Randomized Vitamin D Supplementation in Vitamin D Deficient Obese Children from West Virginia

Objective: Vitamin D (Vit D) defi ciency is a very common problem in obese children, but clinical guidelines for maintenance or treatment have not been published for this population. The aim was to assess the benefi t of 2 months Vit D supplementation given to defi cient obese children from WV. Design: Vit D defi cient obese children were prospectively recruited. Exclusion criteria included <8 years, and medical conditions that may affect Vit D homeostasis. Participants were randomized into two supplement groups: 5,000IU/day (Group A) or 50,000IU/week (Group B). Serum 25(OH)D levels were measured at baseline and post-treatment. Results: Sixty obese children were screened of whom 39 (65%) were defi cient (<20ng/ml). Of the 39 recruited, 26 completed the study. The mean serum 25(OH)D after 2 months treatment were signifi cantly higher in Group B (p= 0.02), but most reached normal levels (>30ng/ml). Conclusions: Two months Vit D supplementation (5000IU/day or 50,000IU/week) was suffi cient to normalize 25(OH)D levels in Vit D defi cient obese West Virginian children. Research Article Randomized Vitamin D Supplementation in Vitamin D Defi cient Obese Children from West Virginia Yoram Elitsur* and Deborah L Preston Department of Pediatrics, Gastroenterology Division, Marshall University, Joan C Edwards School of Medicine, Huntington, WV, USA Dates: Received: 23 November, 2016; Accepted: 07 December, 2016; Published: 08 December, 2016 *Corresponding author: Yoram Elitsur, MD, 1600 Medical Center Drive, Suite 3500, Huntington, WV 25701, Tel: 304-691-1381; Fax: 304-691-1769; E-mail:


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has also been recognized including the immune system, endocrine system (diabetes, obesity), infection, and other conditions [1][2][3][4]. Vit D can be acquired by children through sun exposure, specifi c foods with high Vit D content and/or foods supplemented with Vit D, or direct supplementation. Obesity and Vit D defi ciency are known epidemics throughout the world [5]. In a large report, high rates of Vit D defi ciency were documented in American children, and several high risk factors were identifi ed including: obesity, ethnicity, female gender, and sun exposure time [6]. To date, the published Recommended Dietary Allowances (RDA) of Vit D for normal, healthy children, have been found insuffi cient for those children belonging to those high risk groups [6]. In a recent review of the subject, the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guideline on Nutrition recognized that children with high risk conditions were not specifi cally addressed, and allowed for Vit D dose changes depending on local circumstances in different communities [7]. Others recommended following Vit D serum levels (25(OH)D) every 6 months in order to prevent defi ciency in children [8]. The current RDA for normal weight healthy children older than 8 years is 3,000IU-4,000IU/day and normal serum 25(OH)D is defi ned as >30ng/ml [7,9,10].
The obesity rate in children living in West Virginia was reported as one of the highest in the United States [11]. Obesity has been recognized as a major high risk condition for Vit D defi ciency in children, but no offi cial RDA or recommended therapeutic dose for Vit D defi cient obese children have been

Patient population
We have calculated that the number of patients needed is > 40 children (estimated sample size when alpha-0.05, power-80%, delta-0.19). Accordingly, we prospectively screened 60 obese children who attended the Pediatric Gastroenterology clinic for various clinical symptoms. Exclusion criteria included children <8 years, inability to swallow pills, and the following medical conditions: hypercalcemia, mal-absorption syndromes (celiac disease, cystic fi brosis, IBD), endocrine diseases that affect Vit D or calcium homeostasis (hypo/hyperthyroidism), diseases or medications that affect bone metabolism (steroids), or diseases that may affect the immune system (immunosuppressive meds, biologic medications) [12,13]. Obesity was defi ned according to the CDC BMI chart (>95%tile). Children with Vit D defi ciency (< 20ng/ml), who met the eligibility criteria, (4,000IU/day) was insuffi cient to maintain adequate serum levels (>30ng/ml) in over 20% of them [6]. The higher dose (50,000IU/week) was chosen as it was recommended by the Endocrine Society's practice guidelines for normal weight children, and was successfully used in Vit D defi cient children with chronic diseases [10,14,15). The study period was assigned 8 weeks as previous data showed that it was safe [7,10,14,15].
The study's primary outcome was to investigate the success rate of each dose to achieve normal serum levels after 2 months of supplementation. The secondary outcome was to assess the compliance rate between both modes of administration (daily vs. weekly).

Statistical analysis
Statistical analyses were performed using GraphPad Prism for Windows version 6.02 (GraphPad Software, Inc. La Jolla, CA). A non-parametrical test (Mann Whitney test) was used to assess the difference between the groups. A one way ANOVA was used to assess the differences between the mean seasonal data. Chi-square analysis was used to determine the differences in the compliance data.  (Table 1). Mean Vit D levels post-treatment were signifi cantly lower in Group A compared to Group B (p = 0.027), but both groups' averages were within the defi ned suffi cient levels (>30ng/ml) ( Table   1) Table 1). suffi cient to achieve normal levels (>30ng/ml). As expected, none of our patients reached toxicity levels (> 150ng/ml). The handful of pediatric cases reported with Vit D toxicity suggested that the supplementation dose associated with toxicity is much higher (factor of >100) than the doses used in our study [17][18][19]. Consequently, under our study's conditions, Vit D toxicity was very unlikely.

Discussion
Obesity rates in children from West Virginia were reported as one of the highest in the United States [11]. Obesity has been recognized as a major risk factor for Vit D defi ciency [6]. Unfortunately, the status of serum Vit D levels in West Virginian children has not been well studied. In a single study, Robinson C et al. [20], assessed Vit D status in West Virginian children who were referred to their endocrine clinic. The study showed that 23.7% of the cohort were Vit D defi cient (<20ng/ ml) and that obesity was signifi cantly associated with Vit D defi ciency [20]. The effi cacy of Vit D supplementation was not examined in that study.
The association between obesity and Vit D defi ciency has been well established but whether there is a causal relationship is unknown. It was suggested that the reason for lower Vit D levels in obese subjects is related to the slow release of Vit D from the skin into the circulation [20]. Moreover, an inverse correlation was found between Vit D levels and BMI after oral intake of Vit D or when radiation (sun exposure) was the source of supplementation [20]. Nonetheless, the regulatory interaction between obesity and Vit D defi ciency is not known [5]. Some suggested that Vit D defi ciency precedes obesity in adults, while in a pediatric study from the Brazilian Amazon showed that the obesity related gene (FTO rs9939609) was more pronounced in Vit D defi cient children [22,23]. In a bidirectional Mendelian randomization analysis it was concluded that obesity is a causal factor in the development of Vit D defi ciency but not vice versa (24). Vit D production in AA [6,21,26,27]. Although those factors were not examined in our study, they may explain the different success rates noted between our study (Caucasian patients) and Kelly's study (AA patients) who received the same daily doses of Vit D supplementation (5,000IU/day) [25].
We acknowledge the following limitations in our study; (a) the study included a small number of participants and was limited to 2 months of supplementation. A larger and prolonged study (>6 months) might have resulted in different Vit D levels in both groups. (b) Other sources of Vit D supplementation were not measured including sun exposure and dietary intake. Nonetheless, the Vit D supplementation given to the study participants was much higher than the children's average daily Vit D intake through their diet or via sun exposure (http:// dietarysupplementdatabase.usda.nih.gov; [28]), (c) Several known risk factors for Vit D defi ciency could not be assessed in the present study including gender and ethnicity. Accordingly, we conclude that our results are limited to obese Caucasian children from West Virginia and cannot be extrapolated to other pediatric populations. Future larger pediatric studies that include different ethnicities and gender variability are clearly warranted.

Conclusions
In summary, there are no guideline recommendations to prevent or treat Vit D defi ciency in obese children. In the present study we investigated the effi cacy of two Vit D supplementation doses, 5,000IU/day vs. 50,000IU/week, in Caucasian Vit D defi cient obese children. We concluded that after 2 months, both doses were adequate to achieve normal serum 25(OH)D levels. Future larger studies will be needed to substantiate our results.