Vitamin D deficiency

From Wikipedia, the free encyclopedia
  (Redirected from Hypovitaminosis D)
Jump to: navigation, search

Vitamin D deficiency, or hypovitaminosis D, most commonly results from inadequate sunlight exposure (in particular sunlight with adequate ultraviolet B rays).[1] Vitamin D deficiency can also be caused by inadequate nutritional intake of vitamin D, disorders limiting vitamin D absorption, and conditions impairing vitamin D conversion into active metabolites—including certain liver, kidney, and hereditary disorders.[2] Deficiency impairs bone mineralization, leading to bone softening diseases as rickets in children. It can also worsen osteomalacia and osteoporosis in adults, leading to an increased risk of bone fractures.[1][2] Muscle weakness is also a common symptom of vitamin D deficiency, further increasing the risk of fall and fracture in adults.[1] Ultraviolet B rays from sunlight is a large source of vitamin D. Salmon, herring, and mackerel, are also sources of Vitamin D. Milk is often fortified with vitamin D. Sometimes bread, juices, and other dairy products are fortified with vitamin D as well. Many multivitamins now contain vitamin D in different amounts.[1]

History[edit]

The role of diet in the development of rickets was determined by Edward Mellanby between 1918 and 1920.[3] In 1921, Elmer McCollum identified an antirachitic substance found in certain fats that could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D.[3] The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid 7-dehydrocholesterol, the precursor of vitamin D.

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 quart since the 1930s, leading to a dramatic decline in the number of rickets cases.[4]

Pathophysiology[edit]

Normal Synthesis of Vitamin D

Vitamin D deficiencies are often caused by decreased exposure of the skin to sunlight. People with a darker pigment of skin or increased amounts of melanin in their skin, may have decreased production of Vitamin D.[1] Melanin absorbs ultraviolet B radiation from the sun and reduces vitamin D production.[1] Sunscreen can also reduce vitamin D production.[1] Medications may speed up the metabolism of vitamin D, causing a deficiency.[1] Some types of liver diseases and kidney diseases can decrease vitamin D production leading to a deficiency.[1] The liver is required to transform vitamin D into 25-hydroxyvitamin D. This is an inactive metabolite of vitamin D but is a necessary precursor (building block) to create the active form of vitamin D.[5] In liver disease, the 25-hydroxyvitamin D may not be formed, leading to a vitamin D deficiency.[5] The kidneys are responsible for converting 25-hydroxyvitamin D to 1,25-hydroxyvitamin D.[5] This is the active form of vitamin D in the body. Kidney disease often prevents 1,25-hydroxyvitamin D from being formed, leading to a vitamin D deficiency.[5] Intestinal conditions that result in malabsorption of nutrients may also contribute to vitamin D deficiency by decreasing the amount of vitamin D absorbed via diet.[5] In addition, a vitamin D deficiency may lead to decreased absorption of calcium by the intestines, resulting in increased production of osteoclasts that may break down a person's bone matrix.[6] In states of hypocalcemia, calcium will leave the bones and may give rise to secondary hyperparathyroidism, which is a response by the body to increase serum calcium levels.[6] The body does this by increasing renal reabsorption of calcium and continuing to take calcium away from the bones.[6] If prolonged, this may lead to osteoporosis in adults and rickets in children.[6]

Classifications[edit]

Mapping of several bone diseases onto levels of vitamin D (calcidiol) in the blood[7]
Normal bone vs. Osteoporosis

Vitamin D deficiency is typically diagnosed by measuring the concentration of the 25-hydroxyvitamin D in the blood, which is the most accurate measure of vitamin D status.[8]

  • Deficiency: <20ng/mL
  • Insufficient: 20–29 ng/mL
  • Normal: 30–100 ng/mL

Vitamin D levels falling within this normal range both avoid clinical manifestations of vitamin D insufficiency as well as vitamin D toxicity from taking in too much vitamin D.[8]

Characteristics[edit]

Child with rickets

Vitamin D deficiency can be asymptomatic, but may also cause several problems including:

  • Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility.
  • Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility.
  • Increased risk of fracture[9][10]
  • Rickets, a childhood disease characterized by impeded growth and deformity of the long bones.[11] The earliest sign of subclinical vitamin D deficiency is craniotabes, abnormal softening or thinning of the skull.[12]
  • Muscle aches and weakness (in particular the limb girdles)[13]
  • Muscle twitching (fasciculations) is commonly seen due to reduced ionised calcium, arising from a low vitamin D.[14][15]
  • Light-headedness
  • Periodontitis, local inflammatory bone loss that can result in tooth loss.[16]
  • Pre-eclampsia: Vitamin D deficiency is correlated with the development of pre-eclampsia in pregnancy.[citation needed] Maternal vitamin D deficiency may affect the baby, causing overt bone disease from before birth and impairment of bone quality after birth.[11][17]
  • Depression: Hypovitaminosis D is a risk factor for depression. Some studies have found that low levels of vitamin D are correlated with depressed feelings and are found in patients who have been diagnosed with depression.[18]

Risk factors[edit]

Those most likely to be affected by vitamin D deficiency are people with little or exposure to sun light.[19] Climate, dress habits, avoiding sun exposure and too much sunscreen protection limit the production of vitamin D.[19]

Age[edit]

Elderly people have a higher risk having a vitamin D deficiency due to a combination of several risk factors, including: decreased sunlight exposure, decreased intake of vitamin D in the diet, and decreased skin thickness which leads to further decreased absorption of vitamin D from sunlight.[20]

Malnutrition[edit]

Although rickets and osteomalacia are now rare in Britain, osteomalacia outbreaks in some immigrant communities included women with seemingly adequate daylight outdoor exposure wearing Western clothing.[21] 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.[22][23][24] 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.[citation needed] In sunny countries, 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.[24] Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are about 20% stronger than at sea level on the same latitude,[25] almost two-thirds of 500 children had mild rickets in the late 1920s.[26] An increase in the proportion of animal protein in the 20th-century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases.[4][27][28]

Obesity[edit]

There is an increased risk of vitamin D deficiency in people who are considered overweight or obese based on their body mass index (BMI) measurement.[29] Obese individuals have lower levels of the circulating form of vitamin D, due to the likelihood of decreased bioavailability of vitamin D3 from food and sunlight due to the distribution in adipose tissue.[citation needed] Alternatively, vitamin D is fat-soluble therefore excess amounts can be stored in fat tissue and used during winter, when sun exposure is limited.[30]

Sun exposure[edit]

The use of sunscreen with a sun protection factor of 8 can theoretically inhibit more than 95% of vitamin D production in the skin.[4] In practice, however, sunscreen is applied so as to have a negligible effect on vitamin D status.[31] The vitamin D status of those in Australia and New Zealand is unlikely to have been affected by campaigns advocating sunscreen.[32] Instead, wearing clothing is more effective at reducing the amount of skin exposed to UVB and reducing natural vitamin D synthesis. Clothing which covers a large portion of the skin, when worn on a consistent and regular basis, such as the burqa, is correlated with lower vitamin D levels and an increased prevalence of hypovitaminosis D.[33]

Regions far from the equator have a high seasonal variation of the amount and intensity of sunlight. In the UK the prevalence of low vitamin D status in children and adolescents is found to be higher in winter than in summer.[34] Lifestyle factors such as indoor versus outdoor work and time spent in outdoor recreation play an important role.

Habitation and living conditions[edit]

Hypovitaminosis D has been associated with urbanisation in terms of both air pollution, which blocks UV light, and an increase in the number of people working indoors. The elderly are generally exposed to less UV light due to hospitalisation, immobility, institutionalisation, and being housebound, leading to decreased levels of vitamin D.[35]

Darker skin color[edit]

The reduced pigmentation of light-skinned individuals may result in higher vitamin D levels[7] and that, because melanin acts like a sun-block, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes. Sub-Saharan African people are at a higher risk to be vitamin deficient due to their skin color and the melanin levels.[citation needed] The natural selection hypothesis suggests that lighter skin color evolved to optimise vitamin D production in extreme northern and southern latitudes.[36]

Malabsorption[edit]

Rates of vitamin D deficiency are higher among people with untreated celiac disease,[37][38] inflammatory bowel disease, exocrine pancreatic insufficiency from cystic fibrosis, and short bowel syndrome,[38] which can all produce problems of malabsorption.

Critical illness[edit]

Vitamin D deficiency is associated with increased mortality in critical illness.[39] People who take vitamin D supplements before being admitted for intensive care are less likely to die than those who do not take vitamin D supplements.[39] Additionally, vitamin D levels decline during stays in intensive care.[40] Vitamin D3 (cholecalciferol) or calcitriol given orally may reduce the mortality rate without significant adverse effects.[40]

Diagnosis[edit]

The serum concentration of 25(OH)D is typically used to determine vitamin D status. Most vitamin D is converted to 25(OH)D in the serum, giving an accurate picture of vitamin D status.[41]

The level of serum 1,25(OH)D is not usually used to determine vitamin D status because it often is regulated by other hormones in the body such as parathyroid hormone.[41] The levels of 1,25(OH)D can remain normal even when a person may be vitamin D deficient.[41]

Serum level of 25(OH)D is the laboratory test ordered to indicate whether or not a person has vitamin D deficiency or insufficiency.[41]

It is also considered reasonable to treat at-risk persons with vitamin D supplementation without checking the level of 25(OH)D in the serum, as vitamin D toxicity has only been rarely reported to occur.[41]

Levels of 25(OH)D that are consistently above 200 ng/mL (500 nmol/L) are thought to be potentially toxic, although data from humans are sparse. Vitamin D toxicity usually results from taking supplements in excess.[citation needed] Hypercalcemia is often the cause of symptoms, and levels of 25(OH)D above 150 ng/mL (375 nmol/L) are usually found, although in some cases 25(OH)D levels may appear to be normal. Periodic measurement of serum calcium in individuals receiving large doses of vitamin D is recommended.[2]

Screening[edit]

The official recommendation from the United States Preventive Services Task Force is that for persons that do not fall within an at-risk population and are asymptomatic, there is not enough evidence to prove that there is any benefit in screening for vitamin D deficiency.[42]

Treatment[edit]

The amount of vitamin D recommended for all infants, children, and adolescents has recently increased – from 400 to 600 IU per day. The National Academy of Medicine (NAM) released the Consensus Report on Dietary Reference Intakes for Calcium and Vitamin D on November 30, 2010. The recommendation was for 600 IU of vitamin D a day for those 1–70 and 800 IU for those over 70 years of age.[43] As of October 2008, the American Pediatric Association advises vitamin D supplementation of 400 IU/day (10 μg/d) from birth onwards.[44][45] (1 IU vitamin D is the biological equivalent of 0.025 μg cholecalciferol/ergocalciferol.) The daily dose of 400 IU is required to prevent rickets and possibly also a wide range of chronic nonskeletal diseases.[46] 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 north of 55°N get 800 IU/day from October to April.[47] Health Canada recommends 400IU/day (10 μg/d).[48] Infant formula is generally fortified with vitamin D. Hypovitaminosis D is common in postmenopausal women, regardless of whether they are healthy or have other medical conditions.[49]

The replacement of vitamin D needs for treating Vitamin D deficiency depends on the severity of the deficiency. Treatment involves an initial high-dosage treatment phase until the required serum levels are reached, followed by the maintenance of the acquired levels. The lower the 25(OH)D serum concentration is before treatment, the higher is the dosage that is needed in order to quickly reach an acceptable serum level.

The initial high-dosage treatment can be given on a daily or weekly basis or can be given in form of one or several single doses (also known as stoss therapy, from the German word "Stoß" meaning push).[50]

Therapy prescriptions vary, and there is no consensus yet on how best to arrive at an optimum serum level. While per mole vitamin D3 is more potent to raise 25(OH)D blood levels than vitamin D2,[51] per IU both D2 and D3 are equal for maintaining 25(OH)D status.[52]

Initial phase[edit]

Daily or weekly dose[edit]

For treating rickets, the American Academy of Pediatrics (AAP) has recommended that pediatric patients receive an initial two- to three-month treatment of "high-dose" vitamin D therapy. In this regime, the daily dose of cholecalciferol is 1,000 IU for newborns, 1,000 to 5,000 IU for 1- to 12-months old infants, and 5,000 IU for patients over 1 year of age.[50]

For adults, other dosages have been called for. A review of 2008/2009 recommended dosages of 1,000 IU cholecalciferol per 10 nmol/l required serum increase, to be given daily over two to three months.[53] In another proposed cholecalciferol loading dose guideline for vitamin D-deficient adults, a weekly dosage is given, up to a total amount that is proportional to the required serum increase (up to the level of 75 nml/l) and, within certain body weight limits, to body weight.[54]

Single-dose therapy[edit]

Alternatively, a single-dose therapy is used for instance if there are concerns regarding the patient's compliance. The single-dose therapy can be given as an injection, but is normally given in form of an oral medication.[50]

Maintenance phase[edit]

Once the desired serum levels has been achieved, be it by a high daily or weekly dose or by a single-dose therapy, the AAP recommendation calls for a maintenance supplementation of 400 IU for all age groups, with this dosage being doubled for premature infants, dark-skinned infants and children, children who reside in areas of limited sun exposure (>37.5° latitude), obese patients, and those on certain medications.

Special cases[edit]

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 kidney dialysis patients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism.[55] Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily).

Epidemiology[edit]

The estimated percentage of the population with a vitamin D deficiency varies based on the threshold used to define a deficiency.

Percentage of

U.S. population

Definition of

insufficiency

Study Reference
69.5% 25(OH)D less than 30 ng/mL Chowdury et al. 2014 [56]
77% 25(OH)D less than 30 ng/mL Ginde et al. 2009 [57]
36% 25(OH)D less than 20 ng/mL Ginde et al. 2009 [57]
6% 25(OH)D less than 10 ng/mL Ginde et al. 2009 [57]

Recommendations for 25(OH)D serum levels vary across authorities, and probably vary based on factors like age; calculations for the epidemiology of vitamin D deficiency depend on the recommended level used.[58]

A 2011 Institute of Medicine report set the sufficiency level at 20 ng/ml (50 nmol/l), while in the same year The Endocrine Society defined sufficient serum levels at 30 ng/ml and others have set the level as high as 60 ng/ml.[59] As of 2011 most reference labs used the 30 ng/ml standard.[59][60]:435[61]

Applying the IOM standard to NHANES data on serum levels, for the period from 1988 to 1994 22% of the US population was deficient, and 36% were deficient for the period between 2001 and 2004; applying the Endocrine Society standard, 55% of the US population was deficient between 1988 and 1994, and 77% were deficient for the period between 2001 and 2004.[59]

In 2011 the Centers for Disease Control and Prevention applied the IOM standard to NHANES data on serum levels collected between 2001 and 2006, and determined that 32% of Americans were deficient during that period (8% at risk of deficiency, and 24% at risk of inadequacy).[59][62]

Research[edit]

A great deal of research has been conducted to understand whether low levels of vitamin D may cause or be a result of other conditions.

Some evidence suggests hypovitaminosis D may be associated with a worse outcome for some cancers, but evidence is insufficient to recommend that vitamin D be prescribed for people with cancer.[63] Taking vitamin D supplements has no significant effect on cancer risk.[64] Vitamin D3, however, appears to decrease the risk of death from cancer but concerns with the quality of the data exist.[65]

Vitamin D deficiency is thought to play a role in the pathogenesis of non-alcoholic fatty liver disease.[66][67]

Some studies have indicated that vitamin D deficiency may play a role in immunity. Those with vitamin D deficiency may have trouble fighting off certain types of infections. It has also been thought to correlated with cardiovascular disease, type 1 diabetes, type 2 diabetes, and some cancers.[68]

See also[edit]

References[edit]

  1. ^ a b c d e f g h i Holick, Michael F.; Chen, Tai C. (2008-04-01). "Vitamin D deficiency: a worldwide problem with health consequences". The American Journal of Clinical Nutrition. 87 (4): 1080S–1086S. ISSN 0002-9165. PMID 18400738. 
  2. ^ a b c Vitamin D at Merck Manual of Diagnosis and Therapy Professional Edition
  3. ^ a b Rajakumar K (August 2003). "Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective". Pediatrics. 112 (2): e132–5. doi:10.1542/peds.112.2.e132. PMID 12897318. 
  4. ^ a b c Holick MF (December 2004). "Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease". The American Journal of Clinical Nutrition. 80 (6 Suppl): 1678S–88S. PMID 15585788. 
  5. ^ a b c d e AUDRAN, MAURICE; KUMAR, RAJIV (1985-12-01). "The Physiology and Pathophysiology of Vitamin D". Mayo Clinic Proceedings. 60 (12). doi:10.1016/S0025-6196(12)64791-0. ISSN 0025-6196. 
  6. ^ a b c d Sunyecz, John A (2008). "The use of calcium and vitamin D in the management of osteoporosis". Therapeutics and Clinical Risk Management. 4 (4): 827–836. ISSN 1176-6336. PMC 2621390Freely accessible. PMID 19209265. 
  7. ^ a b Heaney RP (December 2004). "Functional indices of vitamin D status and ramifications of vitamin D deficiency". The American Journal of Clinical Nutrition. 80 (6 Suppl): 1706S–9S. PMID 15585791. 
  8. ^ a b G, Ritu; Gupta, Ajay (2014-02-21). "Vitamin D Deficiency in India: Prevalence, Causalities and Interventions". Nutrients. 6 (2): 729–775. doi:10.3390/nu6020729. 
  9. ^ Cherniack; Levis; Troen (2008). "Hypovitaminosis D: a widespread epidemic". Geriatrics. Retrieved 14 April 2015. 
  10. ^ Winzenberg T, Jones G (2013). "Vitamin D and bone health in childhood and adolescence". Calcif Tissue Int (Review). 92 (2): 140–50. doi:10.1007/s00223-012-9615-4. PMID 22710658. 
  11. ^ a b Elidrissy AT (2016). "The Return of Congenital Rickets, Are We Missing Occult Cases?". Calcif Tissue Int (Review). 99 (3): 227–36. doi:10.1007/s00223-016-0146-2. PMID 27245342. 
  12. ^ Yorifuji J, Yorifuji T, Tachibana K, Nagai S, Kawai M, Momoi T, Nagasaka H, Hatayama H, Nakahata T (2008). "Craniotabes in Normal Newborns: The Earliest Sign of Subclinical Vitamin D Deficiency". The Journal of Clinical Endocrinology & Metabolism. 93 (5): 1784–8. doi:10.1210/jc.2007-2254. PMID 18270256. 
  13. ^ "Vitamin D deficiency in adults". Australian Prescriber (33): 103–6. 2010. 
  14. ^ Reid, P.G. (2012). "Acute Management of Calcium Disorders". Topics in Companion Animal Medicine. 27: 167–171. 
  15. ^ Holick, M.F. (2008). "Vitamin D: a D-Lightful health perspective". Nutrition Reviews. 66 (2): S182–S194. doi:10.1111/j.1753-4887.2008.00104.x. 
  16. ^ Wang, Chin-Wei; McCauley, Laurie K. (30 September 2016). "Osteoporosis and Periodontitis". Current Osteoporosis Reports. 14: 284–291. doi:10.1007/s11914-016-0330-3. PMID 27696284. 
  17. ^ Paterson CR, Ayoub D (2015). "Congenital rickets due to vitamin D deficiency in the mothers". Clin Nutr (Review). 34 (5): 793–8. doi:10.1016/j.clnu.2014.12.006. PMID 25552383. 
  18. ^ Parker, GB; Brotchie, H; Graham, RK (15 January 2017). "Vitamin D and depression". Journal of Affective Disorders. 208: 56–61. doi:10.1016/j.jad.2016.08.082. PMID 27750060. 
  19. ^ a b Kennel, Kurt, MD et al., Vitamin D Deficiency in Adults: When to Test and How to Treat, Mayo Clinic Proceedings, August 2010, pp752–758
  20. ^ Janssen, Hennie CJP; Samson, Monique M.; Verhaar, Harald JJ (2002-04-01). "Vitamin D deficiency, muscle function, and falls in elderly people". The American Journal of Clinical Nutrition. 75 (4): 611–615. ISSN 0002-9165. PMID 11916748. 
  21. ^ Dunnigan MG, Henderson JB (2007). "An epidemiological model of privational rickets and osteomalacia". Proceedings of the Nutrition Society. 56 (3): 939–56. doi:10.1079/PNS19970100. PMID 9483661. 
  22. ^ Robertson I, Ford JA, McIntosh WB, Dunnigan MG (2007). "The role of cereals in the aetiology of nutritional rickets: The lesson of the Irish National Nutrition Survey 1943–8". British Journal of Nutrition. 45 (1): 17–22. doi:10.1079/BJN19810073. PMID 6970590. 
  23. ^ Clements, M. R. (1989). "The problem of rickets in UK Asians". Journal of Human Nutrition and Dietetics. 2 (2): 105–116. doi:10.1111/j.1365-277X.1989.tb00015.x. 
  24. ^ a b Pettifor JM (2004). "Nutritional rickets: Deficiency of vitamin D, calcium, or both?". The American Journal of Clinical Nutrition. 80 (6 Suppl): 1725S–9S. PMID 15585795. 
  25. ^ US National Institutes Of Health, National cancer Institute
  26. ^ Weick MT (1967). "A history of rickets in the United States". The American Journal of Clinical Nutrition. 20 (11): 1234–41. PMID 4862158. 
  27. ^ Garrison, R., Jr., Somer, E., The nutrition desk reference(1997)
  28. ^ DuPuis, E. Melanie (2002). Nature's Perfect Food: How Milk Became America's Drink. ISBN 978-0-8147-1938-1. [page needed]
  29. ^ Pereira-Santos, M.; Costa, P. R. F.; Assis, A. M. O.; Santos, C. a. S. T.; Santos, D. B. (2015-04-01). "Obesity and vitamin D deficiency: a systematic review and meta-analysis". Obesity Reviews. 16 (4): 341–349. doi:10.1111/obr.12239. ISSN 1467-789X. 
  30. ^ Alpert PT, Shaikh U (2007). "The effects of Vitamin D Deficiency and Insufficiency on the Endocrine and Paracrine Systems". Biological Research for Nursing. 9 (2): 11–129. doi:10.1177/1099800407308057. PMID 17909164. 
  31. ^ Norval M, Wulf HC (2009). "Does chronic sunscreen use reduce vitamin D production to insufficient levels?". British Journal of Dermatology. 161 (4): 732–6. doi:10.1111/j.1365-2133.2009.09332.x. PMID 19663879. 
  32. ^ Nowson CA, Margerison C (August 2002). "Vitamin D intake and vitamin D status of Australians". The Medical Journal of Australia. 177 (3): 149–52. PMID 12149085. 
  33. ^ Bandgar, TR; NS Shah. "Vitamin D and Hip Fractures: Indian Scenario". Journal of the Association of Physicians of India. 58 (September 2010). Retrieved 2010-09-15. Social and religious customs that require people to wear concealing clothing, veiling and traditional attire, such as the burqa, salvar kameez, and sari significantly prevents sun exposure. 
  34. ^ Cashman KD (2007). "Vitamin D in childhood and adolescence". Postgraduate Medical Journal (Review). 83 (978): 230–5. doi:10.1136/pgmj.2006.052787. PMC 2600028Freely accessible. PMID 17403948. 
  35. ^ Mithal; Wahl; Bonjour; Burckhardt; Dawson-Hughes; El-Hajj Fuleihan (2009). "Global vitamin D status and determinants of hypovitaminosis D". Osteoporosis International. 20: 1807–1820. doi:10.1007/s00198-009-0954-6. Retrieved 2015-04-12.  Missing |last6= in Authors list (help)
  36. ^ Yuen AW, Jablonski NG (January 2010). "Vitamin D: in the evolution of human skin colour". Medical Hypotheses. 74 (1): 39–44. doi:10.1016/j.mehy.2009.08.007. PMID 19717244. 
  37. ^ Caruso R, Pallone F, Stasi E, Romeo S, Monteleone G (2013). "Appropriate nutrient supplementation in celiac disease". Ann Med (Review). 45 (8): 522–31. doi:10.3109/07853890.2013.849383. PMID 24195595. 
  38. ^ a b Margulies SL, Kurian D, Elliott MS, Han Z (2015). "Vitamin D deficiency in patients with intestinal malabsorption syndromes--think in and outside the gut". J Dig Dis (Review). 16 (11): 617–33. doi:10.1111/1751-2980.12283. PMID 26316334. 
  39. ^ a b Bjelakovic, G; Gluud, L. L.; Nikolova, D; Whitfield, K; Wetterslev, J; Simonetti, R. G.; Bjelakovic, M; Gluud, C (2014). "Vitamin D supplementation for prevention of mortality in adults". The Cochrane Database of Systematic Reviews. 1: CD007470. doi:10.1002/14651858.CD007470.pub3. PMID 24414552. 
  40. ^ a b Putzu, A; Belletti, A; Cassina, T; Clivio, S; Monti, G; Zangrillo, A; Landoni, G (9 November 2016). "Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials". Journal of Critical Care. 38: 109–114. doi:10.1016/j.jcrc.2016.10.029. PMID 27883968. 
  41. ^ a b c d e Kennel, Kurt A.; Drake, Matthew T.; Hurley, Daniel L. (2010). "Vitamin D Deficiency in Adults: When to Test and How to Treat". Mayo Clinic Proceedings. 85 (8): 752–758. doi:10.4065/mcp.2010.0138. ISSN 0025-6196. PMC 2912737Freely accessible. PMID 20675513. 
  42. ^ "Final Recommendation Statement: Vitamin D Deficiency: Screening - US Preventive Services Task Force". www.uspreventiveservicestaskforce.org. Retrieved 2017-12-01. 
  43. ^ http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx
  44. ^ "Dietary Supplement Fact Sheet: Vitamin D". National Institutes of Health. Archived from the original on 2007-09-10. Retrieved 2007-09-10. 
  45. ^ Kingsbury, Kathleen (2008-10-13). "Kids Aren't Getting Enough Vitamin D". Time Health & Science. Time Inc. Retrieved 15 November 2008. 
  46. ^ Greer F (2009). "Recommended vitamin D intake in children: reasons for the recent increase". Consultant for Pediatricians. 8 (9): 323–329. 
  47. ^ Canadian mothers and babies don't get enough vitamin D 2007 Canadian Paediatric Society Recommendation
  48. ^ Vitamin D Supplementation for Breastfed Infants – 2004 Health Canada Recommendation
  49. ^ Mosoni A.M.; Menoyo I.; Bocanera R.; Pezzotto S.M.; Morosano M.E. (2014). "Hypovitaminosis D and associated risk factors in postmenopausal women". Health. 6 (11): 1180–1190. 
  50. ^ a b c Lee JY, So TY, Thackray J (2013). "A review on vitamin d deficiency treatment in pediatric patients". The Journal of Pediatric Pharmacology and Therapeutics : JPPT : the Official Journal of PPAG (Review). 18 (4): 277–91. doi:10.5863/1551-6776-18.4.277. PMC 3979050Freely accessible. PMID 24719588. 
  51. ^ Heaney RP, Recker RR, Grote J, Horst RL, Armas LA (2011). "Vitamin D3Is More Potent Than Vitamin D2in Humans". The Journal of Clinical Endocrinology & Metabolism. 96 (3): E447. doi:10.1210/jc.2010-2230. PMID 21177785. 
  52. ^ Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD (2008). "Vitamin D2 is as Effective as Vitamin D3 in Maintaining Circulating Concentrations of 25-Hydroxyvitamin D". The Journal of Clinical Endocrinology and Metabolism. 93 (3): 677–681. doi:10.1210/jc.2007-2308. PMC 2266966Freely accessible. PMID 18089691. 
  53. ^ Moyad MA (2009). "Vitamin D: a rapid review". Dermatology Nursing / Dermatology Nurses' Association. 21 (1): 25–30, 55. PMID 19283958.  Section Dosage of Vitamin D Needed To Achieve 35 to 40 ng/ml (90–100 nmol/L). Re-published from Moyad MA (2008). "Vitamin D: a rapid review". Urologic Nursing (Review). 28 (5): 343–9, 384; quiz 350. PMID 18980100. 
  54. ^ van Groningen L, Opdenoordt S, van Sorge A, Telting D, Giesen A, de Boer H (April 2010). "Cholecalciferol loading dose guideline for vitamin D-deficient adults". Eur. J. Endocrinol. 162 (4): 805–11. doi:10.1530/EJE-09-0932. PMID 20139241. 
  55. ^ Holick MF (November 2005). "The vitamin D epidemic and its health consequences". The Journal of Nutrition. 135 (11): 2739S–48S. PMID 16251641. 
  56. ^ Chowdhury, R; Kunutsor, S; Vitezova, A; Oliver-Williams, C; Chowdhury, S; Kiefte-de-Jong, JC; Khan, H; Baena, CP; Prabhakaran, D; Hoshen, MB; Feldman, BS; Pan, A; Johnson, L; Crowe, F; Hu, FB; Franco, OH (1 April 2014). "Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies". BMJ (Clinical research ed.). 348: g1903. doi:10.1136/bmj.g1903. PMC 3972416Freely accessible. PMID 24690623. 
  57. ^ a b c Ginde, AA; Liu, MC; Camargo CA, Jr (23 March 2009). "Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004". Archives of Internal Medicine. 169 (6): 626–32. doi:10.1001/archinternmed.2008.604. PMC 3447083Freely accessible. PMID 19307527. 
  58. ^ "Vitamin D". NIH Office of Dietary Supplements. February 11, 2016. Retrieved 6 December 2016. 
  59. ^ a b c d Hoel, David G.; Berwick, Marianne; de Gruijl, Frank R.; Holick, Michael F. (19 October 2016). "The risks and benefits of sun exposure 2016". Dermato-Endocrinology. 8 (1): e1248325. doi:10.1080/19381980.2016.1248325. PMC 5129901Freely accessible. PMID 27942349. 
  60. ^ Ross AC, Taylor CL, Yaktine AL, Del Valle HB (2011). Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C: National Academies Press. ISBN 0-309-16394-3. 
  61. ^ Holick, MF; Binkley, NC; Bischoff-Ferrari, HA; Gordon, CM; Hanley, DA; Heaney, RP; Murad, MH; Weaver, CM; The Endocrine Society (July 2011). "Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline". The Journal of Clinical Endocrinology and Metabolism. 96 (7): 1911–30. doi:10.1210/jc.2011-0385. PMID 21646368. 
  62. ^ "Vitamin D Status: United States, 2001–2006" (PDF). CDC NCHS Data Brief (59). March 2011. 
  63. ^ Buttigliero C, Monagheddu C, Petroni P, Saini A, Dogliotti L, Ciccone G, Berruti A (2011). "Prognostic Role of Vitamin D Status and Efficacy of Vitamin D Supplementation in Cancer Patients: A Systematic Review". The Oncologist. 16 (9): 1215–27. doi:10.1634/theoncologist.2011-0098. PMC 3228169Freely accessible. PMID 21835895. 
  64. ^ Bolland, Mark J; Grey, Andrew; Gamble, Greg D; Reid, Ian R (2014). "The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: A trial sequential meta-analysis". The Lancet Diabetes & Endocrinology. 2 (4): 307–320. doi:10.1016/S2213-8587(13)70212-2. PMID 24703049. 
  65. ^ Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C (2014). "Vitamin D supplementation for prevention of mortality in adults". Cochrane Database of Systematic Reviews. 1: CD007470. doi:10.1002/14651858.cd007470.pub3. PMID 24414552. 
  66. ^ Eliades M, Spyrou E, Agrawal N, Lazo M, Brancati FL, Potter JJ, Koteish AA, Clark JM, Guallar E, Hernaez R (2013). "Meta-analysis: Vitamin D and non-alcoholic fatty liver disease". Alimentary Pharmacology & Therapeutics. 38 (3): 246–54. doi:10.1111/apt.12377. PMID 23786213. 
  67. ^ Wang, X; Li, W; Zhang, Y; Yang, Y; Qin, G (2015). "Association between vitamin D and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: results from a meta-analysis". International journal of clinical and experimental medicine. 8 (10): 17221–34. PMC 4694215Freely accessible. PMID 26770315. 
  68. ^ G, Ritu; Gupta, Ajay (2014-02-21). "Vitamin D Deficiency in India: Prevalence, Causalities and Interventions". Nutrients. 6 (2): 729–775. doi:10.3390/nu6020729. 

External links[edit]