Seema Kumar

Relationships between 25-Hydroxyvitamin D Levels and Plasma Glucose and Lipid Levels in Pediatric Outpatients

OBJECTIVE To study the relationships between serum vitamin D levels and plasma glucose or lipid levels in children and adolescents. STUDY DESIGN We conducted a retrospective record review of pediatric outpatients (age, 2-18 years) with simultaneous measurement of 25-hydroxyvitamin D (25[OH] D) and fasting plasma glucose (n = 302) or 25(OH) D and a lipid panel (n = 177). Pearson correlation coefficient was used to estimate the correlation between 25(OH) D and logarithmic transformed plasma glucose or lipid levels. Plasma glucose and lipid levels were compared in subjects with 25(OH) D concentrations greater or less than 30 ng/mL. RESULTS 25(OH) D levels were inversely correlated with fasting plasma glucose levels (r = -0.20, P < .001). Lower 25(OH) D levels were also associated with lower serum high-density lipoprotein cholesterol (HDL) concentrations (r = 0.41; P < or = .001). The relationship between 25(OH) D levels and fasting glucose and HDL levels did not vary significantly with sex, age, body mass index z-score, or season. Children who were vitamin D insufficient (25[OH] D < or =30 ng/mL) had higher fasting plasma glucose (P = .002) and lower HDL levels (P < .001) than children who were vitamin D sufficient (25[OH] D >30 ng/mL). CONCLUSIONS Low 25(OH) D levels in children and adolescents are associated with higher plasma glucose and lower HDL concentrations.

Review of Childhood Obesity: From Epidemiology, Etiology, and Comorbidities to Clinical Assessment and Treatment

Abstract Childhood obesity has emerged as an important public health problem in the United States and other countries in the world. Currently 1 in 3 children in the United States is afflicted with overweight or obesity. The increasing prevalence of childhood obesity is associated with emergence of comorbidities previously considered to be “adult” diseases including type 2 diabetes mellitus, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and dyslipidemia. The most common cause of obesity in children is a positive energy balance due to caloric intake in excess of caloric expenditure combined with a genetic predisposition for weight gain. Most obese children do not have an underlying endocrine or single genetic cause for their weight gain. Evaluation of children with obesity is aimed at determining the cause of weight gain and assessing for comorbidities resulting from excess weight. Family‐based lifestyle interventions, including dietary modifications and increased physical activity, are the cornerstone of weight management in children. A staged approach to pediatric weight management is recommended with consideration of the age of the child, severity of obesity, and presence of obesity‐related comorbidities in determining the initial stage of treatment. Lifestyle interventions have shown only modest effect on weight loss, particularly in children with severe obesity. There is limited information on the efficacy and safety of medications for weight loss in children. Bariatric surgery has been found to be effective in decreasing excess weight and improving comorbidities in adolescents with severe obesity. However, there are limited data on the long‐term efficacy and safety of bariatric surgery in adolescents. For this comprehensive review, the literature was scanned from 1994 to 2016 using PubMed using the following search terms: childhood obesity, pediatric obesity, childhood overweight, bariatric surgery, and adolescents.

A Small Molecule Antagonist Inhibits Thyrotropin Receptor Antibody-Induced Orbital Fibroblast Functions Involved in the Pathogenesis of Graves Ophthalmopathy

CONTEXT Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. OBJECTIVE The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). DESIGN Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. MAIN OUTCOME MEASURES cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed. RESULTS Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production. CONCLUSIONS Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.

Pediatric Endocrine Surgery: A 20-Year Experience at the Mayo Clinic

CONTEXT Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high-volume endocrine surgeons. SETTING The study was conducted at the Mayo Clinic (a tertiary referral center). PATIENTS Patients were <19 years old and underwent an endocrine operation (1993-2012). MAIN OUTCOME MEASURES Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed. RESULTS A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horners syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushings syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively. CONCLUSION Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons.

Perspectives on pediatric bariatric surgery: identifying barriers to referral

BACKGROUND Pediatric obesity is a growing problem affecting the health of our youth. We sought to identify the barriers to pediatric bariatric referral at a tertiary referral center. METHODS We performed a survey of pediatricians and family practitioners at a single institution to assess their perspectives on pediatric obesity. RESULTS A total of 61 physicians completed the survey (response rate 46%). All believed pediatric obesity is a major problem, and 82.0% noted an increase in the incidence during a mean period of 15 years (range 3-25). Of the 61 physicians, 88.5% used nonoperative weight loss techniques, with only 1.8% reporting satisfactory results. However, 42.6% had referred a patient (adult or pediatric) for a bariatric procedure, of whom 84.6% were satisfied with the operative outcomes. Despite the high satisfaction with bariatric procedures, 88.5% would be unlikely or would never refer a child for a bariatric procedure, and 44.3% would be somewhat or very likely to refer an adolescent. CONCLUSION Physicians caring for children recognize the growing problem of childhood and adolescent obesity. Despite the poor outcomes with nonoperative methods and the high satisfaction with the outcomes of bariatric procedures, physicians are still reluctant to refer children and adolescents for surgical weight loss procedures.

Relationships Between Thyroid Function and Lipid Status or Insulin Resistance in a Pediatric Population

BACKGROUND In adults without thyroid disease, increasing levels of thyroid-stimulating hormone (TSH) within the range of that considered normal have been shown to be associated with increases in total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, and with decreases in high-density lipoprotein cholesterol. Serum TSH has also been found to be positively associated with fasting and postload insulin concentrations and negatively associated with insulin sensitivity in euthyroid adults. We hypothesized that such relationships also exist in euthyroid children and adolescents. METHODS This was a retrospective record review of pediatric outpatients (ages 2-18 years) having measurements of TSH or free thyroxine (T4) and a concurrent lipid panel, fasting glucose, or fasting insulin. Pearson correlation coefficient was used to estimate the correlation between TSH or free T4 and logarithmic transformed lipid, plasma glucose, or insulin levels. Lipid levels, fasting plasma glucose, insulin, and homeostasis model assessment (HOMA) were also compared between subjects with TSH levels in the high normal range (2.5-5 mIU/L) and those with TSH in the low normal range (0.3-2.4 mIU/L). RESULTS TSH levels were positively correlated with triglyceride levels (r = 0.10, p = 0.001). Conversely, free T4 levels were inversely correlated with triglyceride levels (r = -0.10, p = 0.011). TSH levels were also positively correlated with fasting insulin (r = 0.26, p = 0.002) and with HOMA (r = 0.27, p = 0.001). These associations remained significant after adjustment for age, gender, and body mass index z-score. Children who had TSH levels between 2.5 and 5.0 mIU/L had higher triglycerides (p = 0.003), insulin levels (p = 0.040), and HOMA (p = 0.021) than those having TSH values between 0.3 and 2.4 mIU/L. CONCLUSIONS In euthyroid children without a history of hypo- or hyperthyroidism, increasing levels of TSH and decreasing levels of free T4 are associated with higher triglyceride levels and elevated markers of insulin resistance. Whether these findings carry implications regarding optimal TSH levels in children at increased risk for cardiovascular disease awaits further study.

Response to vitamin D3 supplementation in obese and non-obese caucasian adolescents

Background/Aims: Vitamin D deficiency is highly prevalent in obese children, and obese children tend to respond poorly to vitamin D supplementation. The objective of the study was to compare the response to vitamin D3 supplementation (2,000 IU once daily for 12 weeks) between obese and non-obese Caucasian adolescents. Methods: The study design was open label non-randomized. It was carried out at a single center. Eighteen obese adolescents (aged 12–18 years) and the same number of age-, gender- and season-matched non-obese adolescents received vitamin D3 (2,000 IU/day) orally for 12 weeks. Total serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone, calcium and phosphorus were measured at baseline and at the end of the 12-week period. Results: The mean baseline 25(OH)D level was higher in the non-obese compared to the obese subjects (mean 28.9 vs. 25.2 ng/ml; p = 0.029). The increment in 25(OH)D levels following vitamin D supplementation was significantly lower in the obese adolescents (mean change 5.8 vs. 9.8 ng/ml; p = 0.019). Conclusions: Higher doses of vitamin D are required to treat vitamin D deficiency in obese adolescents compared to their non-obese peers.

Effect of vitamin D3 supplementation on serum 25(OH)D, lipids and markers of insulin resistance in obese adolescents: a prospective, randomized, placebo-controlled pilot trial.

Background/Aims: To determine the effect of vitamin D3 supplementation on 25-hydroxyvitamin D [25(OH)D], lipid profile and markers of insulin resistance in obese adolescents. Methods: In this double-blind, randomized, placebo-controlled trial, 58 obese adolescents (n = 58; 12-18 years of age) received either vitamin D3 (2,000 IU/day) or placebo for 12 weeks. Total 25(OH)D, fasting plasma glucose, insulin and lipid profile were measured at baseline and following supplementation. Results: The trial was completed by 44/58 enrolled participants. At the end of the 12 weeks, total serum 25(OH)D concentrations increased to a modest degree (median 6 ng/ml) in the vitamin D-supplemented group (p < 0.001). Supplementation showed no detectable changes in fasting plasma glucose, insulin, homeostatic model of assessment index (HOMA-IR), lipids and highly sensitive C-reactive protein. Conclusions: 12 weeks of vitamin D3 supplementation in obese adolescents with 2,000 IU once daily resulted in a modest increase in 25(OH)D concentration in obese adolescents, but did not affect the lipid profile and markers of insulin resistance and inflammation. Further studies with higher doses of vitamin D3 and/or longer duration of supplementation are needed to understand if vitamin D3 supplementation can impact lipid profiles and markers of insulin resistance and inflammation in obese children.

ADHD, Stimulant Treatment, and Growth: A Longitudinal Study

BACKGROUND AND OBJECTIVE: There is ongoing concern that stimulant medications may adversely affect growth. In a sample of attention-deficit/hyperactivity disorder (ADHD) cases and controls from a population-based birth cohort, we assessed growth and the association between stimulant treatment and growth. METHODS: Subjects included childhood ADHD cases (N = 340) and controls (N = 680) from a 1976 to 1982 birth cohort (N = 5718). Height and stimulant treatment information were abstracted from medical records and obtained during a prospective, adult follow-up study. For each subject, a parametric penalized spline smoothing method modeled height over time, and the corresponding height velocity was calculated as the first derivative. Peak height velocity (PHV) age and magnitude were estimated from the velocity curves. Among stimulant-treated ADHD cases, we analyzed height Z scores at the beginning, at the end, and 24 months after the end of treatment. RESULTS: Neither ADHD itself nor treatment with stimulants was associated with differences in magnitude of PHV or final adult height. Among boys treated with stimulants, there was a positive correlation between duration of stimulant usage before PHV and age at PHV (r = 0.21, P = .01). There was no significant correlation between duration of treatment and change in height Z scores (r = −0.08 for beginning vs end change, r = 0.01 for end vs 24 months later change). Among the 59 ADHD cases treated for ≥3 years, there was a clinically insignificant decrease in mean Z score from beginning (0.48) to end (0.33) of treatment (P = .06). CONCLUSIONS: Our findings suggest that ADHD treatment with stimulant medication is not associated with differences in adult height or significant changes in growth.

Cholecalciferol Supplementation Does Not Influence β-Cell Function and Insulin Action in Obese Adolescents: A Prospective Double-Blind Randomized Trial

BACKGROUND There is increasing interest in the extraskeletal effects of vitamin D, particularly in the obese state with regard to the development of insulin resistance and diabetes. OBJECTIVE The objective of the study was to determine the effect of 2 doses of cholecalciferol (vitamin D3) supplementation on insulin action (Si) and pancreatic β-cell function in obese adolescents. METHODS We performed a 12-wk double-blind, randomized comparison of the effect of vitamin D3 supplementation on Si and β-cell function in obese Caucasian adolescents (body mass index > 95(th) percentile). The subjects were randomly assigned to receive either 400 IU/d (n = 25) or 2000 IU/d (n = 26) of vitamin D3. Each subject underwent a 7-sample 75 g oral glucose tolerance test, with glucose, insulin, and C-peptide measurements, to calculate Si and β-cell function as assessed by the disposition index (DI), with use of the oral minimal model before and after supplementation. A total of 51 subjects aged 15.0 ± 1.9 y were enrolled. Included for analysis at follow-up were a total of 46 subjects (20 male and 26 female adolescents), 23 in each group. RESULTS Initial serum 25-hydroxyvitamin D [25(OH)D] was 24.0 ± 8.1 μg/L. There was no correlation between 25(OH)D concentrations and Si or DI. There was a modest but significant increase in 25(OH)D concentration in the 2000 IU/d group (3.1 ± 6.5 μg/L, P = 0.04) but not in the 400 IU/d group (P = 0.39). There was no change in Si or DI following vitamin D3 supplementation in either of the treatment groups (all P > 0.10). CONCLUSIONS The current study shows no effect from vitamin D3 supplementation, irrespective of its dose, on β-cell function or insulin action in obese nondiabetic adolescents with relatively good vitamin D status. Whether obese adolescents with vitamin D deficiency and impaired glucose metabolism would respond differently to vitamin D3 supplementation remains unclear and warrants further studies. This trial was registered at clinicaltrials.gov as NCT00858247.