Vitamin D is a key hormone that plays a role in calcium and phosphorus metabolism and is essential for bone health, especially in the pediatric population. However, recent data have suggested that vitamin D may have extra-skeletal actions as well, and may play a role in several conditions including obesity, asthma, and type 1 diabetes. This has led to increased interest in screening for vitamin D deficiency in many child and adolescent populations.
But what is the best way to screen for vitamin D deficiency, and who should be screened? Are there potential benefits of screening for vitamin D deficiency and treatment in the absence of obvious bone mineralization abnormalities or hypocalcemia? This article summarizes current thoughts on the importance of vitamin D in children and adolescents and possible associations with other conditions such as obesity, asthma, and type 1 diabetes mellitus.
The Deal with the D's
Vitamin D is a fat-soluble vitamin that is essential for calcium homeostasis and metabolic bone health. Very few foods contain vitamin D naturally, thus synthesis of vitamin D in the skin is the major natural source of vitamin D. Exposure to ultraviolet B (UV-B) light converts 7-dehydrocholesterol in the skin to pre-vitamin D3, which is subsequently converted to cholecalciferol or vitamin D3. Many factors influence vitamin D synthesis in the skin including time of day, geographic location, season of the year, skin pigmentation, and use of sun block. Infants and children who have darker skin pigmentation have been shown to need 5 to 10 times longer sunlight exposure to produce the same amount of vitamin D when compared with children who have lighter skin pigmentation.1 However, as sun exposure in children can be unpredictable, and the safe level of sun exposure for vitamin D conversion is not known, the most dependable way to ensure adequate vitamin D levels is either through consumption of vitamin D through the diet (mainly with vitamin D fortified foods) or with vitamin D supplements. The Institute of Medicine (IOM) dietary reference intakes for vitamin D intake are as follows: infants and children younger than age 1 year: 400 IU/day; children older than age 1 year to 18 years: 600 IU/day; adults age 19 years and older: at least 600 IU/day.2 The American Academy of Pediatrics (AAP) recommends that all breast-fed/partially breast-fed babies and infants receiving less than 1,000 mL of vitamin D fortified formula per day need to be supplemented with 400 IU of vitamin D. Children and adolescents receiving less than 400 IU of vitamin D from fortified foods or milk in their diet should receive a vitamin D supplement of 400 IU/day.3
Patients who are at increased risk for vitamin D deficiency should receive at least 2 to 3 times these requirements. These patients include people who are taking medications like glucocorticoids, ketoconazole, antiepileptics, and antiretroviral agents.
There are two forms of vitamin D. Vitamin D3 (cholecalciferol) is the form of vitamin D synthesized in the skin and found in animal products. It is available as a supplement in the United States. Vitamin D2 (ergocalciferol) differs from vitamin D3 structurally but exerts similar biological effects. It is plant derived and available as a pharmaceutical in the US.4
Vitamin D obtained from sun exposure, food, and/or supplements is biologically inert and must undergo two hydroxylations in the body for activation (Figure 1). Vitamin D2 or D3 is transported to the liver through the blood stream where it is converted to 25-hydroxyvitamin D (25(OH)D; also known as calcidiol) via the hepatic enzyme 25-hydroxylase. 25(OH)D is the major circulating form of vitamin D and the most accurate indicator of vitamin D status in the body. 25(OH)D is subsequently converted in the kidney to the active form of vitamin D, or 1,25-dihydroxyvitamin D (1,25(OH)2D; also known as calcitriol) via 1-alpha hydroxylase. Synthesis of 1,25(OH)2D is regulated by parathyroid hormone, and it exerts its effects by acting on the vitamin D receptor (VDR). Active 1,25(OH)2D facilitates intestinal absorption of dietary calcium and phosphorus. 1,25(OH)2D is commercially available as calcitriol.
Synthesis of active vitamin D.
Classification of Vitamin D Sufficiency
Interestingly, there is not a consensus among the Endocrine Society, AAP, Pediatric Endocrine Society, and IOM as to what constitutes a normal or sufficient 25(OH)D level, which makes screening and treatment tricky. Up until 1998 vitamin D deficiency was defined as a blood level of 25(OH)D of less than 10 ng/mL (25 nmol/L), mainly based on reports of nutritional rickets.5 In 2011, the Endocrine Society developed guidelines on vitamin D sufficiency that were based on observational and clinical trials in populations with high risk for vitamin D deficiency.6 The Endocrine Society guidelines recommend 25(OH)D levels of at least 30 ng/mL (75 nmol/L) to maintain optimal musculoskeletal heath with the ideal level between 40 and 60 ng/mL (100–150 nmol/L). They consider 25(OH)D levels between 20 and 29.9 ng/mL (52–72 nmol/L) as insufficient and levels <20 ng/mL (50 nmol/L) as deficient.
The IOM guidelines differ slightly from those of the Endocrine Society Guidelines and are based on vitamin D effects on bone and mineral homeostasis in the general healthy population.2,7 The IOM defines vitamin D sufficiency as a 25(OH)D level of >20 ng/mL, and a 25(OH)D level of less than 12 ng/mL (30 nmol/L) as vitamin D deficiency.
The AAP also considers serum 25(OH) D levels of >20 ng/mL (50 nmol/L) as sufficient.8,9 The AAP guidelines consider 25(OH)D levels of 15 to 20 ng/mL (37.5–50 nmol/L) as insufficient, <15 ng/mL (37.5 nmol/L) as deficient, and <5 ng/ml (12.5 nmol/L) as severely deficient.9
Prevalence of Vitamin D Deficiency
In the US, the overall prevalence of vitamin D deficiency (defined in these studies as 25(OH)D of <20 ng/mL [50 nmol/L]) in otherwise healthy children and adolescents ranges from 15% to 54%.8,10,11 The prevalence of vitamin D deficiency is higher in adolescents as compared to younger children, and higher in adolescents with darker skin pigmentation and adolescents who are obese.11 Vitamin D deficiency/insufficiency has likely increased over time due to less sun exposure, increased use of sunscreen, and changes in diet.
Block the Sunblock?
Sunscreen is recommended to prevent damage to the skin and decrease the risk of skin cancer. However, sunscreen blocks UV-B absorption in the skin, thus interfering with vitamin D synthesis. A sunscreen with a sun protection factor (SPF) of 8 can decrease vitamin D3 synthetic capacity by 95%, and SPF 15 can decrease it by 98%.9,12 Ten to 15 minutes of exposure to the midday sun (between 1,000 and 1,500 hours) in the spring, summer, and fall is considered adequate for people with a lighter skin pigmentation for adequate vitamin D synthesis, after which application of a sunscreen with an SPF of at least 15 is recommended to prevent damaging effects of chronic excessive exposure to sunlight.9
Who Needs Screening for Vitamin D Insufficiency/Deficiency?
The AAP does not currently recommend routine screening for vitamin D deficiency in healthy children and adolescents, including in children who are obese and children with darker skin pigmentation, as there is insufficient evidence of a cost-benefit to universal screening in reducing fracture risk.13 The AAP does recommend screening in children and adolescents with conditions associated with decreased bone mass and/or recurrent fractures. The Endocrine Society recommends that people at risk of vitamin D deficiency be screened (Table 1), in whom a prompt response to optimization of vitamin D status could be expected.6
Conditions Associated with Vitamin D Deficiency in Children and Adolescents
Vitamin D and Obesity
Low vitamin D levels are often found in people who are obese regardless of age. In a meta-analysis completed in 2015, the prevalence of vitamin D deficiency was found to be 33% higher in adults who were obese and up to 37% higher in children and adolescents who were obese compared to people who were not.14 Furthermore, the prevalence of vitamin D deficiency in people who were obese was found to be 24% higher than in the people who were overweight. However, do the low 25(OH)D levels reflect true deficiency? Vitamin D, being one of the fat-soluble vitamins, is distributed into the adipose tissue, muscle, and serum, all of which are increased in people who are obese. Therefore, the lower vitamin D could be a result of volumetric dilution effect, and whole-body stores of vitamin D may be adequate.15 Due to this dilution effect, people who are obese may need larger loading doses of vitamin D than people who are normal weight to achieve the same serum levels of 25(OH)D. Conversely, the decrease of 25(OH)D on stopping vitamin D supplements may be slower due to redistribution from other tissue stores.
It has also been postulated that low 25(OH)D levels in people who are obese may be due to increased storage of vitamin D in adipose tissue, impaired release of vitamin D from adipose tissue, or lower availability of vitamin D synthesized in the skin. Wortsman et al.16 assessed the effect of obesity on the cutaneous production and intestinal absorption of vitamin D. Their results suggested that obesity did not affect the cutaneous synthesis of vitamin D; however, the release of vitamin D from the skin into the circulation may be altered due to sequestration in the adipose tissue of the skin. They also found that body mass index (BMI) was inversely correlated with serum vitamin D concentrations. They concluded that the >50% decreased bioavailability of cutaneously synthesized vitamin D3 in the people who were obese could account for the consistent observation that obesity is associated with vitamin D deficiency.
If obesity is associated with lower vitamin D, then the next obvious question would be: does the lower 25(OH)D cause increased bone turnover and weaker bones in patients who are obese? Male adolescents who are obese have been shown to have larger and stronger bones at the lower leg (tibia) and lower arm (radius) than their peers who were normal weight;17 female adolescents who are obese have been found to have higher bone mineral density than normal weight controls.18 It is thought that elevated leptin concentration, increased aromatization of androgens to estrogen in the adipose tissue, and greater mechanical loading may be responsible for counteracting the effect of low circulating 25(OH)D. However, it is to be noted that children who are obese are still at increased risk of fractures.19 At the present time, there is no conclusive evidence that lower 25(OH)D in children who are obese causes negative consequences on bone health.
Some studies have suggested that vitamin D deficiency in children and adolescents who are obese may worsen metabolic complications associated with obesity, including insulin resistance and correction of poor vitamin D status, and may lead to a decrease in hyperinsulinism.20,21 Despite these studies, the current evidence is insufficient to draw definitive conclusions regarding the clinical significance of low 25(OH)D levels in children.
Does vitamin D play a role in the development of obesity? In a meta-analysis that included 26 randomized clinical trials, vitamin D supplementation alone or combined with calcium in comparison to placebo did not show a significant effect on BMI, weight, or fat mass.21 Based on evidence to date, although many people who are obese have a low 25(OH)D, it has not conclusively been proven that the lower vitamin D levels cause any clinical effects.
In any case, children who are obese have the same risk of developing true vitamin D deficiency as any other child due to conditions such as lack of adequate sunlight, nutritional deficiencies, or chronic illnesses. To normalize the serum vitamin D levels to those comparable with standard targets for age, children who are obese will need an increased amount of vitamin D supplementation than children with normal BMI to bring them to the same cut off levels, due to possible dilution as discussed above.
Vitamin D and Asthma
A concurrent rise in the prevalence of asthma and vitamin D deficiency worldwide has led many to speculate that there is an association between the two conditions. VDRs have been found on human bronchial smooth muscle cells and may potentially be involved in airway remodeling.22
In various studies, children with asthma were not more likely to have low 25(OH)D as compared to controls; however, asthma severity and control has been linked to lower serum levels of 25(OH)D.23,24 These effects may be due to the immunomodulatory effects of vitamin D on immune cells like macrophages, T and B lymphocytes, and dendritic cells.25 A systematic review and meta-analysis of vitamin D supplementation to prevent asthma exacerbations found that vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall.26 Although important questions remain, these analyses challenge the need for additional placebo-controlled trials.
Vitamin D and Immune Function
Historically, cod liver oil was used in the treatment of tuberculosis during the late 19th and 20th centuries, likely the first evidence of a possible role of vitamin D in immune function. Cells of the immune system have been shown to express 1-alpha hydroxylase and thus can synthesize the active form of vitamin D, which supports an immune-modulatory role of vitamin D. In addition, the VDR is found in almost all cells of the immune system, especially the antigen presenting cells (macrophages and dendritic cells) and activated T lymphocytes, which suggest a role of vitamin D on immune function.5 Vitamin D is thought to inhibit interleukins and tumor necrosis factor and to inhibit the maturation and differentiation of dendritic cells. The net effect is the reduction of the antigen presenting cells to the T cells, thus favoring T-cell tolerance.27
Autoimmunity develops as a consequence of decreased tolerance to self-antigens. Therefore, it can be inferred that vitamin D deficiency may decrease immune tolerance and thereby play a role in development of autoimmune diseases. Several observational studies and meta-analyses have shown an association between circulating levels of vitamin D and autoimmune endocrine disorders, such as type 1 diabetes mellitus (T1DM), adrenal insufficiency, and autoimmune thyroid disease.28 It is possible that vitamin D deficiency may affect normal immune function and predispose to the development of autoimmune diseases; however, additional studies are needed.
Does Vitamin D Deficiency Play a Role in Development of Type 1 Diabetes Mellitus?
As VDRs have been found in many cells outside of the bone and skeletal system, including the pancreas and most of the immune cells, many have questioned a possible association between vitamin D status and T1DM. However, studies looking at a possible association have led to conflicting data. 25(OH)D levels have been found to be lower in children with T1DM as compared to controls.29,30 In addition, observational studies have suggested that vitamin D supplementation in infants may reduce the risk of T1DM in later life.31 In contrast, other large studies in children and adults have found no significant association between serum 25(OH)D and the development of T1DM or benefits of vitamin D supplementation.32,33 Thus, at this point, there is not sufficient evidence to advise vitamin D supplementation in people who are at risk for or being treated for T1DM. However, the maintenance of normal levels of 25(OH)D should be encouraged.
Much of the evidence supporting a role of vitamin D in extra-skeletal conditions has not been definitively proven; therefore, it is not possible to specify a relationship between vitamin D and health outcomes other than bone health at the current time. Further research is needed to establish causality and should help further inform us of any changes in recommendations of vitamin D intake on other health outcomes.
- Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet. 1982;1(8263):74–76. https://doi.org/10.1016/S0140-6736(82)90214-8 PMID: doi:10.1016/S0140-6736(82)90214-8 [CrossRef]
- Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–58. https://doi.org/10.1210/jc.2010-2704 PMID: doi:10.1210/jc.2010-2704 [CrossRef]
- Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142–1152. doi:. doi:10.1542/peds.2008-1862 [CrossRef]
- Holick MF. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017;18(2):153–165. https://doi.org/10.1007/s11154-017-9424-1 PMID: doi:10.1007/s11154-017-9424-1 [CrossRef]
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–281. https://doi.org/10.1056/NEJMra070553 PMID: doi:10.1056/NEJMra070553 [CrossRef]
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930. https://doi.org/10.1210/jc.2011-0385 PMID: doi:10.1210/jc.2011-0385 [CrossRef]
- Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab. 2012;97(4):1146–1152. https://doi.org/10.1210/jc.2011-2218 PMID: doi:10.1210/jc.2011-2218 [CrossRef]
- Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158(6):531–537. https://doi.org/10.1001/archpedi.158.6.531 PMID: doi:10.1001/archpedi.158.6.531 [CrossRef]
- Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy MDrug 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(2):398–417. https://doi.org/10.1542/peds.2007-1894 PMID: doi:10.1542/peds.2007-1894 [CrossRef]
- Mansbach JM, Ginde AA, Camargo CA Jr, . Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D?Pediatrics. 2009;124(5):1404–1410. https://doi.org/10.1542/peds.2008-2041 PMID: doi:10.1542/peds.2008-2041 [CrossRef]
- Saintonge S, Bang H, Gerber LM. Implications of a new definition of vitamin D deficiency in a multiracial us adolescent population: the National Health and Nutrition Examination Survey III. Pediatrics. 2009;123(3):797–803. https://doi.org/10.1542/peds.2008-1195PMID: doi:10.1542/peds.2008-1195 [CrossRef]
- Matsuoka LY, Ide L, Wortsman J, MacLaughlin JA, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987;64(6):1165–1168. https://doi.org/10.1210/jcem-64-6-1165 PMID: doi:10.1210/jcem-64-6-1165 [CrossRef]
- Golden NH, Abrams SACommittee on Nutrition. Optimizing bone health in children and adolescents. Pediatrics. 2014;134(4):e1229–e1243. https://doi.org/10.1542/peds.2014-2173 PMID: doi:10.1542/peds.2014-2173 [CrossRef]
- Pereira-Santos M, Costa PR, Assis AM, Santos CA, Santos DB. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev. 2015;16(4):341–349. https://doi.org/10.1111/obr.12239 PMID: doi:10.1111/obr.12239 [CrossRef]
- Walsh JS, Bowles S, Evans AL. vitamin D in obesity. Curr Opin Endocrinol Diabetes Obes. 2017;24(6):389–394. https://doi.org/10.1097/MED.0000000000000371 PMID: doi:10.1097/MED.0000000000000371 [CrossRef]
- Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72(3):690–693. https://doi.org/10.1093/ajcn/72.3.690 PMID: doi:10.1093/ajcn/72.3.690 [CrossRef]
- Vandewalle S, Taes Y, Van Helvoirt M, et al. Bone size and bone strength are increased in obese male adolescents. J Clin Endocrinol Metab. 2013;98(7):3019–3028. https://doi.org/10.1210/jc.2012-3914 PMID: doi:10.1210/jc.2012-3914 [CrossRef]
- Fintini D, Brufani C, Grossi A, et al. Gender differences in bone mineral density in obese children during pubertal development. J Endocrinol Invest. 2011;34(4):e86–e91. https://doi.org/10.1007/BF03347097 PMID: doi:10.1007/BF03347097 [CrossRef]
- Kessler J, Koebnick C, Smith N, Adams A. Childhood obesity is associated with increased risk of most lower extremity fractures. Clin Orthop Relat Res. 2013;471(4):1199–1207. https://doi.org/10.1007/s11999-012-2621-z PMID: doi:10.1007/s11999-012-2621-z [CrossRef]
- Ekbom K, Marcus C. Vitamin D deficiency is associated with prediabetes in obese Swedish children. Acta Paediatr. 2016;105(10):1192–1197. https://doi.org/10.1111/apa.13363 PMID: doi:10.1111/apa.13363 [CrossRef]
- Chandler PD, Wang L, Zhang X, et al. Effect of vitamin D supplementation alone or with calcium on adiposity measures: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2015;73(9):577–593. https://doi.org/10.1093/nutrit/nuv012 PMID: doi:10.1093/nutrit/nuv012 [CrossRef]
- Bossé Y, Maghni K, Hudson TJ. 1alpha,25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes. Physiol Genomics. 2007;29(2):161–168. https://doi.org/10.1152/physiolgenomics.00134.2006PMID: doi:10.1152/physiolgenomics.00134.2006 [CrossRef]
- Dogru M, Kirmizibekmez H, Yesiltepe Mutlu RG, Aktas A, Ozturkmen S. Clinical effects of vitamin D in children with asthma. Int Arch Allergy Immunol. 2014;164(4):319–325. https://doi.org/10.1159/000366279 PMID: doi:10.1159/000366279 [CrossRef]
- Vo P, Bair-Merritt M, Camargo CA. The potential role of vitamin D in the link between obesity and asthma severity/control in children. Expert Rev Respir Med. 2015;9(3):309–325. https://doi.org/10.1586/17476348.2015.1042457 PMID: doi:10.1586/17476348.2015.1042457 [CrossRef]
- Berraies A, Hamzaoui K, Hamzaoui A. Link between vitamin D and airway remodeling. J Asthma Allergy. 2014;7:23–30. PMID:24729717
- Jolliffe DA, Greenberg L, Hooper RL, et al. vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 2017;5(11):881–890. https://doi.org/10.1016/S2213-2600(17)30306-5 PMID: doi:10.1016/S2213-2600(17)30306-5 [CrossRef]
- Altieri B, Muscogiuri G, Barrea L, et al. Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. Rev Endocr Metab Disord. 2017;18(3):335–346. https://doi.org/10.1007/s11154-016-9405-9 PMID: doi:10.1007/s11154-016-9405-9 [CrossRef]
- Muscogiuri G, Mitri J, Mathieu C, et al. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur J Endocrinol. 2014;171(3):R101–R110. https://doi.org/10.1530/EJE-14-0158 PMID: doi:10.1530/EJE-14-0158 [CrossRef]
- Liu C, Lu M, Xia X, et al. Correlation of serum vitamin D level with type 1 diabetes mellitus in children: a meta-analysis. Nutr Hosp. 2015;32(4):1591–1594. PMID:26545522
- Greer RM, Portelli SL, Hung BS, et al. Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes. Pediatr Diabetes. 2013;14(1):31–41. https://doi.org/10.1111/j.1399-5448.2012.00890.x PMID: doi:10.1111/j.1399-5448.2012.00890.x [CrossRef]
- Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008;93(6):512–517. https://doi.org/10.1136/adc.2007.128579 PMID: doi:10.1136/adc.2007.128579 [CrossRef]
- Simpson M, Brady H, Yin X, et al. No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia. 2011;54(11):2779–2788. https://doi.org/10.1007/s00125-011-2278-2 PMID: doi:10.1007/s00125-011-2278-2 [CrossRef]
- Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care. 2010;33(7):1443–1448. https://doi.org/10.2337/dc09-2297 PMID: doi:10.2337/dc09-2297 [CrossRef]
Conditions Associated with Vitamin D Deficiency in Children and Adolescents
Darker skin pigmentation or limited sun exposure
Chronic kidney disease
Malabsorption: inflammatory bowel disease, celiac disease, cystic fibrosis, radiation enteritis, eating disorders
Medications: anticonvulsants, gluco-corticoids, antifungals like ketoconazole, antiretroviral agents, cholestyramine