Title: Vitamin D and health - The missing vitamin in humans
Abstract: Severe vitamin D deficiency may cause rickets in infants or children and osteomalacia in adults, though it is now uncommon in developed countries. However, subclinical vitamin D deficiency is more prevalent, and it is associated with osteoporosis and higher incidence of falls or fractures. It was reported that 96% children with rickets were breastfed, since breast milk contains inadequate vitamin D. The American Academy of Pediatrics 2008 recommended infants who were exclusively or partially breastfed required 400 international units vitamin D daily from the first few days of life. Furthermore, since vitamin D receptors are present all over the body, insufficient vitamin D status may correlate with several extra-skeletal effects, such as pregnancy-related complications and immune dysfunction. This paper discusses the researches regarding system-based vitamin D effects, the possible risk factors leading to vitamin D deficiency, and the recommendations of vitamin D requirements. It is well-known that vitamin D can be obtained by sun exposure or limited natural dietary sources. The American Academy of Dermatology declared ultraviolet radiation to be a known skin carcinogen, so it may not be safe or efficient to obtain vitamin D via sun exposure or other artificial sources. Therefore, many pediatricians and physicians recommend appropriate vitamin D supplementation to achieve optimal plasma concentration. Trials assessing the effects of vitamin D repletion and establishing its optimum serum level are ongoing. Medical advice for vitamin D supplementation should be individualized accordingly. Severe vitamin D deficiency may cause rickets in infants or children and osteomalacia in adults, though it is now uncommon in developed countries. However, subclinical vitamin D deficiency is more prevalent, and it is associated with osteoporosis and higher incidence of falls or fractures. It was reported that 96% children with rickets were breastfed, since breast milk contains inadequate vitamin D. The American Academy of Pediatrics 2008 recommended infants who were exclusively or partially breastfed required 400 international units vitamin D daily from the first few days of life. Furthermore, since vitamin D receptors are present all over the body, insufficient vitamin D status may correlate with several extra-skeletal effects, such as pregnancy-related complications and immune dysfunction. This paper discusses the researches regarding system-based vitamin D effects, the possible risk factors leading to vitamin D deficiency, and the recommendations of vitamin D requirements. It is well-known that vitamin D can be obtained by sun exposure or limited natural dietary sources. The American Academy of Dermatology declared ultraviolet radiation to be a known skin carcinogen, so it may not be safe or efficient to obtain vitamin D via sun exposure or other artificial sources. Therefore, many pediatricians and physicians recommend appropriate vitamin D supplementation to achieve optimal plasma concentration. Trials assessing the effects of vitamin D repletion and establishing its optimum serum level are ongoing. Medical advice for vitamin D supplementation should be individualized accordingly. Rickets, a condition with impaired mineralization of bone tissue and growth plates, may result in weak bones in infants and children. The word “rickets” was first used in 1634.1O'Riordan J.L. Bijvoet O.L. Rickets before the discovery of vitamin D.Bonekey Rep. 2014; 3: 478PubMed Google Scholar From reports of the Royal Infirmary in Manchester, cod liver oil was found to heal rickets.1O'Riordan J.L. Bijvoet O.L. Rickets before the discovery of vitamin D.Bonekey Rep. 2014; 3: 478PubMed Google Scholar In 1822, Sniadecki pointed out the relationship between sunlight and rickets.2Mozolowski W. Jedrzej Sniadecki (1768-1838) on the cure of rickets..Nature. 1939; 143: 121-124Crossref Scopus (49) Google Scholar At the end of World War I, when rickets was an untreatable major problem in Vienna, Harriet Chick led a group from the British Medical Research Council to study it.3Chick H. Dalyell E.J. Hume M. Mackay H.M.M. Henderson-Smith H. Wimberger H. The aetiology of rickets in infants: prophylactic and curative observations at the Vienna University Kinderklinik.Lancet. 1922; 2: 7-11Abstract Scopus (19) Google Scholar They concluded both cod liver oil and sun exposure could heal rickets. In 1922, McCollum et al. coined the term “Vitamin D” in papers suggesting the existence of a vitamin which promotes calcium deposition.4McCollum E.V. Simmonds N. Becker J.E. Shipley P.G. Studies on the experimental demonstration of the existence of a vitamin which promotes calcium deposition.J Biol Chem. 1922; 53: 293-312Google Scholar Vitamin D is a fat-soluble vitamin. Its processing flow diagram is shown in Fig. 1. Few foods naturally contain vitamin D (oily fish, such as sardines, herring, tuna, mackerel, salmon, and cod liver oil, egg yolks, shiitake mushrooms, liver or organ meats), so dermal synthesis after ultraviolet-B (UVB) radiation remains the major route to obtain vitamin D, accounting for 90% of vitamin D replenishment.5Antonucci R. Locci C. Clemente M.G. Chicconi E. Antonucci L. Vitamin D deficiency in childhood: old lessons and current challenges.J Pediatr Endocrinol Metab. 2018; 31: 247-260Crossref PubMed Scopus (78) Google Scholar Cholecalciferol (vitamin D3) is from animal sources and ergocalciferol (vitamin D2) is from plants.6World Health Organization Vitamin and mineral requirements in human nutrition.2nd ed. World Health Organization, Geneva2005Google Scholar Cholesterol-like precursor (7-dehydrocholesterol) in skin epidermal cells can be converted after UVB radiation (wavelength 290–315 nm) into pre-vitamin D, which also isomerizes to vitamin D3. Both vitamin D3 and D2 are biologically inactive. They need further enzymatic conversion to its active forms. First, it undergoes 25-hydroxylation in liver to 25(OH)D (calcidiol), the major circulating form of vitamin D, with a half-life of 2–3 weeks. Then it is converted in kidneys through 1-alpha-hydroxylation to its most active form, 1,25(OH)2D (calcitriol), with a half-life of 4–6 h. This process is driven by parathyroid hormone (PTH) and other mediators, including hypophosphatemia and growth hormone.7Misra M. Pacaud D. Petryk A. Collett-Solberg P.F. Kappy M. Drug and therapeutics committee of the Lawson Wilkins pediatric endocrine society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations.Pediatrics. 2008; 122: 398-417Crossref PubMed Scopus (997) Google Scholar, 8Adams J.S. Hewison M. Update in vitamin D.J Clin Endocrinol Metab. 2010; 95: 471-478Crossref PubMed Scopus (707) Google Scholar The 1-alpha-hydroxylation also takes place in non-renal sites, such as alveolar macrophages, osteoblasts, lymph nodes, placenta, colon, breasts and keratinocytes, suggesting possible autocrine-paracrine role of 1,25(OH)2D.7Misra M. Pacaud D. Petryk A. Collett-Solberg P.F. Kappy M. Drug and therapeutics committee of the Lawson Wilkins pediatric endocrine society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations.Pediatrics. 2008; 122: 398-417Crossref PubMed Scopus (997) Google Scholar, 8Adams J.S. Hewison M. Update in vitamin D.J Clin Endocrinol Metab. 2010; 95: 471-478Crossref PubMed Scopus (707) Google Scholar It functions through a vitamin D receptor (VDR) that is universally expressed in nucleated cells. Its most important biological role is promoting enterocyte differentiation and intestinal calcium absorption, facilitating calcium homeostasis. At the time of hypocalcemia, the plasma level of ionized calcium falls and this is detected by parathyroid gland calcium receptors. PTH is secreted by parathyroid gland, which stimulates 1-alpha-hydroxylation in kidneys to make more 1,25(OH)2D from circulating 25(OH)D. The elevation of 1,25(OH)2D increases calcium transport within intestines, bones, and kidneys, and further regulates the osteoblast and osteoclast activity. As plasma calcium rises back to normal, further secretion of PTH decreases. This physiologic loop of vitamin D and calcium homeostasis demonstrates that sufficient circulating 25(OH)D is essential to maintain adequate 1,25(OH)2D synthesis and plasma calcium level.6World Health Organization Vitamin and mineral requirements in human nutrition.2nd ed. World Health Organization, Geneva2005Google Scholar However, vitamin D deficiency may result in inadequate circulating 25(OH)D, which decreases 1,25(OH)2D synthesis and calcium absorption, elevating PTH levels. It is reasonable that nutritionists should focus on plasma 25(OH)D and PTH level to assess vitamin D clinically. Additionally, because VDRs are found not only in small intestine, but also in colon, osteoblasts, activated T and B lymphocytes, mononuclear cells, beta islet cells and major organs, such as brain, heart, skin, gonads, prostate and breasts,8Adams J.S. Hewison M. Update in vitamin D.J Clin Endocrinol Metab. 2010; 95: 471-478Crossref PubMed Scopus (707) Google Scholar coexisting extra-skeletal effects of vitamin D deficiency are to be expected. Table 1.Table 1Outlines of Vitamin D and health.Discovery of vitamin DMetabolism and bioactivity of vitamin DSkeletal and extra-skeletal effects of vitamin D Vitamin D and bone health Can vitamin D prevent falls and fractures? Vitamin D Need in Pregnancy and Lactation Vitamin D and immune system Vitamin D and other systemic effectsVitamin D deficiency Definition of vitamin D deficiency Risk factors of vitamin D deficiency Recommended vitamin D requirement Vitamin D supplementation Vitamin D intoxication and complications Open table in a new tab Severe vitamin D deficiency may cause rickets in infants or children and osteomalacia in adults, although these are uncommon diseases in most developed countries. However, subclinical vitamin D deficiency is more prevalent, and may be associated with osteoporosis and higher incidence of falls or fractures. Bone mineral deposition begins in pregnancy, especially during the third trimester.9Abrams S.A. In utero physiology: role in nutrient delivery and fetal development for calcium, phosphorus, and vitamin D.Am J Clin Nutr. 2007; 85: 604S-607SCrossref PubMed Google Scholar Bone mass increases about 40 times from birth to adulthood, with 90% of peak bone mass achieved at the end of the second decade of life.10Bachrach L.K. Acquisition of optimal bone mass in childhood and adolescence.Trends Endocrinol Metab. 2001; 12: 22-28Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar Childhood and adolescence are critical periods for bone mineral deposition.11Golden N.H. Abrams S.A. Committee on NutritionOptimizing bone health in children and adolescents.Pediatrics. 2014; 134: e1229-e1243Crossref PubMed Scopus (275) Google Scholar A 2010 public health evaluation concluded that calcium supplementation of healthy children did not significantly decrease the incidence of fractures.12Winzenberg T.M. Powell S. Shaw K.A. Jones G. Vitamin D supplementation for improving bone mineral density in children.Cochrane Database Syst Rev. 2010; 10: CD006944Google Scholar A healthy balanced diet that fulfilled the recommended calcium intake was superior to routine calcium supplementations.11Golden N.H. Abrams S.A. Committee on NutritionOptimizing bone health in children and adolescents.Pediatrics. 2014; 134: e1229-e1243Crossref PubMed Scopus (275) Google Scholar, 12Winzenberg T.M. Powell S. Shaw K.A. Jones G. Vitamin D supplementation for improving bone mineral density in children.Cochrane Database Syst Rev. 2010; 10: CD006944Google Scholar However, due to limited natural dietary sources of vitamin D and insufficient sun exposure in most children and adolescents, vitamin D supplementation is necessary. Routine screening of 25(OH)D levels is not recommended, except for those with higher risk (as listed in Table 2), or in children who present with poor growth, gross motor delay or unusual irritabilities; those who are hospitalized or institutionalized with limited sun exposure; or those with elevated serum alkaline phosphatase (ALP) levels (>500IU/L in neonates or >1000IU/L in children up to 9 years).7Misra M. Pacaud D. Petryk A. Collett-Solberg P.F. Kappy M. Drug and therapeutics committee of the Lawson Wilkins pediatric endocrine society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations.Pediatrics. 2008; 122: 398-417Crossref PubMed Scopus (997) Google Scholar, 13Holick M.F. Binkley N.C. Bischoff-Ferrari H.A. Gordon C.M. Hanley D.A. Heaney R.P. et al.Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2011; 96: 1911-1930Crossref PubMed Scopus (6795) Google Scholar, 14Weydert J.A. Vitamin D in children's health.Children. 2014; 1: 208-226https://doi.org/10.3390/children1020208Crossref PubMed Scopus (16) Google ScholarTable 2Risk factors of Vitamin D deficiency.Inadequate cutaneous vitamin D synthesis Dark skin Age (infants, adolescents and elderly) Obesity Physical blocking of ultraviolet-B exposure (clothing, using of sun screens, …) Geographic-related factors (higher latitude, winter season, lower altitude, …)Inadequate dietary intake of vitamin D Unbalanced dietVegetarians, eating disorders (anorexia nervosa, bulimia nervosa, …) Malabsorption syndromeIntestinal malabsorption (Celiac disease, Crohn's disease, ulcerative colitis, …)Pancreatic insufficiency (Cystic fibrosis)Cholestasis syndrome (Biliary atresia)Following gut resection (short bowel syndrome)Perinatal factors Maternal vitamin D deficiency during pregnancy Prematurity Exclusively breastfed beyond three to six months of ageGenetic or endocrine disorders Chronic liver/renal diseases Hyperparathyroidism, growth hormone deficiency, diabetes mellitus Hereditary resistance of vitamin DMedications Anticonvulsants (Carbamazepine, phenytoin, phenobarbital, topiramate) Antiretroviral agents for treating human immunodeficiency virus Azole antifungal agents (Ketoconazole) Glucocorticoid Open table in a new tab Since vitamin D is essential for calcium homeostasis and bone metabolism, discussion of vitamin D supplementation and prevention of falls and fractures is worthwhile. However, the evidence is contradictory. Several meta-analyses showed decreasing risks of falls in the elderly after vitamin D repletion with doses 700–1000 international units (IU) per day (relative risk (RR) about 20%), especially in those with underlying low vitamin D levels.15Bischoff-Ferrari H.A. Dawson-Hughes B. Staehelin H.B. Orav J.E. Stuck A.E. Theiler R. et al.Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.BMJ. 2009; 339: b3692Crossref PubMed Scopus (995) Google Scholar A meta-analysis in 2007 concluded that combination approach (800IU vitamin D plus 1200 mg calcium daily) was more effective in reducing hip fractures and mortality in institutionalized patients.16Tang B.M. Eslick G.D. Nowson C. Smith C. Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis.Lancet. 2007; 370: 657-666Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar However, subsequent reviews stated that vitamin D alone or in combination with calcium did not significantly reduce the risk of falls and fractures in community-dwelling adults.17Kahwati L.C. Weber R.P. Pan H. Gourlay M. LeBlanc E. Coker-Schwimmer M. et al.Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2018; 319: 1600-1612Crossref PubMed Scopus (118) Google Scholar Furthermore, combination therapy with vitamin D and calcium might increase the incidence of renal stones.17Kahwati L.C. Weber R.P. Pan H. Gourlay M. LeBlanc E. Coker-Schwimmer M. et al.Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2018; 319: 1600-1612Crossref PubMed Scopus (118) Google Scholar Another large trial by Sanders et al. found an even higher risk of falls and fractures when using high-dose vitamin D (single high dose 500000IU annually, resulting in chronic serum 25(OH)D > 40 ng/mL), so intermittent high-dose regimen should be avoided.18Sanders K.M. Stuart A.L. Williamson E.J. Simpson J.A. Kotowicz M.A. Young D. et al.Annual high-dose oral vitamin D and falls and fractures in olde women: a randomized controlled trial.JAMA. 2010; 303: 1815-1822Crossref PubMed Scopus (1088) Google Scholar Several studies indicated the association between maternal vitamin D deficiency and an increasing risk of pre-eclampsia, gestational diabetes mellitus, preterm birth, small-for-gestational age infants, and impaired fetal bone formation.19World Health Organization Guideline: vitamin D supplementation in pregnant women. World Health Organization, Geneva2012Google Scholar A Cochrane systematic review in 2016 stated that daily or intermittent vitamin D supplementation in pregnant women could increase serum 25(OH)D concentration at term and reduce the incidence of pre-eclampsia, preterm birth and low birth weight, although the quality of the evidence was low to moderate.20De-Regil L.M. Palacios C. Lombardo L.K. Peña-Rosas J.P. Vitamin D supplementation for women during pregnancy.Cochrane Database Syst Rev. 2016; 1CD008873Google Scholar However, combination therapy with vitamin D and calcium might increase the risk of preterm birth.20De-Regil L.M. Palacios C. Lombardo L.K. Peña-Rosas J.P. Vitamin D supplementation for women during pregnancy.Cochrane Database Syst Rev. 2016; 1CD008873Google Scholar With limited evidence available to evaluate the benefits and harm of vitamin D supplementation during pregnancy, this intervention is not recommended by the World Health Organization as routine antenatal care.21World Health Organization WHO recommendations on antenatal care for a positive pregnancy experience. World Health Organization, Geneva2016Google Scholar However, Oxford University Hospital suggested the decision of maternal vitamin D supplementation should be discussed with all pregnant and breastfeeding women.22Mackillop L. Vitamin D supplementation in pregnancy. Oxford University Hospitals NHS Foundation Trust, 2017Google Scholar Higher dosage of vitamin D (started from 1000IU per day) in combination with calcium-replete diet (at least 1000 mg calcium daily) is indicated in high-risk non-Caucasian women with BMI >30 kg/m2, living in higher latitude, or delivering during the period November to March.22Mackillop L. Vitamin D supplementation in pregnancy. Oxford University Hospitals NHS Foundation Trust, 2017Google Scholar More recently, a meta-analysis also demonstrated that vitamin D supplementation during pregnancy could reduce the risk of small-for-gestational-age infants and improve infant growth after birth.23Bi W.G. Nuyt A.M. Weiler H. Leduc L. Santamaria C. Wei S.Q. Association between vitamin D supplementation during pregnancy and offspring growth, morbidity, and mortality: a systematic review and meta-analysis.JAMA Pediatr. 2018; 172: 635-645Crossref PubMed Scopus (92) Google Scholar Two thousand IU supplement daily did not increase the risk of fetal and neonatal death or incidence of congenital malformations.23Bi W.G. Nuyt A.M. Weiler H. Leduc L. Santamaria C. Wei S.Q. Association between vitamin D supplementation during pregnancy and offspring growth, morbidity, and mortality: a systematic review and meta-analysis.JAMA Pediatr. 2018; 172: 635-645Crossref PubMed Scopus (92) Google Scholar Further guidelines and recommendations for optimal serum 25(OH)D level in pregnancy, timing of vitamin D supplementation, and dosing safety and efficacy should be established. As for breastfeeding women, a report in 2006 showed that higher maternal vitamin D intake (4000–6400IU per day) might achieve sufficient vitamin D concentration in breast milk for exclusively breastfed infants.24Basile L.A. Taylor S.N. Wagner C.L. Horst R.L. Hollis B.W. The effect of high-dose vitamin D supplementation on serum vitamin D levels and milk calcium concentration in lactating women and their infants.Breastfeed Med. 2006; 1: 27-35Crossref PubMed Scopus (91) Google Scholar Elsewhere, it was found to be more efficient to give at least 400IU daily for exclusively breastfed infants.7Misra M. Pacaud D. Petryk A. Collett-Solberg P.F. Kappy M. Drug and therapeutics committee of the Lawson Wilkins pediatric endocrine society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations.Pediatrics. 2008; 122: 398-417Crossref PubMed Scopus (997) Google Scholar As mentioned above, VDRs are present all over the body including antigen-presenting cells, with known direct effects on innate and adaptive immunity. The relationships between vitamin D and these illnesses are discussed below. Tuberculosis (TB) — There is an association between vitamin D deficiency and TB. It was reported in 2008 that UVB radiation had beneficial effects on TB therapy.25Nnoaham K.E. Clarke A. Low serum vitamin D levels and tuberculosis: a systemic review and meta-analysis.Int J Epidemiol. 2008; 37: 113-119Crossref PubMed Scopus (526) Google Scholar However, Martineau et al. concluded that supplementation of vitamin D did not show significant improvement in clinical outcomes.26Martineau A.R. Timms P.M. Bothamley G.H. Hanifa Y. Islam K. Claxton A.P. et al.High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.Lancet. 2011; 377: 242-250Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Respiratory tract infections — A prospective trial by Camargo found an inverse association between cord-blood 25(OH)D level and the risk of developing upper respiratory tract infection by 3 months and wheezing at 15 months of age.27Camargo Jr., C.A. Ingham T. Wickens K. Thadhani R. Silvers K.M. Epton M.J. et al.Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.Pediatrics. 2011; 127: e180-e187Crossref PubMed Scopus (413) Google Scholar Newborns born with 25(OH)D < 20 ng/mL had six-fold higher risk of respiratory syncytial virus-related bronchiolitis at 1 year old compared with those of 25(OH)D > 30 ng/mL.28Belderbos M.E. Houben M.L. Wilbrink B. Lentjes E. Bloemen E.M. Kimpen J.L. et al.Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis.Pediatrics. 2011; 127: e1513-e1520Crossref PubMed Scopus (248) Google Scholar A recent meta-analysis of 25 trials in 2017 showed reducing incidence of acute respiratory tract infection after vitamin D supplementation (OR 0.88, 95% CI 0.81–0.96), which is more significant in patients with severe vitamin D deficiency (<10 ng/mL).29Martineau A.R. Jolliffe D.A. Hooper R.L. Greenberg L. Aloia J.F. Bergman P. et al.Vitamin D supplementation to prevent acute respiratory tract infection: systematic review and meta-analysis of individual participant data.BMJ. 2017; 356: i6583Crossref PubMed Scopus (1128) Google Scholar Asthma — Maternal vitamin D intake during pregnancy may be associated with children's risk of developing wheezing episodes thereafter.27Camargo Jr., C.A. Ingham T. Wickens K. Thadhani R. Silvers K.M. Epton M.J. et al.Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma.Pediatrics. 2011; 127: e180-e187Crossref PubMed Scopus (413) Google Scholar A cross-sectional study observed the 25(OH)D level between asthma and healthy groups.30Alyasin S. Momen T. Kashef S. Alipour A. Amin R. The relationship between serum 25 hydroxy vitamin d levels and asthma in children.Allergy Asthma Immunol Res. 2011; 3: 251-255Crossref PubMed Scopus (83) Google Scholar It showed that vitamin D concentration was directly correlated with forced exploratory volume/forced vital capacity (FEV1/FVC) ratio and predicted FEV1, meaning that lower 25(OH)D level was more significantly associated with asthmatic status. A Cochrane systematic review in 2016 documented that vitamin D supplementation had benefits on reducing risk of exacerbation requiring systemic glucocorticoids (RR 0.63, 95% CI 0.45–0.88) and risk of at least one exacerbation requiring emergency department visit or hospitalization or both (OR 0.39, 95% CI 0.19–0.78).31Martineau A.R. Cates C.J. Urashima M. Jensen M. Griffiths A.P. Nurmatov U. et al.Vitamin D for the management of asthma.Cochrane Database Syst Rev. 2016; 9: CD011511PubMed Google Scholar Atopic dermatitis (AD) — A meta-analysis by Kim demonstrated that serum 25(OH)D level was lower in patients with AD.32Kim M.J. Kim S.N. Lee Y.W. Choe Y.B. Ahn K.J. Vitamin D status and efficacy of vitamin D supplementation in atopic dermatitis: a systematic review and meta-analysis.Nutrients. 2016; 8: E789Crossref PubMed Scopus (77) Google Scholar A small randomized clinical trial also found beneficial effects of vitamin D supplementation in children with winter-related AD.33Camargo Jr., C.A. Ganmaa D. Sidbury R. Erdenedelger Kh Radnaakhand N. Khandsuren B. Randomized trial of vitamin D supplementation for winter-related atopic dermatitis in children.J Allergy Clin Immunol. 2014; 134: 831-835Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar On the contrary, another systematic review in 2012 did not show a significant benefit in clinical outcomes (including pruritus, sleep loss, number of flares, or need of further therapies) after vitamin D intervention.34Bath-Hextall F.J. Jenkinson C. Humphreys R. Williams H.C. Dietary supplements for established atopic eczema.Cochrane Database Syst Rev. 2012; 2: CD005205PubMed Google Scholar 1,25(OH)2D also functions as an inhibitor of dendritic cell maturation, which reduces the activation of acquired immunity and may increase the risk of autoimmune disease,35Ponsonby A.L. McMichael A. van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research.Toxicology. 2002; 181–182: 71-78Crossref PubMed Scopus (194) Google Scholar such as type I diabetes, multiple sclerosis, and inflammatory bowel disease.5Antonucci R. Locci C. Clemente M.G. Chicconi E. Antonucci L. Vitamin D deficiency in childhood: old lessons and current challenges.J Pediatr Endocrinol Metab. 2018; 31: 247-260Crossref PubMed Scopus (78) Google Scholar However, because reports conflict on the association between vitamin D status and these diseases, supplementation is not recommended at present. Observational studies demonstrated the association between vitamin D deficiency and the risk of hypertension or cardiovascular events, higher incidence of cancers, more musculoskeletal pain or migraine, and neuropsychiatric disorders such as schizophrenia, dementia or depression.14Weydert J.A. Vitamin D in children's health.Children. 2014; 1: 208-226https://doi.org/10.3390/children1020208Crossref PubMed Scopus (16) Google Scholar However, current evidence for vitamin D intervention in treating or preventing these diseases is lacking. The best indicator of human body's vitamin D status is the concentration of serum 25(OH)D.36Institute of Medicine, Food and Nutrition Board Dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington, DC2011Google Scholar The optimal 25(OH)D level for either skeletal or extra-skeletal health varies for different populations. In adults, the essential level of vitamin D is determined through studies of calcium homeostasis, bone mineralization and PTH levels. Adult PTH has negative correlation with serum 25(OH)D level, though this relationship is weak in children. The Institute of Medicine (IOM) concluded a serum level of 20 ng/mL was optimal for skeletal health,36Institute of Medicine, Food and Nutrition Board Dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington, DC2011Google Scholar whereas other experts, including the Endocrine Society (ENDO), the International Osteoporosis Foundation (IOF), the National Osteoporosis Foundation (NOF) and the American Geriatrics Society (AGS) stated that at least 30 ng/mL was needed for disease prevention.13Holick M.F. Binkley N.C. Bischoff-Ferrari H.A. Gordon C.M. Hanley D.A. 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