Metabolomics/Nutrition/Vitamin D

thumb|W:Cholecalciferol (D3) thumb|Calcium regulation in the human body.The Parathyroid Glands and Vitamin F 1094 Walter F., PhD. Boron Medical Physiology: A Cellular And Molecular Approaoch Elsevier/Saunders 2003 978-1-4160-2328-9 The role of vitamin D is shown in orange. Vitamin D is a group of fat-soluble secosteroids, the two major physiologically relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D without a subscript refers to either D2 or D3 or both. Vitamin D is produced in the skin of vertebrates after exposure to ultraviolet B light, and occurs naturally in a small range of foods. In some countries staples such as milk, flour and margarine are artificially fortified with vitamin D, and it is also available as a supplement in pill form.Institute of Medicine (IOM). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1997) Access date: 2010-04-14 Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcidiol. Circulating calcidiol may then be converted into calcitriol, the biologically active form of vitamin D, either in the kidneys or by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders. Adams JS Hewison M Update in vitamin D J Clin Endocrinol Metab 2010 Feb 95 2 471–8 20133466 10.1210/jc.2009-1773 2840860 When synthesized in the kidneys, calcitriol circulates as a hormone, regulating, among other things, the concentration of calcium and phosphate in the bloodstream, promoting the healthy mineralization, growth and remodeling of bone, and the prevention of hypocalcemic tetany. Vitamin D insufficiency can result in thin, brittle, or misshapen bones, while sufficiency prevents rickets in children and osteomalacia in adults, and, together with calcium, helps to protect older adults from osteoporosis. Vitamin D also modulates neuromuscular function, reduces inflammation, and influences the action of many genes that regulate the cell proliferation|proliferation, cell differentiation|differentiation and apoptosis of cells.http://ods.od.nih.gov/factsheets/vitamind.asp Dietary Supplement Fact Sheet: Vitamin D National Institutes of Health Office of Dietary Spplements 2010-04-11 Forms Name Chemical composition Structure Vitamin D1 molecular compound of ergocalciferol with lumisterol, 1:1 Vitamin D2 ergocalciferol (made from ergosterol) File:Ergocalciferol.svg|70px|Note double bond at top center. Vitamin D3 cholecalciferol (made from 7-dehydrocholesterol in the skin). File:Cholecalciferol.svg|70px Vitamin D4 22-dihydroergocalciferol File:22-Dihydroergocalciferol.png|70px Vitamin D5 sitocalciferol (made from 7-dehydrositosterol) File:VitaminD5 structure.png|80px Several forms (vitamers) of vitamin D have been discovered (see table). The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. These are known collectively as calciferol.Dorland's Illustrated Medical Dictionary, under Vitamin (Table of Vitamins) Ergocalciferol|Vitamin D2 was chemically characterized in 1932. In 1936 the chemical structure of Cholecalciferol|vitamin D3 was established and resulted from the ultraviolet|ultraviolet irradiation of 7-dehydrocholesterol.History of Vitamin D University of California, Riverside, Vitamin D Workshop. Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.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 (made from ergosterol) is produced by invertebrates, fungus and plants in response to UV irradiation; it is not produced by vertebrates. Little is known about the biologic function of vitamin D2 in nonvertebrate species. Because ergosterol can more efficiently absorb the ultraviolet radiation that can damage DNA, RNA and protein it has been suggested that ergosterol serves as a sunscreening system that protects organisms from damaging high energy ultraviolet radiation.14985208 2004 Holick MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis 79 3 362–71 The American journal of clinical nutrition Vitamin D3 is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm.April 2010 These wavelengths are present in sunlight when the UV index is greater than 3. 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, vitamin D3 can be made in the skin. Depending on the concentration of UVB rays and the minutes of exposure, an equilibrium can develop in the skin, and vitamin D degrades as fast as it is generated.April 2010 Production in the skin thumb|The epidermal strata of the skin. Production is greatest in the stratum basale (colored red in the illustration) and stratum spinosum (colored orange). The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis (skin)|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. Cholecalciferol is produced photochemically in the skin from 7-dehydrocholesterol; 7-dehydrocholesterol is produced in relatively large quantities in the skin of most vertebrate animals, including humans.12514284 2003 Crissey SD Ange KD Jacobsen KL Slifka KA Bowen PE Stacewicz-Sapuntzakis M Langman CB Sadler W Kahn S Serum concentrations of lipids, vitamin d metabolites, retinol, retinyl esters, tocopherols and selected carotenoids in twelve captive wild felid species at four zoos 133 1 160–6 The Journal of nutrition The naked mole rat appears to be naturally cholecalciferol deficient as serum 25-OH vitamin D levels are undetectable.8384476 1993 Yahav S Buffenstein R Cholecalciferol supplementation alters gut function and improves digestibility in an underground inhabitant, the naked mole rat (Heterocephalus glaber), when fed on a carrot diet 69 1 233–41 The British journal of nutrition 10.1079/BJN19930025 Interestingly, the naked mole rat is resistant to aging, maintains healthy vascular function17468332 2007 Csiszar A Labinskyy N Orosz Z Xiangmin Z Buffenstein R Ungvari Z Vascular aging in the longest-living rodent, the naked mole rat 293 2 H919–27 10.1152/ajpheart.01287.2006 American journal of physiology. Heart and circulatory physiology and is the longest lived of all rodents.18180931 2008 Buffenstein R Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species 178 4 439–45 10.1007/s00360-007-0237-5 Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology In some animals, the presence of fur or feathers blocks the UV rays from reaching the skin. In birds and fur-bearing mammals, vitamin D is generated from the oily secretions of the skin deposited onto the fur and obtained orally during grooming.Sam D. Stout Sabrina C. Agarwal Stout Samuel D. Bone loss and osteoporosis: an anthropological perspective Kluwer Academic/Plenum Publishers New York 2003 0-306-47767-X In 1923, it was established that when 7-Dehydrocholesterol|7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced. Alfred Fabian Hess showed that "light equals vitamin D".UNRAVELING THE ENIGMA OF VITAMIN D U.S. National Academy of Sciences Adolf Otto Reinhold Windaus|Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928, for his work on the constitution of sterols and their connection with vitamins.http://nobelprize.org/nobel_prizes/chemistry/laureates/1928/windaus-bio.html Windaus biography at Nobelprize.org 1959-06-09 2010-03-25 In the 1930s he clarified further the chemical structure of vitamin D. Human cultures can play a big role in determining sun exposure in their Vitamin D level. For example, Women and children living in Kabul, Afghanistan as well as immigrants in the Netherlands have been limited outdoor time and wear clothing that cover their hands, face, and legs. Manaseki-Holland, S. et al., 2008. Vitamin D status of socio-economically deprived children in Kabul, Afghanistan. International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Für Vitamin- Und Ernährungsforschung. Journal International De Vitaminologie Et De Nutrition, 78(1), 16-20. Stellinga-Boelen, A.A.M. et al., 2007. Vitamin D levels in children of asylum seekers in The Netherlands in relation to season and dietary intake. European Journal of Pediatrics, 166(3), 201-206. Synthesis mechanism (form 3) photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is previtamin D3|pre-vitamin D3.400px Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 in a antarafacial hydride [1,7] Sigmatropic shift. At room temperature the transformation of previtamin-D3 to vitamin D3 takes about 12 days to complete.400px Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes. This hydroxylation reaction occurs in the endoplasmic reticulum and requires NADPH, O2 and Mg2+ yet it is not a cytochrome P450 enzyme. Once made the product is stored in the hepatocytes until it is needed and then can be released into the plasma where it will be bound to an α-globulin. 25-hydroxycholecalciferol is then transported to the proximal tubules of the kidneys where it can be hydroxylated by one of two enzymes to different forms of vitamin D, one of which is active vitamin D (1,25-OH D) and another which is inactive vitamin D (24,25-OH D). The enzyme 1α-hydroxylase which is activated by parathyroid hormone (and additionally by low calcium or phosphate) forms the main biologically active vitamin D hormone with a C1 hydroxylation forming 1,25-dihydroxycholecalciferol (1,25(OH)2D3, also known as calcitriol). A separate enzyme hydroxylates the C24 atom forming 24R,25(OH)2D3 when 1α-hydroxylase is not active, this inactivates the molecule from any biological activity. Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end).400px Mechanism of action Following the final converting step in the kidney, calcitriol (the physiologically active form of vitamin D) is released into the circulation. By binding to vitamin D-binding protein (VDBP), a carrier protein in the blood plasma|plasma, calcitriol is transported to various target organs. Calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the Cell nucleus|nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The vitamin D receptor belongs to the nuclear receptor superfamily of steroid hormone receptor|steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organ (biology)|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 calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.15585788 2004 Holick MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease 80 6 Suppl 1678S–88S The American journal of clinical nutrition The VDR is known to be involved in cell proliferation and cellular differentiation|differentiation. Vitamin D also #Role in immunomodulation|affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T cell|T and B cells.Vitamin D The Physicians Desk Reference. 2006 Thompson Healthcare. Apart from VDR activation, various alternative mechanisms of action are known. An important one of these is its role as a natural inhibitor of signal transduction by hedgehog signaling pathway|hedgehog (a hormone involved in morphogenesis).16895439 2006 Bijlsma MF Spek CA Zivkovic D Van De Water S Rezaee F Peppelenbosch MP Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion 4 8 e232 10.1371/journal.pbio.0040232 1502141 PLoS biologyhttp://www.medscape.com/viewarticle/713649_3 Hedgehog signaling and Vitamin D Medscape.com 2009-12-18 2010-03-25 Nutrition Vitamin D is naturally produced by the human body when exposed to direct sunlight. In many countries, such foods as milk, yogurt, margarine, Cooking oil|oil spreads, breakfast cereal, pastries, and bread are food fortification|fortified with vitamin D2 and/or vitamin D3.12149085 2002 Nowson CA Margerison C Vitamin D intake and vitamin D status of Australians 177 3 149–52 The Medical journal of Australia In the United States and Canada, for example, fortified milk typically provides 100 IU per cup (1 IU is the biological equivalent of 0.025 μg), or a quarter of the estimated adequate intake for adults over age 50.http://www.uvadvantage.org/portals/0/pres/ The Vitamin D Pandemic and its Health Consequences Holick Michael May 2007 34th European Symposium on Calcified Tissues Copenhagen 2010-03-29 In the United States (U.S.), typical diets provide about 100 IU/day. The NIH has set the safe upper limit at 2000 IU/day.http://ods.od.nih.gov/factsheets/vitamind.asp Dietary Supplement Fact Sheet: Vitamin D Ods.od.nih.gov 2010-03-25http://www.iom.edu/Activities/Nutrition/DRIVitDCalcium.aspx Dietary Reference Intakes for Vitamin D and Calcium Iom.edu 2010-03-25 The optimal level of 25-hydroxyvitamin D vitamin D in adults is 75–80 nmol/l.Over and undernutrition: challenges and approaches 69 Proceedings of the Nutrition Society A study by Semira Manaseki-Holland, M. Zulf Mughal, Zulfiqar Bhutta and M. Qasem Shams showed that in developing countries such as Iran, Saudi Arabia, India, China, And Syria children are low on Vitamin D. This is due to lack of fish, eggs , and liver in their diet and a general lack of access to diverse foods. Manaseki-Holland, S. et al., 2008. Vitamin D status of socio-economically deprived children in Kabul, Afghanistan. International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Für Vitamin- Und Ernährungsforschung. Journal International De Vitaminologie Et De Nutrition, 78(1), 16-20. A study showed that the top food sources of vitamin D for Asian women was meat, cereals and eggs. The top food sources of vitamin D in Caucasian women is meat, fish and cereals. The study showed that Caucasian women had a higher overall vitamin D intake. Relative contributions of different food groups to vitamin D intake in Asian and Caucasian UK women: results from the Vitamin D 69 Proceedings of the Nutrition Society Natural sources thumb|Fatty fish, such as salmon, are natural sources of vitamin D. Natural sources of vitamin D include: Fatty fish species, such as: Catfish, 85 g (3 oz) provides 425 IU Salmon, cooked, 100 g (3.5 oz) provides 360 IU Mackerel, cooked, 100 g (3.5 oz), 345 IU Sardines, canned in oil, drained, 50 g (1.75 oz), 250 IU Tuna, canned in oil, 100 g (3.5 oz), 235 IU Eel, cooked, 100 g (3.5 oz), 200 IU A whole egg (food)|egg, provides 20 IU Beef liver, cooked, 100 g (3.5 oz), provides 15 IU Fish liver oils, such as cod liver oil, 1 Tablespoon|Tbs. (15 ml) provides 1,360 IU Mushrooms are the only vegan source of vitamin D. (after UV light or sunlight exposure)http://articles.latimes.com/2008/mar/31/health/he-eat31 If mushrooms see the light — Los Angeles Times Articles.latimes.com 2008-03-31 2010-03-2519281276 2009 Koyyalamudi SR Jeong SC Song CH Cho KY Pang G Vitamin D2 formation and bioavailability from Agaricus bisporus button mushrooms treated with ultraviolet irradiation 57 8 3351–5 10.1021/jf803908q Journal of agricultural and food chemistry Measuring vitamin D status A blood calcidiol (25-hydroxy-vitamin D) level is a satisfactory way to determine the cumulative effect of sun and diet in relation to vitamin DStanding Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride(1997)., . page 235 although serum 25(OH)D levels do not indicate the amount of vitamin D stored in other body tissues.18689406 2008 Jones G Pharmacokinetics of vitamin D toxicity 88 2 582S–586S The American journal of clinical nutrition In overweight persons increased fat mass is inversely associated with 25OHD levels.16027959 2005 Lucas JA Bolland MJ Grey AB Ames RW Mason BH Horne AM Gamble GD Reid IR Determinants of vitamin D status in older women living in a subtropical climate. 16 12 1641–8 10.1007/s00198-005-1888-2 Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA16932872 2006 Bolland MJ Grey AB Ames RW Mason BH Horne AM Gamble GD Reid IR Determinants of vitamin D status in older men living in a subtropical climate. 17 12 1742–8 10.1007/s00198-006-0190-2 Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA This association may confound the reported relationships between low vitamin D status and conditions which occur more commonly in obesity11434789 2001 Field AE Coakley EH Must A Spadano JL Laird N Dietz WH Rimm E Colditz GA Impact of overweight on the risk of developing common chronic diseases during a 10-year period. 161 13 1581–6 Archives of internal medicine 10.1001/archinte.161.13.1581 as the circulating 25(OH)D underestimates their total body stores.10966885 2000 Wortsman J Matsuoka LY Chen TC Lu Z Holick MF Decreased bioavailability of vitamin D in obesity. 72 3 690–3 The American journal of clinical nutrition A concentration of over 15 ng/ml (>37.5 nmol/L) is recommended.April 2010 Higher levels (>30 ng/ml or >75 nmol/L) are proposed by some as desirable for achieving optimum health but there is not enough evidence to support them.Scientific Advisory Committee on Nutrition (2007) Update on Vitamin D Position Statement by the Scientific Advisory Committee on Nutrition 2007 Office of Dietary Supplements • National Institutes of Health Dietary Supplement Fact Sheet: Vitamin D 20194237 2010 Pittas AG Chung M Trikalinos T Mitri J Brendel M Patel K Lichtenstein AH Lau J Balk EM Systematic review: Vitamin D and cardiometabolic outcomes 152 5 307–14 10.1059/0003-4819-152-5-201003020-00009 Annals of internal medicine 2010-03-2520194238 2010 Wang L Manson JE Song Y Sesso HD Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events 152 5 315–23 10.1059/0003-4819-152-5-201003020-00010 Annals of internal medicine 2010-03-25 A study of highly sun exposed (tanned) heathy young skateboarders and surfers in Hawaii found levels below the proposed higher minimum of 30 ng/ml in 51% of the subjects. The highest 25(OH)D concentration was around 60 ng/ml (150nmol/L).17426097 2007 Binkley N Novotny R Krueger D Kawahara T Daida YG Lensmeyer G Hollis BW Drezner MK Low vitamin D status despite abundant sun exposure 92 6 2130–5 10.1210/jc.2006-2250 The Journal of clinical endocrinology and metabolism A similar <using the same data> study in Hawaii found a range of (11–71 ng/mL) in a population with prolonged extensive skin exposure while as part of the same study Wisconsin breastfeeding mothers were given supplements. The range of circulating 25(OH)D levels in women in the supplementated group was from 12–77 ng/mL. It is noteworthy that the levels in the supplemented population in Wisconsin were higher than the sun exposed group in Hawaii (which again included surfers because it was the same data set).17218096 2007 Hollis BW Wagner CL Drezner MK Binkley NC Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. 103 3-5 631–4 10.1016/j.jsbmb.2006.12.066 1868557 The Journal of steroid biochemistry and molecular biology Vitamin D toxicity is usually the result of taking supplements in excess, when toxic symptoms occur the serum 25(OH)D levels are usually found to be elevated >150 ng/mL (>375 nmol/L). Vitamin D at Merck Manual of Diagnosis and Therapy Professional Edition] Deficiency Wikipedia:Hypovitaminosis D Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun although it is also found in those with abundant exposure to bright sunlight.18234141 2008 Schoenmakers I Goldberg GR Prentice A Abundant sunshine and vitamin D deficiency 99 6 1171–3 10.1017/S0007114508898662 2758994 The British journal of nutrition Deficiency results in impaired bone mineralization, and leads to bone softening diseases15989379 2005 Grant WB Holick MF Benefits and requirements of vitamin D for optimal health: a review 10 2 94–111 Alternative medicine review including: Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones which can be caused by calcium or phosphorus deficiency as well as a lack of vitamin D; today it is largely found in low income countries in Africa, Asia or the Middle East17943890 2007 Lerch C Meissner T Interventions for the prevention of nutritional rickets in term born children 4 CD006164 10.1002/14651858.CD006164.pub2 Cochrane database of systematic reviews (Online) Lerch Christian and in those with genetic disorders such as pseudovitamin D deficiency rickets.10.1136/pmj.76.896.369 Pseudovitamin D deficiency rickets---a report from the Indian subcontinent 2000 Zargar A. H. Postgraduate Medical Journal 76 369 10824056 Mithal A Wani AI Laway BA Masoodi SR Bashir MI Ganie MA 896 1741602 Rickets was first described in 1650 by Francis Glisson who said it had first appeared about 30 years previously in the counties of Dorset and Somerset.7503834 1994 Gibbs D Rickets and the crippled child: an historical perspective 87 12 729–32 1294978 Journal of the Royal Society of Medicine In 1857 John Snow (physician)|John Snow suggested the rickets then widespread in Britain was being caused by the adulteration of bakers bread with alum.12777415 2003 Dunnigan M Commentary: John Snow and alum-induced rickets from adulterated London bread: an overlooked contribution to metabolic bone disease 32 3 340–1 International journal of epidemiology 10.1093/ije/dyg160 The role of diet in the development of rickets10.1016/0003-9861(55)90106-5 The role of vitamin D and intestinal phytase in the prevention of rickets in rats on cereal diets*1 1955 Pileggi V Archives of Biochemistry and Biophysics 58 194 13259690 De Luca HF Steenbock H 15069221 1972 Ford JA Colhoun EM McIntosh WB Dunnigan MG Biochemical response of late rickets and osteomalacia to a chupatty-free diet 3 5824 446–7 1786011 British medical journal 10.1136/bmj.3.5824.446 was determined by Edward Mellanby between 1918–1920.12897318 2003 Rajakumar K Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective 112 2 e132–5 Pediatrics 10.1542/peds.112.2.e132 Nutritional rickets exists in countries with intense year round sunlight such as Nigeria and can occur without vitamin D deficiency.18197991 2008 Oramasionwu GE Thacher TD Pam SD Pettifor JM Abrams SA Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children 100 2 387–92 10.1017/S0007114507901233 The British journal of nutrition10584471 1999 Fischer PR Rahman A Cimma JP Kyaw-Myint TO Kabir AR Talukder K Hassan N Manaster BJ Staab DB Nutritional rickets without vitamin D deficiency in Bangladesh 45 5 291–3 Journal of tropical pediatrics 10.1093/tropej/45.5.291 Although rickets and osteomalacia are now rare in Britain there have been outbreaks in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing.9483661 1997 Dunnigan MG Henderson JB An epidemiological model of privational rickets and osteomalacia. 56 3 939–56 The Proceedings of the Nutrition Society Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals.6970590 1981 Robertson I Ford JA McIntosh WB Dunnigan MG The role of cereals in the aetiology of nutritional rickets: the lesson of the Irish National Nutrition Survey 1943-8 45 1 17–22 The British journal of nutrition 10.1079/BJN1981007310.1111/j.1365-277X.1989.tb00015.x15585795 2004 Pettifor JM Nutritional rickets: deficiency of vitamin D, calcium, or both? 80 6 Suppl 1725S–9S The American journal of clinical nutrition The dietary risk factors for rickets include abstaining from animal foods.9483661 1997 Dunnigan MG Henderson JB An epidemiological model of privational rickets and osteomalacia 56 3 939–56 The Proceedings of the Nutrition Society10.1079/BJN20051558 Vitamin D deficiency remains the main cause of rickets among young infants in most countries, because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate UVB exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh where the disease occurs among older toddlers and children it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products.15585795 2004 Pettifor JM Nutritional rickets: deficiency of vitamin D, calcium, or both? 80 6 Suppl 1725S–9S The American journal of clinical nutrition Rickets was formerly a major public health problem among the US population; in Denver where ultraviolet rays are approximately 20% stronger than at sea level on the same latitudeUS National Institutes Of Health, National cancer Institute almost two thirds of 500 children had mild rickets in the late 1920s.4862158 1967 Weick MT A history of rickets in the United States 20 11 1234–41 The American journal of clinical nutrition An increase in the proportion of animal proteinGarrison, R., Jr., Somer, E., The nutrition desk reference(1997) in the 20th century American diet coupled with increased consumption of milkE. Melanie DuPuis., Nature's Perfect Food: How Milk Became America's Drink(2002) 10232644 1999 Teegarden D Lyle RM Proulx WR Johnston CC Weaver CM Previous milk consumption is associated with greater bone density in young women 69 5 1014–7 The American journal of clinical nutrition fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain,12520530 2003 Holick MF Vitamin D: A millenium perspective 88 2 296–307 10.1002/jcb.10338 Journal of cellular biochemistryStewart B. Leavitt http://pain-topics.org/pdf/vitamind-report.pdf Vitamin D – A Neglected ‘Analgesic’ for Chronic Musculoskeletal Pain Pain-Topics.org 2009-03-25 there is no persuasive evidence of lower vitamin D status in chronic pain sufferers.19084336 2009 Straube S Andrew Moore R Derry S McQuay HJ Vitamin D and chronic pain 141 1-2 10–3 10.1016/j.pain.2008.11.010 Pain There are associations between low 25(OH)D levels and a very wide range of diseases,18417640 2008 Melamed ML Muntner P Michos ED Uribarri J Weber C Sharma J Raggi P Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004 28 6 1179–85 10.1161/ATVBAHA.108.165886 2705139 Arteriosclerosis, thrombosis, and vascular biology including several autoimmune diseases.17990825 2007 Tavera-Mendoza LE White JH Cell defenses and the sunshine vitamin 297 5 62–5, 68–70, 72 Scientific American 10.1038/scientificamerican1107-6218852350 2008 Evatt ML Delong MR Khazai N Rosen A Triche S Tangpricha V Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease 65 10 1348–52 10.1001/archneur.65.10.1348 2746037 Archives of neurology However such associations were found in observational studies and are not conclusive evidence of a causal link (see correlation does not imply causation); a systemic review found no effect of vitamin D supplements. One leadingHolick., M., The Vitamin D Solution: A 3- Step Strategy to Cure Our Most Common Health Problem (2010) proponent of the view that the optimal concentration of 25(OH)D is at least 30 ng/ml10.1016/j.jacc.2008.08.050 Vitamin D DeficiencyAn Important, Common, and Easily Treatable Cardiovascular Risk Factor? 2008 Lee J Okeefe J Bell D Hensrud D Holick M Journal of the American College of Cardiology 52 1949 19055985 24 defines vitamin D deficiency as a 25(OH)D level of under 20 ng/ml (50 nmol/l); applying this criterion he regards 30% to 50% of the United States population as suffering from vitamin D deficiency.10.1016/j.jacc.2009.02.031 Reply 2009 O'Keefe James H. Lee John H. Bell David S. H. Holick Michael F. Journal of the American College of Cardiology 53 2012 This includes areas with abundant sun exposure, such as Hawaii and southern Arizona, where over 50% of inhabitants have 25(OH)D level of under 20 ng/ml.18326598 2008 Jacobs ET Alberts DS Foote JA Green SB Hollis BW Yu Z Martínez ME Vitamin D insufficiency in southern Arizona 87 3 608–13 The American journal of clinical nutrition10.1210/jc.2006-2250 Low Vitamin D Status despite Abundant Sun Exposure 2007 Binkley N. Novotny R. Krueger D. Kawahara T. Daida Y. G. Lensmeyer G. Hollis B. W. Drezner M. K. Journal of Clinical Endocrinology & Metabolism 92 2130 Such metrics16825677 2006 Bischoff-Ferrari HA Giovannucci E Willett WC Dietrich T Dawson-Hughes B Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. 84 1 18–28 The American journal of clinical nutrition depart from more typical definitions of vitamin deficiency, which are based on prevention of overt deficiency symptoms or comparable biologic indicators.10.1016/j.jacc.2008.12.070 Vitamin D, Outdoor Happiness, and the Meaning of Deficiency 2009 Mozaffarian Dariush Journal of the American College of Cardiology 53 2011 Still higher levels are advocated by some. It is hypothesized that as humans live today, 25-Hydroxyvitamin D3 1-alpha-hydroxylase operates well below its V(max) because of 'chronic substrate deficiency' and the definitions of “sufficient” includes the criterion that parathyroid hormone levels be not lowered further by increasing 25(OH)D levels. According to this school of thought optimal nutritional vitamin D status is achieved when circulating 25(OH)D exceeded 40 ng/mL (100 nmol/L) However, no study has demonstrated a health benefit for the suggested goal of minimizing PTH levels in normal individuals.10.1038/jid.2009.353 Toxicity Wikipedia hypervitaminosis D In healthy adults, sustained intake of 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months;Vitamin D. The Merck Manuals Vitamin D those with certain medical conditions are far more sensitive to vitamin D and develop hypercalcaemia in response to any increase in vitamin D nutrition, while maternal hypercalcaemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities. European Food and Safety authority., Tolerable Upper Intake Limits for Vitamins And Minerals(2006) Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. For infants (birth to 12 months) the tolerable Upper Limit (maximum amount that can be tolerated without harm) is set at 25 micrograms/day (1000 IU). 1000 micrograms/day (40,000 IU) in infants has produced toxicity within 1 month.01 004 k BABBBEAE Vitamin D The U.S. Dietary Reference Intake Tolerable Upper Intake Level (upper limit) of vitamin D for children and adults is set at 50 micrograms/day (2,000 IU). Vitamin D overdose causes hypercalcemia and the main symptoms of vitamin D overdose are those of hypercalcemia: anorexia, nausea, and vomiting can occur, frequently followed by polyuria, polydipsia, weakness, nervousness, pruritus, and ultimately, renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop.Vitamin D - Toxicity at Merck Manual of Diagnosis and Therapy Professional Edition Vitamin D toxicity is treated by discontinuing vitamin D supplementation and restricting calcium intake. Kidney damage may be irreversible. Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.Vieth R Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety The American Journal of Clinical Nutrition 69 5 842–56 1999 May 10232622 http://www.ajcn.org/cgi/content/full/69/5/842 This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentrations of vitamin D precursors produced in the skin reach an Chemical equilibrium|equilibrium, and any further vitamin D that is produced is degraded.Holick MF Environmental factors that influence the cutaneous production of vitamin D The American Journal of Clinical Nutrition 61 3 Suppl 638S–645S 1995 March 7879731 http://www.ajcn.org/cgi/reprint/61/3/638S According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day. According to Holick, "the skin has a large capacity to produce cholecalciferol"; his experiments indicate that "[W]hole-body exposure to one minimal erythemal dose of simulated solar ultraviolet radiation is comparable with taking an oral dose of between 250 and 625 micrograms (10 000 and 25 000 IU) vitamin D." The similar effect of supplementation and whole body exposure to one erythemal dose prompted a researcher Hathcock JN, Shao A, Vieth R, Heaney R Risk assessment for vitamin D The American Journal of Clinical Nutrition 85 1 6–18 2007 January 17209171 http://www.ajcn.org/cgi/content/full/85/1/6 to suggest that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit. Supplements and skin synthesis have a different effect on serum 25(OH)D concentrations; endogenously synthesized vitamin D3 travels in plasma almost exclusively on vitamin D-binding protein (VDBP), providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol. Orally administered vitamin D produces swift hepatic delivery and increases in plasma 25-hydroxycholecalciferol. The richest food source of vitamin D — wild salmon — would require 35 ounces a day to provide 10,000IU.Lu Z, Chen TC, Zhang A, et al. An evaluation of the vitamin D3 content in fish: Is the vitamin D content adequate to satisfy the dietary requirement for vitamin D? The Journal of Steroid Biochemistry and Molecular Biology 103 3-5 642–4 2007 March 17267210 2698592 10.1016/j.jsbmb.2006.12.010 Recommending supplementation, when those supposedly in need of it are labeled healthy, has proved contentious, and doubt exists concerning long term effects of attaining and maintaining serum 25(OH)D of at least 80nmol/L by supplementation.Lisa Tseng 2003 Controversies in Vitamin D Supplementation Nutrition Bytes 9 1 http://escholarship.org/uc/item/4m84d4fn A Toronto study concluded, "skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D". The uniform occurrence of low serum 25(OH)D in Indians living in India.19753759 2009 Harinarayan CV Joshi SR Vitamin D status in India--its implications and remedial measures. 57 40–8 The Journal of the Association of Physicians of India and Chinese in China,20197091 2010 Lips P Worldwide status of vitamin D nutrition. 10.1016/j.jsbmb.2010.02.021 The Journal of steroid biochemistry and molecular biology does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes; the leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless, saying, "I see no risk, no downside, there's only a potential benefit".CBC Dark-skinned immigrants urged to take vitamin D Tuesday, February 16, 2010 CBC newsSTEPHEN STRAUSS: SCIENCE FRICTION The vitamin D debate Feb. 13, 2008 CBC Analysis and viewpoint Whether the toxicity of oral intake of vitamin D is due to that route being unnatural, as suggested by Fraser,Haddad JG, Matsuoka LY, Hollis BW, Hu YZ, Wortsman J Human plasma transport of vitamin D after its endogenous synthesis The Journal of Clinical Investigation 91 6 2552–5 1993 June 8390483 443317 10.1172/JCI116492 is not known, but there is evidence to suggest that dietary vitamin D may be carried by lipoprotein particlesSpeeckaert MM, Taes YE, De Buyzere ML, Christophe AB, Kaufman JM, Delanghe JR Investigation of the potential association of vitamin D binding protein with lipoproteins Annals of Clinical Biochemistry 47 2 143–50 2010 March 20144976 10.1258/acb.2009.009018 into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages.Hsu JJ, Tintut Y, Demer LL Vitamin D and osteogenic differentiation in the artery wall Clinical Journal of the American Society of Nephrology 3 5 1542–7 2008 September 18562594 10.2215/CJN.01220308 These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Health effects Immune system VDR ligands have been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages. Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi.Janet Raloff, The Antibiotic Vitamin Science News, Vol 170, November 11, 2006, pages 312-31717463418 2007 Martineau AR Wilkinson RJ Wilkinson KA Newton SM Kampmann B Hall BM Packe GE Davidson RN Eldridge SM A single dose of vitamin D enhances immunity to mycobacteria. 176 2 208–13 10.1164/rccm.200701-007OC American journal of respiratory and critical care medicine9269215 1997 Muhe L Lulseged S Mason KE Simoes EA Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. 349 9068 1801–4 10.1016/S0140-6736(96)12098-5 Lancet Suggestions of a link between Vitamin D and the onset of multiple sclerosis posited that this is due to the immune-response suppression properties of Vitamin D17179460 2006 Munger KL Levin LI Hollis BW Howard NS Ascherio A Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. 296 23 2832–8 10.1001/jama.296.23.2832 JAMA and that vitamin D is required to activate a histocompatibility gene (HLA-DRB1*1501) necessary for differentiating between self and foreign proteins in a subgroup of individuals genetically predisposed to MS.http://www.sciencenews.org/view/generic/id/40626/title/Molecular_link_between_vitamin__D_deficiency_and_MS Science News / Molecular Link Between Vitamin D Deficiency And MS 2009-02-25 Whether vitamin D supplements during pregnancy can lessen the likelihood of the child developing MS later in life is not known;http://news.bbc.co.uk/2/hi/health/7871598.stm Vitamin D helps control MS gene BBC News 5 February 2009 2010-03-25http://www.mssociety.ca/en/research/medmmo_20090205.htm Genetic Study Supports Vitamin D Deficiency as an Environmental Factor in MS Susceptibility. Multiple Sclerosis Society of Canada. 5 February 2009 Mssociety.ca 2010-03-25 however, vitamin D fortification has been suggested to have caused a pandemic of allergic disease20016691 2009 Wjst M Introduction of oral vitamin D supplementation and the rise of the allergy pandemic. 5 1 8 10.1186/1710-1492-5-8 2794851 Allergy, asthma, and clinical immunology and an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life has been found .15699498 2004 Hyppönen E Sovio U Wjst M Patel S Pekkanen J Hartikainen AL Järvelinb MR Infant vitamin d supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966 1037 84–95 10.1196/annals.1337.013 Annals of the New York Academy of Sciences Veteran vitamin D researcher Hector DeLuca has cast doubt on whether vitamin D affects MS.10.1073/pnas.1001119107 UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production 2010 Becklund B. R. Severson K. S. Vang S. V. Deluca H. F. Proceedings of the National Academy of Sciences 107 6418 Influenza Lack of vitamin D synthesis is a possible explanation for high rates of influenza infection during winter; however, see flu season for the factors apart from vitamin D that are also hypothesized to influence rates of infection during winter. Influenza virus transmission is dependent on relative humidity and temperature Anice C. Lowen Mubareka, Samira; Steel, John; Palese, Peter PLoS Pathogens 3 10 e151 http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0030151&ct=1 10.1371/journal.ppat.0030151 2007 Cancer The molecular basis for thinking vitamin D has the potential to prevent cancer lies in its role in a wide range of cellular mechanisms central to the development of cancer.18034918 2008 Ingraham BA Bragdon B Nohe A Molecular basis of the potential of vitamin D to prevent cancer 24 1 139–49 10.1185/030079908X253519 Current medical research and opinion These effects may be mediated through vitamin D receptors expressed in cancer cells. Polymorphism (biology)|Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an increased risk of breast cancer.14749534 2003 Buyru N Tezol A Yosunkaya-Fenerci E Dalay N Vitamin D receptor gene polymorphisms in breast cancer 35 6 550–5 Experimental & molecular medicine Women with mutations in the VDR gene had an increased risk of breast cancer.Chen WY, Bertone-Johnson ER, Hunter DJ, Walter Willett|Willett WC, Hankinson SE. Associations Between Polymorphisms in the Vitamin D Receptor and Breast Cancer Risk. Cancer Epidemiology, Biomarkers, & Prevention. 2005; 14(10):2335-2339. A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked increase in some cancer risks in countries with less sun and another Meta-analysis|metastudy found correlations between vitamin D levels and cancer. The authors suggested that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast cancer|breast and ovarian cancer risks by 30%.16380576 2006 Garland CF Garland FC Gorham ED Lipkin M Newmark H Mohr SB Holick MF The role of vitamin D in cancer prevention 96 2 252–61 10.2105/AJPH.2004.045260 1470481 American journal of public healthhttp://news.bbc.co.uk/2/hi/health/4563336.stm Vitamin D 'can lower cancer risk' BBC News 28 December 2005 2006-03-2317296473 2007 Gorham ED Garland CF Garland FC Grant WB Mohr SB Lipkin M Newmark HL Giovannucci E Wei M Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis 32 3 210–6 10.1016/j.amepre.2006.11.004 American journal of preventive medicine17169713 2006 Garland CF Mohr SB Gorham ED Grant WB Garland FC Role of ultraviolet B irradiance and vitamin D in prevention of ovarian cancer 31 6 512–4 10.1016/j.amepre.2006.08.018 American journal of preventive medicine Low levels of vitamin D in serum have been correlated with breast cancer disease progression and bone metastases. However, the vitamin D levels of a population do not depend on the solar irradiance to which they are exposed.18458986 2009 Hagenau T Vest R Gissel TN Poulsen CS Erlandsen M Mosekilde L Vestergaard P Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. 20 1 133–40 10.1007/s00198-008-0626-y Osteoporosis international18593774 2008 Engelman CD Fingerlin TE Langefeld CD Hicks PJ Rich SS Wagenknecht LE Bowden DW Norris JM Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. 93 9 3381–8 10.1210/jc.2007-2702 2567851 The Journal of clinical endocrinology and metabolism19926773 2010 Borges CR Rehder DS Jarvis JW Schaab MR Oran PE Nelson RW Full-length characterization of proteins in human populations. 56 2 202–11 10.1373/clinchem.2009.134858 Clinical chemistry20219959 2010 Millen AE Wactawski-Wende J Pettinger M Melamed ML Tylavsky FA Liu S Robbins J Lacroix AZ Leboff MS Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women's Health Initiative Calcium plus Vitamin D Clinical Trial 10.3945/ajcn.2009.28908 The American journal of clinical nutrition Moreover there are genetic factors involved with cancer incidence and mortality which are more common in northern latitudes.19214504 2009 Helgadottir H Andersson E Villabona L Kanter L Van Der Zanden H Haasnoot GW Seliger B Bergfeldt K Hansson J The common Scandinavian human leucocyte antigen ancestral haplotype 62.1 as prognostic factor in patients with advanced malignant melanoma. 58 10 1599–608 10.1007/s00262-009-0669-8 Cancer immunology, immunotherapy : CII15034213 2004 De Petris L Bergfeldt K Hising C Lundqvist A Tholander B Pisa P Van Der Zanden HG Masucci G Correlation between HLA-A2 gene frequency, latitude, ovarian and prostate cancer mortality rates. 21 1 49–52 10.1385/MO:21:1:49 Medical oncology (Northwood, London, England) A 2006 study found that taking the U.S. RDA of vitamin D (400 IU per day) cut the risk of pancreatic cancer by 43% in a sample of more than 120,000 people from two long-term health surveys.16985031 2006 Skinner HG Michaud DS Giovannucci E Willett WC Colditz GA Fuchs CS Vitamin D intake and the risk for pancreatic cancer in two cohort studies 15 9 1688–95 10.1158/1055-9965.EPI-06-0206 Cancer epidemiology, biomarkers & preventionhttp://news.bbc.co.uk/2/hi/health/5334534.stm Health | Vitamin D 'slashes cancer risk' BBC News 2006-09-15 2010-03-25 However, in male smokers a 3-fold increased risk for pancreatic cancer in the highest compared to lowest quintile of serum 25-hydroxyvitamin D concentration has been found.10.1158/0008-5472.CAN-06-1876 A Prospective Nested Case-Control Study of Vitamin D Status and Pancreatic Cancer Risk in Male Smokers 2006 Stolzenberg-Solomon R. Z. Vieth R. Azad A. Pietinen P. Taylor P. R. Virtamo J. Albanes D. Cancer Research 66 10213 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). Martin Mittelstaedt http://www.theglobeandmail.com/life/article756975.ece Vitamin D casts cancer prevention in new light Global and Mail 28 April 2007 2007-04-28 http://web.archive.org/web/20090622092244/http://www.theglobeandmail.com/life/article756975.ece 2009-06-2217556697 2007 Lappe JM Travers-Gustafson D Davies KM Recker RR Heaney RP Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial 85 6 1586–91 The American journal of clinical nutrition Although the study was criticized on several grounds18065602 2007 Ojha RP Felini MJ Fischbach LA Vitamin D for cancer prevention: valid assertion or premature anointment? 86 6 1804–5; author reply 1805–6 The American journal of clinical nutrition including failing to take into account a long term overall increase in cancer found in a another study of vitamin D intake17549593 2007 Robien K Cutler GJ Lazovich D Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women's Health Study 18 7 775–82 10.1007/s10552-007-9020-x Cancer causes & control in 2007 the Canadian Cancer Society, (a national community-based organization of volunteers) recommended that all adults begin taking 1,000 IU per day (five times more than the government says they need) .http://www.cancer.ca/ontario/about%20us/media%20centre/od-media%20releases/canadian%20cancer%20society%20announces%20vitamin%20d%20recommendation.aspx?sc_lang=en Canadian Cancer Society announces Vitamin D recommendation, 08 June 2007 Cancer.ca 2010-03-25http://montreal.ctv.ca/servlet/an/plocal/CTVNews/20070608/cancer_recommendations_070608/20070608/?hub=MontrealHome/canadian%20cancer%20society%20announces%20vitamin%20d%20recommendation.aspx?sc_lang=en Canadian Cancer Society recommends vitamin D. CTV.ca News Staff Montreal.ctv.ca 2010-03-25 A US National Cancer Institute study analyzed data from the third national Health and Nutrition Examination Survey to examine the relationship between levels of circulating vitamin D in the blood and cancer mortality in a group of 16,818 participants aged 17 and older. It found no support for an association between 25(OH)D and total cancer mortality.17971526 2007 Freedman DM Looker AC Chang SC Graubard BI Prospective study of serum vitamin D and cancer mortality in the United States 99 21 1594–602 10.1093/jnci/djm204 Journal of the National Cancer Institute Unlike other studies, this one was carried out prospective cohort study|prospectively, meaning that participants were followed looking forward, and the researchers used actual blood tests to measure the amount of vitamin D in blood, rather than trying to infer vitamin D levels from potentially inaccurate predictive models.10.1093/jnci/djm235 Study Finds No Connection between Vitamin D and Overall Cancer Deaths 2007 Savage L. Widener A. JNCI Journal of the National Cancer Institute 99 1561 Cardiovascular disease A report from the National Health and Nutrition Examination Survey (NHANES) involving nearly 5,000 participants found that low levels of vitamin D were associated with an increased risk of peripheral artery disease (PAD). The incidence of PAD was 80% higher in participants with the lowest vitamin D levels (<17.8 ng/mL). Cholesterol levels were found to be reduced in gardeners in the UK during the summer months.8935479 1996 Grimes DS Hindle E Dyer T Sunlight, cholesterol and coronary heart disease. 89 8 579–89 QJM Low levels of vitamin D are associated with an increase in high blood pressure and cardiovascular risk. Numerous observational study|observational studies show this link, but of two systemic reviews one found only weak evidence of benefit from supplements and the other found no evidence of a beneficial effect whatsoever.20194237 2010 Pittas AG Chung M Trikalinos T Mitri J Brendel M Patel K Lichtenstein AH Lau J Balk EM Systematic review: Vitamin D and cardiometabolic outcomes. 152 5 307–14 10.1059/0003-4819-152-5-201003020-00009 Annals of internal medicine 2010-03-2520194238 2010 Wang L Manson JE Song Y Sesso HD Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. 152 5 315–23 10.1059/0003-4819-152-5-201003020-00010 Annals of internal medicine 2010-03-2519476421 2009 Nemerovski CW Dorsch MP Simpson RU Bone HG Aaronson KD Bleske BE Vitamin D and cardiovascular disease. 29 6 691–708 10.1592/phco.29.6.691 Pharmacotherapy There is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Calcifediol (25-hydroxy-vitamin D) is implicated in the etiology of atherosclerosis, especially in non-Caucasians.11949730 2001 Rajasree S Rajpal K Kartha CC Sarma PS Kutty VR Iyer CS Girija G Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease. 17 6 567–71 European journal of epidemiology 10.1023/A:101455960004210.1210/jc.2009-1797 Vitamin D, Adiposity, and Calcified Atherosclerotic Plaque in African-Americans 2010 Freedman BI Wagenknecht LE Hairston KG Bowden DW Carr JJ Hightower RC Gordon EJ Xu J Langefeld CD Journal of Clinical Endocrinology & Metabolism 95 1076 Freedman et al. (2010) have found that serum vitamin D correlates in African Americans, but not in Euro-Americans, with calcified atheroscleratic plaque. "Higher levels of 25-hydroxyvitamin D seem to be positively correlated with aorta and carotid CP in African Americans but not with coronary CP. These results contradict what is observed in individuals of European descent".8740896 1995 Creemers PC Du Toit ED Kriel J DBP (vitamin D binding protein) and BF (properdin factor B) allele distribution in Namibian San and Khoi and in other South African populations. 9 3 185–9 Gene geography One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL. A review of vitamin D status in India concluded that studies uniformly point to low 25(OH)D levels in Indians despite abundant sunshine, and suggested a public health need to fortify Indian foods with vitamin D might exist.19753759 2009 Harinarayan CV Joshi SR Vitamin D status in India--its implications and remedial measures 57 40–8 The Journal of the Association of Physicians of India However the levels found in India are consistent with many other studies of tropical populations which have found that even an extreme amount of sun exposure, such as incured by rural Indians,19263699 2008 Goswami R Kochupillai N Gupta N Goswami D Singh N Dudha A Presence of 25(OH) D deficiency in a rural North Indian village despite abundant sunshine 56 755–7 The Journal of the Association of Physicians of India does not raise 25(OH)D levels to the levels typically found in Europeans,20197091 2010 Lips P Worldwide status of vitamin D nutrition 10.1016/j.jsbmb.2010.02.021 The Journal of steroid biochemistry and molecular biology10.1017/S0007114508898662 Abundant sunshine and vitamin D deficiency 2008 Schoenmakers I Goldberg GR Prentice Ann British Journal of Nutrition 99 Mortality Using information from the National Health and Nutrition Examination Survey a group of researchers 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.Melamed ML, Michos ED, Post W, Astor B 25-hydroxyvitamin D levels and the risk of mortality in the general population Archives of Internal Medicine 168 15 1629–37 2008 August 18695076 2677029 10.1001/archinte.168.15.1629 The study evaluated whether low serum vitamin D levels were associated 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. Shortening of leukocyte telomeres is a marker of aging. 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). Vitamin D can inhibit proinflammatory overeaction and slow the turnover of leukocytes, longer leukocyte telomere length is achieved by the body maintaining the optimal vitamin D concentration.Richards JB, Valdes AM, Gardner JP, et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women The American Journal of Clinical Nutrition 86 5 1420–5 2007 November 17991655 2196219 http://www.ajcn.org/cgi/content/full/86/5/1420 Complex regulatory mechanisms control metabolism, recent epidemiologic evidence suggests that there is a narrow range of vitamin D levels in which vascular function is optimized. Levels above or below this natural human homeostasis|homeostasis of vitamin D increase mortality. Overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.Tuohimaa P Vitamin D and aging The Journal of Steroid Biochemistry and Molecular Biology 114 1-2 78–84 2009 March 19444937 10.1016/j.jsbmb.2008.12.020Keisala T, Minasyan A, Lou YR, et al. Premature aging in vitamin D receptor mutant mice The Journal of Steroid Biochemistry and Molecular Biology 115 3-5 91–7 2009 July 19500727 10.1016/j.jsbmb.2009.03.007Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A Vitamin D, nervous system and aging Psychoneuroendocrinology 34 Suppl 1 S278–86 2009 December 19660871 10.1016/j.psyneuen.2009.07.003 Mental health Vitamin D deficiency may also play a role in depression and other psychological issues. Though some research has been conducted which indicates a relationship, much more research is needed in this area.Vitamin D CouncilWeb MD Vitamin D is involved in normal hair growth. Does D matter? The role of vitamin D in hair disorders and hair follicle cycling. Dermatol Online J. 2010 Feb 15;16(2). See also W:Mushrooms and Vitamin D W:Risks and benefits of sun exposure W:Vitamin D and influenza References External links Vitamin D Fact Sheet from the U.S. National Institutes of Health Vitamin D Caveat? (Conclusion regarding African Americans needing lower levels of vitamin D based on a single study which used a lab known for faulty measurements and directly contradicted by a larger and better controlled study ) Skepticism Grows Regarding Widespread Vitamin D Supplementation Vitamin D better than vaccines at preventing flu, report claims