REVIEW URRENT C OPINION
Update on vitamin D during childhood Steven A. Abrams a and Dov Tiosano b
Purpose of review We propose to review several recent key clinically oriented topics related to vitamin D and health in children. Recent findings We found a very large number of recent clinical studies related to vitamin D. However, most are association studies with few physiological or clinical trials that are adequately powered for clinical outcomes. Key results are available related to pulmonary disease and allergic disorders. Recent studies have also evaluated the relationship of vitamin D to bone health as well as new insights into genetic conditions related to vitamin D metabolism. Summary Recent studies generally support the recommendations of the Institute of Medicine related to vitamin D intake but there is new and increasing evidence that some health conditions, such as pulmonary diseases in children, might benefit from close monitoring of vitamin D status. However, controlled trials are mostly lacking and there is an inadequate basis from recent studies to recommend high dose vitamin D pending the results of controlled trials. Keywords calcium metabolism, hypercalcium, rickets, vitamin D, vitamin D receptor
INTRODUCTION In November 2010, the Institute of Medicine (IOM) released updated recommendations for calcium and vitamin D in the diet [1]. Since then, thousands of peer-reviewed and other articles have appeared in the medical and lay literature about vitamin D. With this review, we will consider some specific recent findings related to pediatrics. Our goal is to focus on the insights gained in a small number of areas based and new research primarily released, and to provide updates regarding genetic factors related to vitamin D metabolism in children. Research into outcomes related to disease conditions of vitamin D supplementation and status is challenging to conduct. Some of the reasons for this are shown in Table 1.
diet, race and obesity in determining these relationships. We will consider several recent articles in this area that are representative of very recent research published on this topic. Tolppanen et al. [2 ] used an epidemiological approach to evaluate the relationship between serum 25(OH)D and respiratory symptoms including asthma and pulmonary function using a cohort of 3323 children who were about 10 years of age and part of the well characterized Avon Longitudinal Study of Parents and Children. Surprisingly, they found a small positive association between serum 25-hydroxyvitamin D3 [25(OH)D3] and wheezing and no significant relationship serum 25(OH)D3 and pulmonary function. &
PULMONARY AND ALLERGIC DISEASE An association between vitamin D and pulmonary function and disease has long been hypothesized. Anecdotal descriptions abound of asthmatic children who improved with vitamin D supplementation. Reports of an association between low serum 25-hydroxyvitamin D (25(OH)D) levels in the plasma and worse pulmonary disease exist. These, however, are limited by the challenges in determining the effects of key covariates, specially
a
United States Department of Agriculture/Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA and bPediatric Endocrinology, Rambam Healthcare Campus, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel Correspondence to Steven A. Abrams, MD, USDA/ARS Children’s Nutrition Research Center, 1100 Bates St, Houston, TX 77030, USA. Tel: +1 713 798 7164; fax: +1 713 798 7119; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:51–55 DOI:10.1097/01.med.0000436252.53459.ef
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KEY POINTS Evidence relating prenatal vitamin D status to allergic or respiratory symptoms remains inconclusive. Supplemental vitamin D above current recommendations is not associated with improved calcium absorption in children. Studies in hereditary vitamin D resistant rickets (HVDRR) patients show that after puberty, in the absence of vitamin D activity, sex hormones have a major role in calcium absorption. Accumulating findings highlight the role of vitamin D binding protein as an important factor influencing vitamin D levels and action. Mutations in CYP24A1 cause infantile hypercalcemia and may lead to renal calcinosis later in life.
This study has several limitations inherent in using birth cohorts studied over a long period of time. It is not optimal for answering the question as to whether very low, or even very high levels of serum 25(OH)D are associated with respiratory function or disease in children. The results may indicate the presence of a U-shaped curve in the relationship between 25(OH)D and outcomes, although this is not described in the results. This study does suggest that on a population basis, higher levels of 25(OH)D may not improve asthma outcomes and that the trials must be done without bias; that is, they should look for the possibility that supplementation worsens pulmonary function as well as improves it.
A recent study looked at a different, yet important issue related to this theme. In 2011, Camargo et al. [3] described the relationship between cord blood 25(OH)D and pulmonary symptoms later in life. They found a negative relationship between cord 25(OH)D and wheezing episodes by 5 years of age but not asthma. Of note is that the effect sizes were small and that the data were primarily analyzed by vitamin D level groups, in which the largest effect was seen in those with very low 25(OH)D levels ( 75 nmol/l (24% in this study), may reflect their other health characteristics that lead to higher sun exposure and vitamin D status. Furthermore, these comparisons leave out the largest group of most healthy populations, which is individuals who have 25(OH)D between 50 and 75 nmol/l. Comparisons of highest and lowest serum 25(OH)D level groups, leaving out the middle group, may misleadingly suggest that there is a &
Table 1. Challenges in conducting controlled studies of vitamin D and its effects on disease outcomes General Large variability in background 25(OH)D status Large variability in dose response to supplements due to body mass and possibly genetics Difficulty in controlling sunshine exposure Variable dietary intake of calcium, magnesium and other nutrients that will affect PTH and vitamin D metabolism Challenges in monitoring compliance with vitamin regimens Difficulties in fully controlling for race, gender, body mass index and similar covariates Specific to pregnancy and pediatrics Ethical and practical limitations in drawing repeated blood samples Ethical concerns about the use of placebo in pregnancy or in infant Difficulty in adjusting for effects of infant diet on bone mineral metabolism Ethical limitations in conducting controlled trials in children in which there may not be a benefit to the subjects involved Large variability in diagnosis and staging of common pediatric disorders including asthma and inflammatory bowel disease Challenges of dealing with effects of rapid growth and puberty in interpreting biological outcomes Difficulty in using DXA and similar techniques in pregnancy and early infancy
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Update on vitamin D during childho od Abrams and Tiosano
benefit to the highest 25(OH)D group compared with the more common intermediate values for serum 25(OH)D in the population. Taken together, these data provide minimal support for a major role of vitamin D either prenatally or early in life in affecting the risk of pulmonary or allergic disease with the possible exception of those who have 25(OH)D levels below 50 nmol/l, the level set by the IOM as appropriate for determining the recommended dietary allowance (RDA).
BONE HEALTH Recent studies related to bone health in children and vitamin D has focused on two practical issues, the relationship between vitamin D intake and calcium absorption and the relationship with fractures in children. We evaluated calcium absorption before and after supplementation with 1000 IU/day of vitamin D in 4–8-year-old healthy children [5]. We found no effect of the supplement on absorption but did find an effect of the supplement on decreasing parathyroid hormone levels. These data are consistent with previous research summarized by the IOM that indicated that vitamin D supplementation to achieve 25(OH)D levels above 40–50 nmol/l is unlikely to affect calcium absorption in healthy children. Whether there are physiological advantages of statistically lower PTH levels without apparent biological effects of higher 25(OH)D levels in some healthy children is uncertain. A key outcome in pediatrics is the relationship between vitamin D status or intake and fractures. This relationship has been difficult to identify because of the challenges of identifying unexpected low impact fractures versus clearly traumatic fractures and the difficulties in adjusting for age, activity, diet, body composition, ethnicity and many other factors affecting the likelihood of an otherwise healthy children developing a fracture. Using a case–control approach, Ryan et al. [6 ] evaluated 76 cases of African–American children with forearm fractures. Although they reported a significantly higher fracture rate among those children with low 25(OH)D, the differences in both mean and proportion of children with 25-OHD < 20 ng/dl were virtually identical (P > 0.4 for both relationships). Of note is that the fracture group had a significantly higher BMI. It is likely that the small increased risk of fracture seen in the adjusted model for low 25(OH)D was related to other factors or associated with a small number of children with very deficient vitamin D status rather than directly associated with a 25(OH)D < 20 ng/mL.
Regardless, these data are a reminder that very small case–control and similar approaches to determining the effects of low 25(OH)D levels on biological outcomes are not definitive and controlled trials or larger population studies are needed. This is specially true in relationship to outcomes in healthy children wherein other factors are likely to be associated with a bone health outcome.
HEREDITARY VITAMIN D RESISTANT RICKETS Studies in HVDRR patients who lack any vitamin D activity serve as an experiment by nature to study the native role of vitamin D in humans. Critical lessons related to vitamin D metabolism can be learned from patients with defects in vitamin D metabolism such as HVDRR. Lessons from patients with defects in vitamin D metabolism are as follows: (1) Absence of 1,25OH2D3 or vitamin D receptor (VDR) activity in utero dose not affect normal fetal development. (2) Ligand-independent actions of the vitamin D receptor maintain hair follicle homeostasis. (3) During infancy and childhood, with a low or normal calcium diet, absorption of calcium is vitamin D-dependent. (4) During and after puberty, with a low or normal calcium diet, calcium absorption can be vitamin D-independent. (5) After infancy and childhood, in the interrelations between vitamin D, calcium absorption, and PTH, factors such as sex hormones and prolactin have a major role. (6) Vitamin D binding protein polymorphic variants play an important role in vitamin D levels and effects. (7) Mutations in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase lead to infantile hypercalcemia, hypercalciuria and nephrocalcinosis.
&&
HVDDR is characterized by severe rickets, hypocalcemia, hypophosphatemia, elevated serum PTH and 1,25(OH)2D3, and alopecia. During infancy and childhood, HVDRR patients require huge doses of intravenous and oral calcium supplementation to maintain near normal serum calcium levels and to treat rickets [7]. Surprisingly, there is spontaneous normalization of serum calcium, phosphate and alkaline phosphatase levels after puberty, without the need for calcium supplementation [8]. Recently, Tiosano et al. [9] showed that during infancy and childhood, the active, vitamin D-dependent calcium absorption in HVDRR patients receiving a
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low calcium diet is very low. However, after puberty, for at least 10 years, their calcium absorption during low calcium diet increased to a normal level, indicating that after puberty, even in the absence of vitamin D activity, calcium absorption can occur appropriately in the presence of sex hormones. Furthermore, HVDRR patients show normal areal BMD and bone structure after puberty. Overall, the evidence from HVDRR patients reveals that calcium absorption is highly vitamin D-dependent during infancy until the end of puberty, after which there is a period of about 10 years in which mechanisms other than D-dependent ones are substantially involved in intestinal calcium absorption. In concordance with these observations, Valcour et al. [10 ] studied the relationship between serum PTH and 25(OH)D levels in individuals throughout the lifespan and found that the incidence of a serum PTH greater than 65 pg/ml in the presence of 25(OH)D of 20 ng/ml is 27% below the age of 20 years, 34% at the age of 20–40, 45% between 40–60 and 52% above 60 years. These differences may reflect the potential influence of sex hormones on calcium absorption. Similar results that emphasize the impact of age on the PTH, 25(OH)D relationship and may reflect the role as sex hormone in this relationship were found previously [11]. &
VITAMIN D METABOLISM AND MINERALIZATION In the absence of vitamin D, specially during infancy and childhood, less calcium is absorbed leading to increased PTH secretion to enhance the release of calcium and phosphorus from the bone. This is necessary to maintain normal calcium levels for the essential neuromuscular function. In the kidney, PTH leads to phosphaturia and enhances 1-alphahydroxylase activity to generate 1,25(OH)2D. Recently, Libden et al. [12 ] in a seminal study reported that in addition to the well documented data that the mineralization inhibitor Opn is a 1,25(OH)2D-responsive gene [13], 1,25(OH)2D increases pyrophosphate (PPi) levels via the transcriptional control especially Ank and Enpp3 expression and that this mechanism played a crucial role in the 1,25(OH)2D-mediated suppression of mineral incorporation to maintain normal serum calcium levels. The absence of an intact vitamin D receptor in the HVDRR patients explains why they achieved normal bone mineralization once their serum phosphorus and calcium levels were normalized. &&
VITAMIN D BINDING PROTEIN The ongoing discussion as to what is the optimal serum 25(OH)D levels and the understanding that there is a tissue-specific conversion of 25(OH)D to 54
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1,25(OH)2D has brought attention to the role of vitamin D binding protein (DBP) (also known as group-specific component, Gc) in vitamin D metabolism. Almost all vitamin D metabolites circulate bound to DBP with high affinity and to serum albumin with low affinity. Furthermore, DBP serves as the ligand for the megalin/cubulin complex that mediates entry of bound 25(OH)D into renal tubular cells and monocytes [14]. A key feature of DBP is the three polymorphic variants of this protein, the Gc1F, Gc1S and Gc2 genotypes. Gc1F has the highest affinity to 25OHD2 and 1,25(OH)2D3 and Gc2 the lowest. Carpenter et al. [15 ] demonstrated that GC genotype affects circulating 25(OHD) independently of its effect on circulating DBP and that the genetic variance of the common Gc2 allele affects circulating levels of the DBP protein, which in turn affects circulating 25-OHD in young children. Chun et al. [14] have shown that Monocytes cultured in DBP/ serum showed more potent induction of cathelicidin by 25(OH)D3 or 1,25(OH)2D3 when compared with DBPþ/ serum. Likewise, DBP added to serum-free medium attenuated 25OHD3/1,25(OH)2D3 responses. Human serum containing low-affinity Gc2-1S or Gc2-2, respectively, induced higher cathelicidin levels by 25(OH)D relative to cells cultured with high affinity Gc1F-1F. In concordance with these results, several studies showed association between the Gc1F allele and increased risk of chronic obstructive pulmonary disease and syphilis infection [15 ]. It is possible that individuals with the low affinity Gc2-1S and Gc2-2 need low levels of 25(OH)D and individuals with the high affinity Gc1F-1F phenotype need higher vitamin D levels. &&
&&
HYPERCALCEMIA AND VITAMIN D Vitamin D metabolism defects are mainly related to hypocalcaemia, rickets and osteomalcia. Yet, in some cases, alterations in vitamin D metabolism can cause hypercalcemia as can subcutaneous fat necrosis. The appropriate plasma calcium level is maintained by three major hormones; PTH, 1,25(OH)2D3 and calcitonin. They act primarily at bone, kidney and small intestine. Hypercalcemia can be divided into PTH-related and non-PTHrelated. The common denominator for the nonPTH causes of hypercalcemia are elevated serum 1,25(OH)2D3 levels. That may be because of the overproduction of 1,25(OH)2D3 as seen in granulomatous diseases [16], impaired catabolism of 1,25(OH)2D3 and vitamin D intoxication. Normally, analyses of vitamin D metabolites in healthy persons who are receiving high doses of vitamin D have shown that in contrast to sharp Volume 21 Number 1 February 2014
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Update on vitamin D during childho od Abrams and Tiosano
increases in levels of serum 25(OH)D3 and its inactive products, serum 1,25(OH)2D3 D3 levels remain within the normal reference range, indicating tight regulative mechanisms. Recently, Schlingmann et al. [17] and others [18] have reported that patients with idiopathic infantile hypercalcemia have an exaggerated and prolonged increase in the levels of active 1,25(OH)2D3 after receiving prophylactic vitamin D, reflecting impaired catabolism of 1,25(OH)2D3 due to a mutation in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25(OH)2D3 degradation. The clinical presentation spectrum varies from failure to thrive, dehydration, hypotonia, lethargy and vomiting during infancy to late presentation of nephrocalcinosis. Laboratory and imaging tests reveal hypercalcemia, suppressed parathyroid hormone, hypercalciuria, elevated 1,25(OH)2D3, 25(OH)D3 and nephrocalcinosis. The treatment modalities in these cases varies from withdrawal of vitamin D supplementation, parenteral rehydration, diuretic therapy (furosemide 2 mg/kg/day), corticosteroids (methylprednisolone 3–4 mg/kg/ day) and the administration of bisphosphonates (pamidronate 1 mg/kg, single dose) to acute hemodiafiltration in severe cases. Clinical concern for hypercalcemia related to vitamin D intoxication has increased recently because of the marketing of highly concentrated vitamin D containing drops for infant and small child use in the USA. This clinical entity in otherwise healthy children may be on the rise and is of concern [19].
CONCLUSION Recent studies related to vitamin D have emphasized specific clinical conditions that may be associated with low serum 25(OH)D and physiological mechanisms underlying the role of vitamin D in both calcium absorption and other biological processes. Progress in these areas is rapid and provides new insights, specially mechanistic ones, but clinical outcome data remain mixed, largely because of a limited number of well performed controlled clinical trials. Acknowledgements This work is a publication of the US Department of Agriculture (USDA)/Agricultural Research Service (ARS) Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, and Texas Children’s Hospital, Houston, Texas. This project has been funded in part with federal funds from the USDA/ARS under Cooperative Agreement number 58–6250–6– 001. Contents of this publication do not necessarily
reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011. 2. Tolppanen AM, Sayers A, Granell R, et al. Prospective association of & 25-hydroxyvitamin D3 and d2 with childhood lung function, asthma, wheezing, and flexural dermatitis. Epidemiology 2013; 24:310–319. This study provides some evidence of an epidemiological relationship between vitamin D and pulmonary and dermatologic conditions. 3. Camargo CA, Ingham T, Wickens K, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011; 127:; e180. 4. Jones AP, Palmer D, Zhang G, Prescott SL. Cord blood 25-hydroxyvitamin D3 & and allergic disease during infancy. Pediatrics 2012; 130:e1128–e1135. This study identified a significant relationship between cord blood 25(OH)D values and allergic disorders later in early childhood. 5. Abrams SA, Hawthorne KM, Chen Z. Supplementation with 1000 IU/day of vitamin D leads to parathyroid hormone suppression, but not increased fractional calcium absorption, in 4 to 8 year old children: a double-blind, randomized controlled trial. Am J Clin Nutr 2013; 97:217–233. 6. Ryan LM, Teach SJ, Singer SA, et al. Bone mineral density and vitamin D && status among African American children with forearm fractures. Pediatrics 2012; 130:e553–e560. This case-control study suggested that children with low vitamin D status had a greater risk of bone fractures, but it is not clear if this is a true cause and effect relationship 7. Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J Pediatr 1992; 121:803–808. 8. Hochberg Z, Benderli A, Levy J, et al. 1,25-Dihydroxyvitamin D resistance, rickets, and alopecia. Am J Med 1984; 77:805–811. 9. Tiosano D, Hadad S, Chen Z, et al. Calcium absorption, kinetics, bone density and structure in prepubertal, pubertal and adult patients with Hereditary Vitamin D Resistance Rickets (HVDRR). J Clin Endocrinol Metab 2011; 96:3701–3709. 10. Valcour A, Blocki F, Hawkins DM, Rao SD. Effects of age and serum & 25-OH-vitamin D on serum parathyroid hormone levels. J Clin Endocrinol Metab 2012; 97:3989–3995. This study illustrates the changing relations between vitamin D and PTH at different ages. 11. Arabi A, Baddoura R, El-Rassi R, el-Hajj FG. Age but not gender modulates the relationship between PTH and vitamin D. Bone 2010; 47:408–412. 12. Libden L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in && mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122:1803–1805. This study explores the interaction between vitamin D metabolism and mineralization. 13. Meyer MG, Goetsch PD, Pike PW. Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone. J Steroid Biochem Mol Biol 2010; 121:136–141. 14. Chun RF, Lauridsen AL, Suon L, et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 2010; 95:3368–3376. 15. Carpenter TO, Zhang JH, Parra E. Vitamin D binding protein is a key && determinant of 25-hydroxyvitamin D levels in infants and toddlers. J Bone Miner Res 2013; 28:213–221. This study explores the link between vitamin D binding protein and serum vitamin D levels. 16. Kallas M, Green F, Hewison M, et al. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab 2010; 95:3111–3117. 17. Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med 2011; 365:410–421. 18. Dauber A, Nguyen TT, Sochett E, et al. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J Clin Endocrinol Metab 2012; 9:E268–E274. 19. Vanstone MB, Oberfield SE, Shader L, et al. Hypercalcemia in children receiving pharmacologic doses of vitamin D. Pediatrics 2012; 129:e1060–e1063.
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Update on vitamin D during childhood Steven A. Abrams a and Dov Tiosano b
Purpose of review We propose to review several recent key clinically oriented topics related to vitamin D and health in children. Recent findings We found a very large number of recent clinical studies related to vitamin D. However, most are association studies with few physiological or clinical trials that are adequately powered for clinical outcomes. Key results are available related to pulmonary disease and allergic disorders. Recent studies have also evaluated the relationship of vitamin D to bone health as well as new insights into genetic conditions related to vitamin D metabolism. Summary Recent studies generally support the recommendations of the Institute of Medicine related to vitamin D intake but there is new and increasing evidence that some health conditions, such as pulmonary diseases in children, might benefit from close monitoring of vitamin D status. However, controlled trials are mostly lacking and there is an inadequate basis from recent studies to recommend high dose vitamin D pending the results of controlled trials. Keywords calcium metabolism, hypercalcium, rickets, vitamin D, vitamin D receptor
INTRODUCTION In November 2010, the Institute of Medicine (IOM) released updated recommendations for calcium and vitamin D in the diet [1]. Since then, thousands of peer-reviewed and other articles have appeared in the medical and lay literature about vitamin D. With this review, we will consider some specific recent findings related to pediatrics. Our goal is to focus on the insights gained in a small number of areas based and new research primarily released, and to provide updates regarding genetic factors related to vitamin D metabolism in children. Research into outcomes related to disease conditions of vitamin D supplementation and status is challenging to conduct. Some of the reasons for this are shown in Table 1.
diet, race and obesity in determining these relationships. We will consider several recent articles in this area that are representative of very recent research published on this topic. Tolppanen et al. [2 ] used an epidemiological approach to evaluate the relationship between serum 25(OH)D and respiratory symptoms including asthma and pulmonary function using a cohort of 3323 children who were about 10 years of age and part of the well characterized Avon Longitudinal Study of Parents and Children. Surprisingly, they found a small positive association between serum 25-hydroxyvitamin D3 [25(OH)D3] and wheezing and no significant relationship serum 25(OH)D3 and pulmonary function. &
PULMONARY AND ALLERGIC DISEASE An association between vitamin D and pulmonary function and disease has long been hypothesized. Anecdotal descriptions abound of asthmatic children who improved with vitamin D supplementation. Reports of an association between low serum 25-hydroxyvitamin D (25(OH)D) levels in the plasma and worse pulmonary disease exist. These, however, are limited by the challenges in determining the effects of key covariates, specially
a
United States Department of Agriculture/Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA and bPediatric Endocrinology, Rambam Healthcare Campus, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel Correspondence to Steven A. Abrams, MD, USDA/ARS Children’s Nutrition Research Center, 1100 Bates St, Houston, TX 77030, USA. Tel: +1 713 798 7164; fax: +1 713 798 7119; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2014, 21:51–55 DOI:10.1097/01.med.0000436252.53459.ef
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Growth and development
KEY POINTS Evidence relating prenatal vitamin D status to allergic or respiratory symptoms remains inconclusive. Supplemental vitamin D above current recommendations is not associated with improved calcium absorption in children. Studies in hereditary vitamin D resistant rickets (HVDRR) patients show that after puberty, in the absence of vitamin D activity, sex hormones have a major role in calcium absorption. Accumulating findings highlight the role of vitamin D binding protein as an important factor influencing vitamin D levels and action. Mutations in CYP24A1 cause infantile hypercalcemia and may lead to renal calcinosis later in life.
This study has several limitations inherent in using birth cohorts studied over a long period of time. It is not optimal for answering the question as to whether very low, or even very high levels of serum 25(OH)D are associated with respiratory function or disease in children. The results may indicate the presence of a U-shaped curve in the relationship between 25(OH)D and outcomes, although this is not described in the results. This study does suggest that on a population basis, higher levels of 25(OH)D may not improve asthma outcomes and that the trials must be done without bias; that is, they should look for the possibility that supplementation worsens pulmonary function as well as improves it.
A recent study looked at a different, yet important issue related to this theme. In 2011, Camargo et al. [3] described the relationship between cord blood 25(OH)D and pulmonary symptoms later in life. They found a negative relationship between cord 25(OH)D and wheezing episodes by 5 years of age but not asthma. Of note is that the effect sizes were small and that the data were primarily analyzed by vitamin D level groups, in which the largest effect was seen in those with very low 25(OH)D levels ( 75 nmol/l (24% in this study), may reflect their other health characteristics that lead to higher sun exposure and vitamin D status. Furthermore, these comparisons leave out the largest group of most healthy populations, which is individuals who have 25(OH)D between 50 and 75 nmol/l. Comparisons of highest and lowest serum 25(OH)D level groups, leaving out the middle group, may misleadingly suggest that there is a &
Table 1. Challenges in conducting controlled studies of vitamin D and its effects on disease outcomes General Large variability in background 25(OH)D status Large variability in dose response to supplements due to body mass and possibly genetics Difficulty in controlling sunshine exposure Variable dietary intake of calcium, magnesium and other nutrients that will affect PTH and vitamin D metabolism Challenges in monitoring compliance with vitamin regimens Difficulties in fully controlling for race, gender, body mass index and similar covariates Specific to pregnancy and pediatrics Ethical and practical limitations in drawing repeated blood samples Ethical concerns about the use of placebo in pregnancy or in infant Difficulty in adjusting for effects of infant diet on bone mineral metabolism Ethical limitations in conducting controlled trials in children in which there may not be a benefit to the subjects involved Large variability in diagnosis and staging of common pediatric disorders including asthma and inflammatory bowel disease Challenges of dealing with effects of rapid growth and puberty in interpreting biological outcomes Difficulty in using DXA and similar techniques in pregnancy and early infancy
52
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Update on vitamin D during childho od Abrams and Tiosano
benefit to the highest 25(OH)D group compared with the more common intermediate values for serum 25(OH)D in the population. Taken together, these data provide minimal support for a major role of vitamin D either prenatally or early in life in affecting the risk of pulmonary or allergic disease with the possible exception of those who have 25(OH)D levels below 50 nmol/l, the level set by the IOM as appropriate for determining the recommended dietary allowance (RDA).
BONE HEALTH Recent studies related to bone health in children and vitamin D has focused on two practical issues, the relationship between vitamin D intake and calcium absorption and the relationship with fractures in children. We evaluated calcium absorption before and after supplementation with 1000 IU/day of vitamin D in 4–8-year-old healthy children [5]. We found no effect of the supplement on absorption but did find an effect of the supplement on decreasing parathyroid hormone levels. These data are consistent with previous research summarized by the IOM that indicated that vitamin D supplementation to achieve 25(OH)D levels above 40–50 nmol/l is unlikely to affect calcium absorption in healthy children. Whether there are physiological advantages of statistically lower PTH levels without apparent biological effects of higher 25(OH)D levels in some healthy children is uncertain. A key outcome in pediatrics is the relationship between vitamin D status or intake and fractures. This relationship has been difficult to identify because of the challenges of identifying unexpected low impact fractures versus clearly traumatic fractures and the difficulties in adjusting for age, activity, diet, body composition, ethnicity and many other factors affecting the likelihood of an otherwise healthy children developing a fracture. Using a case–control approach, Ryan et al. [6 ] evaluated 76 cases of African–American children with forearm fractures. Although they reported a significantly higher fracture rate among those children with low 25(OH)D, the differences in both mean and proportion of children with 25-OHD < 20 ng/dl were virtually identical (P > 0.4 for both relationships). Of note is that the fracture group had a significantly higher BMI. It is likely that the small increased risk of fracture seen in the adjusted model for low 25(OH)D was related to other factors or associated with a small number of children with very deficient vitamin D status rather than directly associated with a 25(OH)D < 20 ng/mL.
Regardless, these data are a reminder that very small case–control and similar approaches to determining the effects of low 25(OH)D levels on biological outcomes are not definitive and controlled trials or larger population studies are needed. This is specially true in relationship to outcomes in healthy children wherein other factors are likely to be associated with a bone health outcome.
HEREDITARY VITAMIN D RESISTANT RICKETS Studies in HVDRR patients who lack any vitamin D activity serve as an experiment by nature to study the native role of vitamin D in humans. Critical lessons related to vitamin D metabolism can be learned from patients with defects in vitamin D metabolism such as HVDRR. Lessons from patients with defects in vitamin D metabolism are as follows: (1) Absence of 1,25OH2D3 or vitamin D receptor (VDR) activity in utero dose not affect normal fetal development. (2) Ligand-independent actions of the vitamin D receptor maintain hair follicle homeostasis. (3) During infancy and childhood, with a low or normal calcium diet, absorption of calcium is vitamin D-dependent. (4) During and after puberty, with a low or normal calcium diet, calcium absorption can be vitamin D-independent. (5) After infancy and childhood, in the interrelations between vitamin D, calcium absorption, and PTH, factors such as sex hormones and prolactin have a major role. (6) Vitamin D binding protein polymorphic variants play an important role in vitamin D levels and effects. (7) Mutations in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase lead to infantile hypercalcemia, hypercalciuria and nephrocalcinosis.
&&
HVDDR is characterized by severe rickets, hypocalcemia, hypophosphatemia, elevated serum PTH and 1,25(OH)2D3, and alopecia. During infancy and childhood, HVDRR patients require huge doses of intravenous and oral calcium supplementation to maintain near normal serum calcium levels and to treat rickets [7]. Surprisingly, there is spontaneous normalization of serum calcium, phosphate and alkaline phosphatase levels after puberty, without the need for calcium supplementation [8]. Recently, Tiosano et al. [9] showed that during infancy and childhood, the active, vitamin D-dependent calcium absorption in HVDRR patients receiving a
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Growth and development
low calcium diet is very low. However, after puberty, for at least 10 years, their calcium absorption during low calcium diet increased to a normal level, indicating that after puberty, even in the absence of vitamin D activity, calcium absorption can occur appropriately in the presence of sex hormones. Furthermore, HVDRR patients show normal areal BMD and bone structure after puberty. Overall, the evidence from HVDRR patients reveals that calcium absorption is highly vitamin D-dependent during infancy until the end of puberty, after which there is a period of about 10 years in which mechanisms other than D-dependent ones are substantially involved in intestinal calcium absorption. In concordance with these observations, Valcour et al. [10 ] studied the relationship between serum PTH and 25(OH)D levels in individuals throughout the lifespan and found that the incidence of a serum PTH greater than 65 pg/ml in the presence of 25(OH)D of 20 ng/ml is 27% below the age of 20 years, 34% at the age of 20–40, 45% between 40–60 and 52% above 60 years. These differences may reflect the potential influence of sex hormones on calcium absorption. Similar results that emphasize the impact of age on the PTH, 25(OH)D relationship and may reflect the role as sex hormone in this relationship were found previously [11]. &
VITAMIN D METABOLISM AND MINERALIZATION In the absence of vitamin D, specially during infancy and childhood, less calcium is absorbed leading to increased PTH secretion to enhance the release of calcium and phosphorus from the bone. This is necessary to maintain normal calcium levels for the essential neuromuscular function. In the kidney, PTH leads to phosphaturia and enhances 1-alphahydroxylase activity to generate 1,25(OH)2D. Recently, Libden et al. [12 ] in a seminal study reported that in addition to the well documented data that the mineralization inhibitor Opn is a 1,25(OH)2D-responsive gene [13], 1,25(OH)2D increases pyrophosphate (PPi) levels via the transcriptional control especially Ank and Enpp3 expression and that this mechanism played a crucial role in the 1,25(OH)2D-mediated suppression of mineral incorporation to maintain normal serum calcium levels. The absence of an intact vitamin D receptor in the HVDRR patients explains why they achieved normal bone mineralization once their serum phosphorus and calcium levels were normalized. &&
VITAMIN D BINDING PROTEIN The ongoing discussion as to what is the optimal serum 25(OH)D levels and the understanding that there is a tissue-specific conversion of 25(OH)D to 54
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1,25(OH)2D has brought attention to the role of vitamin D binding protein (DBP) (also known as group-specific component, Gc) in vitamin D metabolism. Almost all vitamin D metabolites circulate bound to DBP with high affinity and to serum albumin with low affinity. Furthermore, DBP serves as the ligand for the megalin/cubulin complex that mediates entry of bound 25(OH)D into renal tubular cells and monocytes [14]. A key feature of DBP is the three polymorphic variants of this protein, the Gc1F, Gc1S and Gc2 genotypes. Gc1F has the highest affinity to 25OHD2 and 1,25(OH)2D3 and Gc2 the lowest. Carpenter et al. [15 ] demonstrated that GC genotype affects circulating 25(OHD) independently of its effect on circulating DBP and that the genetic variance of the common Gc2 allele affects circulating levels of the DBP protein, which in turn affects circulating 25-OHD in young children. Chun et al. [14] have shown that Monocytes cultured in DBP/ serum showed more potent induction of cathelicidin by 25(OH)D3 or 1,25(OH)2D3 when compared with DBPþ/ serum. Likewise, DBP added to serum-free medium attenuated 25OHD3/1,25(OH)2D3 responses. Human serum containing low-affinity Gc2-1S or Gc2-2, respectively, induced higher cathelicidin levels by 25(OH)D relative to cells cultured with high affinity Gc1F-1F. In concordance with these results, several studies showed association between the Gc1F allele and increased risk of chronic obstructive pulmonary disease and syphilis infection [15 ]. It is possible that individuals with the low affinity Gc2-1S and Gc2-2 need low levels of 25(OH)D and individuals with the high affinity Gc1F-1F phenotype need higher vitamin D levels. &&
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HYPERCALCEMIA AND VITAMIN D Vitamin D metabolism defects are mainly related to hypocalcaemia, rickets and osteomalcia. Yet, in some cases, alterations in vitamin D metabolism can cause hypercalcemia as can subcutaneous fat necrosis. The appropriate plasma calcium level is maintained by three major hormones; PTH, 1,25(OH)2D3 and calcitonin. They act primarily at bone, kidney and small intestine. Hypercalcemia can be divided into PTH-related and non-PTHrelated. The common denominator for the nonPTH causes of hypercalcemia are elevated serum 1,25(OH)2D3 levels. That may be because of the overproduction of 1,25(OH)2D3 as seen in granulomatous diseases [16], impaired catabolism of 1,25(OH)2D3 and vitamin D intoxication. Normally, analyses of vitamin D metabolites in healthy persons who are receiving high doses of vitamin D have shown that in contrast to sharp Volume 21 Number 1 February 2014
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Update on vitamin D during childho od Abrams and Tiosano
increases in levels of serum 25(OH)D3 and its inactive products, serum 1,25(OH)2D3 D3 levels remain within the normal reference range, indicating tight regulative mechanisms. Recently, Schlingmann et al. [17] and others [18] have reported that patients with idiopathic infantile hypercalcemia have an exaggerated and prolonged increase in the levels of active 1,25(OH)2D3 after receiving prophylactic vitamin D, reflecting impaired catabolism of 1,25(OH)2D3 due to a mutation in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25(OH)2D3 degradation. The clinical presentation spectrum varies from failure to thrive, dehydration, hypotonia, lethargy and vomiting during infancy to late presentation of nephrocalcinosis. Laboratory and imaging tests reveal hypercalcemia, suppressed parathyroid hormone, hypercalciuria, elevated 1,25(OH)2D3, 25(OH)D3 and nephrocalcinosis. The treatment modalities in these cases varies from withdrawal of vitamin D supplementation, parenteral rehydration, diuretic therapy (furosemide 2 mg/kg/day), corticosteroids (methylprednisolone 3–4 mg/kg/ day) and the administration of bisphosphonates (pamidronate 1 mg/kg, single dose) to acute hemodiafiltration in severe cases. Clinical concern for hypercalcemia related to vitamin D intoxication has increased recently because of the marketing of highly concentrated vitamin D containing drops for infant and small child use in the USA. This clinical entity in otherwise healthy children may be on the rise and is of concern [19].
CONCLUSION Recent studies related to vitamin D have emphasized specific clinical conditions that may be associated with low serum 25(OH)D and physiological mechanisms underlying the role of vitamin D in both calcium absorption and other biological processes. Progress in these areas is rapid and provides new insights, specially mechanistic ones, but clinical outcome data remain mixed, largely because of a limited number of well performed controlled clinical trials. Acknowledgements This work is a publication of the US Department of Agriculture (USDA)/Agricultural Research Service (ARS) Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, and Texas Children’s Hospital, Houston, Texas. This project has been funded in part with federal funds from the USDA/ARS under Cooperative Agreement number 58–6250–6– 001. Contents of this publication do not necessarily
reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011. 2. Tolppanen AM, Sayers A, Granell R, et al. Prospective association of & 25-hydroxyvitamin D3 and d2 with childhood lung function, asthma, wheezing, and flexural dermatitis. Epidemiology 2013; 24:310–319. This study provides some evidence of an epidemiological relationship between vitamin D and pulmonary and dermatologic conditions. 3. Camargo CA, Ingham T, Wickens K, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011; 127:; e180. 4. Jones AP, Palmer D, Zhang G, Prescott SL. Cord blood 25-hydroxyvitamin D3 & and allergic disease during infancy. Pediatrics 2012; 130:e1128–e1135. This study identified a significant relationship between cord blood 25(OH)D values and allergic disorders later in early childhood. 5. Abrams SA, Hawthorne KM, Chen Z. Supplementation with 1000 IU/day of vitamin D leads to parathyroid hormone suppression, but not increased fractional calcium absorption, in 4 to 8 year old children: a double-blind, randomized controlled trial. Am J Clin Nutr 2013; 97:217–233. 6. Ryan LM, Teach SJ, Singer SA, et al. Bone mineral density and vitamin D && status among African American children with forearm fractures. Pediatrics 2012; 130:e553–e560. This case-control study suggested that children with low vitamin D status had a greater risk of bone fractures, but it is not clear if this is a true cause and effect relationship 7. Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J Pediatr 1992; 121:803–808. 8. Hochberg Z, Benderli A, Levy J, et al. 1,25-Dihydroxyvitamin D resistance, rickets, and alopecia. Am J Med 1984; 77:805–811. 9. Tiosano D, Hadad S, Chen Z, et al. Calcium absorption, kinetics, bone density and structure in prepubertal, pubertal and adult patients with Hereditary Vitamin D Resistance Rickets (HVDRR). J Clin Endocrinol Metab 2011; 96:3701–3709. 10. Valcour A, Blocki F, Hawkins DM, Rao SD. Effects of age and serum & 25-OH-vitamin D on serum parathyroid hormone levels. J Clin Endocrinol Metab 2012; 97:3989–3995. This study illustrates the changing relations between vitamin D and PTH at different ages. 11. Arabi A, Baddoura R, El-Rassi R, el-Hajj FG. Age but not gender modulates the relationship between PTH and vitamin D. Bone 2010; 47:408–412. 12. Libden L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in && mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122:1803–1805. This study explores the interaction between vitamin D metabolism and mineralization. 13. Meyer MG, Goetsch PD, Pike PW. Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone. J Steroid Biochem Mol Biol 2010; 121:136–141. 14. Chun RF, Lauridsen AL, Suon L, et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 2010; 95:3368–3376. 15. Carpenter TO, Zhang JH, Parra E. Vitamin D binding protein is a key && determinant of 25-hydroxyvitamin D levels in infants and toddlers. J Bone Miner Res 2013; 28:213–221. This study explores the link between vitamin D binding protein and serum vitamin D levels. 16. Kallas M, Green F, Hewison M, et al. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab 2010; 95:3111–3117. 17. Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med 2011; 365:410–421. 18. Dauber A, Nguyen TT, Sochett E, et al. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J Clin Endocrinol Metab 2012; 9:E268–E274. 19. Vanstone MB, Oberfield SE, Shader L, et al. Hypercalcemia in children receiving pharmacologic doses of vitamin D. Pediatrics 2012; 129:e1060–e1063.
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