000 IU of vitamin D during the fall and winter months (when typically the country's northern latitude prevents sufficient sun-stimulated production of vitamin D). [cite news| url=http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070608/cancer_recommendations_070608/20070608?hub=Health | title= Canadian Cancer Society Recommends Vitamin D | work=CTV News |date=8 June 2007 | accessdate=2007-06-09] At latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required. [http://amateurastronomy.org/Events/EH473.html Fun with UVB] Includes calculations and measurements of UVB levels at various angles of solar rays.] Individuals clad in full body coverings during all their outdoor activity, most notably women wearing burquas in daylight, are at risk of vitamin D deficiency. This poses a lifestyle-related health risk mostly for female residents of conservative Muslimnations in the Middle East, but also for strict adherents in other parts of the world.cite journal |author=Saadi HF, Dawodu A, Afandi BO, Zayed R, Benedict S, Nagelkerke N |title=Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women |journal=Am. J. Clin. Nutr. |volume=85 |issue=6 |pages=1565–71 |year=2007 |pmid=17556694 |doi=]
Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a
half-lifeof about 20 to 29 days. However, the synthesis of bioactive vitamin D hormone is tightly regulated and vitamin D toxicity usually occurs only if excessive doses (prescription forms or rodenticideanalogs) are taken.cite web| title = RODENTICIDES, source: Journal of Veterinary Medicine, archives, vol. 27, May, 1998| work =| publisher = IPM Of Alaska, Solving Pest Problems Sensibly| date =| url = http://www.homestead.com/ipmofalaska/files/rodenticides.html | accessdate = 2006-07-07 ] Although normal food and pill vitamin D concentration levels are far too low to be toxic in adults, because of the high vitamin Acontent in codliver oil, it is possible to reach toxic levels of vitamin A (but not vitamin D) via this route, [cite journal |author=Bendich A, Langseth L |title=Safety of vitamin A |url= http://www.ajcn.org/cgi/content/full/83/2/191journal=Am J Clin Nutr |volume=49 |issue=2 |pages=358–71 |year=1989 |pmid=2492745 |issn=] if taken in multiples of the normal dose in an attempt to increase the intake of vitamin D. Most historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.cite journal |author=Vieth R |title=Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety |url= http://www.ajcn.org/cgi/content/full/69/5/842| journal=Am J Clin Nutr |volume=69 |issue=5 |pages=842–56 |year=1999 |pmid=10232622 |issn=]
Exposure to sunlight for extended periods of time does not cause vitamin D toxicity. This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded. [cite journal |author=Holick M |title=Environmental factors that influence the cutaneous production of vitamin D |journal=Am J Clin Nutr |volume=61 |issue=3 Suppl |pages=638S–645S |year=1995 |pmid=7879731 |issn=] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.
The exact long-term safe dose of vitamin D is not entirely known, but dosages up to 250 micrograms (10,000 IU) /day in healthy adults are believed to be safe., and all known cases of vitamin D toxicity with hypercalcemia have involved intake of or over 1,000 micrograms (40,000 IU)/day. The U.S.
Dietary Reference IntakeTolerable Upper Intake Level (UL) of vitamin D for children and adults is 50 micrograms/day (2,000 IU/day), although this is widely presumed to be below actual physiological daily requirements. In adults, sustained intake of 2500 micrograms/day (100,000 IU) can produce toxicity within a few months. For infants (birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU/day), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004, leading to 1 death. [ [http://www.poison.org/prevent/documents/TESS%20Annual%20Report%202004.pdf 2004 Annual Report] of the American Association of Poison Control Centers Toxic Exposure Surveillance System.] The "Nutrition Desk Reference" states "The threshold for toxicity is 500 to 600 micrograms [vitamin D] per kilogram body weight per day." [Garrison RH, Somer E (1990) "The Nutrition Desk Reference", Second Edition. p. 40. New Canaan, CT: Keats.] The US EPApublished an oral LD50 of 619 mg/kg for female rats. [US Environmental Protection Agency. "Cholecalciferol (Vitamin D3) Chemical Profile 12/84". Chemical Fact Sheet Number 42. Washington, DC. December 1, 1984.]
Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose.
Some symptoms of vitamin D toxicity are a result of
hypercalcemia(an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure. ["Complete Guide to Vitamins, Minerals ans Supplements", Fisher Books, Tucsan AZ, 1988, p42] Gastrointestinalsymptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria(excessive production of urine), polydipsia(increased thirst), weakness, nervousness, pruritus(itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop. In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity. [cite journal | author=Adams JS, Lee G | title=Gains in bone mineral density with resolution of vitamin D intoxication | url=http://www.annals.org/cgi/content/full/127/3/203| journal=Ann Intern Med | year=1997 | pages=203–206 | volume=127 | issue=3 | pmid=9245225] Another study showed elevated risk of ischaemic heart diseasewhen 25D was above 89 ng/mL. [cite journal | author=Rajasree S, Rajpal K, Kartha CC, Sarma PS, Kutty VR, Iyer CS, Girija G | title=Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease Full Text| journal=Eur J Epidemiol | year=2001 | pages=567–71 | volume=17 | issue=6 | pmid=11949730 | doi = 10.1023/A:1014559600042 ]
Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with
corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.
Role in immunomodulation
The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive
immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressiveeffects.cite journal |author=Nagpal S, Na S, Rathnachalam R |title=Noncalcemic actions of vitamin D receptor ligands |journal=Endocr. Rev. |volume=26 |issue=5 |pages=662–87 |year=2005 |month=August |pmid=15798098 |doi=10.1210/er.2004-0002 |url=]
Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of
regulatory T cells, as well as effects on cytokinesecretion patterns. [cite journal | author= Yee YK, Chintalacharuvu SR, Lu J, Nagpal S. | title= Vitamin D receptor modulators for inflammation and cancer | journal= Mini Rev Med Chem.| year=2005 | volume= 5| issue= 8| pages= 761–78 | pmid= 16101412 | doi = 10.2174/1389557054553785 ] VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression. [cite journal | author= van Etten E, Mathieu C. | title= Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts | journal= J Steroid Biochem Mol Biol. | year=2005 | volume= 97| issue= 1-2| pages= 93–101 | pmid= 16046118 | doi= 10.1016/j.jsbmb.2005.06.002 ]
VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the
phagocyticactivity of macrophages. Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptidethat is produced in macrophages triggered by bacteria, viruses, and fungi. [Janet Raloff, [http://www.sciencenews.org/articles/20061111/bob9.asp "The Antibiotic Vitamin"] Science News, Vol 170, November 11, 2006, pages 312-317] Vitamin D deficiency tends to increase the risk of infections, such as influenzacite journal |author=Cannell JJ, Vieth R, Umhau JC, "et al" |title=Epidemic influenza and vitamin D |journal=Epidemiol. Infect. |volume=134 |issue=6 |pages=1129–40 |year=2006 |pmid=16959053 |doi=10.1017/S0950268806007175] and tuberculosiscite journal |author=Nnoaham KE, Clarke A |title=Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis |journal=Int J Epidemiol |volume=37 |issue=1 |pages=113–9 |year=2008 |pmid=18245055 |doi=10.1093/ije/dym247] cite journal |author=Gibney KB, MacGregor L, Leder K, "et al" |title=Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa |journal=Clin. Infect. Dis. |volume=46 |issue=3 |pages=443–6 |year=2008 |pmid=18173355 |doi=10.1086/525268] cite journal |author=Martineau AR, Wilkinson RJ, Wilkinson KA, "et al" |title=A single dose of vitamin D enhances immunity to mycobacteria |journal=Am. J. Respir. Crit. Care Med. |volume=176 |issue=2 |pages=208–13 |year=2007 |pmid=17463418 |doi=10.1164/rccm.200701-007OC] . In a 1997 study, Ethiopianchildren with rickets were 13 times more likely to get pneumoniathan children without rickets. [cite journal |author=Muhe L, Lulseged S, Mason KE, Simoes EA |title=Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children |journal=Lancet |volume=349 |issue=9068 |pages=1801–4 |year=1997 |month=June |pmid=9269215 |doi=10.1016/S0140-6736(96)12098-5 |url=]
These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (
rheumatoid arthritis, psoriatic arthritis), dermatological conditions ( psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases ( systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection. However the effects of supplementation with vitamin D, as yet, remain unclear, and supplementation may be inadvisable for individuals with sarcoidosisand other diseases involving vitamin D hypersensitivity. [United Kingdom Food Standards Agency; Expert Group on Vitamins and Minerals; Professor Michael Langdon, Chairman. (2003 May). Safe Upper Levels for Vitamins and Minerals. Retrieved Aug. 12, 2006 from http://www.food.gov.uk/multimedia/pdfs/vitmin2003.pdf] cite journal |author=Vieth R |title=Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety |url= http://www.ajcn.org/cgi/content/full/69/5/842| journal=Am J Clin Nutr |volume=69 |issue=5 |pages=842–56 |year=1999 |pmid=10232622 |issn=] cite journal | author=Abreu MT, et al. | title=Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density | journal=Gut | year=2004 | pages=1129–1136 | volume=53 | issue=8 | pmid=15247180 | doi = 10.1136/gut.2003.036657 ] cite web |url=http://www.sciencedaily.com/releases/2008/01/080125223302.htm |title=Vitamin D Deficiency Study Raises New Questions About Disease And Supplements |accessdate=2008-02-13 |format= |work=] cite journal |author=Marshall TG |title=Vitamin D discovery outpaces FDA decision making |journal=Bioessays |volume=30 |issue=2 |pages=173–82 |year=2008 |pmid=18200565 |doi=10.1002/bies.20708]
A 2006 study published in the
Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D. [cite journal | author=Munger KL. , Levin, LI,Hollis BW , Howard, NS , Ascherio A | title= Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis | journal=Journal of the American Medical Association | year=2006 | pages=2832–2838 | volume=296 | issue=23 | pmid= 17179460 | doi = 10.1001/jama.296.23.2832 ]
Role in cancer prevention and recovery
Canadian Cancer Societyrecommends that adults should consider supplementeing with 1,000 IU of vitamin D per day during the fall and winter. They base this recommendation on the growing evidence for a link between vitamin D and a reduced risk for colorectal, breast and prostate cancers. [ [http://www.cancer.ca/Canada-wide/About%20us/Media%20centre/CW-Media%20releases/CW-2007/Canadian%20Cancer%20Society%20Announces%20Vitamin%20D%20Recommendation.aspx?sc_lang=en Canadian Cancer Society Announces Vitamin D Recommendation] . June 8, 2007.]
The vitamin D hormone, calcitriol, has been found to induce death of
cancercells " in vitro" and " in vivo". Although the anti-cancer activity of vitamin D is not fully understood, it is thought that these effects are mediated through vitamin D receptors expressed in cancer cells, and may be related to its immunomodulatory abilities. The anti-cancer activity of vitamin D observed in the laboratory has prompted some to propose that vitamin D supplementation might be beneficial in the treatment or prevention of some types of cancer.
A search of primary and review medical literature published between 1970 and 2007 found an increasing body of research supporting the hypothesis that the active form of vitamin D has significant, protective effects against the development of cancer. Epidemiological studies show an inverse association between sun exposure, serum levels of 25(OH)D, and intakes of vitamin D and risk of developing and/or surviving cancer. The protective effects of vitamin D result from its role as a nuclear transcription factor that regulates cell growth, differentiation,
apoptosisand a wide range of cellular mechanisms central to the development of cancer. [cite journal |author=Ingraham BA, Bragdon B, Nohe A |title=Molecular basis of the potential of vitamin D to prevent cancer |journal=Curr Med Res Opin |volume= 24|issue= | pages = 139|year=2007 |pmid=18034918 |doi=10.1185/030079907X253519] In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysisof 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancerrisk by 50%, and breast and ovarian cancerrisks by 30%. [cite news| url=http://news.bbc.co.uk/2/hi/health/4563336.stm| title= Vitamin D 'can lower cancer risk'| work=BBC News|date=28 December 2005| accessdate=2006-03-23] Research has also shown a beneficial effect of high levels of calcitriol on patients with advanced prostate cancer. [cite journal |author=Beer T, Myrthue A |title=Calcitriol in the treatment of prostate cancer |journal=Anticancer Res |volume=26 |issue=4A |pages=2647–51 |year= 2006 |pmid=16886675] A randomized intervention study involving 1,200 women, published in June 2007, reports that vitamin D supplementation (1,100 international units (IU)/day) resulted in a 60% reduction in cancer incidence, during a four-year clinical trial, rising to a 77% reduction for cancers diagnosed "after" the first year (and therefore excluding those cancers more likely to have originated prior to the vitamin D intervention).cite news| author= Martin Mittelstaedt| url=http://www.theglobeandmail.com/servlet/story/RTGAM.20070428.wxvitamin28/BNStory/specialScienceandHealth/home | title=Vitamin D casts cancer prevention in new light | work=Global and Mail |date=28 April 2007| accessdate=2007-04-28 ] cite journal| author= Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.| title=Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial |journal=Am J Clin Nutr. |volume=85 |issue=6 |pages=1586–91 |year= 2007 |pmid=17556697] In 2006, a study at Northwestern Universityfound that taking the U.S. RDA of vitamin D (400 IU per day) cut the risk of pancreatic cancerby 43% in a sample of more than 120,000 people from two long-term health surveys. [cite journal |author=Skinner HG, Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS |title=Vitamin D intake and the risk for pancreatic cancer in two cohort studies |url=http://cebp.aacrjournals.org/cgi/content/full/15/9/1688|journal=Cancer Epidemiol. Biomarkers Prev. |volume=15 |issue=9 |pages=1688–95 |year=2006 |pmid=16985031 |doi=10.1158/1055-9965.EPI-06-0206] [ [http://news.bbc.co.uk/1/hi/health/5334534.stm BBC NEWS | Health | Vitamin D 'slashes cancer risk' ] ]
A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers.cite journal |author=Tuohimaa P, Pukkala E, Scélo G, "et al" |title=Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation |journal=Eur. J. Cancer |volume=43 |issue=11 |pages=1701–12 |year=2007 |pmid=17540555 |doi=10.1016/j.ejca.2007.04.018] Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight. [cite news| url=http://news.bbc.co.uk/2/hi/health/4458085.stm | title= Vitamin D 'aids lung cancer ops' | work=BBC News |date=22 April 2005 | accessdate=2006-03-23]
A scientific review undertaken by the
National Cancer Institutefound no link between baseline vitamin D status and overall cancer mortality. They did find that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels "80 nmol/L or higher associated with a 72% risk reduction". [cite journal |author=Freedman DM, Looker AC, Chang SC, Graubard BI |title=Prospective study of serum vitamin D and cancer mortality in the United States |journal=J. Natl. Cancer Inst. |volume=99 |issue=21 |pages=1594–602 |year=2007 |pmid=17971526 |doi=10.1093/jnci/djm204]
Role in cardiovascular disease prevention
Research indicates that vitamin D may play a role in preventing or reversing
coronary disease. [ Lack of vitamin D may increase heart disease risk http://www.americanheart.org/presenter.jhtml?identifier=3052800 American Heart Association rapid access journal report 01/07/2008 ] [ [http://newswise.com/articles/view/541493/ Newswise: Men with Low Vitamin D May Have Increased Risk of Heart Attack] Retrieved on June 9, 2008.] Vitamin D deficiency is associated with an increase in high blood pressureand cardiovascularrisk. When researchers monitored the vitamin D levels, blood pressure and other cardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years, they found that those people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels. [ [http://www.my-blood-pressure.com/vitamind-deficiency.html Low vitamin D levels linked to cardiovascular risk ] ]
A report from the
National Health and Nutrition Examination Survey(NHANES) found that low levels of vitamin D were associated with an increased risk of peripheral artery disease(PAD). Researchers divided 4,839 participantes in NHANES into quartiles (four groups) based on their blood levels of vitamin D, and found that increasing levels of vitamin D were associated with a lower prevalenceof PAD. The authors adjusted for other factors which could influence the development of PAD (such as smoking and high cholesterol) and found that among participants with the lowest vitamin D levels (<17.8 ng/ mL) PAD was 80% more common than in individuals with the highest levels (>29.2 ng/mL) of vitamin D.
Researchers publishing in the Journal of "Circulation" studied the blood levels of vitamin D in 1739 middle-aged children of partipants in the
Framingham Heart Studyin Framinhgam, Massachussetts(their mean age was 59 years; 55% were women; all were white) who did not have any prior history of cardiovascular disease. These subjects were followed for a meanof 5.4 years. The authors adjusted for other conventional risk factors for cardiovascular disease which could have confounded the results and still found that among the 120 individuals in this group who suffered a first cardiovascular event, those who had the lowest levels of vitamin D were most likely to have had an event. Individuals with lowest levels of vitamin D (<15 ng/mL) had a 62% increased risk (95% confidence interval 1.11 to 2.36, P=0.01) for having a first cardiovascular event compared with those with vitamin D levels of 15 ng/mL. This effect was evident in participants with hypertension, but not in those without hypertension. [cite journal |author=Wang TJ, Pencina MJ, Booth SL, "et al" |title=Vitamin D deficiency and risk of cardiovascular disease |journal=Circulation |volume=117 |issue=4 |pages=503–11 |year=2008 |month=January |pmid=18180395 |doi=10.1161/CIRCULATIONAHA.107.706127 |url=]
In a study of 34 middle-aged men, researchers found that low levels of vitamin D were associated with
hypertension, elevated VLDL triglycerides, and impaired insulin metabolism.cite journal |author=Lind L, Hänni A, Lithell H, Hvarfner A, Sörensen OH, Ljunghall S |title=Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men |journal=Am. J. Hypertens. |volume=8 |issue=9 |pages=894–901 |year=1995 |month=September |pmid=8541004 |doi=10.1016/0895-7061(95)00154-H |url=]
As with cancer incidence, a qualitative inverse correlations was found between coronary disease incidence and serum vitamin D levels of 32.0 versus 35.5 ng/mL.cite journal| author= Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R.| title=Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study|journal=Int J Epidemiol.|volume=19 |issue=3 |pages=559–563 |year= 1990 |pmid=2262248 | doi = 10.1093/ije/19.3.559 ] Cholesterol levels were found to be reduced in gardeners in the UK during the summer months.cite journal| author= Grimes DS, Hindle E, Dyer T.| title=Sunlight cholesterol and coronary heart disease|journal=Quarterly Journal of Medicine|volume=89 |issue=8 |pages=579–589 |year= 1996 |pmid=8935479]
Heart attacks peak in winter and decline in summer in temperatecite journal| author= Spencer FA, Goldberg RJ, Becker RC, Gore JM.| title=Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction|journal=J Am Coll Cardiol. |volume=31 |issue=6 |pages=1226–33 |year= 1998 |pmid=9581712 | doi = 10.1016/S0735-1097(98)00098-9 ] but not tropical latitudes.cite journal| author= Ku CS, Yang CY, Lee WJ, Chiang HT, Liu CP, Lin SL.| title=Absence of a seasonal variation in myocardial infarction onset in a region without temperature extremes|journal=Cardiology. |volume=89 |issue=4 |pages=277–82 |year= 1998 |pmid=9643275 | doi = 10.1159/000006800 ]
The issue of vitamin D in heart health has not yet been settled. Exercise may account for some of the benefit attributed to vitamin D, since vitamin D levels are higher in physically active persons. [cite journal |author=Scragg R, Holdaway I, Singh V, Metcalf P, Baker J, Dryson E |title=Serum 25-hydroxyvitamin D3 is related to physical activity and ethnicity but not obesity in a multicultural workforce |journal=Aust N Z J Med |volume=25 |issue=3 |pages=218–23 |year=1995 |pmid=7487689 |doi= |url=] Moreover, there may be an upper limit after which cardiac benefits decline. One study found an elevated risk of
ischaemic heart diseasein Southern India in individuals whose vitamin D levels were above 89 ng/mL. [cite journal | author=Rajasree S, Rajpal K, Kartha CC, Sarma PS, Kutty VR, Iyer CS, Girija G | title=Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease Full Text| journal=Eur J Epidemiol | year=2001 | pages=567–71 | volume=17 | issue=6 | pmid=11949730 | doi = 10.1023/A:1014559600042 ] These sun-living groups results do not generalize to sun-deprived urban dwellers. Among a group with heavy sun exposure, taking supplemental vitamin D are unlikely to result in blood levels over the ideal range, while urban dwellers not taking supplemental vitamin D may fall under the levels recognized as ideal, and being below the preferable levels may cause adverse affects on the health of each group.
Role in all-cause mortality
Low vitamin D levels are associated with cancer, diabetes, and hypertension, and in increased mortality among patients undergoing dialysis. Using the
National Health and Nutrition Examination SurveyMelamed and coworkers at the Albert Einstein College of Medicineevaluated whether low serum vitamin D levels were associated with mortality in the general population. The researchers studied the association of low vitamin D levels with all-cause mortality, cancer, and cardiovascular disease (CVD) mortality among 13,331 diverse American adults who were 20 years or older. Vitamin D levels of these participants were collected over a 6-year period (from 1988 through 1994), and individuals were passively followed for mortality through the year 2000. The researchers found that being older, female, nonwhite, having diabetes, a current smoker, and having a higher body mass indexwere all independently associated with a greater risk of being vitamin D deficient, while greater physical activity, vitamin D supplementation, and evaluating subjects in a non-winter season (greater exposure to sunshine) were all associated with higher levels. During a medianof 8.7 years of follow-up, there were 1806 deaths, including 777 (43%) from CVD. The authors divided the participants into 4 groups (quartiles) based on their serum vitamin D levels, and adjusted for baseline demographics, season, and CVD risk factors. Being in the lowest quartile (vitamin D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46). The adjusted models of CVD and cancer mortality revealed a higher risk, but it was not statistically significant. The authors concluded that having low levels of vitamin D (<17.8 ng/mL) was independently associated with an increase in all-cause mortality in the general population. [cite journal |author=Melamed ML, Michos ED, Post W, Astor B |title=25-hydroxyvitamin D levels and the risk of mortality in the general population |journal=Arch. Intern. Med. |volume=168 |issue=15 |pages=1629–37 |year=2008 |month=Aug |pmid=18695076 |doi=10.1001/archinte.168.15.1629 |url=]
Among many factors that may be responsible for vitamin Ds apparent beneficial effect on all-cause mortality is its effect on
telomeres and its potential effect on slowing aging. "Richards and coworkers" examined whether vitamin D concentrations would slow the rate of shortening of leukocytetelomeres (a marker of aging). The authors stated that vitamin D is a potent inhibitorof the proinflammatoryresponse and slows the turnover of leukocytes. Leukocyte telomere length (LTL) predicts the development of aging-related disease, and length of these telomeres decreases with each cell division and with increased inflammation (more common in the elderly). Researchers measured serum vitamin D concentrations in 2160 women aged 18-79 years (mean age: 49.4) from a large population-based cohort of twins. This study divided the group into thirds [tertiles http://en.wiktionary.org/wiki/tertile] based on vitamin D levels, and found that increased age was significantly associated with shorter LTL (r = -0.40, P < 0.0001). Higher serum vitamin D concentrations were significantly associated with longer LTL (r = 0.07, P = 0.0010), and this finding persisted even after adjustment for age (r = 0.09, P < 0.0001) and other variables that independently could affect LTL (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity). The difference in LTL between the highest and lowest tertiles of vitamin D was highly significant (P = 0.0009), and the authors stated that this was equivalent to 5.0 years of aging. The authors concluded that higher vitamin D levels, (easily modifiable through nutritional supplementation), were associated with longer LTL, which underscores the potentially beneficial effects of vitamin D on aging and age-related diseases. [cite journal |author=Richards JB, Valdes AM, Gardner JP, "et al" |title=Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women |journal=Am. J. Clin. Nutr. |volume=86 |issue=5 |pages=1420–5 |year=2007 |month=Nov |pmid=17991655 |pmc=2196219 |doi= |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=17991655]
Notes and References
* [http://ods.od.nih.gov/factsheets/vitamind.asp Vitamin D Fact Sheet] from the
U.S. National Institutes of Health
* [http://www.dairycouncilofca.org/PDFs/vitaminD.pdf Vitamin D: An Old Vitamin With New Health Implications]
* [http://www.beyonddiscovery.org/content/view.txt.asp?a=414 History of Vitamin D]
* [http://www.vitamindcouncil.org/ The Vitamin D Council]
* CBC Radio, Quirks & Quarks, June 7, 2008, [http://www.cbc.ca/quirks/archives/07-08/jun07.html The Vitamin D Miracle Cure] A Canadian science show hosted by Bob McDonald
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